Journal articles on the topic 'Zhong ban chang'

Abstract Cancer immunotherapy refers to the approach leveraging patients’ immune system against tumor, which has gained tremendous progress hallmarked by immune checkpoint blockade and adoptive cell therapies. However, contemporary strategies suffer from limited responses, adverse side effects, and low tissue penetration due to utilization of macromolecules, calling for more efficacious and safer alternative strategies. SHP1 is a protein tyrosine phosphatase (PTP) primarily expressed in hematopoietic cells and has been shown to negatively regulate immune responses in T cells and natural killer (NK) cells, and SHP1 deletion in these cells has shown to promote their anti-tumor functions. Recent studies also demonstrated that inducible SHP1 knockout inhibited tumor growth in vivo through immune activation. Although presented as an attractive target, no high-quality small molecule inhibitors have been reported for SHP1 due to its undruggable nature. Through high-throughput screening and extensive medicinal chemistry, we have acquired the first-in-class SHP1 covalent inhibitor M029, which shows >25-fold selectivity against SHP2, its closest analogues and >60-fold selectivity against other PTPs and cysteine-based proteins. Further proteomics studies reveal that M029 is superiorly selective for SHP1 in cellulo. Additionally, M029 is stable in 100-fold excessive glutathione with a half-life of >35 hours and non-toxic up to 100 µM to healthy cells, such high stability was also reflected by its oral bioavailability with a F% of 10%. M029 treatment significantly activated T cell receptor signaling in T cells and NK cells killing effects in vitro. Furthermore, oral dosage of M029 significantly delayed tumor progression in mice bearing MC38 tumors through enhanced T cell and NK cell infiltration and activation and prolonging of T cell exhaustion. To validate that the compound acted through immune activation, we dosed the mice with anti-CD8+ or anti-NK1.1 during M029 treatment, both of which abolished the compound efficacy, corroborating with its mechanism of action. Meanwhile, to assess the compound safety, we dosed the mice up to 100 mg/kg for 8 days, where no significant body weight change or cytokine storm were observed. Collectively, we have developed the first SHP1 covalent inhibitor with high selectivity and strong anti-tumor efficacy. This study is the first characterization of pharmacological SHP1 inhibition as cancer immunotherapy and solidified its potential as an immunotherapeutic target. The development of M029 will also enlighten drug discovery strategies against SHP1 or other undruggable PTPs. Citation Format: Zihan Qu, Frederick Nguele Meke, Zheng Zhang, Yunpeng Bai, Aaron D. Krabill, Christine S. Muli, Brenson A. Jassim, Jiajun Dong, Jinyue Li, Nguyen Yuyen, Andy W. Tao, Darci T. Trader, Zhong-Yin Zhang. Discovery of the first-in-class SHP1 covalent inhibitor for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1973.

This paper focuses on the change of the meaning of “gospel” in Chinese context since the 17th Century. In the late Ming dynasty, Catholic missionaries were the first to translate “gospel” into Chinese with their writings about the Bible. Then the term became intermingled with traditional Chinese belief of seeking blessings. After the ban on Christianity imposed by the Emperor Yong Zheng, Chinese Catholics hid their faith and disguised it as Buddhism, Taoism and folk religions. At the end of the 19th century, “gospel” was connected to colonialism and became a trigger for Sino-Western conflict. The critique of and hostility toward the term abruptly arose. In the 20th century, “gospel” turned into a new concept, which went beyond its religious connotation and gradually referred to all kinds of “good news”.

The aim of this paper is to define the institutional difference between the aristocratic lineage ruling the service fief of the Western Zhou era and the royal dynasty, reigning over the independent state of the Eastern Zhou era. Different approaches to the genesis of the Qin State are discussed in this paper: the archaeological approach and the “Zhou fiefdom” approach. The first one lacks data directly describing the political process. The problem of the second one is its being based practically on one written source that postdates the events described by 500 years. Therefore, to escape the failures of these methods, the author developed a specific approach that would both deal with political and institutional data on the one side while using data from different sources contemporary to the events in question. Data explicated from Bu Qi gui, Qin gong zhong and Guo ji zi Bai pan – three inscriptions on the bronze vessels dating between IX and VII centuries BC was scrutinized and compared. Two of them were cast by Qin rulers and the third describes the events leading to the creation of the Qin domain. Comparing information of these sources with the data from Sima Qian’s Shi ji allows to determine the precise moment of the Qin domain being transformed into the Qin State and show the institutional innovations that went along with this process. The interior political change of this time is described (i.e. the political crisis of royal inheritance) as well as the exterior change in Qin’s place inside the hierarchy of Zhou domains, particularly the changing relations between the Qin State and the domain of Xiao Guo. This clarified the place that the process of territorial expansion had in this transformation. As a hypothesis, the author built a model presenting the properties distinguishing a service fief and an independent state.

Traditional Chinese medicine (TCM) divides fracture treatment into three stages. Many TCM herbs and formulas have been used to treat fractures for thousands of years. However, research regarding the Chinese herbal products (CHPs) that should be used at different periods of treatment is still lacking. This study aims to identify the CHPs that should be used at different periods of treatment as well as confirm the TCM theory of fracture periods medicine. We used prescriptions of TCM outpatients with fracture diagnoses analyzed using the Chang Gung Research Database (CGRD) from 2000 to 2015. According to the number of days between the date of the fracture and the clinic visit date, all patients were assigned to one of three groups. Patients with a date gap of 0-13 days were assigned to the early period group; those with a date gap of 14-82 days were assigned to the middle period group; and those with a date gap of 83-182 days were assigned to the late period group. We observed the average number of herbal formulas prescribed by the TCM doctor at each visit was 2.78, and the average number of single herbs prescribed was 6.47. The top three prescriptions in the early fracture period were Zheng-gu-zi-jin-dang, Shu-jing-huo-xue-tang, and Wu-ling-san. In the middle fracture period, the top three formulas were Zheng-gu-zi-jin-dang, Shu-jing-huo-xue-tang, and Zhi-bai-di-huang-wan. In the late fracture period, the top three formulas were Shu-jing-huo-xue-tang, Gui-lu-er-xian-jiao, and Du-huo-ji-sheng-tang. The main single herbs used in the early fracture period were Yan-hu-suo, Gu-sui-bu, and Dan-shen. From the middle to the late period, the most prescribed single herbs were Xu-duan, Gu-sui-bu, and Yan-hu-suo. We concluded that the results showed that the CGRD utilization pattern roughly meets the TCM theory at different fracture periods.

In recent years, many attempts have been made to improve the sensory properties of SnO2, including design of sensors based on one-dimensional nanostructures of this material, such as nanofibers, nanotubes or nanowires. One of the simpler methods of producing one-dimensional tin oxide nanomaterials is to combine the electrospinning method with a sol-gel process. The purpose of this work was to produce SnO2 nanowires using a hybrid electrospinning method combined with a heat treatment process at the temperature of 600 °C and to analyze the morphology and structure of the one-dimensional nanomaterial produced in this way. Analysis of the morphology of composite one-dimensional tin oxide nanostructures showed that smooth, homogeneous and crystalline nanowires were obtained. Full Text: PDF ReferencesN. Dharmaraj, C.H. Kim, K.W. Kim, H.Y. Kim, E.K. Suh, "Spectral studies of SnO2 nanofibres prepared by electrospinning method", Spectrochim. Acta - Part A Mol. Biomol. Spectrosc. 64, (2006) CrossRef N. Gao, H.Y. Li, W. Zhang, Y. Zhang, Y. Zeng, H. Zhixiang, ... & H. Liu, "QCM-based humidity sensor and sensing properties employing colloidal SnO2 nanowires", Sens. Actuators B Chem. 293, (2019), 129-135. CrossRef W. Ge, Y. Chang, V. Natarajan, Z. Feng, J. Zhan, X. Ma, "In2O3-SnO2 hybrid porous nanostructures delivering enhanced formaldehyde sensing performance", J.Alloys and Comp. 746, (2018) CrossRef M. Zhang, Y. Zhen, F. Sun, C. Xu, "Hydrothermally synthesized SnO2-graphene composites for H2 sensing at low operating temperature", Mater. Sci. Eng. B. 209, (2016), 37-44. CrossRef Y. Zhang, X. He, J. Li, Z. Miao, F. Huang, "Fabrication and ethanol-sensing properties of micro gas sensor based on electrospun SnO2 nanofibers", Sens. Actuators B Chem. 132, (2008), 67-73. CrossRef W.Q. Li, S.Y. Ma, J. Luo, Y.Z. Mao, L. Cheng, D.J. Gengzang, X.L. Xu, S H. Yan, "Synthesis of hollow SnO2 nanobelts and their application in acetone sensor", Mater. Lett. 132, (2014), 338-341. CrossRef E. Mudra, I. Shepa, O. Milkovic, Z. Dankova, A. Kovalcikova, A. Annusova, E. Majkova, J. Dusza, "Effect of iron doping on the properties of SnO2 nano/microfibers", Appl. Surf. Sci. 480, (2019), 876-881. CrossRef P. Mohanapriya, H. Segawa, K. Watanabe, K. Watanabe, S. Samitsu, T.S. Natarajan, N.V. Jaya, N. Ohashi, "Enhanced ethanol-gas sensing performance of Ce-doped SnO2 hollow nanofibers prepared by electrospinning", Sens. Actuators B Chem. 188, (2013), 872-878. CrossRef W.Q. Li, S.Y. Ma, Y.F. Li, X.B. Li, C.Y. Wang, X.H. Yang, L. Cheng, Y.Z. Mao, J. Luo, D.J. Gengzang, G.X. Wan, X.L. Xu, "Preparation of Pr-doped SnO2 hollow nanofibers by electrospinning method and their gas sensing properties", J.Alloys and Comp. 605, (2014), 80-88. CrossRef X.H. Xu, S.Y. Ma, X.L. Xu, T. Han, S.T. Pei, Y. Tie, P.F. Cao, W.W. Liu, B.J. Wang, R. Zhang, J.L. Zhang, "Ultra-sensitive glycol sensing performance with rapid-recovery based on heterostructured ZnO-SnO2 hollow nanotube", Mater. Lett, 273, (2020), 127967. CrossRef F. Li, X. Gao, R. Wang, T. Zhang, G. Lu, Sens. "Study on TiO2-SnO2 core-shell heterostructure nanofibers with different work function and its application in gas sensor", Actuators B Chem, 248, (2017), 812-819. CrossRef S. Bai, W. Guo, J. Sun, J. Li, Y. Tian, A. Chen, R. Luo, D. Li, "Synthesis of SnO2–CuO heterojunction using electrospinning and application in detecting of CO", Sens Actuators B Chem, 226, (2016), 96-103. CrossRef H. Du, P.J. Yao, Y. Sun, J. Wang, H. Wang, N. Yu, "Electrospinning Hetero-Nanofibers In2O3/SnO2 of Homotype Heterojunction with High Gas Sensing Activity", Sensors, 17, (2017), 1822. CrossRef X. Wang, H. Fan, P. Ren, "Electrospinning derived hollow SnO2 microtubes with highly photocatalytic property", Catal. Commun. 31, (2013), 37-41. CrossRef L. Cheng, S.Y. Ma, T.T. Wang, X.B. Li, J. Luo, W.Q. Li, Y.Z. Mao, D.J Gengzang, "Synthesis and characterization of SnO2 hollow nanofibers by electrospinning for ethanol sensing properties", Mater. Lett. 131, (2014), 23-26. CrossRef P.H. Phuoc, C.M. Hung, N.V. Toan, N.V. Duy, N.D. Hoa, N.V. Hieu, "One-step fabrication of SnO2 porous nanofiber gas sensors for sub-ppm H2S detection", Sens. Actuators A Phys. 303, (2020), 111722. CrossRef A.E. Deniz, H.A. Vural, B. Ortac, T. Uyar, "Gold nanoparticle/polymer nanofibrous composites by laser ablation and electrospinning", Matter. Lett. 65, (2011), 2941-2943. CrossRef S. Sagadevan, J. Podder, "Investigation on Structural, Surface Morphological and Dielectric Properties of Zn-doped SnO2 Nanoparticles", Mater. Res. 19, (2016), 420-425. CrossRef

Recently, the club from Malang is facing sad news. Several mass media reported an event about Indonesian football over the tragedy of riots in the Liga 1 Indonesia match at Malang's Kanjuruhan Stadium which is the home of the Arema FC club. The riot occurred when the match between Arema FC and Persebaya Surabaya was held on Saturday, October 1, 2022, at 20.00.. When the incident happened, it had shocked the world of football. Some media began to change the headline of the news into a riot event at Malang's Kanjuruhan stadium. One of them is Kompas.id media, where media journalists Kompas.id shape and frame an event that will later become a headline in their media. So this study aims to find out how the writing of media journalists Kompas.id through Syntactic, Script, Thematic and Rhetorical Structures in framing the tragedy of the riot at Malang's Kanjuruhan Stadium which will later be used as a report. The method used in this study is a descriptive qualitative method with framing analysis of Zhong Dang Pan and Gerald M. Kosicki models. The results of this study show that journalists Kompas.id in framing the tragedy of the riot at Malang's Kanjuruhan Stadium more prominent information related to the causes and mistakes committed by security forces and the organizing committee in the content of the news text with different discussion themes in each report, so that the news led to this opinion ofthe public who viewed The image of the police and the organizing committee is also bad for the community. It can be seen from the four framing structures observed in this study, namely (Syntax, Script, Thematic, Rhetorical).

McLean M, Thompson D, Zhang H-P, Brinsmead M, Smith R. Corticotrophin-releasing hormone and β-endorphin in labour. Eur J Endocrinol 1994;131:167–72. ISSN 0804–4643 The objectives of this study were to determine whether the maternal plasma corticotrophin-releasing hormone (CRH) concentration influences the amount of uterine contractility induced by infused oxytocin during induction of labour, and secondly to assess changes in CRH and β-endorphin in response to stress during labour. Serial plasma CRH and β-endorphin measurements were made in 40 women undergoing induction of labour and correlated with uterine contractility, cervical dilatation, length of labour, analgesic usage and fetal distress. The plasma CRH concentration did not change throughout labour. In subjects receiving infused oxytocin there was a significant positive correlation between plasma CRH and the amount of uterine activity, and a high plasma CRH level was associated with shorter labour. The plasma β-endorphin level rose with progressive cervical dilatation and fell after epidural anaesthesia. The plasma CRH level did not correlate with the plasma β-endorphin level or rise with fetal distress. We conclude that high levels of maternal plasma CRH are associated with an increase in the uterine contractile response to infused oxytocin. The maternal plasma CRH level does not vary in response to maternal or fetal stress, but β-endorphin secretion does rise in response to the stress of labour and is influenced by pain perception. Mark McLean, Endocrine Unit, John Hunter Hospital, Locked Bag 1, Newcastle Mail Centre, Newcastle, NSW 2310, Australia

Accurate evaluation of start of season (SOS) changes is essential to assess the ecosystem’s response to climate change. Smoothing method is an understudied factor that can lead to great uncertainties in SOS extraction, and the applicable situation for different smoothing methods and the impact of smoothing parameters on SOS extraction accuracy are of critical importance to be clarified. In this paper, we use MOD13Q1 normalized difference vegetation index (NDVI) data and SOS observations from eight agrometeorological stations on the Qinghai–Tibetan Plateau (QTP) during 2001–2011 to compare the SOS extraction accuracies of six popular smoothing methods (Changing Weight (CW), Savitzky-Golay (SG), Asymmetric Gaussian (AG), Double-logistic (DL), Whittaker Smoother (WS) and Harmonic Analysis of NDVI Time-Series (HANTS)) for two types of different SOS extraction methods (dynamic threshold (DT) with 9 different thresholds and double logistic (Zhang)). Furthermore, a parameter sensitivity analysis for each smoothing method is performed to quantify the impacts of smoothing parameters on SOS extraction. Finally, the suggested smoothing methods and reference ranges for the parameters of different smoothing methods were given for grassland phenology extraction on the QTP. The main conclusions are as follows: (1) the smoothing methods and SOS extraction methods jointly determine the SOS extraction accuracy, and a bad denoising performance of smoothing method does not necessarily lead to a low SOS extraction accuracy; (2) the default parameters for most smoothing methods can result in acceptable SOS extraction accuracies, but for some smoothing methods (e.g., WS) a parameter optimization is necessary, and the optimal parameters of the smoothing method can increase the R2 and reduce the RMSE of SOS extraction by up to 25% and 331%; (3) The main influencing factor of the SOS extraction using the DT method is the stability of the minimum value in the NDVI curve, and for the Zhang method the curve shape before the peak of the NDVI curve impacts the most; (4) HANTS is the most stable method no matter with (fitness = 35.05) or without parameter optimization (fitness = 33.52), which is recommended for QTP grassland SOS extraction. The findings of this study imply that remote sensing-based vegetation phenology extraction can be highly uncertain, and a careful selection and parameterization of the time-series smoothing method should be taken to achieve an accurate result.

Ni-rich layered oxides (LiNixCoyMnzO2, x≥0.8, x+y+z=1) would fulfil the energy density requirements of the automobile industry since they offer outstanding capacities at relatively high mean voltages and sufficient power densities1-3. However, the materials still show significant capacity and voltage fade which requires substantial research. Recently we have shown that the electronic structure is the key to understand the performance but also the failure of the materials1. Thus, we intend to modify the electronic structure using anionic dopants such as Boron. Thus, homogenous B-substituted NCM811s (BNCM811_x%, x% means the x at. % of Boron) are synthesized and the materials reveal a significant change in the electronic structure as evident from x-ray photoelectron spectroscopy (XPS) and near edge x-ray absorption spectroscopy (NEXAFS). Interestingly, a shift of the so called H2-H3 peak4 to higher potentials was observed by Boron substitution and BNCM811s_2% shows relative higher initial discharge capacity (Figure 1A.) at a slightly higher mean voltage, but a lower cycling stability compared to NCM811 (Figure 1B.). The H2-H3 differential capacity peak (Figure 1C) might also include oxygen release5, which is one of the main reasons restricting the cycling stability. Near edge x-ray absorption spectroscopy (NEXAFS) shows that the H2-H3 peak corresponds to a reaction from Ni3+ to Ni2+ (upon charge) and Ni2+ to Ni3+ (upon discharge) which suggest a reaction like NiO2 ⥂ NiO + ½ O2 as the underlying process. At the same time, an Oxygen K peak at 531 eV appears in the NEXAFS spectra, which was assigned to O-O formation in the host structure of Li-rich materials6, 7. Note that the electronic structure of the materials was determined in 5 mAh/g steps over the H2-H3 peak and due to the high resolution, this process became visible for the first time. The findings suggest that dimer formation is not only a phenomenon of Li-rich materials but can also be found in Ni-rich layered oxides at high states of charge. The origin of dimer formation and oxygen release can be traced back to the electronic configuration of Ni. Charge transfer multiplet calculations reveal, that Ni2+ reacts to covalent Ni3+ upon charge (and vice versa upon discharge)1. Ni3+ has a 3d7 electronic state, whose low spin configuration is more preferred than its high spin configuration. Thus, Ni3+ is more prone to Jahn-Teller (JT) distortions and tends to form covalent bonds. Consequently, the electrons are more bound to the individual sites making a further oxidation of the transition metal almost impossible. In conclusion, Boron substitution helps us to understand the function and failure of layered oxides in Li-ion batteries on an atomistic scale and the findings can be used as a design guide for future materials. K. Kleiner, C. A. Murray, C. Grosu, B. Ying, M. Winter, P. Nagel, S. Schuppler and M. Merz, Journal of The Electrochemical Society, 2021. J. Zhao, W. Zhang, A. Huq, S. T. Misture, B. Zhang, S. Guo, L. Wu, Y. Zhu, Z. Chen and K. Amine, Advanced Energy Materials, 2017, 7, 1601266. S.-J. Yoon, K.-J. Park, B.-B. Lim, C. S. Yoon and Y.-K. Sun, Journal of the Electrochemical Society, 2014, 162, A3059. S. Jamil, G. Wang, L. Yang, X. Xie, S. Cao, H. Liu, B. Chang and X. Wang, Journal of Materials Chemistry A, 2020, 8, 21306-21316. K. Märker, P. J. Reeves, C. Xu, K. J. Griffith and C. P. Grey, Chemistry of Materials, 2019, 31, 2545-2554. E. Hu, X. Yu, R. Lin, X. Bi, J. Lu, S. Bak, K.-W. Nam, H. L. Xin, C. Jaye and D. A. Fischer, Nature Energy, 2018, 3, 690-698. K. Kleiner, B. Strehle, A. R. Baker, S. J. Day, C. C. Tang, I. Buchberger, F.-F. Chesneau, H. A. Gasteiger and M. Piana, Chemistry of Materials, 2018, 30, 3656-3667. Figure 1

Abstract Cell death pathways are desired targets of small molecule inhibitors since their deregulation plays an important role in chemotherapy resistance. Obatoclax binds to the BH3 pocket of anti-apoptotic BCL-2 family proteins, inhibiting their interactions with pro-apoptotic BCL-2 family members. Before we found potent obatoclax activity in MLL/AF4+ cell lines and 6 MLL rearranged (MLL+) leukemias. In apoptosis assays of the cell lines obatoclax increases TUNEL staining but minimally activates caspase 3 (Rege ASH 2005; Zhang AACR 2007). In this study, we tested the cytotoxicity of obatoclax in additional MLL+ leukemias and investigated its mechanism of action with a focus on autophagy (ATG), since ATG proteins such as beclin 1 also interact with anti-apoptotic BCL-2 family members. Methods: MLL partner genes were determined by molecular/cytogenetic methods. 17 primary MLL+ leukemias including the original 6 (12 ALL/11 infants, 1 child; 3 AML/1 each infant, child, adolescent; 2 bilineal/2 infants) were tested in MTT assays after 72 h obatoclax exposures. MTT assays on cytotoxic drug-obatoclax combinations were performed in a primary MLL/AF4+ ALL and interactions were studied by response surface modeling. MCL-1/BAK complex inhibition was tested in this ALL by co-IP/immunoblot analysis. Cell death and ATG were studied in obatoclax treated RS4:11 and/or SEM-K2 cells by PI flow, LC3 and p62 Western blot analysis and EM, using doxorubicin as a control for apoptosis. Gene expression changes after vehicle treatment vs. obatoclax treatment at the IC50 and IC90 for 6 h were studied using Affymetrix HG_U133 Plus2.0 arrays. Differentially expressed genes overall and those specifically associated with ATG were queried by ANOVA (p<0.01, ≥50% change in mean expression considered as significant). Q-RT PCR analysis of basal expression levels of select ATG genes (BECN1, WIPI1, MAP1LC3B) was performed in 10 of the 17 primary cases and correlations with the IC50 values were determined using Pearson correlation coefficients and their levels of significance. Changes in the expression patterns of these genes after vehicle treatment vs. treatment with obatoclax at the IC50 for 6 h and 48 h were compared in 6 cases by Q-RT PCR and cluster analysis. Results: MLL partner genes were AF4, ENL and other in 6, 5 and 1 ALL, respectively; AF9 in 2 and AF6 in 1 AML; and AF4 and ENL in 1 each bilineal leukemia. The single agent IC50’s of obatoclax suggested greater sensitivity in ALL (13–834 nM; median 104 nM) than AML (243–488nM; median 341 nM), and were 79 nM and 508 nM in the bilineal leukemias. In addition to synergy with ARAC, ADR, VP16 and DEX (Zhang AACR 2007) there was synergy with LASP and VCR in the primary MLL/AF4+ ALL. In the same ALL obatoclax decreased MCL-1/BAK dimers, suggesting interaction with the MCL-1 target, and obatoclax increased high molecular weight MCL-1/BAK complexes and decreased MCL-1, the latter of which would also decrease MCL-1/BAK dimers. Obatoclax treatment of RS4:11 and SEM-K2 cells increased PI staining and LC-3I to LC-3II conversion; EM analysis of SEM-K2 cells revealed phagophores, autophagosomes and autophagolysosomes indicative of ATG induction. Lack of p62 accumulation showed that ATG was not blocked. EM findings of apoptosis occurred in SEM-K2 cells after doxorubicin exposure. ATG was not the most affected pathway in microarray analyses of obatoclax treated SEM-K2 and RS4:11 cells, but specific analysis of ATG-related genes showed WIPI1 and MAP1LC3B upregulation. Moreover, the basal expression of BECN1 was positively correlated with obatoclax activity in the 10 primary cases (r =0.659; p=0.038), which is consistent with importance of this pathway in the drug response. ATG gene expression analysis in obatoclax treated primary MLL+ cases identified 2 patient clusters; in one cluster obatoclax decreased BECN1 and increased WIPI1 expression; in the other ATG gene expression changes were more variable. Conclusions: Obatoclax induces cell death in MLL+ leukemias via the ATG pathway even though they are apoptosis competent. This is distinct from the apoptosis activation in other cancer cell types and indicates that the targets of obatoclax are disease-specific. The activity in a broad spectrum of MLL+ leukemias indicates that obatoclax is a promising molecularly targeted agent for this population.

This paper explains about the performance of graphene nanopowder (GNP) based saturable absorber (SA) at 1.5-micron region which is prepared by dissolution in polyvinyl alcohol (PVA) polymer. Two different GNP flakes thickness (AO2-8 nm and AO4-60 nm) are tested. By applying a solution casting method, three weight ratio of GNP to PVA (12.04, 8.03 and 3.11 wt.%) have been prepared and fabricated as a composite thin film. To characterize for the SA performance, 4 mm2 area of GNP-PVA thin film is embedded in a 14 meters long ring cavity with 3 meters Erbium doped fiber (EDF) as a gain medium. Our characterization results show that the GNP-PVA thin film act as a Q-switcher which produce stable laser pulses for 12.04 wt.% with maximum repetition rate of 39.22 kHz and shortest pulse width of 11.79 µs. Meanwhile, unstable Q-switched pulses of 8.03 wt.% and 3.11 wt.% have been observed with recorded signal to noise ratio (SNR) of only 21 dB and 17 dB, respectively. The threshold pumping power for Q-switched lasing to emerge is recorded as low as 30 mW. Apparently, it shows that GNP concentration and flakes thickness in fabricated SA composite plays vital role in the performance of generated Q-switch laser, particularly at 1.5 µm region. Full Text: PDF ReferencesT. Hasan, Z. Sun, F. Wang, F. Bonaccorso, P.H. Tan, A.G. Rozhin, A.C. Ferrari, "Nanotube–Polymer Composites for Ultrafast Photonics", Adv. Mater. 21, 3874 (2009). CrossRef Q. Bao, H. Zhang, Y. Wang, Z. Ni, Y. Yan, Z.X. Shen, K.P. Loh, D.Y. Tang, "Atomic-Layer Graphene as a Saturable Absorber for Ultrafast Pulsed Lasers", Adv. Funct. Mater. 19, 3077 (2009). CrossRef Z. Luo, M. Zhou, J. Weng, G. Huang, H. Xu, C. Ye, Z. Cai, Opt. Lett. 35(21), 3709 (2010). CrossRef D. Popa, Z. Sun, T. Hasan, F. Torrisi, F. Wang, A.C. Ferrari, "Graphene Q-switched, tunable fiber laser", Appl. Phys. Lett. 98, 3106 (2011). CrossRef Y.M. Chang, H. Kim, J.H. Lee, Y. Song, "Multilayered graphene efficiently formed by mechanical exfoliation for nonlinear saturable absorbers in fiber mode-locked lasers", Appl. Phys. Lett. 97, 211102 (2010). CrossRef M. Jiang, Z. Ren, Y. Zhang, B. Lu, R. Zhang, J. Guo, Y. Zhou, J. Bai, "Passive Q-Switching with Graphene Saturable Absorber in Nd:YAG Operating at 1064nm", Mater. Sci. Forum 694, 700 (2011). CrossRef N. Hussin, M.H. Ibrahim, F. Ahmad, H. Yahaya, S.W. Harun, "Graphene Nanoplatelets (GnP)-PVA Based Passive Saturable Absorber", Telkomnika 15(2), 814 (2017). CrossRef F.C. Mat, M. Yasin, A.A. Latiff, S.W. Harun, Photonics Letters of Poland 9, 100 (2017). CrossRef E.K. Ng, K.Y. Lau, H.K. Lee, N.M. Yusoff, A.R. Sarmani, M.F. Omar, M.A. Mahdi, "L-band femtosecond fiber laser based on a reduced graphene oxide polymer composite saturable absorber", Opt. Mater. Express 11, 59 (2021). CrossRef N.H.M. Apandi, S.N.F. Zuikafly, N. Kasim, M.A. Mohamed, S.W. Harun, F. Ahmad, "Observation of dark and bright pulses in q-switched erbium doped fiber laser using graphene nano-platelets as saturable absorber", Bull. Electr. Eng. Inform. 8, 1358 (2019). CrossRef N.U.H.H.B. Zalkepali, N.A. Awang, Y.R. Yuzaile, Z. Zakaria, A.A. Latif and F. Ahmad, "Graphene Nanoplatelets as Saturable Absorber for Mode-locked Fiber Laser Generation", J. Adv. Res. Dyn. Control Syst. 12(2), 602 (2020). CrossRef X. Zhu and S. Chen, "Autoencoder-Based Transceiver Design for OWC Systems in Log-Normal Fading Channel", IEEE Photonics J. 11, 7105109 (2019). CrossRef

SummaryVisualization can reduce the cognitive load of information, allowing users to easily interpret and assess large amounts of data. The purpose of our study was to examine home health data using visual analysis techniques to discover clinically salient associations between patient characteristics with problem-oriented health outcomes of older adult home health patients during the home health service period.Knowledge, Behavior and Status ratings at discharge as well as change from admission to discharge that was coded using the Omaha System was collected from a dataset on 988 deidentified patient data from 15 home health agencies. SPSS Visualization Designer v1.0 was used to visually analyze patterns between independent and outcome variables using heat maps and histograms. Visualizations suggesting clinical salience were tested for significance using correlation analysis.The mean age of the patients was 80 years, with the majority female (66%). Of the 150 visualizations, 69 potentially meaningful patterns were statistically evaluated through bivariate associations, revealing 21 significant associations. Further, 14 associations between episode length and Charlson co-morbidity index mainly with urinary related diagnoses and problems remained significant after adjustment analyses. Through visual analysis, the adverse association of the longer home health episode length and higher Charlson co-morbidity index with behavior or status outcomes for patients with impaired urinary function was revealed.We have demonstrated the use of visual analysis to discover novel patterns that described high-needs subgroups among the older home health patient population. The effective presentation of these data patterns can allow clinicians to identify areas of patient improvement, and time periods that are most effective for implementing home health interventions to improve patient outcomes. Citation: Radhakrishnan K, Monsen KA, Bae S-H, Zhang W. Visual analytics for pattern discovery in home care: Clinical relevance for quality improvement.

Artikel review ini memberikan informasi tentang aplikasi polianilina (PANI) dan kompositnya sebagai sensor gas berbahaya khususnya amonia (NH3). Kajian yang dibahas pada artikel ini meliputi sifat gas NH3, material komposit, kinerja sensor, serta limit deteksi. Tinjauan sensor gas amonia berbasis polimer konduktif polianilina secara menyeluruh diambil dari referensi sepuluh tahun terakhir. Sebagai contoh, komposit polianilina dengan turunan karbon seperti reduced Graphene Oxide (rGO) dan Carbon Nanotube menunjukkan limit deteksi hingga 46 ppb dengan waktu pemulihan hanya 75 detik. Selain itu, komposit PANI dengan logam seperti Ag, Sr dan sebagainya, menunjukkan limit deteksi yang lebih besar yaitu 1 ppm, namun terdapat keunggulan dimana waktu pemulihan hanya 4 deti. Oleh sebab itu, polimer konduktif polianilina menjadi material yang sangat menjanjikan untuk mendeteksi keberadaan gas NH3. Terakhir, mekanisme penginderaan gas amonia terhadap material PANI juga dibahas pada tulisan ini. 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Abstract Background: SHR-A1811 is an ADC comprised of a humanized anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a DNA topoisomerase I inhibitor payload. Here we assessed SHR-A1811 in HER2-expressing/mutated unresectable, advanced, or metastatic solid tumors. Methods: Pts were eligible if they had HER2 positive breast cancer (BC), HER2 positive gastric/GEJ carcinoma, HER2 low-expressing BC, HER2-expressing/mutated NSCLC, or other HER2-expressing/mutated solid tumors, and were refractory or intolerant to standard therapy. SHR-A1811 at doses of 1.0-8.0 mg/kg was given Q3W (IV). The primary endpoints were DLT, safety, and the RP2D. Results: From Sep 7, 2020 to Sep 28, 2022, 250 pts who had undergone a median of 3 prior treatment lines in the metastatic setting received at least one dose of SHR-A1811 in dose escalation, PK expansion, and indication expansion part. As of data cutoff on Sep 28, 2022, 1 pt experienced DLT. Treatment-related adverse events (TRAEs) were reported in 243 (97.2%) pts. Grade ≥3 TRAEs, serious TRAEs, and treatment-related deaths were reported in 131 (52.4%), 31 (12.4%), and 3 (1.2%) pts, respectively. Interstitial lung disease (AESI) was reported in 8 (3.2%) pts. Exposures of SHR-A1811, total antibody, and the payload were generally proportional to dose from 3.2 to 8.0 mg/kg. ORR was 61.6% (154/250, 95% CI 55.3-67.7) in all pts. Objective responses were observed in pts with HER2 positive BC (88/108, ORR 81.5%, 95% CI 72.9-88.3), HER2-low BC (43/77, ORR 55.8%, 95% CI 44.1-67.2), urothelial carcinoma (7/11), colorectal cancer (3/10), gastric/GEJ carcinoma (5/9), biliary tract cancer (5/8), NSCLC (1/3), endometrial cancer (1/2), and H&N cancer (1/1). Subgroup analyses of ORR are shown in Table 1. The 6-month PFS rate was 73.9% in all pts. Conclusions: SHR-A1811 was well-tolerated and showed promising antitumor activity in heavily pretreated advanced solid tumors. Table 1. Subgroup analyses of ORR No. of prior treatment lines in metastatic setting in all pts (N=250) HER2 positive BC (N=108) HER2-low BC (N=77) Other tumor types (N=65) ≤3 81.8% (45/55) 58.7% (27/46) 36.7% (18/49) >3 81.1% (43/53) 51.6% (16/31) 31.3% (5/16) Prior anti-HER2 therapies in pts with BC (N=185)* HER2 positive BC (N=108) HER2-low BC (N=77) All BC (N=185) Any 82.2% (88/107, 73.7-89.0) 68.8% (11/16, 41.3-89.0) 80.5% (99/123, 72.4-87.1) Trastuzumab 81.9% (86/105, 73.2-88.7) 75.0% (9/12, 42.8-94.5) 81.2% (95/117, 72.9-87.8) Pertuzumab 83.0% (39/47, 69.2-92.4) 100% (5/5, 47.8-100) 84.6% (44/52, 71.9-93.1) Pyrotinib 86.9% (53/61, 75.8-94.1) 71.4% (5/7, 29.0-96.3) 85.3% (58/68, 74.6-92.7) Lapatinib 80.0% (28/35, 63.1-91.6) 100% (1/1, 2.5-100) 80.6% (29/36, 64.0-91.8) T-DM1 82.4% (14/17, 56.6-96.2) 100% (3/3, 29.2-100) 85.0% (17/20, 62.1-96.8) Other HER2-ADC (except T-DM1)** 60.0% (9/15, 32.3-83.7) 50.0% (2/4, 6.8-93.2) 57.9% (11/19, 33.5-79.8) ORR in pts with tumor types other than BC (N=65) HER2 IHC3+ or IHC2+/ISH+ (N=36) HER2 IHC2+/ISH- or IHC1+ or unknown (N=29) All other tumor types (N=65) % (n/N) 38.9% (14/36) 31.0% (9/29) 35.4% (23/65) ORR was shown as % (n/N, 95% CI) or % (n/N). *ORR is calculated using the number of subjects previously treated with anti-HER2 cancer therapy in advanced/metastatic setting as denominator; 2-sided 95% CIs are estimated using Clopper-Pearson method. **Includes RC48-ADC, A166, DP303c, MRG002, ARX788, TAA013, DX126-262, PF-06804103, and BAT8001. Citation Format: Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min-Hee Ryu, Jee Hyun Kim, John Park, Yahua Zhong, Weiqing Han, Caigang Liu, Mark Voskoboynik, Qun Qin, Jian Zhang, Minal Barve, Ana Acuna-Villaorduna, Vinod Ganju, Seock-Ah Im, Changsheng Ye, Yongmei Yin, Amitesh C. Roy, Li-Yuan Bai, Yung-Chang Lin, Chia-Jui Yen, Hui Li, Ki Young Chung, Shanzhi Gu, Jun Qian, Yuee Teng, Yiding Chen, Yu Shen, Kaijing Zhao, Shangyi Rong, Xiaoyu Zhu, Erwei Song. Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 in HER2-expressing/mutated advanced solid tumors: A global phase 1, multi-center, first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT175.

Фиторекультивация почв, загрязненных нефтью и нефтепродуктами, рассматривается как один из перспективных подходов в биотехнологии. Эффективность этого метода зависит от под- бора культур. Объектом исследования являлась загрязненная нефтью аллювиальная дерновая легкосуглинистая почва. Рассматривались варианты с начальным содержанием нефти 5.4 г/кг, 9.7 г/кг и 21.8 г/кг. В качестве фиторемедиантов использовались однодольные и двудольные растения ‒ пшеница яровая (Triticum vulgare L.) и горох посевной (Pisum sativum L). Газохроматографическим методом изучено изменение углеводородного состава после фиторекультивационных мероприятий. На хроматограммах идентифицированы пики гомологов н-алканов диапазона С9‒С36 и углеводороды (УВ) неполярного и малополярного строения, образующие «изопреноидный горб». Стимулируя активность микроорганизмов в прикорневой зоне, рассматриваемые культурыоказывают различное влияние на деструкцию и преобразование остаточной нефти в зависимости от степени загрязнения. Существенное снижение концентрации УВ нефти к концу эксперимента (в 3.8 раза) отмечено в варианте с максимальным содержанием поллютанта в опыте с пшеницей. Отмечается обратная зависимость процентного содержания н-алканов от уровня остаточного содержания нефтепродуктов. Выделено 2 типа распределения неполярных УВ. Для вариантов с низким уровнем загрязнения характерна мономодальная форма. Второй тип имел бимодальное распределение и был типичен для опытных образцов с относительно высокой концентрацией. Профиль н-алканов характеризовался преобладанием четных гомологов в среднемолекулярной области. Полученные данные могут указывать, что наиболее вероятными продуцентами четных парафинов среднемолекулярного диапазона может быть биомасса микробиоты. Библиографические ссылки 1. 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Introdução: A candidemia é uma das infecções nasocomiais mais frequentes a nível mundial e apresenta diferentes espécies de Candida envolvidas com o desenvolvimento dessa patologia. Objetivo: Este estudo analisou os aspectos epidemiológicos e as diferentes espécies de Candida associadas à candidemia. Material e Métodos: Uma revisão de literatura foi realizada, através da leitura de artigos científicos publicados nas bases de dados Pubmed e Scielo nos últimos cinco anos. Utilizou-se as seguintes combinações de descritores: Candidemia, Candidemia e Prevalência, Candidemia e Incidência, Candidemia e Candida. Resultados: A candidemia é a infecção fúngica mais hostil atualmente encontrada e prevalente nas populações estudadas. A população mais afetada são os recém-nascidos. Apresenta altas taxas de mortalidade e disseminação em várias partes do mundo. A nutrição parenteral, a administração de antibióticos de amplo espectro, hospitalização prolongada, cirurgia prévia e colonização por Candida sp são os principais fatores de risco relatados na literatura. Múltiplas espécies fúngicas estão associadas a essa condição, porém C. albicans é a mais predominante, seguida por C. parapsilosis e C. tropicalis. Conclusões: A Candidemia é uma patologia prevalente e apresenta alta incidência e morbimortalidade nas populações estudadas das diferentes partes do mundo. C. albicans é a espécie mais associada, seguida por C. parapsilosis e C. tropicalis. Descritores: Candidemia; Prevalência; Incidência; Candida. Referências Treviño-Rangel RJ, Peña-López CD, Hernández-Rodríguez PA, Beltrán-Santiago D, González GM. Association between Candida biofilm-forming bloodstream isolates and the clinical evolution in patients with candidemia: An observational nine-year single center study in Mexico. Rev Iberoam Micol. 2018;35(1):11-16. Kaur H, Chakrabarti A. Strategies to Reduce Mortality in Adult and Neonatal Candidemia in Developing Countries. J Fungi (Basel). 2017;3(3):41. Wu PF, Liu WL, Hsieh MH, Hii IM, Lee YL, Lin YT et al. Epidemiology and antifungal susceptibility of candidemia isolates of non-albicans Candida species from cancer patients. Emerg Microbes Infect. 2017;6(10):e87. Vasilyeva NV, Raush ER, Rudneva MV, Bogomolova TS, Taraskina AE, Fang Y et al. Etiology of invasive candidosis agents in Russia: a multicenter epidemiological survey. Front Med. 2018;12(1):84-91. Barchiesi F, Orsetti E, Osimani P, Catassi C, Santelli F, Manso E. Factors related to outcome of bloodstream infections due to Candida parapsilosis complex. BMC Infect Dis. 2016;16:387. Barchiesi F, Orsetti E, Mazzanti S, Trave F, Salvi A, Nitti C, Manso E. Candidemia in the elderly: What does it change? PLoS One. 2017;12(5):e0176576. Benedict K, Roy M, Kabbani S, Anderson EJ, Farley MM, Harb S et al. Neonatal and pediatric candidemia: results from population-based active laboratory surveillance in four US locations, 2009-2015. J Pediatric Infect Dis Soc. 2018;7(3):e78-e85. Bhattacharjee P. Epidemiology and antifungal susceptibility of Candida species in a tertiary care hospital, Kolkata, India. Curr Med Mycol. 2016;2(2):20-7. Breda GL, Tuon FF, Meis JF, Herkert PF, Hagen F, de Oliveira LZ, Dias VC, da Cunha CA, Queiroz-Telles F. Breakthrough candidemia after the introduction of broad spectrum antifungal agents: A 5-year retrospective study. Med Mycol. 2018;56(4):406-15 Caggiano G, Lovero G, De Giglio O, Barbuti G, Montagna O, Laforgia N et al. Candidemia in the Neonatal Intensive Care Unit: a retrospective, observational survey and analysis of literature Data. Biomed Res Int. 2017;2017:7901763. Fu J, Ding Y, Wei B, Wang L, Xu S, Qin P, Wei L, Jiang L. Epidemiology of Candida albicans and non-C.albicans of neonatal candidemia at a tertiary care hospital in western China. BMC Infect Dis. 2017;17(1):329. Guzzetti LB, Vescina CM, Gil MF, Gatti BM. Candidemias en pediatría: distribución de especies y sensibilidad a los antifúngicos [Candidemia in Pediatrics: Species distribution and antifungal susceptibility]. Rev Argent Microbiol. 2017;49(4):320-22. Kofteridis DP, Valachis A, Dimopoulou D, Andrianaki AM, Christidou A, Maraki S, Spernovasilis NA, Samonis G. Factors Influencing Non-albicans Candidemia: A Case-Case-Control Study. 2017; 182(7-8):665-72. Kubiak DW, Farmakiotis D, Arons V, Hollins RM, Rostas SE, Weiser LM et al. Utility of in-house fluconazole disk diffusion susceptibility testing in the treatment of candidemia. Diagn Microbiol Infect Dis. 2016;84(3):223-26. Li D, Zhang W, Zheng S, Ma Z, Zhang P, Liu Z. Surveillance study of candidemia in cancer patients in North China. Med Mycol. 2013;51(4):378-84. Li D, Xia R, Zhang Q, Bai C, Li Z, Zhang P. Evaluation of candidemia in epidemiology and risk factors among cancer patients in a cancer center of China: an 8-year case-control study. BMC Infect Dis. 2017;17(1):536. Lortholary O, Renaudat C, Sitbon K, Desnos-Ollivier M, Bretagne S, Dromer F; French Mycoses Study Group. The risk and clinical outcome of candidemia depending on underlying Intensive Care Med. 2017; 43(5):652-62. Lovero G, De Giglio O, Montagna O, Diella G, Divenuto F, Lopuzzo M, Rutigliano S, Laforgia N, Caggiano G, Montagna MT. Epidemiology of candidemia in neonatal intensive care units: a persistent public health problem. Ann Ig. 2016;28(4):282-87. Márquez F, Iturrieta I, Calvo M, Urrutia M, Godoy-Martínez P. Epidemiología y susceptibilidad antifúngica de especies causantes de candidemia en la ciudad de Valdivia, Chile [Epidemiology and antifungal susceptibility of species producing candidemia in Valdivia, Chile]. Rev Chilena Infectol. 2017;34(5):441-46. Pinhati HM, Casulari LA, Souza AC, Siqueira RA, Damasceno CM, Colombo AL. Outbreak of candidemia caused by fluconazole resistant Candida parapsilosis strains in an intensive care unit. BMC Infect Dis. 2016;16(1):433. Siri L, Legarraga P, García P, González T, Rabagliati R. Cambios clínicos y epidemiológicos de candidemias en pacientes adultos desde 2000 a 2013. Rev Chilena Infectol. 2017;34(1):19-26. Spiers R, Smyth B, Lamagni T, Rooney P, Dorgan E, Wyatt T et al. The epidemiology and management of candidemia in Northern Ireland during 2002-2011, including a 12-month enhanced case review. Med Mycol. 2019;57(1):23-9. Tiraboschi IN, Pozzi NC, Farías L, García S, Fernández NB. Epidemiología, especies, resistencia antifúngica y evolución de las candidemias en un hospital universitario de Buenos Aires, Argentina, durante 16 años [Epidemiology, species, antifungal resistance and outcome of candidemia in a university hospital in Buenos Aires, Argentina for 16 years]. Rev Chilena Infectol. 2017;34(5):431-40. Vena A, Bouza E, Valerio M, Padilla B, Paño-Pardo JR, Fernández-Ruiz M et al. Candidemia in non-ICU surgical wards: comparison with medical wards. PLoS One. 2017;12(10):e0185339. Kelly MS, Benjamin DK Jr, Smith PB. The epidemiology and diagnosis of invasive candidiasis among premature infants. Clin Perinatol. 2015;42(1):105-17, viii-ix. Wu JQ, Zhu LP, Ou XT, Xu B, Hu XP, Wang X et al. Epidemiology and risk factors for non-Candida albicans candidemia in non-neutropenic patients at a Chinese teaching hospital. Med Mycol. 2011;49(5):552-55. Navalkele BD, Revankar S, Chandrasekar P. Candida auris: a worrisome, globally emerging pathogen. Expert Rev Anti Infect Ther. 2017;15(9):819-27. Spivak ES, Hanson KE. Candida auris: an Emerging Fungal Pathogen. J Clin Microbiol. 2018;56(2):e01588-17. Colombo AL, Guimarães T, Sukienik T, Pasqualotto AC, Andreotti R, Queiroz-Telles F et al. Prognostic factors and historical trends in the epidemiology of candidemia in critically ill patients: an analysis of five multicenter studies sequentially conducted over a 9-year period Intensive Care Med. 2014;40(10):1489-98. Gehring GM, Carrilho CMM, Pelisson M, Perugini M, Tano ZN. Candidemia: Revisão Bibliográfica. J Infect Control. 2015;4(4):1-19. Lepak A, Andes D. Fungal sepsis: optimizing antifungal therapy in the critical care setting. Crit Care Clin. 2011;27(1):123-47. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50. Wisplinghoff H, Ebbers J, Geurtz L, Stefanik D, Major Y, Edmond MB et al. Nosocomial bloodstream infections due to Candida spp. in the USA: species distribution, clinical features and antifungal susceptibilities. Int J Antimicrob Agents. 2014;43(1):78-81.

At the foot of the Great Wall of China, near the town of Badaling, SOHO Small Office – Home Office in 2000 started constructing 59 detached guesthouses. Each of them was to be equipped with extensive cultural, entertainment, and business facilities. The creators of the project, the owner of the design office, Mr. Shiyi and his wife Mrs. Zhang Xin, invited 12 renowned architects to their endeavor, and gave them total freedom of creation. Although the project was charged with a high level of risk, and its final shape was difficult to predict, it became an unprecedented success, even though available only for a narrow group of affluent residents of the Middle Kingdom, as well as curious tourists from Western Europe and North America. The edifices, constructed over a period of 10 years, are probably more recognized in the western world than in China; it can be attributed to the exhibition of the design at the Venice Biennale in 2002, during which it was honored with a special prize. Additionally, the names of architects, brands in themselves, attracted the attention of critics and experts in architecture, who were particularly interested in the outcome of the encounter of great architectural individualities while creating Commune by the Great Wall. Three Japanese architects took part in the project. Kengo Kuma called his edifice Great Bamboo Wall (2000-2002), from the type of material employed for creating external-wall cladding as well as internal partitions; Shigeru Ban in his design, Bamboo Furniture House, used bamboo veneer lumber to create furniture to be prefabricated and used as the main component in addition to the exterior and interior walls. Finally, Nobuaki Furuya’s Forest House aimed at carrying out his own concept of architecture as a place of safety (asylum). Kanika R’kul, who carries out her designs mainly in Taiwan, presented Shared House that was its form similar to the practice of American modernism. A significant factor turned out to be the education in architecture that R’kul obtained at one of Californian universities, and her familiarity with American modernism as well as the activities of so-called “New York Five”. The motive behind the activities of another architect, Cui Kai, was primarily to obtain different views from inside the house, which was highlighted by the name of the project, See and Seen House. Antonio Ochoa Piccardo from Venezuela, the only author of non-Asian origin, though connected with Asian world for many years via designing edifices for SOHO office, also tried to provide variety of visual experience for the audiences of another guesthouse, Cantilever House. On the one hand, via employing raw concrete, Béton brut, it was homage to Le Corbusier, on the other hand, it expressed respect to the surrounding nature, articulated with using sienna pigment as wall dye. Rocco Yim from Hong Kong, the author of Distorted Courtyard, in a veiled mode drew from the traditions and practices of a typical house with a courtyard, and Kay Ngee Tan from Singapore subjected his design, The Twins, to surrounding nature, using local stone as his building material. The name of another guesthouse, Split House, contains the original design idea of a Chinese architect, Yung Ho Chang. The building was made with one piece that was cut and its parts were diagonally spaced. Two following projects were born from a desire to experiment in the field of mass solutions or the arrangement of the interior; they became an unique interjection of the local landscape and forced the audiences to change their habits. The first, Airport House by Chien Hsueh-Yi from Taiwan, resembled a section of an airport building. The second, the now famous Suitcase House by Gary Chang from Edge Design Institute, allowed for creating multiple spatial combinations with mobile walls and corners hidden under the floor. The crowning element of Commune by the Great Wall is a multi-functional clubhouse designed in 2001 by a world-renowned South Korean architect, Seung H-Sang of the Iroje Architects & Planners design office. As the concept of Commune by the Great Wall developed and new guesthouses were constructed, the clubrooms also enlarged. In 2005 Seung H-Sang returned to the project. The Commune by the Great Wall project supported by SOHO Studios combines pavilions that are extremely modern with more traditional ones; others constitute a subtle link between local color and a playful functionalism. The eleven edifices presented above constituted prototypical solutions, followed by numerous replicas across the land. Currently, Commune by the Great Wall is an exclusive leisure and entertainment area subject to the Kempinski hotel brand with appropriate promotion and an extensive marketing program, e.g. advertisements on websites and in prestigious journals, such as Business Week. A bold experiment from a Chinese developer has become an alternative for tourists from around the world, looking in China not only examples of centuries-old culture, but also the visual signs of a developing country that follows modern trends.

The use of fossil fuels, which have increased rapidly since the Industrial Revolution, is causing serious climate change. To overcome this, interest in clean and sustainable energy sources to replace fossil fuels is increasing worldwide. Among alternative energies, the electricity generation from solar and wind resources is difficult to achieve sustainable energy production regardless of the weather and season. Hence, hydrogen is considered as the most promising energy source to replace fossil fuels because of its clean, storable, sustainable, and transportable characteristics. Recently, reversible fuel cells that can both produce hydrogen with surplus power and generate electricity using the stored hydrogen have attracting attentions as an electrochemical device to promote reliable and economical hydrogen society [1]. Among them, reversible solid oxide cells show high efficiency in a fuel cell mode due to their high operating temperature (700-1000 ℃). However, reversible solid oxide cells exhibit relatively low performance in water-electrolysis cell mode [2]. The main reason of low performance in the solid oxide electrolysis cell mode is the sluggish kinetics of oxygen evolution reactions in air-electrode. Therefore, the electrolysis performance of reversible solid oxide cells can be greatly improved if the air-electrode with high catalytic activity for oxygen evolution reactions is developed. Among many candidate materials for air-electrodes, cobalt-based layered materials are known to have good electrocatalytic properties in oxygen reduction and oxygen evolution reactions with high electronic conductivity (σ = 100–240 S·cm-1 at 450–650 °C) [3, 4]. Herein, we introduce a novel layered structure material, Ba2Co9O14 (BCO), as air-electrode materials for highly efficient and durable reversible solid oxide cells. In order to further enhance the catalytic property of BCO, Nd and Ca are doped into Ba-site. The Nd0.1Ca0.1Ba1.8Co9O14-cell shows a maximum power density of 2.6 W·cm-2 in fuel cell mode, current density of –4.36 A/cm2 under applied voltage of 1.6 V in electrolysis cell mode, at 800 ℃, surpassing previous reported results of air-electrode catalysts for reversible solid oxide cells. References [1] S. E. Hosseini, M. A. Wahid, Renew. Sustain. Energy Rev. 2016, 57, 850. [2] X. Zhang, L. Liu, Z. Zhao, B. Tu, D. Ou, D. Cui, X. Wei, X. Chen, M. Cheng, Nano Lett. 2015, 15, 1703. [3] M. Saqib, I. -G. Choi, H. Bae, K. Park, J. -S. Shin, Y. -D. Kim, J. -I. Lee, M. Jo, Y. -C. Kim, K. -S. Lee, S. -J. Song, E. D. Wachsman, J. -Y. Park, Energy Environ. Sci. 2021, 14, 2472. [4] A. Rolle, N. Preux, G. Ehora, O. Mentré, S. Daviero-Minaud, Solid State Ionics 2011, 184, 31.

This paper deals with the most salient aspects of distance education, and how it has been an issue of great relevance in the pandemic era. However, this is not a current issue, it is a situation that has affected the schooling situation in rural areas since earlier times. The positive and negative aspects of distance education from more than twenty years ago are evaluated and contrasted with the new online education methods. B-learning education and new educational paradigms are evaluated. The main results show that education can take on different effective methodologies as long as appropriate teacher training and education processes are in place. Keywords: B-learning education, distance learning, online education. References [1]V. Guichot, «Hisotria de la educación: reflexiones sobre su objeto, ubicación epistemológica, devenir histórico y tendencias actuales,» Revista Latinoamericana de Estudios Educativos, vol. 2, nº 1, pp. 11-51, 2006. [2]J.Gomera, «josegomera.com,»[Online]. Available: https://josegomera.com/academico/conoce-la-historia-de-la-educacion-a-distancia/#:~:text=La%20historia%20de%20la%20educaci%C3%B3n%20a%20distancia%20universitaria%20en%20Estados,que%20transmite%20cursos%20por%20radio.. [Last access: 30 Mar 2021]. [3]wikipedia, «Historia de internet,» [Online]. Available: https://es.wikipedia.org/wiki/Historia_de_Internet. [Last access: 2 Apr 2021]. [4]F.-J. Hinojo-Lucena, J.-M. Trujillo-Torres, J.-A. Marín-Marín y C. Rodríguez-Jiménez, «B-Learning in Basic Vocational Training Students for the Development of the Module of Applied Sciences I,» Mathematics, vol. 8, nº 1102, pp. 1-13, 2020. [5]«The objective of this research is to measure the perception that teachers had about their own Educators during the COVID-19 Pandemic: A Cross-Analysis of Different Educational Stages,» Sustainiability, vol. 12, nº 10128, pp. 1-13, 2020. [6] C. A. Gutiérrez Pérez, «Construction of Digital Identity through B-Learning Training: Resource Evaluation,» ACM International Conference Proceeding Series, pp. 930-934, 2020. [7]Y. Guo y L. Chen, «An Investigation on Online Learning for K12 in Rural Areas in China during COVID-19 Pandemic,» de 2020 9th International Conference of Educational Innovation through Technology, EITT 2020, Portugal, 2020. [8]Universidad de los Andes, «Universidad de los Andes,» [Online]. Available: https://blended.uniandes.edu.co/caracteristicas-del-blended-learning/#:~:text=Un%20elemento%20caracter%C3%ADstico%20en%20la,de%20su%20proceso%20de%20aprendizaje.. [Last access: 02 Apr 2021]. [9]M. Zhang, A. Tlili, R. Zhuang, J. Yang, T.-W. Chang, H. Wang y R. Huang, «Experiencia china de proporcionar aprendizaje remoto y flexible durante la pandemia de COVID-19: un estudio de caso sobre el mantenimiento de la educación en contextos de crisis,» Lecture Notes in Educational Technology, vol. 3, nº 2, pp. 243-253, 2021. [10]J. Carvajal, F. Suárez y X. Quiñónez, «las TIC en la educación universitaria.,» Universidad Ciencia Y Tecnología, vol. 22, nº 89, pp. 31-35, 2019.

In this letter, we numerically demonstrate a hybrid-core microstructure fiber for low-loss terahertz guidance. Finite element method with circular perfectly matched layer boundary condition is applied to characterize the guiding properties. It is shown that by using a triangular-core inside a square lattice microstructure exhibits ultra-low effective material loss (EML) of 0.169 dB/cm and low confinement loss of 0.087 dB/cm at the operating frequency of 0.75 THz. We also discuss how other guiding properties including power fraction, single mode propagation and dispersion vary with changing of core diameter and operating frequencies. This low-loss microstructure fiber can be effectively used in numerous applications in the THz regime. Full Text: PDF ReferencesJ. J. Bai, J. N. Li, H. Zhang, H. Fang, S. J. Chang, "A porous terahertz fiber with randomly distributed air holes", Appl. Phys. B 103, 2 (2011). CrossRef S. Atakaramians, S. Afshar, B. M. Fischer, D. Abbott, T. M. Monro, "Porous fibers: a novel approach to low loss THz waveguides", Opt. Express 16, 12 (2008). CrossRef K. Wang, D. M. Mittleman, "Metal wires for terahertz wave guiding", Nature 432, 7015 (2004). CrossRef R. Islam, G. K. M. Hasanuzzaman, M. S. Habib, S. Rana, M. A. G. Khan, "Low-loss rotated porous core hexagonal single-mode fiber in THz regime", Opt. Fiber Technol. 24, (2015). CrossRef M. I. Hasan, S. M. A. Razzak, G. K. M. Hasanuzzaman, M. S.Habib, "Ultra-Low Material Loss and Dispersion Flattened Fiber for THz Transmission", IEEE Photon. Technol. Lett. 26, 23 (2014). CrossRef S. F. Kaijage, Z. Ouyang, X. Jin, "Porous-Core Photonic Crystal Fiber for Low Loss Terahertz Wave Guiding", IEEE Photon. Technol. Lett. 25, 15 (2013). CrossRef M. R. Hasan, M. A. Islam, A. A. Rifat, "A single mode porous-core square lattice photonic crystal fiber for THz wave propagation", J. Eur. Opt. Soc. Rapid Publ. 12, 1 (2016). CrossRef M. R. Hasan, M. A. Islam, M. S. Anower, S. M. A. Razzak, "Low-loss and bend-insensitive terahertz fiber using a rhombic-shaped core", Appl. Opt. 55, 30 (2016). CrossRef S. Ali et al. "Ultra-low loss THz waveguide with flat EML and near zero flat dispersion properties", in 9th Int. Conf. on Elect. and Comp. Eng., IEEE, (2016). CrossRef K. Nielsen, H. K. Rasmussen, A. J. Adam, P. C. Planken, O. Bang, P. U. Jepsen, "Bendable, low-loss Topas fibers for the terahertz frequency range", Opt. Express 17, 10 (2009). CrossRef A. W. Snyder, J. D. Love, Optical waveguide theory (London, Chapman & Hall 1983). DirectLink L. Vincetti, A. Polemi, in Antennas and Propagation Society International Symposium, IEEE (2009)G. P. Agrawal, Nonlinear fiber optics (Boston, Academic Press 1989). CrossRef B. S. Williams, "Terahertz quantum-cascade lasers", Nat. Photon. 1, 9 (2007). CrossRef H. W. Hubers et al. "Terahertz quantum cascade laser as local oscillator in a heterodyne receiver", Opt. Express 13, 15 (2005). CrossRef

Electrolytes in Li-ion batteries play a significant role as they influence different aspects directly related to the battery performance, such as safety, voltage window, electrochemical stability, and the formation of solid-electrolyte interphase (SEI). Conventionally, these electrolytes are composed of a lithium salt dissolved in an organic solvent such as ethylene carbonate and propylene carbonate. Regarding safety, these organic electrolytes can be replaced by room-temperature ionic liquids (RTILs), which present lower vapor pressure and non-flammability.1 Moreover, adding polymer to these liquid electrolytes to form polymer gel electrolytes has proven to be a good strategy to avoid dendritic growth and increase electrolyte stability.2 The properties of RTIL electrolytes containing Li salts have been studied in the last decade. Still, the scope has been limited primarily to simple RTILs consisting of one cationic and one anionic species. Inspired by the success of high-entropy alloys (HEAs) for forming stable solid solutions with excellent mechanical properties,3 the concept of high-entropy materials has been recently transferred to electrolytes, where the effect of mixing multiple Li salts is explored.4 However, the number of compositional combinations increases rapidly when multiple salts, cationic and anionic species are introduced, and the explorable compositional space increases even more when polymers are added to the mixture. Automating the electrolyte preparation and characterization can be the key feature to allow the exploration of all the possible electrolyte combinations. In this work, we explain the first preliminary results obtained from an autonomous preparation and characterization of high-entropy electrolytes composed of a mixture of two different lithium salts in ionic liquids consisting of multiple anionic and cationic species. In addition, the adaptation of the autonomous system of preparation and characterization of liquid electrolytes to polymer gel electrolytes is also proposed and explained. References. (1) Niu, H.; Wang, L.; Guan, P.; Zhang, N.; Yan, C.; Ding, M.; Guo, X.; Huang, T.; Hu, X. Recent Advances in Application of Ionic Liquids in Electrolyte of Lithium Ion Batteries. J. Energy Storage 2021, 40, 102659. https://doi.org/10.1016/j.est.2021.102659. (2) Chen, J.; Wu, J.; Wang, X.; Zhou, A.; Yang, Z. Research Progress and Application Prospect of Solid-State Electrolytes in Commercial Lithium-Ion Power Batteries. Energy Storage Mater. 2021, 35, 70–87. https://doi.org/10.1016/j.ensm.2020.11.017. (3) Yeh, J.-W.; Chen, S.-K.; Lin, S.-J.; Gan, J.-Y.; Chin, T.-S.; Shun, T.-T.; Tsau, C.-H.; Chang, S.-Y. Nanostructured High-Entropy Alloys with Multiple Principal Elements: Novel Alloy Design Concepts and Outcomes. Adv. Eng. Mater. 2004, 6 (5), 299–303. https://doi.org/10.1002/adem.200300567. (4) Wang, Q.; Zhao, C.; Wang, J.; Yao, Z.; Wang, S.; Kumar, S. G. H.; Ganapathy, S.; Eustace, S.; Bai, X.; Li, B.; Wagemaker, M. High Entropy Liquid Electrolytes for Lithium Batteries. Nat. Commun. 2023, 14 (1), 440. https://doi.org/10.1038/s41467-023-36075-1.

Hydrogen, which possesses high gravimetric energy density, has recently received great attentions to respond to the seriousness of global climate change [1, 2]. In particular, the alkaline water electrolysis cells (AECs) that can produce hydrogen through electrochemical reactions without greenhouse gas emissions are substantially promising as renewable next-generation energy storage and conversion devices. In AECs, oxygen evolution reactions (OERs) occur at the anode, while hydrogen evolution reactions take place at the cathode [3, 4]. However, the sluggish kinetics of the multi-electron transfer process is a paramount challenge for efficient OER activity. Furthermore, precious metal catalysts such as iridium and ruthenium are still mainly used as an OER catalyst, and their low economic efficiency and durability are acting as major problems in the commercialization stage. Therefore, the reduction of reaction overpotential is crucial to boost catalytic efficiency for OER in AECs. In this study, the OER catalyst study is performed on sulfide-based chalcogenide materials. It has been reported that the sulfide-based chalcogenide materials have shown the excellent catalytic activity because the covalent characteristics between transition metal and chalcogenide is stronger than that of oxide-based catalysts [5]. In particular, among various sulfide-based chalcogenide materials, nickel sulfide-based catalysts have actively studied because they can simply synthesize using a hydrothermal method. Additionally, nickel sulfides have a structurally Ni-Ni metal bond that makes it easy to transfer charge species for OERs. Herein, various transition metals are doped into the nickel sulfide to improve the catalytic activity and electrical conductivity via generation of extra defects in the crystal structure. The crystal structure and catalytic activity of chalcogenide catalysts are analyzed through various physicochemical and electrochemical analysis methods. References [1] Hainan Sun, Xiaomin Xu, Zhiwei Hu, Liu Hao Tjeng, Jie Zhao, Qin Zhang, Hong-Ji Lin, Chien-Te Chen, Ting-Shan Chan, Wei Zhou, Zongping Shao, Journal of Materials Chemistry A 7 (2019) 9924. [2] Thomas E. Mallouk, Nature Chemistry 5 (2013) 362–363. [3] Muhammad Saqib, In-Gyu Choi, Hohan Bae, Kwangho Park, Ji-sup Shin, You-Dong Kim, John-In Lee, Minkyeong Jo, Yeong-Cehol Kim, Kug-Seung Lee, Sun-Ku Song, Eric D. Wachsman and Jun-Young Park, Energy & Environmental Science 14 (2021) 2472–2484. [4] Sung Ryul Choi, John-In Lee, Hyunyoung Park, Sung Won Lee, Dong Yeong Kim, Won Young An, Jung Hyun Kim, Jongsoon Kim, Hyun-seok Cho, Jun-Young Park, Chemical Engineering Journal 409 (2021) 128226. [5] Hatem M. A. Amin, UIf-Peter Apfel, European Journal of Inorganic Chemistry 2020 (2020) 2679–2690. Keywords: Oxygen evolution reaction, Alkaline electrolysis cell, Water splitting, Transition metal, Post-transition metal, Chalcogenide. * Corresponding author: jyoung@sejong.ac.kr (J. Y. Park)

Abstract Background: Dendritic cells (DCs) are vital for initiating antigen-specific T cell-dependent antitumor immune responses. However, emerging evidence reveals that local DCs within the tumor microenvironment (TME) are tolerized to facilitate immune evasion. Reprogramming of DCs is recognized as a promising strategy for tumor immunotherapy. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an inhibitory receptor belonging to the LILR family which is mainly expressed on normal myeloid cells and myeloid-derived malignant cells. It is upregulated on tolerogenic DCs (tolDCs), which exhibit low expression levels of costimulatory molecules and resistance to DC maturation. Targeting LILRB4 to reprogram tolDCs has been reported to be a promising strategy for cancer treatment. Here we report the preclinical development of an LILRB4 antagonist antibody, ATG-034. Method: The protein-based and cell-based binding affinity of ATG-034 were measured using SPR, ELISA and FACS analysis. Fc receptor (FcR) stimulation assay was used to evaluate the ability of ATG-034 to block the interaction of LILRB4 with its ligand fibronectin. ATG-034-mediated enhancement of antigen presentation and co-stimulation ability of DCs was determined by FACS analysis for the change of surface expression of HLA-DR, HLA-ABC, CD86, and CD206. The mixed lymphocyte reaction (MLR) assay was used to assess the immunomodulatory potential of ATG-034. The in vivo antitumor efficacy of ATG-034 was evaluated in a radiation therapy-resistant murine Lewis lung carcinoma (LLC) syngeneic model. Results: ATG-034 binds to LILRB4 protein with a single-digit nM affinity. It potently reversed the fibronectin-mediated inhibition of FcR-driven TNF-α cytokine production. TolDCs were reprogrammed by ATG-034 to immunogenic DCs with significant upregulation of the expression of HLA-DR, HLA-ABC, CD86 and downregulation of the expression of CD206. Furthermore, ATG-034 remarkably reinvigorated tolDCs for priming T cell activation with noticeable upregulation of the expression of CD25 and the secretion of IFN-γ, enhancing antitumor immunity. In addition, 10 mg/kg ATG-034 significantly inhibited the LLC tumor growth in vivo with a TGI of 40.28%, while a benchmark antibody only demonstrated a 24.43% TGI. Conclusion: Our data show that ATG-034 reprograms tolDC, enhancing anti-tumor immunity, and demonstrates potent in vivo anti-tumor efficacy. Therefore, ATG-034 may be a promising strategy for the treatment of cancer. Citation Format: Ao Sun, Enlin Zheng, Huili Cao, Mengshi Cao, Suya Bai, Peng Chen, Linjie Tian, Jay Mei, Bo Shan, Bing Hou. ATG-034, an LILRB4 antagonist antibody, reinvigorates dendritic cells and prevents tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6384.

BackgroundOxidized low-density lipoprotein (oxLDL) particles support low-grade inflammation and have been found in synovial fluid from osteoarthritis (OA) joints [1]. Their component is 7-ketocholesterol (7-KC), which arises as the result of the oxidation of cholesterol [1]. 7-KC acts proinflammatory and it binds to Toll-like receptor (TLR) 4 expressed on macrophages [1]. Activation of TLR4 stimulates the classical macrophage maturation program, resulting in a specific phenotype of inducible nitric oxide synthase positive (iNOS+) and macrophage (M) 1 function, which produce and secrete proinflammatory chemokines and cytokines [2]. M2 macrophages are associated with wound healing by the production of arginase-1 [2,3]. Synovial macrophages are of critical importance in the symptomatology and structural progression of OA since M1 polarized macrophages accumulate in human OA synovial tissue during exacerbation [3]. However, it is not known whether 7-KC can re-program synovial tissue macrophages and support M1 polarization.ObjectivesWe analyzed the influence of 7-KC on the polarization of CD68+ macrophages in the suspension of synovial mononuclear cells (SMCs) in respect to lipopolysaccharide (LPS), as M1 inducer.MethodsMature synovial tissue samples were obtained during alloarthroplasty of the knee (N = 56). Paraffin embedded tissue sections were labelled by double immunofluorescence using a combination of antibodies directed toward CD68 and iNOS, arginase-1, CCL2 or CCL22. Suspension of SMCs was prepared by enzymatic digestion of tissue samples using collagenase IV and gradient density centrifugation. We analyzed intracellular (iNOS, arginase-1, CCL2, and CCL22) and surface (CD91, mannose receptor, HLA-DR, CD80, CD86 and decoy D6) antigens expression in CD68+ cells in the suspension of freshly isolated or 18 hour-cultured SMCs with 7-KC (25 μM), LPS (10 ng/ml), their combination or in the medium only.ResultsiNOS and CCL2 were more frequently labelled in lymphocyte clusters, while arginase-1 and CCL22 were labelled in synovial lining CD68+ cells. Phenotype of CD68+ cells did not change significantly after the 18 hour- culture in the medium only, except the decrease of mannose receptor and CD91, when compared with freshly isolated cells. 7-KC increased the percentage of CD86 expressing CD68+ cells, whereas decreased surface expression of CD91 and chemokine decoy D6, like in the culture with LPS, when compared with cells cultured in the medium only. 7-KC decreased the frequency of arginase-1+/CD68+ cells in the suspension and did not change iNOS+ in CD68+ cells, thus increasing the ratio of iNOS+/arginase-1+ in CD68+ subset. 7-KC was unable to increase CCL2 like LPS in comparison with cells cultured in the medium only. Neither 7-KC nor LPS affected CCL22 expression in the CD68+ subset.ConclusionThese data provide a new perspective in understanding the polarization of macrophages toward the M1 phenotype mediated with oxysterol 7-KC in vitro.References[1]Niki E. Biomarkers of lipid peroxidation in clinical material. Biochim Biophys Acta. 2014;1840(2):809-17.[2]Fernandes TL, Gomoll AH, Lattermann C, Hernandez AJ, Bueno DF, Amano MT. Macrophage: A Potential Target on Cartilage Regeneration. Front Immunol. 2020;11:111.[3]Zhang H, Cai D, Bai X. Macrophages regulate the progression of osteoarthritis. Osteoarthritis Cartilage. 2020;28(5):555-561.AcknowledgementsThe University of Rijeka supported the research by the grants No. Uni-ri-biomed-18-110 and No. Uni-ri-biomed-18-160.Disclosure of InterestsNone declared.

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common and most difficult to cure malignancies worldwide. Identifying new effective therapeutic targets is of great significance for the management of HCC. Cumulative evidence suggests cancer stem cells (CSCs) are key drivers of tumor growth and heterogeneity. Post-transcriptional RNA editing of adenosine to inosine (A-to-I) catalyzed by ADAR1 dramatically alters cellular transcriptome in cancers. However, ADAR1 editase-dependent mechanisms governing hepatic CSC generation have not been elucidated. Therefore, we have systematically and comprehensively investigated ADAR1’s effect on CSC self-renewal in HCC. Methods: An in vitro human hepatocyte differentiation model along with relevant transcriptomic data form GEO and TCGA were analyzed to characterize the oncofetal role of ADAR1. Using genetic approaches, RNA sequencing was performed to identify putative ADAR1-mediated recoding edited genes in HCC cell lines. Clinical implication of GLI1 editing was studied in a cohort of 88 HCC patients. GLI1 editing-mediated change in its promoter activity and protein stability was investigated by dual reporter assay, CHIP, Co-IP, and PLA assays. Functional difference in stemness properties, including abilities of self-renewal, differentiation, tumorigenesis, chemo-resistance and metastasis between wild-type and edited GLI1 (GLI1wt vs. GLI1R701G) and the exact mechanisms were also studied in cell models and mice. Results: Lentiviral ADAR1 wild-type but not editing-defective ADAR1E912A mutant, editing at nt2101 of GLI1 transcript caused arginine-to-glycine substitution at the residue 701. Importantly, increased editing of GLI1 was implicated in the pathogenesis of HCC. Upon editing, C-terminal half of GLI1 harbored a lower susceptibility to the inhibition of SUFU, thus promoting its nuclear translocation and activation. Moreover, GLI1R701G appeared more stable than GLI1wt due to reduced formation of specific K63-GLI1 substrate and β-TrCP-GLI1 complex. Edited GLI1 was found to strongly enhance targeted activation of NANOG and SOX9, resulting in accumulation of hepatic CSCs population, hepatocarcinogenesis, sorafenib-resistance and metastasis. Additionally, GLI1 editing initiated mitophagy via PINK1/Parkin-dependent pathway. Impaired mitophagy effectively antagonized the functions of GLI1R701G on hepatic CSC self-renewal and overcome chemoresistance. Conclusion: The critical advance of this study is that ADAR1 editase activity drives GLI1-dependent maintenance of the hepatic CSC population. Our discovery of a pivotal ADAR1-GLI1-PINK1 self-renewal axis provides the first mechanistic link between RNA-editing-driven malignant progression and mitochondrial homeostasis. Thus, ADAR1 represents a unique therapeutic vulnerability in liver CSCs with active mitophagy mediated by edited GLI1. Citation Format: Jie Luo, Lanqi Gong, Yuma Yang, Jiao Huang, Xiaona Fang, Baifeng Zhang, Ying Tang, Beilei Liu, Ming Liu, Lu Bai, Victor Ho-Fun Lee, Xin-Yuan Guan. ADAR1-dependent RNA editing of GLI1 drives hepatocellular carcinoma stem cell self-renewal by initiating mitophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6064.

Anion Exchange Membrane electrolyzers (AEMELs) have increased in popularity in recent years due to their potential to combine the benefits from proton exchange membrane electrolyzers and traditional alkaline electrolyzers – namely, high current density operation, pressurized H2 discharge and lowering cost by utilizing low-cost earth abundant electrocatalysts and inexpensive component materials. In the AEMEL, the oxygen evolution reaction (OER) electrode plays a critical role dictating the overall efficiency of the cell due to sluggish OER activity and species transport. In our previous study, we optimized the OER electrode structure by investigating the effects of catalyst loading, catalyst type, the porous transport substrate and additive carbon [1] – resulting in an excellent performance of 1.55 V operation at 1.0 A/cm2. Though that study led to high performance, all of those gains were made using KOH electrolyte being fed to the cell, not deionized (DI) water. The use of DI water complicates AEMEL operation as the liquid phase can no longer be relied on to carry any of the ionic charge – this possibly can reduce the electrochemically active surface area (ECSA) [2]. It has also been stated that pure water operation may have negative consequences on cell durability. Therefore, to allow for AEMELs to operate efficiently on DI water, it is important to understand how the ion transport and charge transfer resistance change as cells are transitioned from KOH to DI water operation. It is also important to understand what effects even trace amounts of KOH can have on behavior. Lastly, the effect of the ionomer properties on the OER anode performance should be well-understood. In this study, we investigate the role of alkaline feed pH on the performance and durability of AEMELs. When shifting from alkaline feed to DI water, it will be shown that there is an increase in ohmic and charge transfer resistance, resulting in significant voltage loss. Because the alkaline feed enhances electrode conductivity by connecting catalyst active sites to the conductive ionomer and AEM [2-3], new electrode structures are needed that allow for enhanced ECSA and lower resistances with DI water feeds. In this work, that was accomplished by creating a four-layer electrode structure as well as manipulating the cell operating conditions. Lastly, our team enabled the use of a high IEC ionomer in the anode catalyst layer by introducing a cross-linker and introducing smaller, cryo-milled ionomer particles. This was important to overcome adhesion issues that can come from high water uptake and swelling in high-IEC ionomers [4-5]. This paper will focus not only on performance, but also longevity, with several cells being stably operated for more than 500 hours continuously. References [1]. N. U. Hassan, M. Mandal, B. Zulevi, P. A. Kohl and W. E. Mustain, Electrochim. Acta, 409, 140001 (2021). [2]. Liu, Z. Kang, D. Li, M. Pak, S.M. Alia, C. Fujimoto, G. Bender, Y.S. Kim and A.Z. Weber, J. Electrochem. Soc., 168 (2021) 054522. [3]. Li, A. R. Motz, C. Bae, C. Fujimoto, G. Yang, F. Zhang, K. E. Ayers and Y. S. Kim, Energy Environ. Sci., 14, 3393 (2021). [4]. Li, J. Park Eun, W. Zhu, Q. Shi, Y. Zhou, H. Tian, Y. Lin, A. Serov, B. Zulevi, D.B. Ehren, C. Fujimoto, T. C. Hoon and S.K. Yu, Nat. Energ., 5, 378 (2020). [5]. Liu, Z. Kang, D. Li, M. Pak, S. M. Alia, C. Fujimoto, G. Bender, Y. S. Kim and A. Z. Weber, J. Electrochem. Soc., 168, 054522 (2021).

Background:A disease model of systemic lupus erythematosus (SLE) that predicts short-term outcomes (disease activity and prednisone use) and links them to long-term outcomes (accrual of organ damage and mortality) was previously developed in a single center SLE cohort (Johns Hopkins [JH]) to support health economic analyses (Watson 2015), which has not been comprehensively replicated in other cohorts or contexts.Objectives:As part of an effort to develop and refine this existing disease model, the aim of this study was to replicate the previously estimated network of risk equations for short- and long-term outcomes in the SLICC Inception Cohort, an international cohort of patients (33 centers,11 countries).Methods:The SLICC Inception Cohort enrolled patients fulfilling ACR Classification Criteria for SLE within 15 months of diagnosis from 1999-2011 with annual follow-up through April 2020. The network of risk equations included two linear random effects models to predict (1) change in annual average Systemic Lupus Disease Activity Index (SLEDAI) score based on patient characteristics and the presence of renal, hematological, and immunological involvement in the prior year and (2) average annual prednisone dose based on SLEDAI score in the same year. These equations were then linked to parametric survival models that predicted time to the occurrence of organ damage (system-specific based on the ACR/SLICC Damage Index) and mortality. We compared model performance between the SLICC Cohort and the original analysis from the JH Cohort.Results:In comparison to the JH cohort (N=1354), the SLICC cohort (N=1697) had a smaller fraction of patients of African descent (39% vs 17%) and shorter disease duration at entry (4.8 vs 0.5 years). In the first equation predicting change in annual SLEDAI score, predictors were generally aligned with the same direction and significance, with the exception of renal involvement in the prior period, which had a positive association with change in SLEDAI in the SLICC cohort but was negatively associated in the JH cohort (Table 1). The second equation predicting prednisone dose was also consistent with the original analysis showing a significant positive association between higher disease activity and prednisone use. In all of the parametric survival analyses (individual organ damage and mortality models), coefficients were generally in the same direction and magnitude, though some were no longer significant in the SLICC cohort.Conclusion:The relationships identified in the original analysis were broadly replicated in the SLICC Inception Cohort. Observed differences may reflect differences in the patient populations, structure of the two cohorts (prevalent vs inception), and frequency of visits (quarterly visits in the JH cohort vs annual visits with the SLICC cohort may more closely capture a decrease in SLEDAI associated with treatment specifically related to renal involvement). Additional analyses relaxing the requirement to completely align with the original structure are underway to further assess the predictive accuracy of these models.References:[1]Watson P, et al. Rheumatology (Oxford). 2015;54(4):623-32.JH Cohort(N=1354)SLICC Cohort(N=1697)Female, %92.988.8African descent, %38.816.7Disease duration at entry, mean (SD), years4.8 (6.3)0.5 (0.3)SLEDAI at first visit, mean (SD)3.7 (4.1)5.4 (5.4)Change in average annual SLEDAICoefficientCoefficientConstant1.491*5.762*Annual average SLEDAI in prior period−0.460*−0.755*Male gender−0.080−0.207Log transformation of age−0.241*−1.134*Renal involvement in prior period−0.301*0.627*African descent0.383*0.126Increased DNA binding in prior period0.276*0.939*Low complement in prior period0.484*0.775*Hematological involvement in prior period0.104−0.025Anemia in prior period0.152**0.144Associated annual average prednisone dose (mg/day)Constant3.475*2.738*SLEDAI in same period0.777*0.648**p<0.001; **p<0.05Acknowledgements:We acknowledge the support on this abstract of the following investigators of the Systemic Lupus International Collaborating Clinics:John Hanly - john.hanly@nshealth.caCaroline Gordon - p.c.gordon@bham.ac.ukSang-Cheol Bae - scbae@hanyang.ac.krJuanita Romero-Diaz - juanita.romerodiaz@gmail.comJorge Sanchez-Guerrero - jorge.sanchez-guerrero@uhn.caSasha Bernatsky - sasha.bernatsky@mcgill.caAnn Clarke - aeclarke@ucalgary.caDaniel Wallace - dwallace@ucla.edu/danielwallac@gmail.comDavid Isenberg - d.isenberg@ucl.ac.ukAnisur Rahman - anisur.rahman@ucl.ac.ukJoan Merril - JTMmail@aol.comPaul Fortin - paul.fortin@crchudequebec.ulaval.caDafna Gladman - dafna.gladman@utoronto.caMurray Urowitz - m.urowitz@utoronto.caIan Bruce - ian.bruce@manchester.ac.ukMichelle Petri - mpetri@jhmi.eduEllen Ginzler - ellen.ginzler@downstate.eduMA Dooley - Mary_Dooley@med.unc.eduRosalind Ramsey-Godman - rgramsey@northwestern.eduSusan Manzi - susan.manzi@ahn.org; Susanmanzi@gmail.comAndreas Jonsen - andreas.jonsen@med.lu.seGraciela Alarcon - galarcon@uab.eduRonald van Vollenhoven - r.vanvollenhoven@amsterdamumc.nlCynthia Aranow - CAranow@Northwell.eduMeggan Mackay – mmackay@northwell.eduGuillermo Ruiz-Irastorza - r.irastorza@outlook.esSam Lim - sslim@emory.eduMurat Inanc - drinanc@istanbul.edu.tr; minanc2008@gmail.comKenneth Kalunian - kkalunian@ucsd.eduSoren Jacobsen - sj@dadlnet.dkChristine Peschken - christine.peschken@umanitoba.caDiane Kamen - kamend@musc.eduAnca Askanase - ada20@columbia.eduDisclosure of Interests:Ann E Clarke Consultant of: BMS, AstraZeneca, GSK, and Exagen Diagnostics., Yvan St-Pierre: None declared, Victoria Paly: None declared, Ian N. Bruce Speakers bureau: GSK, UCB, Consultant of: BMS, Eli Lilly, GSK, Astra Zeneca, Merck Serono; UCB, ILTOO, Aurinia, Grant/research support from: Genzyme/Sanofi, GSK, Roche, UCB, Chiara Malmberg: None declared, Andrew Briggs Speakers bureau: Alexion, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Gilead, GSK, Kite, Merck, Novartis, Rhythm, Roche, Sanofi, Takeda, Consultant of: Alexion, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Gilead, GSK, Kite, Merck, Novartis, Rhythm, Roche, Sanofi, Takeda, Yuanhui Zhang Shareholder of: Bristol Myers Squibb., Employee of: Bristol Myers Squibb., Jiyoon Choi Shareholder of: JNJ., Employee of: BMS, Alan Brennan Consultant of: Alan Brennan is a paid consultant on advisory boards regarding cost-effectiveness modelling., Grant/research support from: Alan Brennan received research grants.

Rapid urbanization rates impact significantly on the nature of Land Cover patterns of the environment, which has been evident in the depletion of vegetal reserves and in general modifying the human climatic systems (Henderson, et al., 2017; Kumar, Masago, Mishra, & Fukushi, 2018; Luo and Lau, 2017). This study explores remote sensing classification technique and other auxiliary data to determine LULCC for a period of 50 years (1967-2016). The LULCC types identified were quantitatively evaluated using the change detection approach from results of maximum likelihood classification algorithm in GIS. Accuracy assessment results were evaluated and found to be between 56 to 98 percent of the LULC classification. The change detection analysis revealed change in the LULC types in Minna from 1976 to 2016. Built-up area increases from 74.82ha in 1976 to 116.58ha in 2016. Farmlands increased from 2.23 ha to 46.45ha and bared surface increases from 120.00ha to 161.31ha between 1976 to 2016 resulting to decline in vegetation, water body, and wetlands. The Decade of rapid urbanization was found to coincide with the period of increased Public Private Partnership Agreement (PPPA). Increase in farmlands was due to the adoption of urban agriculture which has influence on food security and the environmental sustainability. The observed increase in built up areas, farmlands and bare surfaces has substantially led to reduction in vegetation and water bodies. The oscillatory nature of water bodies LULCC which was not particularly consistent with the rates of urbanization also suggests that beyond the urbanization process, other factors may influence the LULCC of water bodies in urban settlements. Keywords: Minna, Niger State, Remote Sensing, Land Surface Characteristics References Akinrinmade, A., Ibrahim, K., & Abdurrahman, A. (2012). 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Can Gio mangrove forest (CGM) is located downstream of Ho Chi Minh City (HCMC), situated between an estuarine system of Dong Nai - Sai Gon river and a part of Vam Co river. The CGM is the largest restored mangrove forest in Vietnam and the UNESCO’s Mangrove Biosphere Reserve. The CGM has been gradually facing to numeric challenges of global climate change, environmental degradation and socio-economic development for the last decades. To evaluate sediment quality in the CGM, we collected 13 cores to analyze for sediment grain size, organic matter content, and trace element concentration of Cd, Cr, Cu, Ni, Pb, Zn. Results showed that trace element concentrations ranged from uncontaminated (Cd, Cu, and Zn) to very minor contaminated (Cr, Ni, and Pb). The concentrations were gradually influenced by suspended particle size and the mangrove plants.ReferencesAnh M.T., Chi D.H., Vinh N.N., Loan T.T., Triet L.M., Slootenb K.B.-V., Tarradellas J., 2003. 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We present the temperature dependent elastic and ultrasonic properties of sodium borohydride. The second and third order elastic constants of NaBH4 have been computed in the temperature range 0-300K using Coulomb and Born-Mayer potential. The sodium borohydride crystallizes into NaCl-type structure. The computed values of second order elastic constants have been applied to evaluate the temperature dependent mechanical properties such as bulk modulus, shear modulus, tetragonal modulus, Poisson’s ratio and Zener anisotropy factor and ultrasonic velocity to predict futuristic information about sodium borohydride. The fracture to toughness ratio (bulk modulus/shear modulus) in sodium borohydride varied from 1.91 to 1.62, which shows its behavioral change from ductile to brittle on increasing the temperature. Then, ultrasonic Grüneisen parameters have been computed with the use of elastic constants in the temperature regime 100-300K. The obtained results have been discussed in correlation with available experimental and theoretical results. [1] A. Amudhavalli, M. Manikandan, A. Jemmy Cinthia, R. Rajeswarapalanichamy and K. Iyakutti, Z. Naturforsch. A 72 (2017) 321. [2] D.Singh, P.K.Yadawa and S.K.Sahu, Cryogenics 50 (2010) 476. [3] V. Bhalla, D.Singh and S.K.Jain, Int. J. Comput. Mat. Sc. Eng. 5 (2016) 1650012. [4] S. Kaushik, D. Singh and G. Mishra, Asian J. Chem. 24 (2012) 5655. [5] D. Chernyshov, A. Bosak, V. Dmitriev, Y. Filmchuk and H. Hagemann, Phys. Rev. B 78 (2008)172104. [6] H. Hagemann, S. Gomes, G. Renaudin and K. Yvon, J. Alloys Compd. 363 (2004) 126. [7] Y. Filinchuk, D. Chernyshov and V. Dmitriev, Z. Kristallogr. 223 (2008) 649. [8] Z.Xiao Dong, J.Z. Yi, Z. Bo, H. Z. Feng and H.Y. Qing, Chin. Phys. Lett. 28(2011)076201. [9] T. Ghellab, Z. Charifi, H. Baaziz, Ş. Uğur, G. Uğur and F. Soyalp, Phys. Scr. 91 (2016) 045804. [10] S. Bae, S. Gim, H. Kim and K. Hanna, Appl. Catal. B: Environm. 182 (2016) 541. [11] G. Renaudin, S. Gomes, H. Hagemann, L. Keller and K. Yvon, J Alloys Compd. 375 (2004) 98. [12] P. Vajeeston, P. Ravindran, A. Kjekshus and H. Fjellvåg, J Alloys Compd. 387 (2005) 97. [13] S. Orimo, Y. Nakamori, J.R. Eliseo, A. Zuttel and C. M. Jensen, Chem. Rev. 107 (2007) 4111. [14] A. Istek and E. Gonteki, J. Environ. Bio.7 (2009) 951. [15] R. S. Kumar and A.L. Cornelinus, Appl. Phys. Lett. 87 (2005) 261916. [16] E. Kim, R. Kumar, P. F. Weck, A. L. Cornelius, M. Nicol, S. C. Vogel, J. Zhang, M. Hartl, A.C. Stowe, L. Daemen and Y. Zhao, J. Phys. Chem. Lett. B 111 (2007) 13873. [17] K. Brugger, Phys. Rev. 133 (1964) A1611. [18] P.B. Ghate, Phy. Rev. 139 (1965) A1666 [19] S. Mori, Y. Hiki, J. Phys. Soc. Jpn. 45 (1975) 1449. [20] V. Bhalla, R. Kumar, C. Tripathy and D. Singh, Int. J. Mod. Phys. B 27 (2013) 1350116. [21] D. Singh, S. Kaushik, S. Tripathi, V. Bhalla and A. K. Gupta, Arab. J. Sci. Eng. 39 (2014) 485. [22] K. Brugger, Phys. Rev.137 (1965) 1826. [23] W. P. Mason, Physical Acoustics, vol. IIIB, Academic Press, New York, 1965. [24] M.P. Tosi, Solid State Physics, vol. 12, Academic Press, New York, 1965. [25] Y. Nakamori and S. Orimo, J. Alloy Compd.370(2004)271. [26] D. Singh, D.K. Pandey and P.K. Yadawa, Cent. Eur. J. Phys. 7 (2009) 198. [27] V. Bhalla, D. Singh, G. Mishra and M. Wan, J. Pure Appl. Ultrason. 38 (2016)23. [28] D. Singh, S. Kaushik, S.K. Pandey, G. Mishra and V. Bhalla, VNU J. Sc.: Math. Phys. 32(2016)43. [29] J.P.Watt and L. Peselnick, J.Appl. Phys. 51 (1980) 1525. [30] S.F.Pugh, Philos.Mag. 45 (1954) 823. [31] V. Bhalla, D. Singh and S.K. Jain, Int. J. Thermophys. 37(2016)33. [32] V. Bhalla, D. Singh, S.K. Jain and R. Kumar, Pramana- J. Phys. 86 (2016)135.

BackgroundCT-P13 is an approved biosimilar to EU-approved and US-licensed Infliximab (INX) for the indications of rheumatoid arthritis (RA), adult and paediatric Crohn’s disease, adult and paediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis.ObjectivesThe purpose of this study was to demonstrate equivalence of efficacy and compare PK and safety profiles of CT-P13 and China-approved INX.MethodsIn this randomized, double blinded, multicenter, parallel-group, phase III study, patients with active RA who had been responding inadequately to methotrexate for at least 3 months, were randomized to receive either CT-P13 or China-approved INX. Patients were treated with doses of 3 mg/kg at Weeks 0, 2, 6, then every 8 weeks up to Week 54. Prior to dosing at Week 30, patients randomized to China-approved INX underwent a second randomization either to continue China-approved INX or to switch to CT-P13 at Week 30. Results of patients who underwent transition to CT-P13 were included in the China-approved INX group. The primary efficacy endpoint was change in DAS28 (CRP) from baseline to Week 14, which was analyzed using an analysis of covariance. Equivalence was determined if the 90% CI for the estimate of treatment difference was entirely contained within the predefined equivalence margin of -0.6 to 0.6.Results270 patients were randomly assigned to 2 treatment groups in a 1:1 ratio (136 and 134 patients in the CT-P13 and China-approved INX groups, respectively) and 184 patients completed the study. The least square mean change (standard error) of DAS28 (CRP) from baseline to Week 14, -1.566 [0.1419] and -1.547 [0.1491], was similar between the CT-P13 and China-approved INX groups, respectively. The 90% CI for the estimate of treatment difference (-0.29, 0.25) was contained within the predefined equivalence margin, which demonstrated therapeutic equivalence between the groups. The mean actual values for DAS28 (CRP) decreased from baseline to Week 54 and were similar between the groups (Figure 1). Additional efficacy endpoints, including ACR responses (ACR20 at Week 14; 60.6%, 54.8% and at Week 54; 65.1%, 60.6% in the CT-P13 and China-approved INX groups, respectively), EULAR responses, CDAI, and SDAI, were similar between the groups, even after switching at Week 30. During the study, mean serum INX concentrations were similar between the groups. Between Weeks 14 and 22, mean (percent coefficient of variation) AUCτ were 11156333.615 (44.796) ng·h/mL and 11462884.280 (51.057) ng·h/mL, and Cmax,ss were 66577.2 (31.4) ng/mL and 66356.1 (21.0) ng/mL in the CT-P13 and China-approved INX groups, respectively, which were similar between the groups. Most treatment-emergent AEs were grade 1 or 2 in intensity. One malignancy was reported in the CT-P13 group and no deaths were reported. The proportions of patients with anti-drug antibodies were similar between the groups, even after switching at Week 30. The overall safety profile of CT-P13 was comparable to that of China-approved INX and no new safety issues were observed (Table 1).Table 1.Summary of Safety ResultsNumber of patients (%)CT-P13 (N=136)China-approved Infliximab (N=133)Treatment-emergent AEsTotal115 (84.6%)107 (80.5%)Related97 (71.3%)86 (64.7%)Treatment-emergent serious AEsTotal17 (12.5%)12 (9.0%)Related10 (7.4%)6 (4.5%)Infusion related reaction/ hypersensitivity/anaphylactic reactionsTotal(=Related)20 (14.7%)19 (14.3%)InfectionsTotal45 (33.1%)43 (32.3%)Related36 (26.5%)40 (30.1%)Note: Summary is presented for the safety population who received at least 1 dose (full or partial) of study drug.ConclusionThe study demonstrated that efficacy of CT-P13 is equivalent to that of China-approved INX. Also, the PK and safety profiles of CT-P13 were comparable to those of China-approved INX. No loss of efficacy or difference in safety or immunogenicity was observed after switching from China-approved INX to CT-P13 at Week 30.Disclosure of InterestsJonathan Kay Consultant of: Boehringer Ingelheim GmbH; Pfizer Inc.; Samsung Bioepis; Sandoz Inc., Grant/research support from: Pfizer Inc. (paid to UMass Chan Medical School), Xiaofeng Zeng Grant/research support from: Celltrion, Inc, Lin Chen Grant/research support from: Celltrion, Inc, Kaijiang Tang Grant/research support from: Celltrion, Inc, guixiu shi Grant/research support from: Celltrion, Inc, Lin Liu Grant/research support from: Celltrion, Inc, Lijun Wu Grant/research support from: Celltrion, Inc, Yi Liu Grant/research support from: Celltrion, Inc, Jiankang Hu Grant/research support from: Celltrion, Inc, Shengyun Liu Grant/research support from: Celltrion, Inc, Zheng Yi Grant/research support from: Celltrion, Inc, Sung Hyun Kim Employee of: Celltrion, Inc, YunJu Bae Employee of: Celltrion, Inc, JeeHye Suh Employee of: Celltrion, Inc, Seungjin Rhee Employee of: Celltrion, Inc, SeulGi Lee Employee of: Celltrion, Inc, Chankyoung Hwang Employee of: Celltrion, Inc

The achievement of children's quality of life is undoubtedly linked to the development of positive habits that will continue to be practiced in future lives. This can be done by developing awareness and behavior of a balanced clean and healthy lifestyle. The purpose of this study was to determine the increase in the PHBS ability of children. Various efforts have been made so that children with intellectual disabilities can maintain their cleanliness. The efforts made by the teacher are still not maximal so that the delivery of information about PHBS must be completed by another method, namely demonstration. This research was conducted at SDLB 127710 Pematangsiantar5 with an action research method that refers to the Kurt Lewin model. Data collection techniques used purposive sampling and data analysis with the Wilcoxon test. The results showed an increase in understanding of the PHBS of children with intellectual disabilities able to learn SDLB 127710 Pematangsiantar through the demonstration method. This is evidenced by the increase in the score, where the initial assessment was obtained (59%), while in the first cycle, the average score was good (69.9%). In short, the understanding of children with intellectual disabilities being able to learn about PHBS is increased by using the demonstration method. Keywords: Intellectual Disability Children, PHBS program, Demonstration methods References Agarwal, R. (2017). Importancia de la atención primaria de salud en la sociedad. International Journal of Health Sciences, 1(1), 5–9. Aiello, A. E., Coulborn, R. M., Perez, V., & Larson, E. L. (2008). Effect of hand hygiene on infectious disease risk in the community setting: A meta-analysis. American Journal of Public Health, 98(8), 1372–1381. https://doi.org/10.2105/AJPH.2007.124610 Arip, M. pdfo., & Emilyani, D. 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Heavy metals contamination is a serious threat to all life forms. Long term exposure of heavy metals can lead to different life-threatening medical conditions including cancers of different body parts. Phytoremediation and bioremediation offer a potential eco-friendly solution to such problems. Different microbes can interact with heavy metals in a variety of ways such as biotransformation, oxidation/reduction, and biosorption. Phytoremediation of the heavy metals using plants mostly involves rhizofilteration, phytoextraction, phytovolatization, and Phyto stabilization. A synergistic approach using both plants and microbes has proven much more efficient as compared to the individual applications of microbes or plants. This article aims to highlight the synergistic methods used in bioremediation, emphasizing the potent collaboration between bacteria and plants for environmental cleaning, along with the discussion of the importance of site-specific variables and potential constraints. 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BackgroundSystemic lupus erythematosus (SLE) has heterogeneous organ manifestations that occur in different combinations at an individual patient level. Current SLE clinical trial eligibility criteria and efficacy endpoints, based on legacy disease activity measures, have multiple weaknesses. Understanding the frequency with which different organ manifestations are represented in contemporary SLE cohorts is required, to allow focus on the most frequent and impactful manifestations of disease in both eligibility criteria and endpoints.ObjectivesTo report the prevalence of disease activity in individual organ domains in SLE patients, both overall and in patients meeting the most common disease activity cut-off for clinical trial eligibility (SLEDAI2K ≥6).MethodsWe used data from a multinational SLE cohort, prospectively collected between 2013 and 2020. We analysed data from 4,102 patients with criteria-defined SLE, who contributed 42,345 visits with complete SLEDAI-2K assessments. Disease activity assessed using SLEDAI-2K was categorised according to activity in 9 organ systems: central nervous system (CNS), vasculitis, musculoskeletal, renal, cutaneous, serositis, serological, haematological, and fever. Proportions of organ-specific disease activity in the overall cohort, and stratified by total SLEDAI-2K ≥6 or <6, were calculated.ResultsIn the overall cohort, 3,659 patients (89.2%) had SLEDAI-2K >0 on at least one visit (31,290 visits, 73.9%). Serological disease activity was the most prevalent in the cohort overall, affecting 75.5% of patients at least once, followed by renal (41.6%), cutaneous (36.5%), musculoskeletal (20%) and haematological (19%) activity. Infrequent active manifestations affecting <5% of patients were serositis (3.4%), vasculitis (3.4%), CNS (3.0%) and fever (3%).We further examined the prevalence of domain-specific disease activity in patient visits stratified by a SLEDAI-2K cut-off of 6 (Table 1). In patient visits with a SLEDAI-2K>6 (n = 10,031 visits, 24% of total) the most common manifestations were serological (90%) and renal (73%), followed by cutaneous (26%) and musculoskeletal (14%). Conversely, 7.3% of visits with renal, 6.7% with cutaneous, 5.8% with haematological and 1.3% with musculoskeletal activity did not have a SLEDAI-2K ≥6 (Table 1).Table 1.Frequencies and percentages of patient visits with specific organ system disease activity, stratified by total SLEDAI score cut-off of ≥6 vs <6.All visitsSLEDAI<6SLEDAI≥6n = 42,345n = 32,314n =10,031p-value*Serological25,745 (60.8%)16,740 (51.8%)9,005 (89.8%)<0.001Renal9,684 (22.9%)2,367 (7.3%)7,317 (72.9%)<0.001Cutaneous4,806 (11.3%)2,158 (6.7%)2,648 (26.4%)<0.001Haematological2,615 (6.2%)1,862 (5.8%)753 (7.5%)<0.001Musculoskeletal1,856 (4.4%)422 (1.3%)1,434 (14.3%)<0.001Serositis255 (0.6%)81 (0.3%)174 (1.7%)<0.001Vasculitis250 (0.6%)0250 (2.5%)<0.001CNS200 (0.5%)0200 (2.0%)<0.001Fever149 (0.4%)59 (0.2%)90 (0.9%)<0.001*P-values derived from Pearson’s Chi-Squared tests.ConclusionSerological, renal, cutaneous, musculoskeletal and haematological manifestations predominate in patients with active SLE in our cohort, with other organs only rarely affected. Measures of improvement in SLE trial endpoints could focus on measuring change in these systems, and omit detailed analysis of rare events. Conversely, a notable proportion of patients with active disease in commonly affected organ domains had SLEDAI-2K <6, meaning they would be excluded from clinical trials. Incorporation of organ-specific activity measures and inclusion criteria for SLE clinical trials may overcome this limitation and improve recruitment to and results of trials.AcknowledgementsWe acknowledge the unrestricted project grants received from AstraZeneca, BMS, Eli Lilly, GSK, Janssen, Merck Serono, and UCB to support data collection and project management contributing to this work.Disclosure of InterestsKathryn Connelly: None declared, Rangi Kandane-Rathnayake: None declared, Vera Golder: None declared, Worawit Louthrenoo: None declared, Yi-Hsing Chen: None declared, Jiacai Cho: None declared, Aisha Lateef: None declared, Laniyati Hamijoyo: None declared, Shue Fen Luo: None declared, Yeong-Jian Jan Wu: None declared, Sandra Navarra Consultant of: Biogen, Boehringer Ingelheim, Astra Zeneca, Grant/research support from: Janssen, Novartis, Pfizer, Glaxo Smith Kline, Pfizer, Leonid Zamora: None declared, Zhanguo Li Consultant of: Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma, Grant/research support from: Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma, Sargunan Sockalingam Consultant of: Pfizer, AstraZeneca, ZP Therapeutics, Grant/research support from: Pfizer, AstraZeneca, ZP Therapeutics, Yasuhiro Katsumata Grant/research support from: GlaxoSmithKline K.K. AstraZeneca K.K. Sanofi K.K. Pfizer Japan Inc., Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Asahi Kasei Pharma, Astellas Pharma Inc., Mitsubishi Tanabe Pharma Corporation, Masayoshi Harigai Speakers bureau: AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd, Consultant of: AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma, Grant/research support from: AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Yanjie Hao: None declared, Zhuoli Zhang: None declared, Madelynn Chan: None declared, Jun Kikuchi: None declared, Tsutomu Takeuchi Consultant of: AbbVie, Chugai, Mitsubishi-Tanabe, Grant/research support from: AbbVie, Mitsubishi-Tanabe, Eli Lilly Japan, Shereen Oon: None declared, Sang-Cheol Bae: None declared, Fiona Goldblatt: None declared, Sean O’Neill: None declared, Kristine Ng Consultant of: AbbVie, Annie Law: None declared, BMDB Basnayake: None declared, Nicola Tugnet: None declared, Sunil Kumar: None declared, Cherica Tee: None declared, Michael Tee: None declared, Yoshiya Tanaka Speakers bureau: Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, Grant/research support from: Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Behringer-Ingelheim, C.S. Lau Speakers bureau: AstraZeneca UK Ltd, Consultant of: AstraZeneca Pharmaceuticals LP, Mandana Nikpour Speakers bureau: Actelion, GSK, Janssen, Pfizer, UCB, Paid instructor for: UCB, Consultant of: Actelion, Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB, Grant/research support from: Actelion, Astra Zeneca, BMS, GSK, Janssen, UCB, Alberta Hoi Speakers bureau: UCB, Janssen, Sandoz, Eli Lilly, Consultant of: AbbVie, GSK, Grant/research support from: AstraZeneca, GSK, BMS, Janssen, and Merck Serono, Eric F. Morand Speakers bureau: AstraZeneca, EMD Serono, Gilead, Consultant of: AstraZeneca, BristolMyersSquibb, Biogen, Eli Lilly, EMD Serono, Novartis, Grant/research support from: AbbVie, Amgen, AstraZeneca, BristolMyersSquibb, Biogen, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, UCB.

Development of theoretical ideas about the mechanism of the rheological behaviour of building mixtures and the experimental assessment of their rheological properties is a relevant area of physiochemical research of materials. To assess the changes in rheological properties when varying the component composition of building mixtures, it is important to use quantitative indicators characterising the microstructure of the mixtures. Revealing the regularities of the formation of heterogeneous microstructures makes it possible to assess their correlation with the rheological properties of buildingmixtures at the macro level. The aim of the paper is to discuss the results of the implementation of methodological approaches, theoretical modelling, and experimental assessment of the quantitative indicators of the rheological properties of typical building mixtures.The experimental research methodology is based on the assessment of the rheological properties of heterogeneous dispersed systems (HDS), taking into account fractal-cluster manifestations in their microheterogeneous component. The experiment was carried out using model HDS containing the components of building mixtures. Their rheological properties were determined by rotational viscometry with different compositions of HDS. The fractal dimension D was used for a quantitativeassessment of the structural and rheological properties and identification of the patterns of their change depending on the composition of mixtures. The value was determined by mathematical modelling.We analysed model concepts of the rheological behaviour of building mixtures. It was shown that the existing rheological models of an elastic-viscous-plastic medium did not give a complete description of the processes of formation and destruction of the microstructure of concentrated HDS (building mixtures). We carried out an experimental assessment of the effect of the properties of solid phase particles on the change in the structural and rheological characteristics of HDS, taking into account the fractal-cluster principles of their structure formation.We specified the ideas about the mechanism of rheological behaviour of building mixtures. They take into consideration the processes of the formation and destruction of fractal-cluster formations in the microstructure of HDS. It was shown that the fractal dimension D can be one of the quantitative characteristics of the structural and rheological properties. 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Исследование внутривидовой изменчивости трех функциональных признаков листьев: площади – LA, сухой массы – LDW и удельной площади – SLA показало их взаимообусловленность и зависимость значений признаков от благопритяности условий местообитания и антропогенной нагрузки. Анализ полученных данных исследования показал, что универсальные информационные показатели LA и LDW являются низкими в неблагоприятных и низкопродуктивных местообитаниях и более высокими при изобилии ресурсов в более продуктивных условиях существования. Полученные значения SLA видов растений, произрастающих в сообществах интенсивно эксплуатируемых пастбищ, часто имеют более высокие значения. Возможно, адаптация в условиях постоянного изъятия биомассы на сенокосах и пастбищах идет в первую очередь через сокращение массы листьев при сохранении листовой поверхности. 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Parents play an important role in the development of their children. This research reflects the role of parents in developing children. Through four stages of identification, screening, eligibility, and acceptable results, this method uses a systematic literature review using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) method. The findings from the fourteen articles examined show that parenting skills play an important role in a child's growth and development from birth to death. The determining factor in the development of physical, motoric, moral, language, social-emotional, and life skills aspects is the role of both parents as important teachers for children from birth to adulthood. Parents can also use a variety of parenting strategies and skills, many of which they have learned throughout their lives and passed on to their children, to help their children grow. 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Cobalt dopping Fe-MIL-88B were successfully synthesized -in solvothermal procedure using DMF as solvent and with/without NaOH. The samples were characterized using SEM, BET and TGA techniques. The partly substitution of Fe by Co does not change the octahedral shape of their parent Fe-MIL-88B. Crystallizations conducted in NaOH medium, however, results in rod like with 2-end octahedral shape crystals. The BET specific surface area is 139cm2/g. The TGA data indicated that the presence of Co resulted in an increase in thermal stability of synthesized samples compared to parent Fe-MIL-88B. The CO2 adsorption isotherms in Fe-MIL-88B-Co samples were measured volumetrically at five temperatures:278K, 288K, 298K, 308K, 318K. The obtained results showed that Fe-MIL-88B-Co is a potential adsorbent with a maximum adsortption capacity of 1.2312 mmol/g (at T= 278K). The sample synthesized in alkali medium exhibited a better adsorbent for CO2 storage. Keywords MIL, adsorption, CO2 References [1] S. Chu, Carbon Capture and Sequestration, Science325(2009)1599 [2] R.S. Haszeldine,Carbon Capture and Storage: How Green Can Black Be?, Science325(2009) 1647[3] D.M. D’Alessandro, B. Smit, J.R. Long,Carbon Dioxide Capture: Prospects for New Materials, Angewandte Chemie International Edition. 49(2010) 6058[4] S. Bai, J. Liu, J. Gao, Q. Yang Can Li,Hydrolysis controlled synthesis of amine-functionalized hollow ethane–silica nanospheres as adsorbents for CO2 capture, Microporous and Mesoporous Materials151(2012) 474[5] K. Sumida, D.L. Rogow, J.A. Mason, T.M. McDonald, E.D. Bloch, Z.R. Herm, T.H. Bae, J.R.[6] Long,Carbon Dioxide Capture in Metal–Organic Frameworks, Chemical Reviews, 112(2012) 724[7] J.D. Carruthers, M.A. Petruska, E.A. Sturm, S.M. Wilson,Molecular sieve carbons for CO2 capture, Microporous and Mesoporous Materials,154 (2012) 62[8] X. Yan, L. Zhang, Y. Zhang, K. Qiao, Z. Yan, S. Komarneni,Amine-modified mesocellular silica foams for CO2 capture, Chemical Engineering Journal,168 (2011), 918[9] A. Zukal, C.O. Arean, M.R. Delgado, P. Nachtigall, A. Pulido, J. Mayerova, J. Cˇejka,Combined volumetric, infrared spectroscopic and theoretical investigation of CO2 adsorption on Na-A zeolite,Microporous and Mesoporous Materials 146 (2011) 97[10] S. Keskin, T.M. van Heest, D.S. Sholl, Can Metal–Organic Framework Materials Play a Useful Role in Large‐Scale Carbon Dioxide Separations?, ChemSusChem3 (2010) 879[11] T.M. McDonald, W.R. Lee, J.A. Mason, B.M. Wiers, C.S. Hong, J.R. Long, Capture of Carbon Dioxide from Air and Flue Gas in the Alkylamine-Appended Metal–Organic Framework mmen-Mg2(dobpdc), Journal of the American Chemical Society134 (2012) 7056[12] X. Yan, S. Komarneni, Z. Zhang, Z. Yan(2014),Extremely enhanced CO2 uptake by HKUST-1 metal–organic framework via a simple chemical treatment, Microporous and Mesoporous Materials183 (2014) 69–73[13] Gia-Thanh Vuong, Minh-Hao Pham and Trong-On Do*, Direct synthesis and mechanism of the formation of mixed metal Fe2Ni-MIL-88B†, CrystEngComm, DOI: 10.1039/c3ce41453a[14] Lê Văn Khu, Nguyễn Quốc Anh, Nguyễn Ngọc Hà, Lê Minh Cầm, Tổng hợp, đặc trưng và khảo sát khả năng hấp phụ CO2 của Fe-MIL-88B, Tạp chí xúc tác và hấp phụ 4 (1) (2015) 52[15] K. S. W. Sing, D. H. Everett, R. A. W. Hau et.al, Reporting physisorption data for gas/solid systems with special reference to the determination of surface area and porosity, Pure and Applied Chemistry 57 (1985) 603

This study identifies A10398G alteration of mitochondrial ND3 gene in plasma exosome of 29 non-small cell lung cancer (NSCLC) patients, 31 controls and 13 pairs of tumor tissue and adjacent tissue of NSCLC patients, thereby assessing the relationship between this alteration in plasma exosome and tissue as well as the pathological characteristics of NSCLC patients. Using the PCR-RFLP method, the homoplasmy and heteroplasmy of A10398G were initially identified in mitochondrial DNA from both exosomes and lung tissues. The rate of variant 10398G in plasma exosome was 62.1% in the NSCLC group and 61.3% in the control group. However, there was no statistically significant difference in A10398G between the patient and control groups. The alteration of A10398G in plasma exosome and in tissue correlated with each other (correlation coefficient 0.69; p = 0.009). However, this alteration was not related to age, gender, smoking, alcohol drinks status, tumor size, histological stage and TNM stage. 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Millikan, Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women, Cancer Res 65(17) (2005) 8028-8033. https://doi.org/10.1158/0008-5472.can-05-1428.[10] K. Darvishi, S. Sharma, A.K. Bhat, E. Rai, R.N.K. Bamezai, Mitochondrial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer, Cancer Letts 249(2) (2017) 249-255. https://doi.org/10.1016/j.canlet.2006.09.005.[11] S.H.H. Juo, M.Y. Lu, R.K. Bai, Y.C. Liao, R.B. Trieu, M.L. Yu, L.J.C Wong, A common mitochondrial polymorphism 10398A>G is associated metabolic syndrome in a Chinese population, Mitochondrion 10(3) (2010) 294-299. https://doi.org/10.1016/j.mito.2010.01.001.[12] H. Xu, W. He, H.G. Jiang, H. Zhao, X.H. Peng, Y.H. Wei, J.N. Wei, C.H. Xie, C. Liang, Y.H. Zhong, G. Zhang, D. Deng, Y.F. Zhou, F.X. Zhou, Prognostic value of mitochondrial DNA content and G10398A polymorphism in non-small cell lung cancer, Oncol Rep 30(6) (2013) 3006-3012. https://doi.org/10.3892/or.2013.2783.[13] Y. Qi, Y. Wei, Q. Wang, H. Xu, Y. Wang, A. Yao, H. Yang, Y. Gao, F. Zhou, Heteroplasmy of mutant mitochondrial DNA A10398G and analysis of its prognostic value in non-small cell lung cancer, Oncol Lett 12(5) (2016) 3081-3088. https://doi.org/10.3892/ol.2016.5086.[14] A.M. Czarnecka, T. Krawczyk, M. Zdrozny, J. Lubiński, R.S. Arnold, W. Kukwa, A. Scińska, P. Golik, E. Bartnik, J.A. Petros, Mitochondrial NADH-dehydrogenase subunit 3 (ND3) polymorphism (A10398G) and sporadic breast cancer in Poland, Breast Cancer Res Treat 121(2) (2010) 511-518. https://doi.org/10.1007/s10549-009-0358-5.[15] M. Guescini, S. Genedani, V. Stocchi & L. F.Agnati, Astrocytes and Glioblastoma cells release exosomes carrying mtDNA, J Neural Transm (Vienna), 117(1) (2010) 1–4. https://doi.org/10.1007/s00702-009-0288-8.[16] P. Sansone, C. Savini, I. Kurelac, Q. Chang, L.B. Amato, A. Strillacci, A. Stepanova, L. Iommarini, C. Mastroleo, L. Daly, A. Galkin, B.K. Thakur, N. Soplop, K. Uryu, A. Hoshino, L. Norton, M. Bonafé, M. Cricca, G. Gasparre, D. Lyden, and J. Bromberg, Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer, PNAS, 114(43) (2017) E9066-9075. https://doi.org/10.1073/pnas.1704862114.

The MT-ATP8 gene encodes for A6L protein subunit belonging to the proton channel of the ATP synthase. MT-ATP8 gene’s mutations can affect the structure and function of the ATP synthase, which may cause diseases. In this study, alterations of MT-ATP8 gene were investigated in tumor tissues of patients with breast cancer and control blood samples using PCR combined with direct sequencing and PCR-RFLP methods, data were analyzed using bioinformatics tools and statistical methods. Sequencing results revealed 5 variants of MT-ATP8 gene on 35 breast tumor tissues and 26 blood samples of controls, of which two mutations C8414T and C8417T altered the amino acid sequence of the resulting protein. The C8417T was further screened by PCR-RFLP and was found in 0,98% (1/102) of breast tumor samples. This change lead to substitution of lecine to phenylalanine (L18F) in a highly conserved position of A6L and was predicted as probably damaging to the structure and function of the protein. Additionally, a 9 bp deletion was also observed in a non-coding region of mtDNA in 26,5% (27/102) of breast cancer patients and 27% (7/26) of controls. Thus, these results showed that C8417T variant in the conserved position of MT-ATP8 gene was rare and first identified in a group of breast cancer patients in Vietnam. Keywords Breast cancer, mitochondrial DNA, MT-ATP8 References [1] Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH, Marshall FF, Wallace DC, mtDNA mutations increase tumorigenicity in prostate cancer, Proc Natl Acad Sci U S A (2005), 102(3):719-24.[2] Wang X, The expanding role of mitochondria in apoptosis, Genes Dev (2001), 15(22):2922-33.[3] Jonckheere AI, Smeitink JA, Rodenburg RJ, Mitochondrial ATP synthase: architecture, function and pathology, J Inherit Metab Dis (2012), 35(2):211-25.[4] Grzybowska-Szatkowska L, Slaska B, Rzymowska J, Brzozowska A, Florianczyk B, Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer, Mol Med Rep (2014), 10(4):1772-8.[5] Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR, A method and server for predicting damaging missense mutations, Nat Methods (2010), 7(4):248-9.[6] Thapa S, Lalrohlui F, Ghatak S, Zohmingthanga J, Lallawmzuali D, Pautu JL, Senthil Kumar N, Mitochondrial complex I and V gene polymorphisms associated with breast cancer in mizo-mongloid population, Breast Cancer (2016), 23(4):607-16.[7] Warburg O, On the origin of cancer cells, Science (1956), 123:309-14.[8] Dumas JF, Rousse D, Servais S, Mitochondria and cancer, Cellular Bioenergetics in Health and Diseases: New Perspectives in Mitochondrial Biology (2012), 115-47.[9] Mkaouar-Rebai E, Kammoun F, Chamkha I, Kammoun N, Hsairi I, Triki C, Fakhfakh F, A de novo mutation in the adenosine triphosphatase (ATPase) 8 gene in a patient with mitochondrial disorder, J Child Neurol (2010), 25(6):770-5.[10] Jonckheere AI, Hogeveen M, Nijtmans LG et al., A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy, J Med Genet (2008), 45:129-33.[11] Ware SM, El-Hassan N, Kahler SG et al., Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes, J Med Genet (2009), 46:308-14.[12] Liu VW, Shi HH, Cheung AN, Chiu PM, Leung TW, Nagley P, Wong LC, Ngan HY, High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas, Cancer Res (2001), 61(16):5998-6001.[13] Zhuo G, Feng G, Leng J, et al., A 9-bp deletion homoplasmy in women with polycystic ovary syndrome revealed by mitochondrial genome-mutation screen, Biochem Genet (2010), 48:157-163.[14] Abu-Amero KK, Alzahrani AS, Zou M, Shi Y, Association of mitochondrial DNA transversion mutations with familial medullary thyroid carcinoma/multiple endocrine neoplasia type 2 syndrome, Oncogene (2006), 25:677-84.[15] Bonora E, Porcelli AM, Gasparre G, et al., Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III, Cancer Res (2006), 66:6087-96.[16] Costa-Guda J, Tokura T, Roth SI, Arnold A, Mitochondrial DNA mutations in oxyphilic and chief cell parathyroid adenomas, BMC Endocr Disord (2007); 7:8.[17] Chintha R, Kaipa PR, Sekhar N, Hasan Q, Mitochondria and tumors: A new perspective, Indian J Cancer (2013), 50(3).[18] Tan DJ, Bai RK, Wong LJ, Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer, Cancer Res (2002), 62(4):972-6.[19] Tipirisetti NR, Lakshmi RK, Govatati S, Govatati S, Vuree S, Singh L, Raghunadha Rao D, Bhanoori M, Vishnupriya S, Mitochondrial genome variations in advanced stage breast cancer: a case-control study, Mitochondrion (2013), 13(4):372-8. [20] Ghaffarpour M, Mahdian R, Fereidooni F, Kamalidehghan B, Moazami N, Houshmand M, The mitochondrial ATPase6 gene is more susceptible to mutation than the ATPase8 gene in breast cancer patients, Cancer Cell Int (2014), 14(1):21.[21] Perucca-Lostanlen D, Narbonne H, Hernandez JB, et al., Mitochondrial DNA variations in patients with maternally inherited diabetes and deafness syndrome, Biochem Biophys Res Commun (2000), 277(3):771-5.[22] Bai Y, Guo Z, Xu J, Zhang J, Cui L, Zhang H, Zhang S, The 9-bp deletion at position 8272 in region V of mitochondrial DNA is associated with renal cell carcinoma outcome, Mitochondrial DNA A DNA Mapp Seq Anal (2014), 27(3):1973-5.[23] Jin Y, Yu Q, Zhou D, Chen L, Huang X, Xu G, Huang J, Gao X, Gao Y, Shen L, The mitochondrial DNA 9-bp deletion polymorphism is a risk factor for hepatocellular carcinoma in the Chinese population, Genet Test Mol Biomarkers (2012), 16(5):330-4.[24] Ren W, Li Y, Li R, Feng H, Wu S, Mao Y, Huang L, Mitochondrial intergenic COII/tRNA(Lys) 9-bp deletion, a biomarker for hepatocellular carcinoma? Mitochondrial DNA A DNA Mapp Seq Anal (2015), 27(4):2520-2.[25] Cortopassi GA, Shibata D, Soong NW, Arnheim N, A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues, Proc Natl Acad Sci U S A (1992), 89(16):7370-4.

Introdução: A coroa endocrown é uma restauração indireta confeccionada em cerâmica adesiva em monobloco e cimentada com técnicas adesivas. A coroa possui como retenção a câmara pulpar do dente tratado endodonticamente sem que se utilizem os condutos. Dentes tratados endodonticamente possuem redução da rigidez e resistência devido à perda da integridade estrutural. Este fato pode acarretar em longo prazo falhas biomecânicas. Objetivo: Realizar uma revisão de literatura do tipo narrativa acerca das principais características das endocrowns. Metodologia: A pesquisa foi realizada no período de 20 de Janeiro a 02 de Abril de 2019. Foram utilizados artigos científicos das seguintes bases de dados: SCIELO (Scientific Eletronic Library Online), BVS (Biblioteca Virtual em Saúde), e monografias que atendiam aos requisitos no período entre 2008 a 2019, com exceção de artigos clássicos, em língua nacional, português, bem como em inglês e espanhol. Foram utilizados como descritores isolados, ou combinados, para a busca: "Endocrown”, “Endocrown Prótese”, “Endocrown Prosthesis”, “Endocrown Prótesis”, com um resultado de 31 artigos utilizados. Conclusão: As endocrowns são indicadas para dentes posteriores tratados endodonticamente, confeccionada na maioria das vezes por dissilicato de lítio e apresenta estudos que comprovem que o risco de fratura é inferior às reabilitações sob uso de retentores intrarradiculares. Sob boa indicação e avaliação, é possível obter previsibilidade de sucesso, porém, ainda são necessários mais pesquisas para comprovar cada vez mais a eficácia dessa alternativa.Descritores: Prótese Dentária; Prótese Parcial Fixa; Odontologia.ReferênciasRocca GT, Rizcalla N, Krejci I. Fiber-reinforced resin coating for endocrown preparations: a technical report. Oper Dent. 2013;38(3):242-48.Borges Junior HE, Sábio S, Bender KRF, Costa YM, Mondelli J. Endocrown – avaliação da resistência dos cimentos dentários. Rev Odontol Araçatuba. 2013;34(2):23-6.Dejak B, Młotkowski A. 3D-Finite element analysis of molars restored with endocrowns and posts during masticatory simulation. Dent Mater. 2013;29(12):e309-17.Chang CY, Kuo JS, Lin YS, Chang YH. Fracture resistance and failure modes of CEREC endo-crowns and conventional post and core-supported CEREC crowns. J Dent Sci 2009;4(3):110-17.Carlos RB, Thomas Nainan M, Pradhan S, Sharma R, Benjamin S, Rose R. Restoration of endodontically treated molars using all ceramic endocrowns. Cape Rep Dent. 2013;2013:210763.Magne P, Knezevic A. Simulated fatigue resistance of composite resin versus porcelain CAD/CAM overlay restorations on endodontically treated molars. Quintessence Int. 2009;40(2):125-33.Biacchi GR, Mello B, Basting RT. The endocrown: an alternative approach for restoring extensively damaged molars. J Esthet Restor Dent. 2013;25(6):383-90.Dietschi D, Duc O, Krejci I, Sadan A. Biomechanical considerations for the restoration of endodontically treated teeth: a systematic review of the literature, Part II (Evaluation of fatigue behavior, interfaces, and in vivo studies). Quintessence Int. 2008;39(2):117-29.Mörmann WH, Bindl A, Lüthy H, Rathke A. Effects of preparation and luting system on all-ceramic computer-generated crowns. Int J Prosthodont. 1998;11(4):333-39.Bernardo WM, Nobre MRC, Jatene FB. A prática clinica baseada em evidências. Parte II: buscando as evidências em fontes de informação. Rev Assoc Med Bras. 2004;50(1):104-8.Zavanelli AC, Zavanelli RA, Mazaro JVQ, Lemos CAA, Dias ES, Silva EV, Pinto RC. Coroas Endoncrown: uma revisão de literatura e relato de caso. Arch Health Invest. 2017;6(8):382-89.Rocca GT, Saratti CM, Cattani-Lorente M, Feilzer AJ, Scherrer S, Krejci I. The effect of a fiber reinforced cavity configuration on load bearing capacity and failure mode of endodontically treated molars restored with CAD/CAM resin composite overlay restorations. J Dent. 2015;43(9):1106-15.Gresnigt MM, Özcan M, van den Houten ML, Schipper L, Cune MS. Fracture strength, failure type and Weibull characteristics of lithium disilicate and multiphase resin composite endocrowns under axial and lateral forces. Dent Mater. 2016;32(5):607-14.Rocca GT, Sedlakova P, Saratti CM, Sedlacek R; Gregor L; Rizcalla N et al. Fatigue behavior of resin-modified monolithic CAD-CAM RNC crowns and endocrowns. Dent Mater. 2016;32(12):e338-50.Fages M, Bennasar B. The endocrown: a different type of all-ceramic reconstruction for molars. J Can Dent Assoc. 2013;79:d140.Hayes A, Duvall N, Wajdowicz M, Roberts H. Effect of Endocrown Pulp Chamber Extension Depth on Molar Fracture Resistance. Oper Dent. 2017;42(3):327-34.Gaintantzopoulou MD, El-Damanhoury HM. Effect of Preparation Depth on the Marginal and Internal Adaptation of Computer-aided Design/Computer-assisted Manufacture Endocrowns. Oper Dent. 2016;41(6):607-16.Baratieri LN, Monteiro S JR. Coroas posteriores endocrown. In: Baratieri L N. Odontologia restauradora: fundamentos e técnicas, São Paulo: Santos, 2010. v. 2, cap.30, p.738-55.Rocca GT, Saratti CM, Poncet A, Feilzer AJ, Krejci I. The influence of FRCs reinforcement on marginal adaptation of CAD/CAM composite resin endocrowns after simulated fatigue loading. Odontology. 2016;104(2):220-32.Sedrez-Porto JA, Rosa WL, da Silva AF, Münchow EA, Pereira-Cenci T. Endocrown restorations: A systematic review and meta-analysis. J Dent. 2016;52:8-14.Borgia Botto E, Barón R, Borgia JL. Endocrown: Estudio clínico retrospectivo de una serie de pacientes, en un período de 8 a 19 años. Odontoestomatología 2016;18(28):48-59.Rayyan MR, Alauti RY, Abanmy MA, AlReshaid RM, Bin Ahmad HA. Endocrowns versus post-core retained crowns for restoration of compromised mandibular molars: an in vitro study. Int J Comput Dent. 2019;22(1):39-44.Silva ACC, Santos FB. Opções protéticas para dentes posteriores tratados endodonticamente: revisão de literatura [monografia]. Lagarto - SE: Departamento de Odontologia de Lagarto da Universidade Federal de Sergipe – UFS; 2018.El-Damanhoury HM, Haj-Ali RN, Platt JA. Fracture resistance and microleakage of endocrowns utilizing three CAD-CAM blocks. Oper Dent. 2015;40(2):201-10.Valentina V, Aleksandar T, Dejan L, Vojkan L. Restoring endodontically treated teeth with all-ceramic endo-crowns - case report. Serbian Dent J 2008;55:54-64.Tysowsky GW. The science behind lithium disilicate: a metal-free alternative. Dent Today. 2009;28(3):112-13.Qin F, Zheng S, Luo Z, Li Y, Guo L, Zhao Y et al. Evaluation of machinability and flexural strength of a novel dental machinable glass-ceramic. J Dent. 2009;37(10):776-80.El Ghoul W, Özcan M, Silwadi M, Salameh Z. Fracture resistance and failure modes of endocrowns manufactured with different CAD/CAM materials under axial and lateral loading. J Esthet Restor Dent. 2019;31(4):378-87. El Ghoul WA, Özcan M, Ounsi H, Tohme H, Salameh Z. Effect of different CAD-CAM materials on the marginal and internal adaptation of endocrown restorations: An in vitro study. J Prosthet Dent. 2020;123(1):128-34.Zou Y, Bai J, Xiang J. Clinical performance of CAD/CAM-fabricated monolithic zirconia endocrowns on molars with extensive coronal loss of substance. Int J Comput Dent. 2018;21(3):225-32.

March 2020 marks the coming of bad news to this country. COVID-19 pandemic began to strike and its domino impacts have affected almost all aspects of life, including academic and scientific writing on journal. In the midst of the spirit of working and researching from home, the International Review of Humanities Studies Journal is back to publish for July 2020 edition. The issues discussed are increasingly diverse, marked by the diverse expertises of the respective authors. Domestic contributions can be seen from the articles of the researchers from Universitas Indonesia, particularly from the Faculty of Humanities and the School of Strategic and Global Studies which are interconnected with the scholars from the Indonesian Police College and Al Azhar University.Since this journal is intended to be available internationally, it is also necessary to pay attention to the contributions of foreign authors. Researchers from the University of Uyo, the University of Ilorin, the University of Benin, the University of Lagos, and Delta State University provide interesting views on the issues of humanities in Nigeria. Five articles from various universities in Nigeria are interconnected with independent researchers from the People's Republic of China, who without links to universities or colleges have sent their own independent research articles.This edition begins with Darmoko's writing that discusses the moral complexities of Javanese in the Asmara Djibrat Ludira novel. Darmoko's research emphasises the spiritual role of knight figures who defended their territory and romance. The second article is from Letmiros who also discusses Java. Letmiros saw a mosque in Jogjakarta, namely the Jogokariyan Mosque, as an agent of change as well as a legend. Letmiros argued that by having activities – whether it is spiritual, economic, cultural, or politics – that are conducted in the mosque, mosque can be ordained as an agent of change and branded as legendary, especially in the city of Jogjakarta.The third article is a research carried out during the COVID-19 pandemic. Fera Belinda saw how a new normality, in a tourist village in the Badung-Bali area, is interconnected with local wisdom and health protocols. Fera Belinda's study shows that health science on pandemic like COVID-19 can be analysed together using the humanities approach. Then in the fourth article, we are invited to take a walk to explore Nigerian drama. Inegbe and Rebecca see that a theatre, titled Cemetary Road, has a significant impact on Nigerian society; to the extent that it can be considered a radical impact. Inegbe and Rebecca's research provides new treasure of knowledge, especially for readers in the regions outside Nigeria.In the fifth article, we are invited to see how online studies, especially the use of video technology, are utilised by teachers. Silalahi and Halimi see how the use of two methods, namely the use of video teaching and the use of textual textbook teaching, are compared between the experimental class and the control class. In conclusion, they find that video-based teaching provides better results in the learning process. The next article, by Soekarba and Rosyidah, invites us to see the contribution of the Hadrami group to a community in the Tegal area, Central Java.The impact of the Hadrami (Al Irsyad) group movement was mostly felt in the social and educational fields in the area.The seventh article invites us to get to know Nigeria. Okpevra's research discusses pre-colonial aspects in the Delta State, Nigeria. This research concludes that intergroup relations in the region are influenced by factors of origin, equality of geographical conditions, and similarity of cultural practices. The eighth article invites us to get acquainted with humanities research that is associated with psychological studies of the police. Mayastinasari and Suseno discussed how strengthening the current role of the police influences the public satisfaction, especially in North Sumatra where this research took place.The ninth article is an issue that has been discussed lately. Nwosu discusses the issue of homosexuality in the Catholic group in Nigeria which is interconnected with its society. Although the discussed issues are quite sensitive, the scientific explanation could vividly answers the questions regarding these issues. Next, the tenth article from Akpan and Edem discusses how a film, in this case Frozen, is examined from the perspective of digital technology and digital costumes which is a new contribution in analysing a child-friendly content. The eleventh article of Ademakinwa and Smith discusses a film adapted from a well-known Nigerian novelist in the United States, Chimamanda Adichie. Ademakinwa and Smith's findings state that collective memory, reconstructed through film, can have a more significant impact than that of novels. It can even create a crisis within society if not properly controlled.The twelfth article from Filia and Nurfitri invites us to explore the expression of confessions of love in Japanese. Data on love expressions from these researchers were collected via video interviews. It is interesting to find that the expression of love turns out to depend on the cultural context associated with togetherness and sustainability. The next article, the thirteenth, is a contribution of an independent Chinese researcher named Zhang Guanan. He analysed Chinese folklore, Pi Ying, with wayang kulit – leather puppet – stories. It is interesting to follow how Guanan managed to find the uniqueness of both in his research.The fourteenth article by Sugiharto and Puspitasari discusses the online stalking activities of urban millennial. It is their second research which found that cyber stalking is a natural thing for millennial generation living in urban areas, including following colleagues, friends, spouses, even ex-spouses and friends who have not been associated for a long time. The fifteenth paper from Guanah Akbanu and Obi discusses the practice of online journalism in Nigeria, using artificial intelligence. The case study they chose was how journalists in Edo, Nigeria, perceived the use of AI in their journalistic methods. It was found that the use of AI turned out to be more positive for journalism in the area.The sixteenth article by Sonya Suganda discusses how a commemorative object, stolperschwelle, is useful as an object for narrative of the death. The object that was initially used to commemorate Nazi victims has developed to be the object to commemorate those who are marginalized, including homosexuals, gypsies, and those who are exiled because of political differences. The next contribution, the seventeenth, comes from Zaqiatul, Al Azhar University who discusses how the functioning of suffixes and verbs is interconnected in the realm of Arabic conjugation. The eighteenth article by Hutapea discusses a quite sensitive issue, namely the conflict between the native people of Jogja and the Papuans living in Jogjakarta. This conflict was examined from the perspective of the police, especially how they controlled it. The nineteenth article from Arif Budiman discusses the strategy used by the French interpreter in the film Marlina Murder in Four Acts. The last article by Basuni discusses the problem of the Arabic-Indonesian translation, in the context of the increasingly contextual scripture.Hopefully, this current edition along with the entire articles can enlighten the readers and contribute significantly to the knowledge of humanities studies.

Photo by Sangharsh Lohakare on Unsplash ABSTRACT The public should debate the ethical and social challenges arising from heritable human genome editing (HHGE). The notorious case involving He Jiankui may have led to the disfavor of gene editing and a precautionary approach. While the de facto global moratorium on HHGE is clearly justified considering our current inability to implement it safely and effectively, the difficult ethical considerations should be addressed prior to the ability to initiate widespread HHGE. This piece argues that prospective patients and other members of society beyond the scientific community must be included in the conversation. It emphasizes the potential role of those not directly participating in HHGE science, calling the broader academic community not simply to wait for scientists’ results and only afterward react. Pointing to key historical examples, I contend that scientific progress is intrinsically linked with the surrounding societal discussion and that it is not only scientists who can influence where the HHGE story ends. INTRODUCTION l. Rogue Scientists Chinese biophysicist He Jiankui announced the world’s first genetically modified babies in 2018. Naturally, the treatment aroused the attention of the world’s media, which focused on He’s reckless actions. Indeed, in setting up and carrying out the procedure in question, he flouted norms of good scientific practice on a range of levels—errors paid with time in prison. Since the He controversy, few scientists have aggressively approached heritable human genome editing (HHGE) and challenged the current research norms. The most outspoken exception is the Russian molecular biologist Denis Rebrikov of the Pirogov Russian National Research Medical University. He publicly declared his intention to apply clustered regularly interspaced short palindromic repeats (CRISPR) to embryos to help couples avoid passing serious medical conditions to their children. However, Rebrikov met fierce opposition both inside and beyond Russia and, with leading CRISPR scientists and bioethicists abroad describing him as a “cowboy” who had “weak data” and was trying to “grab some attention.”[1] So far, Rebrikov’s plans have failed to come to fruition. Although there are 126 entries listed in a registry of HHGE research recently created by the World Health Organization (WHO),[2],[3] it seems that clinical HHGE has been paused for the time being. ll. Steering the Conversation A section of the scientific community has been trying to steer the ethical debate on HHGE away from the actions of rogue scientists and back to an issue that is central to the matter—the interests of patients. The majority would agree that the most compelling potential application of germline genome editing is for the prevention of devastating genetic conditions, for example, when both parents carry Huntington’s disease, for which “genome editing offers the only prospect of bearing a healthy, genetically related child.”[4] Despite such justification for scientists to continue pursuing research in the area, there has been a notable reticence in the wider academic community regarding making the ethical case for HHGE and clarifying in which medical situations such a technique might be reasonably applied. Even among those who recognize that the HHGE cases' controversies should not be a reason for panic over designer babies, some believe that starting the ethical debate is premature. A key part of the argument is that the current technological and scientific knowledge available is far from ready to deliver on treatments. A similar stance preventing debate in the wider society is that “difficult questions” about cost, accessibility, and social justice remain.[5] Whether intended or not, the implication is that the position of wider society in the HHGE story should be a reactive one, namely waiting to see what the scientists throw at them and then dealing with it. I argue that there is not only an immediate need for broader academic and societal input on the ethical and social aspects of the HHGE debate but that there is a deep symbiosis between scientific progress and its surroundings, whereby science both shapes and is shaped by the societal environment in which it takes place. The WHO published a position paper, recommendations, and a framework for governance. The framework for governance describes global standards for the governance and oversight of HHGE.[6] The position paper emphasized the importance of global and inclusive dialogue,[7] and many other boards have also called for broad public engagement.[8] It is imperative that WHO’s governance framework meets everyone’s needs. After all, as with any medical treatment, it is not the scientist who developed the treatment or the doctor who delivers it that is most important– that honor falls to the patient. In the case of HHGE, the beneficiaries include those members of society who hope to reproduce. Yet HHGE has the potential to impact society. We all should have an opportunity to be a part of world-changing decisions that lead to the creation are made and feel a responsibility to participate. lll. Shutting Down the Academic Debate At the 30th Annual Conference of the Japanese Association for Bioethics, which took place in late 2018 after He’s experiment, the discussion about HHGE was shut down quickly. Notwithstanding the understandable issues raised with He’s case, one participant after another stood up to voice support for an outright and complete ban on the use of CRISPR.[9] The ban was based on the grounds that editing the human genome would result in a cascade of unforeseen and irreversible consequences for future generations. One participant forcefully argued that “the deoxyribose nucleic acid (DNA) rubicon should never be crossed for above all, it was deeply immoral to do so when there was no way of obtaining the consent of those who would actually stand affected—our descendants.”[10] Another saw it as putting humanity on a slippery slope toward enhancements, and some feared the catastrophic mistakes that might result from their use.[11] While the above event provides just one snapshot of the debate that was taking place around the world at the time, it captures the strong reservations in the scientific community. It is a common view, not only in Japan, that the human genome is something sacred, a relic handed down from generations, that we ought to treasure and preserve. In support of such a view, religious and other more pragmatic reasons are offered. For example, some may fear the disasters that might befall us if we choose to intervene in the process through which we pass our genetic code from one generation to another. Such arguments are certainly still at the heart of the ethical debate, but the foundations upon which they are built are by no means universally accepted. Stanford University bioethicist Henry Greely writes, “the human germline genome” does not exist; instead, each of us has a unique genome.[12] Greely argues that HHGE is no different from the changes our genomes have undergone through numerous medical interventions. For example, synthetic insulin has increased the number of people with DNA variations that lead to diabetes. Those with this condition would have died as a child in the past. However, now they live long enough to be able to reproduce. Similarly, the transition from hunting to farming centuries ago resulted in a greater number of copies in our gene pool of starch-digesting genes. Yet Greely suggested that, practically, HHGE is “not very useful in the near- to midterm” (by which he means “the next several decades”)[13] “mainly because other technologies can attain almost all the important hoped-for benefits of [HHGE], often with lower risk,” citing embryo selection and somatic gene editing as two alternative options. Greely argued that applying HHGE for enhancement beyond disease prevention and is currently not a realistic option because we lack the necessary knowledge. In Greely’s opinion, “how worried should we be [about HHGE]…? A bit, but not very and not about much.”[14] Greely’s assertions that other scientific debates should take precedence and that the concerns are not ripe for debate yet are concerning. lV. Why Shutting Down the Debate Might Not be a Good Idea First, the timeframe described by Greely seems somewhat out of line with that described by leading scientists. As far back as 2018, at the same Summit where He made his revelations, George Q. Daley stressed that HHGE is scientifically feasible here and that the ethical considerations can no longer be put off: “…a number of groups have applied gene editing now to human embryos in the context of in vitro fertilization and attempting to determine variations of a protocol that would enhance the fidelity and reduce mosaicism. I think there has been an emerging consensus that the off-target problem is manageable, and in some cases even infinitesimal. There are some interesting proofs of principles, like diseases such as beta-thalassemia that could potentially be approached with this strategy.”[15] It would also be possible to challenge Greely on various other aspects. One of which would be the number of cases to which HHGE would be relevant and the kinds of moral allowances that might be made, and each case concludes that more urgency is required in the ethical debate. Greely suggests that most people can use preimplantation genetic testing (PGD), which is the embryo selection process, and that perhaps HHGE could apply to couples where both have the same autosomal recessive gene.[16] Greely rules out considering HHGE in cases where PGD is applicable. Greely concedes PGD does not already represent the answer on this topic, as it often fails to provide couples with enough healthy embryos to transfer. As a resolution to this issue, he points to the creation of eggs using induced pluripotent stem cell (iPSC) techniques, whereby eggs can potentially be created from other cells.[17] However, given the extremely limited success of iPSCs in the clinical arena to date, in vitro gametogenesis is a highly speculative solution. Certainly, the progress of iPSC research is not such a safe bet that placing all our hopes on it at the expense of HHGE techniques is currently justified. (Also, it should be noted that making eggs using the iPSC technique is hardly an ethical problem-free area itself.) In summary, the cases of couples looking to conceive that Greely rules out by pointing to PGD should be kept on the HHGE table, as various other scholars have suggested.[18] Many of us debating HHGE are not scientists, so the best we can do is draw from the information we glean from those more technically capable. As a society, we are not just passive observers of science; we should have influence over decisions that impact society. Indeed, even if the available science is not yet at a place where we should be worried about large-scale ethical and social concerns, the story will continue to unfold in the future. While Greely is happy to see the human race “muddle through” the ethical challenges of scientific breakthroughs, such a position fails to recognize that society at large is far from powerless. V. Society Influencing Scientific Progress There are some notable examples of society’s impact on scientific progress. For example, political policies led to the development of nuclear technology for war and strategic deterrence, despite societal objections seen through demonstrations of people protesting using the slogan “no nukes.” Furthermore, the Bush administration drastically limited the use of embryonic stem cells in the 2000s due to a strong religious and cultural influence on policy.[19] Societal debate potentially serves as a powerful factor in guiding science. Where societal acceptance is ambiguous, science tends to operate on its own. But where science would impact life’s fundamental issues like war, how embryos should be valued, or the end of life, society should weigh in and influence the role of science. Societal views on the current global moratorium on HHGE could lead to a ban, as has been advocated.[20] On the other hand, societal views that value HHGE as a way to expand reproductive autonomy may justify permitting its use. Opening an ethics debate about it would enable scientists to pursue technologies that society deems justifiable as well as set limits for where they should stop. Making this process more difficult, the He affair has clearly colored public discourse on HHGE in a way that inhibits debate. In Japan, a sequence of questionnaires in 2016, 2018, and 2019 showed that the widely publicized HHGE scandal led to a significant decline in the acceptance of genome editing technology in general, particularly for human reproduction. Specifically, the surveys revealed a stark rise in disapproval of the technology’s use on fertilized human eggs—from 12 percent in 2018 to 29 percent in 2019.[21] The three scientists that conducted these surveys suggested that “the news of the twin babies in China had a substantial influence on the Japanese public,” damaging the reputation of HHGE.[22] It seems likely that the public distaste for HHGE was prompted by He’s research rather than considerations about the scientific potential of HHGE The change in public opinion may also make politicians and scientists more hesitant when it comes to taking the lead in the HHGE debate. Ultimately, this can restrict the public discussion of the central ethical challenges of the technology and hinder efforts to determine whether there is a responsible path forward other than an outright ban. Stressing the importance of the issue again to potential patients and failing to engage further with the HHGE debate is surely not something society should allow. While there are many important ongoing debates about genetics, like biohacking and DIY hobbyists, HHGE deserves attention as well. In fact, attention to the ethics of HHGE should help — more awareness of how these tools can be applied and what germline genome editing is will make people more alert to the existing danger and better understand how to mitigate it. Perhaps more importantly, a clear message from society to researchers about what objectives are reasonable to pursue regarding the HHGE technologies will facilitate good science. Having a publicly determined criterion would allow scientists to not live in fear that they might be blacklisted for seeking progress in grey areas and instead confidently chase progress where it is allowed. Vl. What Now? HHGE is here (or will be soon) and brings many ethical and social challenges. However, the challenges should not be left to individual scientists and couples in desperate situations to manage alone. Moving toward how these challenges can be met practically, it is helpful to draw a parallel with the issue of implementing human rights. In the early 21st century, political philosopher Michael Freeman of the University of Essex lamented that implementing human rights had been left to lawyers. Although legal experts were clearly essential in putting together the global human rights framework, Freeman’s concern was that they were not best placed to understand implementing human rights in various contexts. Setting out a broader, interdisciplinary approach, he called for social scientists to tackle these difficult questions, ultimately moving human rights forward around the world. Similarly, in medical technology like HHGE, scientists are crucial to the story, but at the same time, they are not trained to deal with all the accompanying challenges. Bioethicists are also important, clarifying the arguments that society needs to resolve. There is a need for even wider input from across the scholarly community. For instance, as with human rights, international and domestic regulation is required, and clearly, the legal community has a role here. Moreover, as described by Freeman, since all law is political in its creation and has impacts across society, political scientists and sociologists can provide impactful input. CONCLUSION We are in it together, and we have roles to play in the discussion of HHGE. Societal discourse does not always trail the scientific reality, but rather, it can condition the path that science will follow. Given the importance of what is at stake, not only for the potential patients, but for humanity, we should not leave the HHGE debate only to scientists, and we should not leave it until later. - [1] Cohen J. “Embattled Russian scientist sharpens plans to create gene-edited babies,” Science, 21 Oct. 2019. doi:10.1126/science.aaz9337. [2] World Health Organization. “WHO issues new recommendations on human genome editing for the advancement of public health,” News release, 12 July 2021, www.who.int/news/item/12-07-2021-who-issues-new-recommendations-on-human-genome-editing-for-the-advancement-of-public-health. [3] World Health Organization. “Human Genome Editing Registry,” https://www.who.int/groups/expert-advisory-committee-on-developing-global-standards-for-governance-and-oversight-of-human-genome-editing/registry. [4] Daley GQ, Lovell-Badge R, and Steffann J. “After the Storm–A Responsible Path for Genome Editing,” New England Journal of Medicine 380, no. 10 (2019): 897-9. doi:10.1056/NEJMp1900504. [5] Daley GQ, Lovell-Badge R, and Steffann J. “After the Storm–A Responsible Path for Genome Editing,” New England Journal of Medicine 380, no. 10 (2019): 897-9. doi:10.1056/NEJMp1900504 [6] World Health Organization. “WHO issues new recommendations on human genome editing for the advancement of public health,” News Release, July 12, 2021, www.who.int/news/item/12-07-2021-who-issues-new-recommendations-on-human-genome-editing-for-the-advancement-of-public-health. [7] WHO 2021. Human Genome Editing: Position Paper, WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing. [8] Daley GQ, Lovell-Badge R, and Steffann J. “After the Storm–A Responsible Path for Genome Editing,” New England Journal of Medicine 380, no. 10 (2019): 897-9. doi:10.1056/NEJMp1900504. [9] 30th Annual Conference of the Japanese Association for Bioethics, 8-9 Dec. 2018, Kyoto Prefectural University, Kyoto. [10] 30th Annual Conference of the Japanese Association for Bioethics, 8-9 Dec. 2018, Kyoto Prefectural University, Kyoto. [11] 30th Annual Conference of the Japanese Association for Bioethics, 8-9 Dec. 2018, Kyoto Prefectural University, Kyoto. [12] Greely HT. “Why the Panic Over ‘Designer Babies’ Is the Wrong Worry,” LeapsMag, 30 Oct. 2017, leapsmag.com/much-ado-about-nothing-much-crispr-for-human-embryo-editing; Greely HT. “CRISPR’d babies: human germline genome editing in the ‘He Jiankui Affair’,” Journal of Law and the Biosciences 2019; 6(1): 111–83. doi: 10.1093/jlb/lsz010; Greely HT. CRISPR People: The Science and Ethics of Editing Humans (Massachusetts: Massachusetts Institute of Technology Press, 2021). [13] Greely HT. “Why the Panic Over ‘Designer Babies’ Is the Wrong Worry,” LeapsMag, 30 Oct. 2017, leapsmag.com/much-ado-about-nothing-much-crispr-for-human-embryo-editing. [14] Greely HT. “Why the Panic Over ‘Designer Babies’ Is the Wrong Worry,” LeapsMag, 30 Oct. 2017, leapsmag.com/much-ado-about-nothing-much-crispr-for-human-embryo-editing. [15] Daley, G. (n.d.). Genome-editing-pathways to Translation. Transcript of the Human-Genome Editing Summit 2018 Hong Kong. Retrieved March 17, 2022, from https://diyhpl.us/wiki/transcripts/human-genome-editing-summit/2018-hong-kong/george-daley-genome-editing-pathways-to-translation/ [16] Greely HT. “CRISPR’d babies: human germline genome editing in the ‘He Jiankui affair’,” Journal of Law and the Biosciences 2019: 6(1): 111–83. doi:10.1093/jlb/lsz010. [17] Greely HT. CRISPR People: The Science and Ethics of Editing Humans (Massachusetts: Massachusetts Institute of Technology Press, 2021). [18] Rasnich R. “Germline genome editing versus preimplantation genetic diagnosis: Is there a case in favour of germline interventions?.” Bioethics 2020; 34(1): 60–9. [19] Murugan, Varnee. “Embryonic stem cell research: a decade of debate from Bush to Obama.” The Yale journal of biology and medicine vol. 82,3 (2009): 101-3. [20] Lander E, Baylis F, Zhang F, et al. “Adopt a moratorium on heritable genome editing,” Nature 2019; 567(7747): 165–8. pmid:30867611. [21] Watanabe D, Sato Y, Tsuda M, and Ohsawa R. Increased awareness and decreased acceptance of genome-editing technology: The impact of the Chinese twin babies. PLoS ONE 2000; 15(1): 1-13. doi:10.1371/journal.pone.0238128. [22] Watanabe D, Sato Y, Tsuda M, and Ohsawa R. Increased awareness and decreased acceptance of genome-editing technology: The impact of the Chinese twin babies. PLoS ONE 2000; 15(1): 1-13. doi:10.1371/journal.pone.0238128.

IntroductionIn this article, I set out to accomplish two tasks. The first is to map coffee and cafés in Mainland China in different historical periods. The second is to focus on coffee and cafés in the socio-cultural milieu of contemporary China in order to understand the symbolic value of the emerging coffee/café-scape. Cafés, rather than coffee, are at the centre of this current trend in contemporary Chinese cities. With instant coffee dominating as a drink, the Chinese have developed a cultural and social demand for cafés, but have not yet developed coffee palates. Historical Coffee Map In 1901, coffee was served in a restaurant in the city of Tianjin. This restaurant, named Kiessling, was run by a German chef, a former solider who came to China with the eight-nation alliance. At that time, coffee was reserved mostly for foreign politicians and military officials as well as wealthy businessmen—very few ordinary Chinese drank it. (For more history of Kiessling, including pictures and videos, see Kiessling). Another group of coffee consumers were from the cultural elites—the young revolutionary intellectuals and writers with overseas experience. It was almost a fashion among the literary elite to spend time in cafés. However, this was negatively judged as “Western” and “bourgeois.” For example, in 1932, Lu Xun, one of the most important twentieth century Chinese writers, commented on the café fashion during 1920s (133-36), and listed the reasons why he would not visit one. He did not drink coffee because it was “foreigners’ food”, and he was too busy writing for the kind of leisure enjoyed in cafés. Moreover, he did not, he wrote, have the nerve to go to a café, and particularly not the Revolutionary Café that was popular among cultural celebrities at that time. He claimed that the “paradise” of the café was for genius, and for handsome revolutionary writers (who he described as having red lips and white teeth, whereas his teeth were yellow). His final complaint was that even if he went to the Revolutionary Café, he would hesitate going in (Lu Xun 133-36). From Lu Xun’s list, we can recognise his nationalism and resistance to what were identified as Western foods and lifestyles. It is easy to also feel his dissatisfaction with those dilettante revolutionary intellectuals who spent time in cafés, talking and enjoying Western food, rather than working. In contrast to Lu Xun’s resistance to coffee and café culture, another well-known writer, Zhang Ailing, frequented cafés when she lived in Shanghai from the 1920s to 1950s. She wrote about the smell of cakes and bread sold in Kiessling’s branch store located right next to her parents’ house (Yuyue). Born into a wealthy family, exposed to Western culture and food at a very young age, Zhang Ailing liked to spend her social and writing time in cafés, ordering her favourite cakes, hot chocolate, and coffee. When she left Shanghai and immigrated to the USA, coffee was an important part of her writing life: the smell and taste reminding her of old friends and Shanghai (Chunzi). However, during Zhang’s time, it was still a privileged and elite practice to patronise a café when these were located in foreign settlements with foreign chefs, and served mainly foreigners, wealthy businessmen, and cultural celebrities. After 1949, when the Chinese Communist Party established the People’s Republic of China, until the late 1970s, there were no coffee shops in Mainland China. It was only when Deng Xiaoping suggested neo-liberalism as a so-called “reform-and-open-up” economic policy that foreign commerce and products were again seen in China. In 1988, ten years after the implementation of Deng Xiaoping’s policy, the Nestlé coffee company made the first inroads into the mainland market, featuring homegrown coffee beans in Yunnan province (China Beverage News; Dong; ITC). Nestlé’s bottled instant coffee found its way into the Chinese market, avoiding a direct challenge to the tea culture. Nestlé packaged its coffee to resemble health food products and marketed it as a holiday gift suitable for friends and relatives. As a symbol of modernity and “the West”, coffee-as-gift meshed with the traditional Chinese cultural custom that values gift giving. It also satisfied a collective desire for foreign products (and contact with foreign cultures) during the economic reform era. Even today, with its competitively low price, instant coffee dominates coffee consumption at home, in the workplace, and on Chinese airlines. While Nestlé aimed their product at native Chinese consumers, the multinational companies who later entered China’s coffee market, such as Sara Lee, mainly targeted international hotels such as IHG, Marriott, and Hyatt. The multinationals also favoured coffee shops like Kommune in Shanghai that offered more sophisticated kinds of coffee to foreign consumers and China’s upper class (Byers). If Nestlé introduced coffee to ordinary Chinese families, it was Starbucks who introduced the coffee-based “third space” to urban life in contemporary China on a signficant scale. Differing from the cafés before 1949, Starbucks stores are accessible to ordinary Chinese citizens. The first in Mainland China opened in Beijing’s China World Trade Center in January 1999, targeting mainly white-collar workers and foreigners. Starbucks coffee shops provide a space for informal business meetings, chatting with friends, and relaxing and, with its 500th store opened in 2011, dominate the field in China. Starbucks are located mainly in the central business districts and airports, and the company plans to have 1,500 sites by 2015 (Starbucks). Despite this massive presence, Starbucks constitutes only part of the café-scape in contemporary Chinese cities. There are two other kinds of cafés. One type is usually located in universities or residential areas and is frequented mainly by students or locals working in cultural professions. A representative of this kind is Sculpting in Time Café. In November 1997, two years before the opening of the first Starbucks in Beijing, two newlywed college graduates opened the first small Sculpting in Time Café near Beijing University’s East Gate. This has been expanded into a chain, and boasts 18 branches on the Mainland. (For more about its history, see Sculpting in Time Café). Interestingly, both Starbucks and Sculpting in Time Café acquired their names from literature, Starbucks from Moby Dick, and Sculpting in Time from the Russian filmmaker Andrei Tarkovsky’s film diary of the same name. For Chinese students of literature and the arts, drinking coffee is less about acquiring more energy to accomplish their work, and more about entering a sensual world, where the aroma of coffee mixes with the sounds from the coffee machine and music, as well as the lighting of the space. More importantly, cafés with this ambience become, in themselves, cultural sites associated with literature, films, and music. Owners of this kind of café are often lovers of foreign literatures, films, and cultures, and their cafés host various cultural events, including forums, book clubs, movie screenings, and music clubs. Generally speaking, coffee served in this kind of café is simpler than in the kind discussed below. This third type of café includes those located in tourist and entertainment sites such as art districts, bar areas, and historical sites, and which are frequented by foreign and native tourists, artists and other cultural workers. If Starbucks cultivates a fast-paced business/professional atmosphere, and Sculpting in Time Cafés an artsy and literary atmosphere, this third kind of café is more like an upscale “bar” with trained baristas serving complicated coffees and emphasising their flavour. These coffee shops are more expensive than the other kinds, with an average price three times that of Starbucks. Currently, cafés of this type are found only in “first-tier” cities and usually located in art districts and tourist areas—such as Beijing’s 798 Art District and Nanluo Guxiang, Shanghai’s Tai Kang Road (a.k.a. “the art street”), and Hangzhou’s Westlake area. While Nestlé and Starbucks use coffee beans grown in Yunnan provinces, these “art cafés” are more inclined to use imported coffee beans from suppliers like Sara Lee. Coffee and Cafés in Contemporary China After just ten years, there are hundreds of cafés in Chinese cities. Why has there been such a demand for coffee or, more accurately, cafés, in such a short period of time? The first reason is the lack of “third space” environments in Mainland China. Before cafés appeared in the late 1990s, stores like KFC (which opened its first store in 1987) and McDonald’s (with its first store opened in 1990) filled this role for urban residents, providing locations where customers could experience Western food, meet friends, work, or read. In fact, KFC and McDonald’s were once very popular with college students looking for a place to study. Both stores had relatively clean food environments and good lighting. They also had air conditioning in the summer and heating in the winter, which are not provided in most Chinese university dormitories. However, since neither chain was set up to be a café and customers occupying seats for long periods while ordering minimal amounts of food or drink affected profits, staff members began to indirectly ask customers to leave after dining. At the same time, as more people were able to afford to eat at KFC and McDonald’s, their fast foods were also becoming more and more popular, especially among young people. As a consequence, both types of chain restaurant were becoming noisy and crowded and, thus, no longer ideal for reading, studying, or meeting with friends. Although tea has been a traditional drink in Chinese culture, traditional teahouses were expensive places more suitable for business meetings or for the cultural or intellectual elite. Since almost every family owns a tea set and can readily purchase tea, friends and family would usually make and consume tea at home. In recent years, however, new kinds of teahouses have emerged, similar in style to cafés, targeting the younger generation with more affordable prices and a wider range of choices, so the lack of a “third space” does not fully explain the café boom. Another factor affecting the popularity of cafés has been the development and uptake of Internet technology, including the increasing use of laptops and wireless Internet in recent years. The Internet has been available in China since the late 1990s, while computers and then laptops entered ordinary Chinese homes in the early twenty-first century. The IT industry has created not only a new field of research and production, but has also fostered new professions and demands. Particularly, in recent years in Mainland China, a new socially acceptable profession—freelancing in such areas as graphic design, photography, writing, film, music, and the fashion industry—has emerged. Most freelancers’ work is computer- and Internet-based. Cafés provide suitable working space, with wireless service, and the bonus of coffee that is, first of all, somatically stimulating. In addition, the emergence of the creative and cultural industries (which are supported by the Chinese government) has created work for these freelancers and, arguably, an increasing demand for café-based third spaces where such people can meet, talk and work. Furthermore, the flourishing of cafés in first-tier cities is part of the “aesthetic economy” (Lloyd 24) that caters to the making and selling of lifestyle experience. Alongside foreign restaurants, bars, galleries, and design firms, cafés contribute to city branding, and link a city to the global urban network. Cafés, like restaurants, galleries and bars, provide a space for the flow of global commodities, as well as for the human flow of tourists, travelling artists, freelancers, and cultural specialists. Finally, cafés provide a type of service that contributes to friendly owner/waiter-customer relations. During the planned-economy era, most stores and hotels in China were State-owned, staff salaries were not related to individual performance, and indifferent (and even unfriendly) service was common. During the economic reform era, privately owned stores and shops began to replace State-owned ones. At the same time, a large number of people from the countryside flowed into the cities seeking opportunities. Most had little if any professional training and so could only find work in factories or in the service industry. However, most café employees are urban, with better educational backgrounds, and many were already familiar with coffee culture. In addition, café owners, particularly those of places like Sculpting in Time Cafe, often invest in creating a positive, community atmosphere, learning about their customers and sharing personal experiences with their regular clients. This leads to my next point—the generation of the 1980s’ need for a social community. Cafés’ Symbolic Value—Community A demand for a sense of community among the generation of the 1980s is a unique socio-cultural phenomenon in China, which paradoxically co-exists with their desire for individualism. Mao Zedong started the “One Child Policy” in 1979 to slow the rapid population growth in China, and the generations born under this policy are often called “the lonely generations,” with both parents working full-time. At the same time, they are “the generation of me,” labelled as spoiled, self-centred, and obsessed with consumption (de Kloet; Liu; Rofel; Wang). The individuals of this generation, now aged in their 20s and 30s, constitute the primary consumers of coffee in China. Whereas individualism is an important value to them, a sense of community is also desirable in order to compensate for their lack of siblings. Furthermore, the 1980s’ generation has also benefitted from the university expansion policy implemented in 1999. Since then, China has witnessed a surge of university students and graduates who not only received scientific and other course-based knowledge, but also had a better chance to be exposed to foreign cultures through their books, music, and movies. With this interesting tension between individualism and collectivism, the atmosphere provided by cafés has fostered a series of curious temporary communities built on cultural and culinary taste. Interestingly, it has become an aspiration of many young college students and graduates to open a community-space style café in a city. One of the best examples is the new Henduoren’s (Many People’s) Café. This was a project initiated by Wen Erniu, a recent college graduate who wanted to open a café in Beijing but did not have sufficient funds to do so. She posted a message on the Internet, asking people to invest a minimum of US$316 to open a café with her. With 78 investors, the café opened in September 2011 in Beijing (see pictures of Henduoren’s Café). In an interview with the China Daily, Wen Erniu stated that, “To open a cafe was a dream of mine, but I could not afford it […] We thought opening a cafe might be many people’s dream […] and we could get together via the Internet to make it come true” (quoted in Liu 2011). Conclusion: Café Culture and (Instant) Coffee in China There is a Chinese saying that, if you hate someone—just persuade him or her to open a coffee shop. Since cafés provide spaces where one can spend a relatively long time for little financial outlay, owners have to increase prices to cover their expenses. This can result in fewer customers. In retaliation, cafés—particularly those with cultural and literary ambience—host cultural events to attract people, and/or they offer food and wine along with coffee. The high prices, however, remain. In fact, the average price of coffee in China is often higher than in Europe and North America. For example, a medium Starbucks’ caffè latte in China averaged around US$4.40 in 2010, according to the price list of a Starbucks outlet in Shanghai—and the prices has recently increased again (Xinhua 2012). This partially explains why instant coffee is still so popular in China. A bag of instant Nestlé coffee cost only some US$0.25 in a Beijing supermarket in 2010, and requires only hot water, which is accessible free almost everywhere in China, in any restaurant, office building, or household. As an habitual, addictive treat, however, coffee has not yet become a customary, let alone necessary, drink for most Chinese. Moreover, while many, especially those of the older generations, could discern the quality and varieties of tea, very few can judge the quality of the coffee served in cafés. As a result, few Mainland Chinese coffee consumers have a purely somatic demand for coffee—craving its smell or taste—and the highly sweetened and creamed instant coffee offered by companies like Nestlé or Maxwell has largely shaped the current Chinese palate for coffee. Ben Highmore has proposed that “food spaces (shops, restaurants and so on) can be seen, for some social agents, as a potential space where new ‘not-me’ worlds are encountered” (396) He continues to expand that “how these potential spaces are negotiated—the various affective registers of experience (joy, aggression, fear)—reflect the multicultural shapes of a culture (its racism, its openness, its acceptance of difference)” (396). Cafés in contemporary China provide spaces where one encounters and constructs new “not-me” worlds, and more importantly, new “with-me” worlds. While café-going communicates an appreciation and desire for new lifestyles and new selves, it can be hoped that in the near future, coffee will also be appreciated for its smell, taste, and other benefits. Of course, it is also necessary that future Chinese coffee consumers also recognise the rich and complex cultural, political, and social issues behind the coffee economy in the era of globalisation. References Byers, Paul [former Managing Director, Sara Lee’s Asia Pacific]. Pers. comm. Apr. 2012. China Beverage News. “Nestlé Acquires 70% Stake in Chinese Mineral Water Producer.” (2010). 31 Mar. 2012 ‹http://chinabevnews.wordpress.com/2010/02/21/nestle-acquires-70-stake-in-chinese-mineral-water-producer›. Chunzi. 张爱玲地图[The Map of Eileen Chang]. 汉语大词典出版 [Hanyu Dacidian Chubanshe], 2003. de Kloet, Jeroen. China with a Cut: Globalization, Urban Youth and Popular Music. Amsterdam: Amsterdam UP, 2010. Dong, Jonathan. “A Caffeinated Timeline: Developing Yunnan’s Coffee Cultivation.” China Brief (2011): 24-26. Highmore, Ben. “Alimentary Agents: Food, Cultural Theory and Multiculturalism.” Journal of Intercultural Studies, 29.4 (2008): 381-98. ITC (International Trade Center). The Coffee Sector in China: An Overview of Production, Trade And Consumption, 2010. Liu, Kang. Globalization and Cultural Trends in China. Honolulu: University of Hawai’i Press, 2004. Liu, Zhihu. “From Virtual to Reality.” China Daily (Dec. 2011) 31 Mar. 2012 ‹http://www.chinadaily.com.cn/life/2011-12/26/content_14326490.htm›. Lloyd, Richard. Neobohemia: Art and Commerce in the Postindustrial City. London: Routledge, 2006. Lu, Xun. “Geming Kafei Guan [Revolutionary Café]”. San Xian Ji. Taibei Shi: Feng Yun Shi Dai Chu Ban Gong Si: Fa Xing Suo Xue Wen Hua Gong Si, Mingguo 78 (1989): 133-36. Rofel, Lisa. Desiring China: Experiments in Neoliberalism, Sexuality, and Public Culture. Durham and London: Duke UP, 2007: 1-30. “Starbucks Celebrates Its 500th Store Opening in Mainland China.” Starbucks Newsroom (Oct. 2011) 31 Mar. 2012. ‹http://news.starbucks.com/article_display.cfm?article_id=580›. Wang, Jing. High Culture Fever: Politics, Aesthetics, and Ideology in Deng’s China. Berkeley, Los Angeles, London: U of California P, 1996. 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Introduction Despite the expansive and multimodal realm of Chinese Boys’ Love (BL) culture (also known as danmei in Chinese), audio works have been notably absent from scholarly discussions, with the focus predominantly being on novels (e.g. Bai; Zhang). This article aims to fill this gap by delving into the transformative impact of sound on narrative engagement within the Chinese BL culture. Focussing on the audio drama adaptations of Grandmaster of Demonic Cultivation (modao zushi, hereafter Grandmaster), originally a serialised Chinese BL novel, this analysis aims to unravel the meticulously crafted BL fantasy in these auditory renditions. The audio drama format delivers an intimate storytelling experience directly to the listener’s ears. Unlike textual media, audio dramas allow listeners to immerse themselves in narratives during various daily activities, deepening their connection with the content. The audio drama Grandmaster, produced by the renowned Chinese platform MissEvan, has garnered a vast fan base and over 640 million plays across three seasons (the episodes and numbers of plays can be found on MissEvan: Season 1, Season 2, and Season 3). Unlike the serialised Web-drama adaption diluted by censorship regulations, the audio drama retains the utmost BL fidelity to the original novel, highlighting the significant potential of this medium in the Chinese BL culture. BL culture has surged in popularity within China, partly due to the export of Japanese culture and the burgeoning Chinese Internet accessibility (Feng). The BL genre encompasses diverse media forms such as novels, fanfiction, comics, animation, and audio/Web dramas, rooted in shared fantasies of romantic love between men. The growing interest in BL culture reflects a response to societal structures like Confucianism and the oppressive education system, which, due to their restrictedness, inadvertently foster the exploration of alternative narratives and identities within the genre (Kwon). While initially inspired by Japanese subculture, Chinese BL has evolved under diverse global influences, including American and other Asian subcultures (Lavin et al.). Chinese BL narratives delve into themes of identity, sexuality, power dynamics, and societal norms, reflecting a rich blend of modern and traditional Chinese culture (Madill and Zhao). Moreover, the rise of BL fandom has empowered female readers to engage in questions about gendered politics, questions that enable them to turn a voyeuristic gaze upon men (Zhang). The versatility of Chinese BL media reflects not only the evolving nature of the genre but also its enduring appeal and cultural significance within contemporary Chinese society. This article initiates a concise review of audio drama in China and the transformative impact of earphone technology, shifting listening experiences from public to intimate settings. It subsequently explores the intricate interplay between Chinese BL novels and audio dramas, elucidating the unique dynamics involved. The analysis then examines specific scenes from Grandmaster, providing insights into its role in facilitating a mesmerising BL audio fantasy. Grandmaster, originating as an Internet novel, has gained a dedicated following. MissEvan, recognising its potential, secured copyrights and commissioned Triones Penguin Studio for a radio drama adaptation in Mandarin. This full-cast dramatisation involves skilled editors, playwrights, and composers, thereby enriching character portrayals and interactions. The professional teamwork and meticulous oversight at each production stage guaranteed regular updates and high audio quality (Shao). Despite the collaborative nature of teamwork, I argue that the power of sound technology personalises the auditory journey as it creates an immersive experience for individual listeners. My analyses mainly rely on research involving actual listeners, along with examinations of specific content within Grandmaster with an idealised listener in consideration, to elucidate the factors contributing to its auditory allure. This examination contributes to a nuanced understanding of Chinese BL culture and its constitutive relationship to audio. From Public Broadcasting to Intimate Voicing: Audio Drama in China Radio broadcasting in China, with roots dating back to the early twentieth century, initially served as a propaganda instrument for mass mobilisation and communication. Chinese storytelling, rooted in acoustics, emphasises the sensory appeal of sound (Chan). It intertwines oral and written traditions in classical literature, particularly fiction and drama (Børdahl). Local vernaculars commonly feature in oral storytelling traditions, whereas Chinese radio programs adopt Mandarin to foster a cohesive national identity via linguistic uniformity. The Communist Party tactically expanded its audience through a radio reception network, establishing a wired broadcasting infrastructure with over 100 million loudspeakers by the 1970s. This revolutionised politics, everyday life, and perceptions of time and space (Li). The interplay between radio and social change reflected China’s pursuit of modernity, as the Communist Party utilised radio to institute a national communication system and monopolise news production. Radio thus served as a crucial tool for constructing and sustaining revolutionary fervor (Lei; He). Radio dramas, often cross-media adaptations from edited films in the 1970s, contributed to everyday sensory pleasure amidst a totalising revolutionary soundscape (Huang). The growth of radio and loudspeaker infrastructure played diverse roles in the revolution, fostering political communication, labour mobilisation, propaganda, surveillance, and even nurturing the Mao cult, turning radio drama into a potent tool for mass mobilisation and communication (Li). As a result, before the widespread availability of televisions in the 1990s, radio structured Chinese people’s daily activities and served as the primary information medium. Technological advancements in earphones, transitioning from larger wired headphones to smaller wireless earbuds like AirPods, have shifted auditory experiences in China from a collective identity tool used in political propaganda to a medium for individualistic entertainment. This change is marked by the personal nature of headphone usage, which can extend social interactions in and beyond physical dimensions (Grusin). The transition from wired headphones to wireless earbuds implements the interiorisation of one person’s body/voice within another, initiating a profound connection that transcends physical limitations (Stankievech). Since 2018, wireless earbuds have exceeded wired headphones in output value in China (Insight and Info), with the online audio market surging to 22 billion yuan in 2021, a 67.9% increase year-on-year. Audiobooks and audio dramas are the most popular genres, with a predominantly female audience under forty who prefer listening at night after work (iimedia). Among audio dramas, BL works generate the most traffic and revenue in China (Y. Wang). Along with such content, putting wireless earbuds inside the ear intensifies the intimacy of listening, transmitting voices directly into the listener’s head and sitting alongside their thoughts (Weldon). This physical closeness underscores the exclusive bond between the listener and the audio content, redefining oral narratives and transforming public and political audio content into a more personal and intimate medium. The use of wireless earbuds even extends listening beyond mere auditory experience, empowering haptic sensations that create an intimate bond. The acousmatic voice envelops the listener’s ears, establishing a connection even before the message’s content is considered (Madsen and Potts). The ear’s sensitivity prompts consciousness and memory, unlocking the imaginative world (C. Wang 91-94). This sensory engagement surpasses traditional auditory limits, resembling a physical encounter where listeners feel like their body has joined with the body of sound. Dermot Rattigan, discussing radio drama, notes how listeners fill the void with mental visualisations and imagination, entering a state of individual ‘virtual reality’ through aural stimulation (Rattigan 118). Drawing from visual psychology, Shaffer likens the soundscape to a dynamic landscape painting, emphasising the fluidity of auditory experiences (Schafer). Listening becomes a multi-dimensional journey involving the entire body and mind, a compelling tool for reception and connection that transcends reality’s boundaries. The advent of MP3 technologies and the podcasting boom also extends the former spatial and temporal limitations of listening. In contrast to traditional real-time broadcasting, MP3 technologies enable voices to persist indefinitely into the future (Madsen and Potts). This temporal flexibility further builds a private sound sphere for listeners (Euritt). Listeners no longer need to share time and space with others around loudspeakers or radios, so they can freely indulge in their subcultural preferences, such as BL stories, without concern for societal judgment. Many listeners strategically incorporate audio dramas into their daily schedule, choosing moments of solitude such as before sleep or upon waking, where they can detach from the expectations of their physical space and identity roles. This is particularly evident among devoted fans of Chinese BL audio dramas, who carve out personal time for these works and seek a quiet space for focussed engagement (Wang 55). This intentional, focussed engagement differs from the typical mode of everyday radio listening as it serves an expanded, widespread dissemination environment that is also highly intimate (Madsen and Potts). Thus, the convergence of temporal flexibility and immersive technology shapes listener engagement and interaction dynamics. The fusion of intimacy, physical closeness, and temporal flexibility heightens the allure of the voice in programs with erotic undertones, such as BL audio dramas. Euritt introduces the concept of ‘breathing out into you’ to explain queer eroticism in podcasts, emphasising shared breaths and potential haptic exchanges that enhance the sensual dimensions of sound (Euritt 27-53). This wireless, intimately riveting auditory experience transforms the soundscape and reshapes contemporary social interactions. This shift is particularly noteworthy for popular Chinese radio and audio content as they began as a public, propaganda-oriented tool and transitioned into forms as novel as the intimate domain of BL audio dramas. This change underscores the transformative power of sound in shaping interactions, surpassing conventional storytelling boundaries, and ushering in a new era of engaging narratives. The 2.5-Dimensional: Auralising Chinese Boys’ Love Fiction The BL genre emerges as a cultural and social force that can potentially challenge traditional Chinese values. Its focus on male-male love inherently questions societal expectations around gender and sexuality in ways that disrupt Confucian ideology’s emphasis on heterosexual marriage and lineage (Welker). Furthermore, the genre’s similarity to the melodramatic ‘soap opera’ storytelling style resonates with Western ideals of individualism and aligns more with a feminist viewpoint that contrasts with the male-dominant heterosexism often found in traditional Chinese narratives (Mumford). This emphasis on individual desires also implicitly disputes the collectivist and socialist values, as well as the importance of the extended family, traditionally embraced in Chinese cultures. In short, the love, sex, and romance depicted in BL represent a departure from traditional Chinese values, positioning the BL genre as a vehicle for cultural exchange and societal transformation in terms of gender norms. The surge of Internet radio and social media in the 2010s has substantially contributed to the professionalisation and commercialisation of Chinese BL audio dramas. MissEvan, a prominent barrage-audio and live-broadcasting Website, has been crucial to this proliferation (Hu et al.). Before the advent of commercial dubbing, enthusiasts of BL novels voluntarily recorded non-profit Chinese audio dramas and disseminated them online. The popularity of BL novels subsequently prompted their adaptation into animation and television dramas, creating a demand for dubbing services. This demand inaugurated a niche for professional voice actors to hone and showcase their skills. The integration of technology and capital by commercial production teams has markedly elevated the quality of Chinese BL audio dramas. Amidst tightening censorship in 2021, Chinese BL online novels and their television/Web-drama adaptations faced restrictions. Audio drama emerged as a less restrictive medium, which can relatively directly present explicit gay relationships (Hu et al.). Listeners of Chinese BL audio dramas typically read the online novel beforehand, engaging in dual consumption for pleasure in both reading and listening (Wang 58). Their engagement transcends plot comprehension, focussing instead on appreciating sophisticated voice performances. Exploring how audio dramas derived from novels can transcend textual narratives and captivate audiences has become a central focus in the production process, highlighting the flourishing landscape of audio drama. The listening process provides informed listeners with a re-experience, offering multiple sensory and emotional pleasures by translating words into voice and sounds. Unlike film and television dubbing, which requires synchronisation with actors’ lip movements and speech rhythms, dubbing for animation, audio dramas, and games gives greater creative autonomy to voice actors. The thriving market for audio dramas has shaped the Chinese dubbing industry, cultivating a devoted fan base for previously overlooked voice actors. The character voices (CVs, also known as voice actors, or VAs) have emerged as central figures, attracting fans and driving media traffic. In the late 2010s, collaborations between MissEvan and renowned CVs resulted in the adaptation of popular online fiction into paid audio dramas, exemplified by Grandmaster, which aired in 2017 and 2018 (Hu et al.). Fans’ motivation for engaging with BL audio dramas extends beyond intertextual and trans-media entertainment but incorporates an appreciation for their beloved CVs, thereby fostering a culture of support within the burgeoning Chinese BL audio drama market. In the storytelling of aural media, CVs are crucial in bridging the auditor’s BL imagination between the text and the characters as their performances breathe life into characters. CVs fill a gap between two-dimensional works (fiction, comic, and animation) and the three-dimensional real world, forging ‘2.5-dimensional’ content. This term originated in the 1970s-80s to describe anime voice actors, who imbue two-dimensional characters with a sense of existence and generate interrelations between the real, fictional, and cyber worlds (Sugawa-Shimada and Annett). In BL audio dramas, CVs commonly stimulate listeners’ sensations through male moans that facilitate an erotic flow between sound and body, arousing desire through the auditory channel. The incorporation of scenes with sexual innuendo between the male protagonists creates a space for listeners to indulge in these moments with earphones on, enveloped in their own private, eroticised sphere of engagement between fiction and reality. The deliberate pauses, gasps, and panting become the silent dialogue that intertwines inner voices with external narratives, enhancing comprehensive sensory engagement for listeners. Audio Fantasy in Grandmaster of Demonic Cultivation Grandmaster is a seminal Chinese BL novel that blends martial arts, supernatural fantasies, and emotional depth. Set in a richly imagined world where immortal cultivation techniques bestow individuals with extraordinary powers, the story follows protagonists Wei Wuxian’s and Lan Wangji’s intertwined fates. Its captivating narrative and nuanced characters have garnered a global fanbase, solidifying its place as a cornerstone of Chinese BL literature and media. The audio drama Grandmaster faithfully mirrors the novel’s narrative structure, unfolding from the protagonist Wei’s perspective after his reincarnation, weaving memories of his past and present life, including his romantic involvement with Lan. Wei’s establishment of the forbidden Demonic Path leads to his death, but he is reincarnated thirteen years later and reunites with Lan. After his reincarnation, Wei gradually realises Lan’s concealed profound affection and scarification for him. Diverging from the television/Web-drama adaptation, which replaces the romance with platonic ‘bromance’ due to censorship (Lei), the audio drama accentuates the impassioned soundscapes of their relationship. The three-season series, comprising episodes of 30-40 minutes, offers the first three episodes for free, with subsequent content requiring payment (approximately four to six dollars per season). Impressively, the series has driven earnings exceeding $1.5 million (Asia Business Leaders). This success highlights the captivating and profitable potential of audio dramas as a BL storytelling medium. Unlike the original novel, which uses an omniscient narrator, the audio drama advances the plot solely through character dialogue. Consequently, listeners navigate the storyline guided by the rhythm of the CVs’ delivery and the accompanying music. Different from Japanese BL audio dramas that feature as ‘voice porn’ for women (Ishida), Grandmaster subtly implies the romance between Lan and Wei, with the most intimate interactions limited to kisses. Rather than sexually explicit content, the drama focusses on the characters’ affective fulfillment after a prolonged thirteen-year anticipation. For instance, in Season 1, Episode 4, Wei attempts to hide his identity and flee from Lan. When Wei creeps back towards Lan’s bed to steal the pass for exiting Lan’s residence, Lan catches him. Rather than simply saying ‘Get off’ as in the novel, Lan instructs Wei in the audio drama to ‘Get off from my body,’ offering listeners additional physical contact cues (the quotes from the novel and audio drama in this article are translations from Chinese to English). Following Wei’s intentional refusal, the CV Wei Chao, portraying Lan, strategically breathes before his next line, ‘then stay like this for the whole night’. The breath conveys Lan’s deep, restrained affection and evokes the listener’s nuanced emotional resonance. To represent Lan’s affection within his minimal and often monosyllabic lines requires the CV to convey emotions through breaths and intonations, which commonly elicit an autonomous sensory meridian response (ASMR) in listeners. ASMR is a tingling sensation often triggered by soft low-tone spoken or whispered voices (Barratt and Davis). Wei Chao intentionally lowers his voice to interpret how Lan’s sighs encapsulate unspoken sentiments (Wei). In contrast, the CV Lu Zhixing employs a playful and sweet tone in his portrayal of Wei Wuxian. When Lu delivers flirtatious lines, online real-time comments frequently express listeners’ admiration, suggesting that his voice is even more captivating than women’s. The contrasting restraint and playfulness intensify the listener’s empathy for Lan’s unspeakable passion. Thus, Lan’s subtle expressions of his restrained love become the primary attraction for listeners (KikuHonda). The high-quality sound further amplifies the breath sounds, making each of Lan’s ‘hmm’ responses—indifferent, melancholy, or indulgent—a nuanced emotional trigger. Listeners, through their wireless earbuds, engage in the meticulously crafted expressions of Lan within a profoundly personal soundscape. This listening mode is a crucial component of the overall enthralling auditory voyage, augmenting the appreciation of the characters’ subdued emotions. The layered integration of music and sound in Grandmaster constructs a three-dimensional sonic storytelling landscape. Effective soundscapes for storytelling are crafted by multiple dimensions: sound source, temporal progression, simultaneous layers, and spatialisation. Sound editing allows for source selection, with listeners experiencing these dimensions as integrated, not separate or sequential (Stedman et al.). The audio drama Grandmaster distinguishes itself from the novel by using voice flashbacks for narrative enhancement. In Season Three, Episode 12, when Lan’s brother recounts Lan’s sacrifice for Wei, particularly the moment when Lan endured severe punishment to save Wei thirteen years ago, the soundscape instantly transports listeners to that intense scene. Listeners vividly hear the swishing force of the whip and its impact, immersing them in the sounds of Lan’s anguish and unwavering love. This direct auditory impact allows listeners to feel as if they are experiencing the events firsthand, physically sensing the hardships encountered by the protagonists in understanding each other’s affection, intensifying their hard-won love. The musical orchestration and vocal interplay are also pivotal to conveying the story. In the storyline, Wei and Lan showcase proficiency in their respective instruments: Wei with the flute and Lan with the guqin (a seven-string Chinese zither). The tonal features of these instruments—the flute’s melodious brightness and the guqin’s deep lingering resonance—symbolise the protagonists’ distinct personalities, adding ingenious layers to their relationship. In the Guanyin Temple scene (Season Three, Episode 13), as Wei confesses to Lan, the initial background music features the flute, guqin, and rain sounds, foreshadowing the confessional moment with Wei’s worries that Lan will not believe his words. As Wei promises to remember Lan’s every word from now on, the music incorporates the guzheng, a Chinese string instrument with a brighter timbre than guqin. The tremolo technique of guzheng is reminiscent of the characters’ heartstring vibrations. Through auditory cues, the narrative climaxes with Wei’s heartfelt confession of love for Lan. When Wei straightforwardly confesses, ‘I fancy you, I love you, I want you, I cannot leave you. … I do not want anyone but you—it cannot be anyone but you’ (Season Three, Episode 13), his heartfelt words are accompanied by layered sounds, including the duet of the flute and guqin, and the sound of thunder and rain, accelerating the affective climax. Lan echoes Wei’s words, underscored by erhu, thereby showing how this string instrument resembles humans’ sobbing voices through its sliding technique, rendering the touching melody. The heartbeat and rain sound with Lan’s panting highlight the painful loneliness of Lan’s thirteen-year wait. The intricate fusion of musical and vocal elements enables listeners to not only hear but also to feel the mutual affection between the characters, culminating in a sense of delight upon the disclosure of their reciprocal love following numerous adventures. Using earbuds amplifies listeners’ capacity to fully receive auditory details and stereo effects, thereby contributing to the popularity of BL audio dramas that skillfully convey unspoken love through detailed soundscapes. Epilogue The Grandmaster audio dramas provide crafted episodes that fulfill fans’ passionate needs that exceed the novel’s scope. In addition to adapting the novel, the team has conceived original mini-dramas that enrich the character images. Listeners can access additional content such as iconic quotes, ringtones, and ‘lullaby’ episodes recorded by the leading CVs, maximising the captivating power of sound and justifying listeners’ investment. The multi-layered use of sounds and instrumental arrangements effectively constructs a three-dimensional soundscape, reinforcing the audience’s understanding of the story and characters. Unlike television/Web-drama adaptations, the audio drama fully amplifies the tragic elements of the novel, pushing the immersed listener’s imagination past textual limitations. While casting choices and modelling in visual adaptions may disappoint viewers’ expectations at times, the audio drama leverages the power of sound to stimulate listeners’ imaginations, encouraging them to visualise their own specific character images. Skillful orchestration, along with sound effects, breaths, and dialogues in Grandmaster intensifies emotional expression, forming a rich and dimensional soundscape and unlocking new possibilities for audio drama artistic expression for Chinese BL fantasy. 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Photo by 187929822 © Victor Moussa | Dreamstime.com INTRODUCTION The nonconsensual taking of a human organ to use in transplantation medicine violates ethical principles, including autonomy, informed consent, and human rights, as well as criminal laws. When such an organ harvesting is not just nonconsensual, but performed in a way that causes a death or uses the pretense of brain death without meeting the criteria, it also violates the dead donor[1] rule.[2] The dead donor rule is both ethical and legal. It prevents organ retrieval that would predictably cause the death of the organ donor.[3] Retrieval of a vital organ is permissible only after a declaration of death.[4] Forced organ harvesting may breach the dead donor rule as it stands. A reimagined, broader dead donor rule could consider a larger timeframe in the forced organ harvesting context. In doing so, the broad dead donor rule could cover intent, premeditation, aiding and abetting, and due diligence failures. A broad definition of forced organ harvesting is ‘‘the removal of one or more organs from a person by means of coercion, abduction, deception, fraud, or abuse of power. . .’’[5] A more targeted definition is “[t]he killing of a person so that their organs may be removed without their free, voluntary and informed consent and transplanted into another person.”[6] In the global organ harvesting context, forced organ harvesting violates the World Health Organization (WHO) Guiding Principle 3, which says “live organ donors should be acting willingly, free of any undue influence or coercion.”[7] Furthermore, WHO states live donors should be “genetically, legally, or emotionally” attached to the recipient. Guiding Principle 1 applies to deceased donors, covers consent, and permits donation absent any known objections by the deceased.[8] Principle 7 says, “Physicians and other health professionals should not engage in transplantation procedures, and health insurers and other payers should not cover such procedures if the cells, tissues or organs concerned have been obtained through exploitation or coercion of, or payment to, the donor or the next of kin of a deceased donor.”[9] There are underground markets in which organ hunters prey on the local poor in countries with low wages and widespread poverty[10] and human trafficking that targets migrants for the purpose of organ harvesting.[11] This paper explores forced harvesting under the backdrop of the dead donor rule, arguing that a human rights violation so egregious requires holding even distant participants in the chain of events accountable. By interfering with resources necessary to carry out bad acts, legislation and corporate and institutional policies can act as powerful deterrents. A broader dead donor rule would highlight the premeditation and intent evidenced well before the act of organ retrieval. I. Background and Evidence In China, there is evidence that people incarcerated for religious beliefs and practices (Falun Gong) and ethnic minorities (Uyghurs) have been subjects of forced organ harvesting. A tribunal (the China Tribunal) found beyond a reasonable doubt that China engaged in forced organ harvesting.[12] Additionally, eight UN Special Rapporteurs found a system of subjecting political prisoners and prisoners of conscience to blood tests and radiological examinations to determine the fitness of their organs.[13] As early as 2006, investigators found evidence of forced organ harvesting from Falun Gong practitioners. [14] Over a million Uyghurs are in custody there, and there is ample evidence of biometric data collection.[15] An Uyghur tribunal found evidence of genocide.[16] “China is the only country in the world to have an industrial-scale organ trafficking practice that harvests organs from executed prisoners of conscience.”[17] Witnesses testified to the removal of organs from live people without ample anesthesia,[18] summonses to the execution grounds for organ removal,[19] methods of causing death for the purpose of organ procurement,[20] removing eyes from prisoners who were alive,[21] and forcing live prisoners into operating rooms.[22] The current extent of executions to harvest organs from prisoners of conscience in China is unknown. The Chinese press has suggested surgeons in China will perform 50,000 organ transplants this year.[23] Doctors Against Forced Organ Harvesting (DAFOR) concluded, “[f]orced organ harvesting from living people has occurred and continues to occur unabated in China.”[24] China continues to advertise in multiple languages to attract transplant tourists.[25] Wait times for organs seem to remain in the weeks.[26] In the United States, it is common to wait three to five years.[27] II. The Nascent System of Voluntary Organ Donation in China In China, throughout the 1990s and early 2000s, the supply of organs for transplant was low, and there was not a national system to register as a donor. A 1984 act permitted death row prisoners to donate organs.[28] In 2005, a Vice Minister acknowledged that 95 percent of all organ transplants used organs from death row prisoners.[29] In 2007 the planning of a voluntary system to harvest organs after cardiac death emerged. According to a Chinese publication, China adopted brain death criteria in 2013.[30] There had been public opposition due partly to cultural unfamiliarity with it.[31] Cultural values about death made it more difficult to adopt a universal brain death definition. Both Buddhist and Confucian beliefs contradicted brain death.[32] Circulatory death was traditionally culturally accepted.[33] The Ministry of Health announced that by 2015 organ harvesting would be purely voluntary and that prisoners would not be the source of organs.[34] There are cultural barriers to voluntary donation partly due to a Confucian belief that bodies return to ancestors intact and other cultural and religious beliefs about respect for the dead.[35] An emphasis on family and community over the individual posed another barrier to the Western approach to organ donation. Public awareness and insufficient healthcare professional knowledge about the process of organ donation are also barriers to voluntary donation.[36] Although the Chinese government claims its current system is voluntary and no longer exploits prisoners,[37] vast evidence contradicts the credibility of the voluntary transplant program in China.[38] III. Dead Donor Rule: A Source of Bioethical Debate It seems tedious to apply this ethical foundation to something as glaring as forced organ harvesting. But the dead donor rule is a widely held recognition that it is not right to kill one person to save another.[39] It acts as a prohibition on killing for the sake of organ retrieval and imposes a technical requirement which influences laws on how death is declared. The dead donor rule prevents organ harvesting that causes death by prohibiting harvesting any organ which the donor agreed to donate only after death prior to an official declaration of death. There is an ongoing ethical debate about the dead donor rule. Many in bioethics and transplant medicine would justify removing organs in specific situations prior to a declaration of death, abandoning the rule.[40] Some use utilitarian arguments to justify causing the death of someone who is unconscious and on life support irreversibly. Journal articles suggest that the discussion has moved to one of timing and organ retrieval.[41] Robert Truog and Franklin Miller are critics of the dead donor rule, arguing that, in practice, it is not strictly obeyed: removing organs while a brain-dead donor is still on mechanical ventilation and has a beating heart and removing organs right after life support is removed and cardio-pulmonary death is declared both might not truly meet the requirement of the dead donor rule, making following the rule “a dubious norm.”[42] Miller and Truog question the concept of brain death, citing evidence of whole body integrated functions that continue indefinitely. They challenge cardio-pulmonary death, asserting that the definition includes as dead, those who could be resuscitated. Their hearts could resume beating with medical intervention. Stopping life support causes death only in those whose lives are sustained by it. Some stipulate that the organ retrieval must not itself cause the death. Some would rejigger the cause of death: Daniel Callahan suggests that the underlying condition causes the death despite removal of life support.[43] But logically, a person could continue life support and be alive, so clearly, removing life support does cause death. Something else would have caused brain death or the circumstance that landed the person on mechanical ventilation. To be more accurate, one could say X caused the irreversible coma and removing life support caused the death itself. Miller and Truog take the position that because withdrawal of life support does cause death, the dead donor rule should be defunct as insincere. To them, retrieving vital organs from a technically alive donor should be permissible under limited conditions. They look to the autonomous choices of the donor or the surrogate (an autonomy-based argument). They appreciate the demand for organs and the ability to save lives, drawing attention to those in need of organs. Live donor organ retrieval arguably presents a slippery slope, especially if a potential donor is close to death, but not so close to label it imminent. They say physicians would not be obligated to follow the orders of a healthy person wishing to have vital organs removed, perhaps to save a close friend or relative. Similarly, Radcliffe-Richards, et al. argue that there is no reason to worry about the slippery slope of people choosing death so they can sell their vital organs, whether for money for their decedents or their creditors.[44] The movement toward permissibility and increased acceptance of medical aid in dying also influence the organ donation arena. The slippery slope toward the end of life has potential to become a realistic concern. Older adults or other people close to death may want to donate a vital organ, like their heart, to a young relative in need. That could greatly influence the timing of a decision to end one’s life. IV. Relating the Dead Donor Rule to Forced Organ Harvesting There is well documented evidence that in China organs have been removed before a declaration of death.[45] But one thing the dead donor rule does not explicitly cover is intent and the period prior to the events leading to death. It tends to apply to a near-death situation and is primarily studied in its relationship to organ donation. It is about death more than it is about life. Robertson and Lavee investigated data on transplantation of vital organs in China and they document cases where the declaration of death was a pretense, insincere, and incorrect. Their aim was to investigate whether the prisoners were in fact dead prior to organ harvesting.[46] (The China Tribunal found that organs have been removed from live prisoners and that organ harvesting has been the cause of death.) They are further concerned with the possible role of doctors as executioners, or at least as complicit in the execution as the organ harvesting so closely follows it. V. A Broader Dead Donor Rule A presumed ethical precursor to the dead donor rule may also be an important ethical extension of the rule: the dead donor rule must also prohibit killing a person who is not otherwise near death for the purpose of post-death organ harvesting. In China, extra-judicial killings of prisoners of conscience are premeditated ― there is ample evidence of blood tests and radiology to ensure organ compatibility and health.[47] To have effective ethical force, the dead donor rule should have an obvious application in preventing intentional killing for an organ retrieval, not just killing by way of organ retrieval. When we picture the dead donor rule, bioethicists tend to envision a person on life support who will either be taken off it and stop breathing or who will be declared brain dead. But the dead donor rule should apply to healthy people subject to persecution at the point when the perpetrator lays the ground for the later killing. At that point, many organizations and people may be complicit or unknowingly contributing to forced organ harvesting. In this iteration of the dead donor rule, complicity in its violations would be widespread. The dead donor rule could address the initial action of ordering a blood or radiology test or collecting any biometric data. Trained physicians and healthcare technicians perform such tests. Under my proposed stretch of the dead donor rule, they too would be complicit in the very early steps that eventually lead to killing a person for their organs. I argue these steps are part of forced organ harvesting and violate the dead donor rule. The donor is very much alive in the months and years preceding the killing. A conspiracy of indifference toward life, religious persecution, ethnic discrimination, a desire to expand organ transplant tourism, and intent to kill can violate this broader dead donor rule. The dead donor rule does not usually apply to the timing of the thought of organ removal, nor the beginning of the chain of events that leads to it. It is usually saved for the very detailed determination of what may count as death so that physicians may remove vital and other organs, with the consent of the donor.[48] But I argue that declaring death at the time of retrieval may not be enough. Contributing to the death, even by actions months or years in advance, matter too. Perhaps being on the deathbed awaiting a certain death must be distinguished from going about one’s business only to wind up a victim of forced organ harvesting. Both may well be declared dead before organ retrieval, but the likeness stops there. The person targeted for future organ retrieval to satisfy a growing transplant tourism business or local demand is unlike the altruistic person on his deathbed. While it may seem like the dead donor rule is merely a bioethics rule, it does inform the law. And it has ethical heft. It may be worth expanding it to the arena of human trafficking for the sake of organ removal and forced organ harvesting.[49] The dead donor rule is really meant to ensure that death was properly declared to protect life, something that must be protected from an earlier point. VI. Complicity: Meaning and Application Human rights due diligence refers to actions that people or institutions must take to ensure they are not contributing to a human rights violation. To advise on how to mitigate risk of involvement or contribution to human rights violations, Global Rights Compliance published an advisory that describes human rights due diligence as “[t]he proactive conduct of a medical institution and transplant-associated entity to identify and manage human rights risks and adverse human rights impacts along their entire value and supply chain.”[50] Many people and organizations enable forced organ harvesting. They may be unwittingly complicit or knowingly aiding and abetting criminal activity. For example, some suppliers of medical equipment and immunosuppressants may inadvertently contribute to human rights abuses in transplantation in China, or in other countries where organs were harvested without consent, under duress, or during human trafficking. According to Global Rights Compliance, “China in the first half of 2021 alone imported ‘a total value of about 24 billion U.S. dollars’ worth of medical technology equipment’, with the United States and Germany among the top import sources.”[51] The companies supplying the equipment may be able to slow or stop the harm by failing to supply necessary equipment and drugs. Internal due diligence policies would help companies analyze their suppliers and purchasers. Corporations, educational institutions, and other entities in the transplantation supply chain, medical education, insurance, or publishing must engage in human rights due diligence. The Global Rights Compliance advisory suggests that journals should not include any ill-gotten research. Laws should regulate corporations and target the supply chain also. All actors in the chain of supply, etc. are leading to the death of the nonconsenting victim. They are doing so while the victim is alive. The Stop Forced Organ Harvesting Act of 2023, pending in the United States, would hold any person or entity that “funds, sponsors, or otherwise facilitates forced organ harvesting or trafficking in persons for purposes of the removal of organs” responsible. The pending legislation states that: It shall be the policy of the United States—(1) to combat international trafficking in persons for purposes of the removal of organs;(2) to promote the establishment of voluntary organ donation systems with effective enforcement mechanisms in bilateral diplomatic meetings and in international health forums;(3) to promote the dignity and security of human life in accordance with the Universal Declaration of Human Rights, adopted on December 10, 1948; and(4) to hold accountable persons implicated, including members of the Chinese Communist Party, in forced organ harvesting and trafficking in persons for purposes of the removal of organs.[52] The Act calls on the President to provide Congress a list of such people or entities and to sanction them by property blocking, and, in the case of non-US citizens, passport and visa denial or revocation. The Act includes a reporting requirement under the Foreign Assistance Act of 1961 that includes an assessment of entities engaged in or supporting forced organ harvesting.[53] The law may have a meaningful impact on forced organ harvesting. Other countries have taken or are in the process of legal approaches as well.[54] Countries should consider legislation to prevent transplant tourism, criminalize complicity, and require human rights due diligence. An expanded dead donor rule supports legal and policy remedies to prevent enabling people to carry out forced organ harvesting. VII. Do Bioethicists Mention Human Rights Abuses and Forced Organ Harvesting Enough? As a field, bioethics literature often focuses on the need for more organs, the pain and suffering of those on organ transplant waitlists, and fairness in allocating organs or deciding who belongs on which waitlist and why. However, some bioethicists have drawn attention to forced organ harvesting in China. Notably, several articles noted the ethical breaches and called on academic journals to turn away articles on transplantation from China as they are based on the unethical practice of executing prisoners of conscience for their organs.[55] The call for such a boycott was originally published in a Lancet article in 2011.[56] There is some acknowledgement that China cares about how other countries perceive it,[57] which could lead to either improvements in human rights or cover-ups of violations. Ill-gotten research has long been in the bioethics purview with significant commentary on abuses in Tuskegee and the Holocaust.[58] Human research subjects are protected by the Declaration of Helsinki, which requires acting in the best interests of research subjects and informed consent among other protections.[59] The Declaration of Helsinki is directed at physicians and requires subjects enroll in medical research voluntarily. The Declaration does not explicitly cover other healthcare professionals, but its requirements are well accepted broadly in health care. CONCLUSION The dead donor rule in its current form really does not cover the life of a non-injured healthy person at an earlier point. If it could be reimagined, we could highlight the link between persecution for being a member of a group like Falun Gong practitioners or Uyghurs as the start of the process that leads to a nonconsensual organ retrieval whether after a proper declaration of death or not. It is obviously not ethically enough to ensure an execution is complete before the organs are harvested. It is abuse of the dead donor rule to have such a circumstance meet its ethical requirement. And obviously killing people for their beliefs or ethnicity (and extra-judicial killings generally) is not an ethically acceptable action for many reasons. The deaths are intentionally orchestrated, but people and companies who may have no knowledge of their role or the role of physicians they train or equipment they sell are enablers. An expanded dead donor rule helps highlight a longer timeframe and expanded scope of complicity. The organ perfusion equipment or pharmaceuticals manufactured in the United States today must not end up enabling forced organ harvesting. With an expanded ethical rule, the “donor is not dead” may become “the donor would not be dead if not for. . .” the host of illegal acts, arrests without cause, forced detention in labor camps, extra-judicial killings, lacking human rights due diligence, and inattention to this important topic. The expanded dead donor rule may also appeal to the bioethics community and justify more attention to laws and policies like the Stop Forced Organ Harvesting Act of 2023. - [1] The word “donor” in this paper describes any person from whom organs are retrieved regardless of compensation, force, or exploitation in keeping with the bioethics literature and the phrase “dead donor rule.” [2] Robertson, M.P., Lavee J. (2022). Execution by organ procurement: Breaching the dead donor rule in China. Am J Transplant, Vol.22,1804– 1812. doi:10.1111/ajt.16969. [3] Robertson, J. A. (1999). Delimiting the donor: the dead donor rule. Hastings Center Report, 29(6), 6-14. [4] Retrieval of non-vital organs which the donor consents to donate post-death (whether opt-in, opt-out, presumed, or explicit according to local law) also trigger the dead donor rule. [5] The Stop Forced Organ Harvesting Act of 2023, H.R. 1154, 118th Congress (2023), https://www.congress.gov/bill/118th-congress/house-bill/1154. [6] Do No Harm: Mitigating Human Rights Risks when Interacting with International Medical Institutions & Professionals in Transplantation Medicine, Global Rights Compliance, Legal Advisory Report, April 2022, https://globalrightscompliance.com/project/do-no-harm-policy-guidance-and-legal-advisory-report/. [7] WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation, as endorsed by the sixty-third World Health Assembly in May 2010, in Resolution WHA63.22 https://apps.who.int/iris/bitstream/handle/10665/341814/WHO-HTP-EHT-CPR-2010.01-eng.pdf?sequence=1. [8] WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation (2010). [9] WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation (2010). [10] Promchertchoo, Pichayada (Oct. 19, 2019). Kidney for sale: Inside Philippines’ illegal organ trade. https://www.channelnewsasia.com/asia/kidney-for-sale-philippines-illegal-organ-trade-857551; Widodo, W. and Wiwik Utami (2021), The Causes of Indonesian People Selling Covered Kidneys from a Criminology and Economic Perspective: Analysis Based on Rational Choice Theory. European Journal of Political Science Studies, Vol 5, Issue 1. [11] Van Reisen, M., & Mawere, M. (Eds.). (2017). Human trafficking and trauma in the digital era: The ongoing tragedy of the trade in refugees from Eritrea. African Books Collective. [12] The Independent Tribunal into Forced Organ Harvesting from Prisoners of Conscience in China (China Tribunal) (2020). https://chinatribunal.com/wp-content/uploads/2020/03/ChinaTribunal_JUDGMENT_1stMarch_2020.pdf [13] UN Office of the High Commissioner, Press Release, China: UN human Rights experts alarmed by ‘organ harvesting’ allegations (UN OTHCHR, 14 June 2021), https://www.ohchr.org/en/press-releases/2021/06/china-un-human-rights-experts-alarmed-organ-harvesting-allegations. [14] David Matas and David Kilgour, Bloody Harvest. The killing of Falun Gong for their organs (Seraphim Editions 2009). [15] How China is crushing the Uyghurs, The Economist, video documentary, July 9, 2019, https://youtu.be/GRBcP5BrffI. [16] Uyghur Tribunal, Judgment (9 December 2021) (Uyghur Tribunal Judgment) para 1, https://uyghurtribunal.com/wp-content/uploads/2022/01/Uyghur-Tribunal-Judgment-9th-Dec-21.pdf. [17] Ali Iqbal and Aliya Khan, Killing prisoners for transplants: Forced organ harvesting in China, The Conversation Published: July 28, 2022. https://theconversation.com/killing-prisoners-for-transplants-forced-organ-harvesting-in-china-161999 [18] Testimony demonstrated surgeries to remove vital organs from live people, killing them, sometimes without ample anesthesia to prevent wakefulness and pain. China Tribunal (2020), p. 416-417. https://chinatribunal.com/wp-content/uploads/2020/03/ChinaTribunal_JUDGMENT_1stMarch_2020.pdf; Robertson MP, Lavee J. (2022), Execution by organ procurement: Breaching the dead donor rule in China. Am J Transplant, Vol.22,1804– 1812. doi:10.1111/ajt.16969. [19] Doctors reported being summoned to execution grounds and told to harvest organs amid uncertainty that the prisoner was in fact dead. China Tribunal (2020), p. 52-53. [20]In testimony to the China Tribunal, Dr. Huige Li noted four methods of organ harvesting from live prisoners: incomplete execution by shooting, after lethal injection prior to death, execution by removal of the heart, and after a determination of brain death prior to an intubation (pretense of brain death). China Tribunal (2020), pp. 54-55. https://chinatribunal.com/wp-content/uploads/2020/03/ChinaTribunal_JUDGMENT_1stMarch_2020.pdf [21] A former military medical student described removing organs from a live prisoner in the late 1990s. He further described his inability to remove the eyes of a live man and his witnessing another doctor forcefully remove the man’s eyes. China Tribunal (2020), p. 330. [22] In 2006, a nurse testified that her ex-husband, a surgeon, removed the eyes of 2,000 Falun Gong practitioners in one hospital between 2001 and 2003. She described the Falun Gong labor-camp prisoners as being forced into operating rooms where they were given a shot to stop their hearts. Other doctors removed other organs. DAFOH Special Report, 2022. https://epochpage.com/wp-content/uploads/sites/3/2022/12/DAFOH-Special-Report-2022.pdf [23] Robertson MP, Lavee J. (2022), Execution by organ procurement: Breaching the dead donor rule in China. Am J Transplant, Vol.22,1804– 1812. doi:10.1111/ajt.16969. [24] DAFOH Special Report, 2022. https://epochpage.com/wp-content/uploads/sites/3/2022/12/DAFOH-Special-Report-2022.pdf; DAFOH’s physicians were nominated for a Nobel Prize for their work to stop forced organ harvesting. Šućur, A., & Gajović, S. (2016). Nobel Peace Prize nomination for Doctors Against Forced Organ Harvesting (DAFOH) - a recognition of upholding ethical practices in medicine. Croatian medical journal, 57(3), 219–222. https://doi.org/10.3325/cmj.2016.57.219 [25] Robertson and Lavee (2022). [26] Stop Organ Harvesting in China, website (organization of the Falun Dafa). https://www.stoporganharvesting.org/short-waiting-times/ [27] National Kidney Foundation, The Kidney Transplant Waitlist – What You Need to Know, https://www.kidney.org/atoz/content/transplant-waitlist [28] Wu, Y., Elliott, R., Li, L., Yang, T., Bai, Y., & Ma, W. (2018). Cadaveric organ donation in China: a crossroads for ethics and sociocultural factors. Medicine, 97(10). [29] Wu, Elliott, et al., (2018). [30] Su, Y. Y., Chen, W. B., Liu, G., Fan, L. L., Zhang, Y., Ye, H., ... & Jiang, M. D. (2018). An investigation and suggestions for the improvement of brain death determination in China. Chinese Medical Journal, 131(24), 2910-2914. [31] Huang, J., Millis, J. M., Mao, Y., Millis, M. A., Sang, X., & Zhong, S. (2012). A pilot programme of organ donation after cardiac death in China. The Lancet, 379(9818), 862-865. [32] Yang, Q., & Miller, G. (2015). East–west differences in perception of brain death: Review of history, current understandings, and directions for future research. Journal of bioethical inquiry, 12, 211-225. [33] Huang, J., Millis, J. M., Mao, Y., Millis, M. A., Sang, X., & Zhong, S. (2015). Voluntary organ donation system adapted to Chinese cultural values and social reality. Liver Transplantation, 21(4), 419-422. [34] Huang, Millis, et al. (2015). [35] Wu, X., & Fang, Q. (2013). Financial compensation for deceased organ donation in China. Journal of Medical Ethics, 39(6), 378-379. [36] An, N., Shi, Y., Jiang, Y., & Zhao, L. (2016). Organ donation in China: the major progress and the continuing problem. Journal of biomedical research, 30(2), 81. [37] Shi, B. Y., Liu, Z. J., & Yu, T. (2020). Development of the organ donation and transplantation system in China. Chinese medical journal, 133(07), 760-765. [38] Robertson, M. P., Hinde, R. L., & Lavee, J. (2019). Analysis of official deceased organ donation data casts doubt on the credibility of China’s organ transplant reform. BMC Medical Ethics, 20(1), 1-20. [39] Miller, F.G. and Sade, R. M. (2014). Consequences of the Dead Donor Rule. The Annals of thoracic surgery, 97(4), 1131–1132. https://doi.org/10.1016/j.athoracsur.2014.01.003 [40] For example, Miller and Sade (2014) and Miller and Truog (2008). [41] Omelianchuk, A. How (not) to think of the ‘dead-donor’ rule. Theor Med Bioeth 39, 1–25 (2018). https://doi-org.ezproxy.cul.columbia.edu/10.1007/s11017-018-9432-5 [42] Miller, F.G. and Truog, R.D. (2008), Rethinking the Ethics of Vital Organ Donations. Hastings Center Report. 38: 38-46. [43] Miller and Truog, (2008), p. 40, citing Callahan, D., The Troubled Dream of Life, p. 77. [44] Radcliffe-Richards, J., Daar, A.S., Guttman, R.D., Hoffenberg, R., Kennedy, I., Lock, M., Sells, R.A., Tilney, N. (1998), The Case for Allowing Kidney Sales, The Lancet, Vol 351, p. 279. (Authored by members of the International Forum for Transplant Ethics.) [45] Robertson and Lavee, (2022). [46] Robertson and Lavee, (2022). [47] China Tribunal (2020). [48] Consent varies by local law and may be explicit or presumed and use an opt-in or opt-out system and may or may not require the signoff by a close family member. [49] Bain, Christina, Mari, Joseph. June 26, 2018, Organ Trafficking: The Unseen Form of Human Trafficking, ACAMS Today, https://www.acamstoday.org/organ-trafficking-the-unseen-form-of-human-trafficking/; Stammers, T. (2022), "2: Organ trafficking: a neglected aspect of modern slavery", Modern Slavery and Human Trafficking, Bristol, UK: Policy Press. https://bristoluniversitypressdigital.com/view/book/978144736. [50] Do No Harm: Mitigating Human Rights Risks when Interacting with International Medical Institutions & Professionals in Transplantation Medicine, Global Rights Compliance, Legal Advisory Report, April 2022, https://globalrightscompliance.com/project/do-no-harm-policy-guidance-and-legal-advisory-report/. [51] Global Rights Compliance, p. 22. [52] The Stop Forced Organ Harvesting Act of 2023, H.R. 1154, 118th Congress (2023). https://www.congress.gov/bill/118th-congress/house-bill/1154. [53] The Stop Forced Organ Harvesting Act of 2023, H.R. 1154, 118th Congress (2023), https://www.congress.gov/bill/118th-congress/house-bill/1154. [54] Global Rights Compliance notes that Belgium, France (passed law on human rights due diligence in the value supply chain), United Kingdom, United States, Canada, Australia, and New Zealand have legal approaches, resolutions, and pending laws. p. 45. [55] For example, Caplan, A.L. (2020), The ethics of the unmentionable Journal of Medical Ethics 2020;46:687-688. [56] Caplan, A.L. , Danovitch, G., Shapiro M., et al. (2011) Time for a boycott of Chinese science and medicine pertaining to organ transplantation. Lancet, 378(9798):1218. doi:10.1016/S0140-6736(11)61536-5 [57] Robertson and Lavee. [58] Smolin, D. M. (2011). The Tuskegee syphilis experiment, social change, and the future of bioethics. Faulkner L. Rev., 3, 229; Gallin, S., & Bedzow, I. (2020). Holocaust as an inflection point in the development of bioethics and research ethics. Handbook of research ethics and scientific integrity, 1071-1090. [59] World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects, adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended multiple times, most recently by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/

Introduction Films with deaf characters often do not focus on the condition of deafness at all. Rather, the characters seem to satisfy a role in the story that either furthers the plot or the audience’s understanding of other hearing characters. The deaf characters can be symbolic, for example as a metaphor for isolation representative of ‘those without a voice’ in a society. The deaf characters’ misunderstanding of auditory cues can lead to comic circumstances, and their knowledge can save them in the case of perilous ones. Sign language, because of its unique linguistic properties and its lack of comprehension by hearing people, can save the day in a story line. Deaf characters are shown in different eras and in different countries, providing a fictional window into their possible experiences. Films shape and reflect cultural attitudes and can serve as a potent force in influencing the attitudes and assumptions of those members of the hearing world who have had few, if any, encounters with deaf people. This article explores categories of literary function as identified by the author, providing examples and suggestions of other films for readers to explore. Searching for Deaf Characters in Film I am a sign language interpreter. Several years ago, I started noticing how deaf characters are used in films. I made a concerted effort to find as many as I could. I referred to John Shuchman’s exhaustive book about deaf actors and subject matter, Hollywood Speaks; I scouted video rental guides (key words were ‘deaf’ or ‘disabled’); and I also plugged in the key words ‘deaf in film’ on Google’s search engine. I decided to ignore the issue of whether or not the actors were actually deaf—a political hot potato in the Deaf community which has been discussed extensively. Similarly, the linguistic or cultural accuracy of the type of sign language used or super-human lip-reading talent did not concern me. What was I looking for? I noticed that few story lines involving deaf characters provide any discussion or plot information related to that character’s deafness. I was puzzled. Why is there signing in the elevator in Jerry Maguire? Why does the guy in Grand Canyon have a deaf daughter? Why would the psychosomatic response to a trauma—as in Psych Out—be deafness rather than blindness? I concluded that not being able to hear carried some special meaning or fulfilled a particular need intrinsic to the plot of the story. I also observed that the functions of deaf characters seem to fall into several categories. Some deaf characters fit into more than one category, serving two or more symbolic purposes at the same time. By viewing and analysing the representations of deafness and deaf characters in forty-six films, I have come up with the following classifications: Deafness as a plot device Deaf characters as protagonist informants Deaf characters as a parallel to the protagonist Sign language as ‘hero’ Stories about deaf/hearing relationships A-normal-guy-or-gal-who-just-happens-to-be-deaf Deafness as a psychosomatic response to trauma Deafness as metaphor Deafness as a symbolic commentary on society Let your fingers do the ‘talking’ Deafness as Plot Device Every element of a film is a device, but when the plot hinges on one character being deaf, the story succeeds because of that particular character having that particular condition. The limitations or advantages of a deaf person functioning within the hearing world establish the tension, the comedy, or the events which create the story. In Hear No Evil (1993), Jillian learns from her hearing boyfriend which mechanical devices cause ear-splitting noises (he has insomnia and every morning she accidentally wakes him in very loud ways, eg., she burns the toast, thus setting off the smoke detector; she drops a metal spoon down the garbage disposal unit). When she is pursued by a murderer she uses a fire alarm, an alarm/sprinkler system, and a stereo turned on full blast to mask the sounds of her movements as she attempts to hide. Jillian and her boyfriend survive, she learns about sound, her boyfriend learns about deafness, and she teaches him the sign for orgasm. Life is good! The potential comic aspects of deafness may seem in this day and age to be shockingly politically incorrect. While the slapstick aspect is often innocent and means no overt harm or insult to the Deaf as a population, deafness functions as the visual banana peel over which the characters figuratively stumble in the plot. The film, See No Evil, Hear No Evil (1989), pairing Gene Wilder with Richard Pryor as deaf and blind respectively, is a constant sight gag of lip-reading miscues and lack-of-sight gags. Wilder can speak, and is able to speech read almost perfectly, almost all of the time (a stereotype often perpetuated in films). It is mind-boggling to imagine the detail of the choreography required for the two actors to convince the audience of their authenticity. Other films in this category include: Suspect It’s a Wonderful Life Murder by Death Huck Finn One Flew over the Cuckoo’s NestThe Shop on Main StreetRead My Lips The Quiet Deaf Characters as Protagonist Informants Often a deaf character’s primary function to the story is to give the audience more information about, or form more of an affinity with, the hearing protagonist. The deaf character may be fascinating in his or her own right, but generally the deafness is a marginal point of interest. Audience attitudes about the hearing characters are affected because of their previous or present involvement with deaf individuals. This representation of deafness seems to provide a window into audience understanding and appreciation of the protagonist. More inferences can be made about the hearing person and provides one possible explanation for what ensues. It is a subtle, almost subliminal trick. There are several effective examples of this approach. In Gas, Food, Lodging (1992), Shade discovers that tough-guy Javier’s mother is deaf. He introduces Shade to his mother by simple signs and finger-spelling. They all proceed to visit and dance together (mom feels the vibrations on the floor). The audience is drawn to feel ‘Wow! Javier is a sensitive kid who has grown up with a beautiful, exotic, deaf mother!’ The 1977 film, Looking for Mr. Goodbar presents film-goers with Theresa, a confused young woman living a double life. By day, she is a teacher of deaf children. Her professor in the Teacher of the Deaf program even likens their vocation to ‘touching God’. But by night she cruises bars and engages in promiscuous sexual activity. The film shows how her fledgling use of signs begins to express her innermost desires, as well as her ability to communicate and reach out to her students. Other films in this category include: Miracle on 34th Street (1994 version)Nashville (1975, dir. Robert Altman)The Family StoneGrand CanyonThere Will Be Blood Deaf Characters as a Parallel to the Protagonist I Don’t Want to Talk about It (1993) from Argentina, uses a deaf character to establish an implied parallel story line to the main hearing character. Charlotte, a dwarf, is friends with Reanalde, who is deaf. The audience sees them in the first moments of the film when they are little girls together. Reanalde’s mother attempts to commiserate with Charlotte’s mother, establishing a simultaneous but unseen story line somewhere else in town over the course of the story. The setting is Argentina during the 1930s, and the viewer can assume that disability awareness is fairly minimal at the time. Without having seen Charlotte’s deaf counterpart, the audience still knows that her story has contained similar struggles for ‘normalcy’ and acceptance. Near the conclusion of the film, there is one more glimpse of Reanalde, when she catches the bridal bouquet at Charlotte’s wedding. While having been privy to Charlotte’s experiences all along, we can only conjecture as to what Reanalde’s life has been. Sign Language as ‘Hero’ The power of language, and one’s calculated use of language as a means of escape from a potentially deadly situation, is shown in The River Wild (1996). The reason that any of the hearing characters knows sign language is that Gail, the protagonist, has a deaf father. Victor appears primarily to allow the audience to see his daughter and grandson sign with him. The mother, father, and son are able to communicate surreptitiously and get themselves out of a dangerous predicament. Signing takes an iconic form when the signs BOAT, LEFT, I-LOVE-YOU are drawn on a log suspended over the river as a message to Gail so that she knows where to steer the boat, and that her husband is still alive. The unique nature of sign language saves the day– silently and subtly produced, right under the bad guys’ noses! Stories about Deaf/Hearing Relationships Because of increased awareness and acceptance of deafness, it may be tempting to assume that growing up deaf or having any kind of relationship with a deaf individual may not pose too much of a challenge. Captioning and subtitling are ubiquitous in the USA now, as is the inclusion of interpreters on stages at public events. Since the inception of USA Public Law 94-142 and section 504 in 1974, more deaf children are ‘mainstreamed’ into public schools than ever before. The Americans with Disabilities Act was passed in 1993, opening the doors in the US for more access, more job opportunities, more inclusion. These are the external manifestations of acceptance that most viewers with no personal exposure to deafness may see in the public domain. The nuts and bolts of growing up deaf, navigating through opposing philosophical theories regarding deaf education, and dealing with parents, siblings, and peers who can’t communicate, all serve to form foundational experiences which an audience rarely witnesses. Children of a Lesser God (1986), uses the character of James Leeds to provide simultaneous voiced translations of the deaf student Sarah’s comments. The audience is ushered into the world of disparate philosophies of deaf education, a controversy of which general audiences may not have been previously unaware. At the core of James and Sarah’s struggle is his inability to accept that she is complete as she is, as a signing not speaking deaf person. Whether a full reconciliation is possible remains to be seen. The esteemed teacher of the deaf must allow himself to be taught by the deaf. Other films in this category include: Johnny Belinda (1949, 1982)Mr. Holland’s OpusBeyond SilenceThe Good ShepherdCompensation A Normal Guy-or-Gal-Who-Just-Happens-to-Be-Deaf The greatest measure of equality is to be accepted on one's own merits, with no special attention to differences or deviations from whatever is deemed ‘the norm.’ In this category, the audience sees the seemingly incidental inclusion of a deaf or hearing-impaired person in the casting. A sleeper movie titled Crazy Moon (1986) is an effective example. Brooks is a shy, eccentric young hearing man who needs who needs to change his life. Vanessa is deaf and works as a clerk in a shop while takes speech lessons. She possesses a joie de vivre that Brooks admires and wishes to emulate. When comparing the way they interact with the world, it is apparent that Brooks is the one who is handicapped. Other films in this category include: Sympathy for Mr. Vengeance (South Korea, 1992)Liar, LiarRequiem for a DreamKung Fu HustleBangkok DangerousThe Family StoneDeafness as a Psychosomatic Response to Trauma Literature about psychosomatic illnesses enumerates many disconcerting and disruptive physiological responses. However, rarely is there a PTSD response as profound as complete blockage of one of the five senses, ie; becoming deaf as a result of a traumatic incident. But it makes great copy, and provides a convenient explanation as to why an actor needn't learn sign language! The rock group The Who recorded Tommy in 1968, inaugurating an exciting and groundbreaking new musical genre – the rock opera. The film adaptation, directed by Ken Russell, was released in 1975. In an ironic twist for a rock extravaganza, the hero of the story is a ‘deaf, dumb, and blind kid.’ Tommy Johnson becomes deaf when he witnesses the murder of his father at the hands of his step-father and complicit mother. From that moment on, he is deaf and blind. When he grows up, he establishes a cult religion of inner vision and self-discovery. Another film in this category is Psych Out. Deafness as a Metaphor Hearing loss does not necessarily mean complete deafness and/or lack of vocalization. Yet, the general public tends to assume that there is utter silence, complete muteness, and the inability to verbalize anything at all. These assumptions provide a rich breeding ground for a deaf character to personify isolation, disenfranchisement, and/or avoidance of the harsher side of life. The deafness of a character can also serve as a hearing character’s nemesis. Mr. Holland’s Opus (1995) chronicles much of the adult life of a beleaguered man named Glenn Holland whose fondest dream is to compose a grand piece of orchestral music. To make ends meet he must teach band and orchestra to apparently disinterested and often untalented students in a public school. His golden son (named Cole, in honor of the jazz great John Coltrane) is discovered to be deaf. Glenn’s music can’t be born, and now his son is born without music. He will never be able to share his passion with his child. He learns just a little bit of sign, is dismissive of the boy’s dreams, and drifts further away from his family to settle into a puddle of bitterness, regrets, and unfulfilled desires. John Lennon’s death provides the catalyst for Cole’s confrontation with Glenn, forcing the father to understand that the gulf between them is an artificial one, perpetuated by the unwillingness to try. Any other disability could not have had the same effect in this story. Other films in this category include: Ramblin’ RoseBabelThe Heart Is a Lonely HunterA Code Unkown Deafness as a Symbolic Commentary on Society Sometimes films show deafness in a different country, during another era, and audiences receive a fictionalized representation of what life might have been like before these more enlightened times. The inability to hear and/or speak can also represent the more generalized powerlessness that a culture or a society’s disenfranchised experience. The Chinese masterpiece To Live (1994) provides historical and political reasons for Fenxi’s deafness—her father was a political prisoner whose prolonged absence brought hardship and untended illness. Later, the chaotic political situation which resulted in a lack of qualified doctors led to her death. In between these scenes the audience sees how her parents arrange a marriage with another ‘handicapped’ comrade of the town. Those citizens deemed to be crippled or outcast have different overt rights and treatment. The 1996 film Illtown presents the character of a very young teenage boy to represent the powerlessness of youth in America. David has absolutely no say in where he can live, with whom he can live, and the decisions made all around him. When he is apprehended after a stolen car chase, his frustration at his and all of his generation’s predicament in the face of a crumbling world is pounded out on the steering wheel as the police cars circle him. He is caged, and without the ability to communicate. Were he to have a voice, the overall sense of the film and his situation is that he would be misunderstood anyway. Other films in this category include: Stille Liebe (Germany)RidiculeIn the Company of Men Let Your Fingers Do the ‘Talking’ I use this heading to describe films where sign language is used by a deaf character to express something that a main hearing character can’t (or won’t) self-generate. It is a clever device which employs a silent language to create a communication symbiosis: Someone asks a hearing person who knows sign what that deaf person just said, and the hearing person must voice what he or she truly feels, and yet is unable to express voluntarily. The deaf person is capable of expressing the feeling, but must rely upon the hearing person to disseminate the message. And so, the words do emanate from the mouth of the person who means them, albeit self-consciously, unwillingly. Jerry Maguire (1996) provides a signed foreshadowing of character metamorphosis and development, which is then voiced for the hearing audience. Jerry and Dorothy have just met, resigned from their jobs in solidarity and rebellion, and then step into an elevator to begin a new phase of their lives. Their body language identifies them as separate, disconnected, and heavily emotionally fortified. An amorous deaf couple enters the elevator and Dorothy translates the deaf man’s signs as, ‘You complete me.’ The sentiment is strong and a glaring contrast to Jerry and Dorothy’s present dynamic. In the end, Jerry repeats this exact phrase to her, and means it with all his heart. We are all made aware of just how far they have traveled emotionally. They have become the couple in the elevator. Other films in this category include: Four Weddings and a FuneralKnowing Conclusion This has been a cursory glance at examining the narrative raison d’etre for the presence of a deaf character in story lines where no discussion of deafness is articulated. A film’s plot may necessitate hearing-impairment or deafness to successfully execute certain gimmickry, provide a sense of danger, or relational tension. The underlying themes and motifs may revolve around loneliness, alienation, or outwardly imposed solitude. The character may have a subconscious desire to literally shut out the world of sound. The properties of sign language itself can be exploited for subtle, undetectable conversations to assure the safety of hearing characters. Deaf people have lived during all times, in all places, and historical films can portray a slice of what their lives may have been like. I hope readers will become more aware of deaf characters on the screen, and formulate more theories as to where they fit in the literary/narrative schema. ReferencesMaltin, Leonard. Leonard Maltin’s 2009 Movie Guide. Penguin Group, 2008.Shuchman, John S. Hollywood Speaks. Urbana and Chicago: University of Illinois Press, 1988. Filmography Babel. Dir. Alejandro Gonzalez Inarritu. Central Films, 2006. DVD. Bangkok Dangerous. Dir. Pang Brothers. Film Bangkok, 1999. VHS. Beyond Silence. Dir. Caroline Link. Miramax Films, 1998. DVD. Children of a Lesser God. Dir. Randa Haines. Paramount Pictures, 1985. DVD. A Code Unknown. Dir. Michael Heneke. MK2 Editions, 2000. DVD. Compensation. Dir. Zeinabu Irene Davis. Wimmin with a Mission Productions, 1999. VHS. Crazy Moon. Dir. Allan Eastman. Allegro Films, 1987. VHS. The Family Stone. Dir. Mike Bezucha. 20th Century Fox, 2005. DVD. Four Weddings and a Funeral. Dir. Mike Newell. Polygram Film Entertainment, 1994. DVD. Gas, Food, Lodging. Dir. Allison Anders. IRS Media, 1992. DVD. The Good Shepherd. Dir. Robert De Niro. Morgan Creek, TriBeCa Productions, American Zoetrope, 2006. DVD. Grand Canyon. Dir. Lawrence Kasdan, Meg Kasdan. 20th Century Fox, 1991. DVD. Hear No Evil. Dir. Robert Greenwald. 20th Century Fox, 1993. DVD. The Heart Is a Lonely Hunter. Dir. Robert Ellis Miller. Warner Brothers, 1968. DVD. Huck Finn. Stephen Sommers. Walt Disney Pictures, 1993. VHS. I Don’t Want to Talk about It. Dir. Maria Luisa Bemberg. Mojame Productions, 1994. DVD. Knowing. Dir. Alex Proyas. Escape Artists, 2009. DVD. Illtown. Dir. Nick Gomez. 1998. VHS. In the Company of Men. Dir. Neil LaBute. Alliance Atlantis Communications,1997. DVD. It’s a Wonderful Life. Dir. Frank Capra. RKO Pictures, 1947. DVD. Jerry Maguire. Dir. Cameron Crowe. TriSTar Pictures, 1996. DVD. Johnny Belinda. Dir. Jean Nagalesco. Warner Brothers Pictures, 1948. DVD. Kung Fu Hustle. Dir. Stephen Chow. Film Production Asia, 2004. DVD. Liar, Liar. Dir. Tom Shadyac. Universal Pictures, 1997. DVD. Looking for Mr. Goodbar. Dir. Richard Brooks. Paramount Miracle on 34th Street. Dir. Les Mayfield. 20th Century Fox, 1994. DVD. Mr. Holland’s Opus. Dir. Stephen Hereck. Hollywood Pictures, 1996. DVD Murder by Death. Dir. Robert Moore. Columbia Pictures, 1976. VHS. Nashville. Dir. Robert Altman. Paramount Pictures, 1975. DVD. One Flew over the Cuckoo’s Nest. Dir. Milos Forman. United Artists, 1975. DVD. The Perfect Circle. Dir. Ademir Kenovic. 1997. DVD. Psych Out. Dir. Richard Rush. American International Pictures, 1968. DVD. The Quiet. Dir. Jamie Babbit. Sony Pictures Classics, 2005. DVD. Ramblin’ Rose. Dir. Martha Coolidge. Carolco Pictures, 1991. DVD. Read My Lips. Dir. Jacques Audiard. Panthe Films, 2001. DVD. Requiem for a Dream. Dir. Darren Aronofsky. Artisan Entertainment, 2000. DVD. Ridicule. Dir. Patrice Laconte. Miramax Films, 1996. DVD. The River Wild. Dir. Curtis Hanson. Universal Pictures, 1995. DVD. See No Evil, Hear No Evil. Dir. Arthur Hiller. TriSTar Pictures,1989. DVD. The Shop on Main Street. Dir. Jan Kadar, Elmar Klos. Barrandov Film Studio, 1965. VHS. Stille Liebe. Dir. Christoph Schaub. T and C Film AG, 2001. DVD. Suspect. Dir. Peter Yates. Tri-Star Pictures, 1987. DVD. Sympathy for Mr. Vengeance. Dir. Park Chan-wook. CJ Entertainments, Tartan Films, 2002. DVD. There Will Be Blood. Dir. Paul Thomas Anderson. Paramount Vantage, Miramax Films, 2007. DVD. To Live. Dir. Zhang Yimou. Shanghai Film Studio and ERA International, 1994. DVD. What the Bleep Do We Know?. Dir. Willam Arntz, Betsy Chasse, Mark Vicente. Roadside Attractions, 2004. DVD.

Photo ID 158378414 © Eduard Muzhevskyi | Dreamstime.com ABSTRACT There is a debate about the ethical implications of using human embryos in stem cell research, which can be influenced by cultural, moral, and social values. This paper argues for an adaptable framework to accommodate diverse cultural and religious perspectives. By using an adaptive ethics model, research protections can reflect various populations and foster growth in stem cell research possibilities. INTRODUCTION Stem cell research combines biology, medicine, and technology, promising to alter health care and the understanding of human development. Yet, ethical contention exists because of individuals’ perceptions of using human embryos based on their various cultural, moral, and social values. While these disagreements concerning policy, use, and general acceptance have prompted the development of an international ethics policy, such a uniform approach can overlook the nuanced ethical landscapes between cultures. With diverse viewpoints in public health, a single global policy, especially one reflecting Western ethics or the ethics prevalent in high-income countries, is impractical. This paper argues for a culturally sensitive, adaptable framework for the use of embryonic stem cells. Stem cell policy should accommodate varying ethical viewpoints and promote an effective global dialogue. With an extension of an ethics model that can adapt to various cultures, we recommend localized guidelines that reflect the moral views of the people those guidelines serve. BACKGROUND Stem cells, characterized by their unique ability to differentiate into various cell types, enable the repair or replacement of damaged tissues. Two primary types of stem cells are somatic stem cells (adult stem cells) and embryonic stem cells. Adult stem cells exist in developed tissues and maintain the body’s repair processes.[1] Embryonic stem cells (ESC) are remarkably pluripotent or versatile, making them valuable in research.[2] However, the use of ESCs has sparked ethics debates. Considering the potential of embryonic stem cells, research guidelines are essential. The International Society for Stem Cell Research (ISSCR) provides international stem cell research guidelines. They call for “public conversations touching on the scientific significance as well as the societal and ethical issues raised by ESC research.”[3] The ISSCR also publishes updates about culturing human embryos 14 days post fertilization, suggesting local policies and regulations should continue to evolve as ESC research develops.[4] Like the ISSCR, which calls for local law and policy to adapt to developing stem cell research given cultural acceptance, this paper highlights the importance of local social factors such as religion and culture. I. Global Cultural Perspective of Embryonic Stem Cells Views on ESCs vary throughout the world. Some countries readily embrace stem cell research and therapies, while others have stricter regulations due to ethical concerns surrounding embryonic stem cells and when an embryo becomes entitled to moral consideration. The philosophical issue of when the “someone” begins to be a human after fertilization, in the morally relevant sense,[5] impacts when an embryo becomes not just worthy of protection but morally entitled to it. The process of creating embryonic stem cell lines involves the destruction of the embryos for research.[6] Consequently, global engagement in ESC research depends on social-cultural acceptability. a. US and Rights-Based Cultures In the United States, attitudes toward stem cell therapies are diverse. The ethics and social approaches, which value individualism,[7] trigger debates regarding the destruction of human embryos, creating a complex regulatory environment. For example, the 1996 Dickey-Wicker Amendment prohibited federal funding for the creation of embryos for research and the destruction of embryos for “more than allowed for research on fetuses in utero.”[8] Following suit, in 2001, the Bush Administration heavily restricted stem cell lines for research. However, the Stem Cell Research Enhancement Act of 2005 was proposed to help develop ESC research but was ultimately vetoed.[9] Under the Obama administration, in 2009, an executive order lifted restrictions allowing for more development in this field.[10] The flux of research capacity and funding parallels the different cultural perceptions of human dignity of the embryo and how it is socially presented within the country’s research culture.[11] b. Ubuntu and Collective Cultures African bioethics differs from Western individualism because of the different traditions and values. African traditions, as described by individuals from South Africa and supported by some studies in other African countries, including Ghana and Kenya, follow the African moral philosophies of Ubuntu or Botho and Ukama, which “advocates for a form of wholeness that comes through one’s relationship and connectedness with other people in the society,”[12] making autonomy a socially collective concept. In this context, for the community to act autonomously, individuals would come together to decide what is best for the collective. Thus, stem cell research would require examining the value of the research to society as a whole and the use of the embryos as a collective societal resource. If society views the source as part of the collective whole, and opposes using stem cells, compromising the cultural values to pursue research may cause social detachment and stunt research growth.[13] Based on local culture and moral philosophy, the permissibility of stem cell research depends on how embryo, stem cell, and cell line therapies relate to the community as a whole. Ubuntu is the expression of humanness, with the person’s identity drawn from the “’I am because we are’” value.[14] The decision in a collectivistic culture becomes one born of cultural context, and individual decisions give deference to others in the society. Consent differs in cultures where thought and moral philosophy are based on a collective paradigm. So, applying Western bioethical concepts is unrealistic. For one, Africa is a diverse continent with many countries with different belief systems, access to health care, and reliance on traditional or Western medicines. Where traditional medicine is the primary treatment, the “’restrictive focus on biomedically-related bioethics’” [is] problematic in African contexts because it neglects bioethical issues raised by traditional systems.”[15] No single approach applies in all areas or contexts. Rather than evaluating the permissibility of ESC research according to Western concepts such as the four principles approach, different ethics approaches should prevail. Another consideration is the socio-economic standing of countries. In parts of South Africa, researchers have not focused heavily on contributing to the stem cell discourse, either because it is not considered health care or a health science priority or because resources are unavailable.[16] Each country’s priorities differ given different social, political, and economic factors. In South Africa, for instance, areas such as maternal mortality, non-communicable diseases, telemedicine, and the strength of health systems need improvement and require more focus[17] Stem cell research could benefit the population, but it also could divert resources from basic medical care. Researchers in South Africa adhere to the National Health Act and Medicines Control Act in South Africa and international guidelines; however, the Act is not strictly enforced, and there is no clear legislation for research conduct or ethical guidelines.[18] Some parts of Africa condemn stem cell research. For example, 98.2 percent of the Tunisian population is Muslim.[19] Tunisia does not permit stem cell research because of moral conflict with a Fatwa. Religion heavily saturates the regulation and direction of research.[20] Stem cell use became permissible for reproductive purposes only recently, with tight restrictions preventing cells from being used in any research other than procedures concerning ART/IVF. Their use is conditioned on consent, and available only to married couples.[21] The community's receptiveness to stem cell research depends on including communitarian African ethics. c. Asia Some Asian countries also have a collective model of ethics and decision making.[22] In China, the ethics model promotes a sincere respect for life or human dignity,[23] based on protective medicine. This model, influenced by Traditional Chinese Medicine (TCM), [24] recognizes Qi as the vital energy delivered via the meridians of the body; it connects illness to body systems, the body’s entire constitution, and the universe for a holistic bond of nature, health, and quality of life.[25] Following a protective ethics model, and traditional customs of wholeness, investment in stem cell research is heavily desired for its applications in regenerative therapies, disease modeling, and protective medicines. In a survey of medical students and healthcare practitioners, 30.8 percent considered stem cell research morally unacceptable while 63.5 percent accepted medical research using human embryonic stem cells. Of these individuals, 89.9 percent supported increased funding for stem cell research.[26] The scientific community might not reflect the overall population. From 1997 to 2019, China spent a total of $576 million (USD) on stem cell research at 8,050 stem cell programs, increased published presence from 0.6 percent to 14.01 percent of total global stem cell publications as of 2014, and made significant strides in cell-based therapies for various medical conditions.[27] However, while China has made substantial investments in stem cell research and achieved notable progress in clinical applications, concerns linger regarding ethical oversight and transparency.[28] For example, the China Biosecurity Law, promoted by the National Health Commission and China Hospital Association, attempted to mitigate risks by introducing an institutional review board (IRB) in the regulatory bodies. 5800 IRBs registered with the Chinese Clinical Trial Registry since 2021.[29] However, issues still need to be addressed in implementing effective IRB review and approval procedures. The substantial government funding and focus on scientific advancement have sometimes overshadowed considerations of regional cultures, ethnic minorities, and individual perspectives, particularly evident during the one-child policy era. As government policy adapts to promote public stability, such as the change from the one-child to the two-child policy,[30] research ethics should also adapt to ensure respect for the values of its represented peoples. Japan is also relatively supportive of stem cell research and therapies. Japan has a more transparent regulatory framework, allowing for faster approval of regenerative medicine products, which has led to several advanced clinical trials and therapies.[31] South Korea is also actively engaged in stem cell research and has a history of breakthroughs in cloning and embryonic stem cells.[32] However, the field is controversial, and there are issues of scientific integrity. For example, the Korean FDA fast-tracked products for approval,[33] and in another instance, the oocyte source was unclear and possibly violated ethical standards.[34] Trust is important in research, as it builds collaborative foundations between colleagues, trial participant comfort, open-mindedness for complicated and sensitive discussions, and supports regulatory procedures for stakeholders. There is a need to respect the culture’s interest, engagement, and for research and clinical trials to be transparent and have ethical oversight to promote global research discourse and trust. d. Middle East Countries in the Middle East have varying degrees of acceptance of or restrictions to policies related to using embryonic stem cells due to cultural and religious influences. Saudi Arabia has made significant contributions to stem cell research, and conducts research based on international guidelines for ethical conduct and under strict adherence to guidelines in accordance with Islamic principles. Specifically, the Saudi government and people require ESC research to adhere to Sharia law. In addition to umbilical and placental stem cells,[35] Saudi Arabia permits the use of embryonic stem cells as long as they come from miscarriages, therapeutic abortions permissible by Sharia law, or are left over from in vitro fertilization and donated to research.[36] Laws and ethical guidelines for stem cell research allow the development of research institutions such as the King Abdullah International Medical Research Center, which has a cord blood bank and a stem cell registry with nearly 10,000 donors.[37] Such volume and acceptance are due to the ethical ‘permissibility’ of the donor sources, which do not conflict with religious pillars. However, some researchers err on the side of caution, choosing not to use embryos or fetal tissue as they feel it is unethical to do so.[38] Jordan has a positive research ethics culture.[39] However, there is a significant issue of lack of trust in researchers, with 45.23 percent (38.66 percent agreeing and 6.57 percent strongly agreeing) of Jordanians holding a low level of trust in researchers, compared to 81.34 percent of Jordanians agreeing that they feel safe to participate in a research trial.[40] Safety testifies to the feeling of confidence that adequate measures are in place to protect participants from harm, whereas trust in researchers could represent the confidence in researchers to act in the participants’ best interests, adhere to ethical guidelines, provide accurate information, and respect participants’ rights and dignity. One method to improve trust would be to address communication issues relevant to ESC. Legislation surrounding stem cell research has adopted specific language, especially concerning clarification “between ‘stem cells’ and ‘embryonic stem cells’” in translation.[41] Furthermore, legislation “mandates the creation of a national committee… laying out specific regulations for stem-cell banking in accordance with international standards.”[42] This broad regulation opens the door for future global engagement and maintains transparency. However, these regulations may also constrain the influence of research direction, pace, and accessibility of research outcomes. e. Europe In the European Union (EU), ethics is also principle-based, but the principles of autonomy, dignity, integrity, and vulnerability are interconnected.[43] As such, the opportunity for cohesion and concessions between individuals’ thoughts and ideals allows for a more adaptable ethics model due to the flexible principles that relate to the human experience The EU has put forth a framework in its Convention for the Protection of Human Rights and Dignity of the Human Being allowing member states to take different approaches. Each European state applies these principles to its specific conventions, leading to or reflecting different acceptance levels of stem cell research. [44] For example, in Germany, Lebenzusammenhang, or the coherence of life, references integrity in the unity of human culture. Namely, the personal sphere “should not be subject to external intervention.”[45] Stem cell interventions could affect this concept of bodily completeness, leading to heavy restrictions. Under the Grundgesetz, human dignity and the right to life with physical integrity are paramount.[46] The Embryo Protection Act of 1991 made producing cell lines illegal. Cell lines can be imported if approved by the Central Ethics Commission for Stem Cell Research only if they were derived before May 2007.[47] Stem cell research respects the integrity of life for the embryo with heavy specifications and intense oversight. This is vastly different in Finland, where the regulatory bodies find research more permissible in IVF excess, but only up to 14 days after fertilization.[48] Spain’s approach differs still, with a comprehensive regulatory framework.[49] Thus, research regulation can be culture-specific due to variations in applied principles. Diverse cultures call for various approaches to ethical permissibility.[50] Only an adaptive-deliberative model can address the cultural constructions of self and achieve positive, culturally sensitive stem cell research practices.[51] II. Religious Perspectives on ESC Embryonic stem cell sources are the main consideration within religious contexts. While individuals may not regard their own religious texts as authoritative or factual, religion can shape their foundations or perspectives. The Qur'an states: “And indeed We created man from a quintessence of clay. Then We placed within him a small quantity of nutfa (sperm to fertilize) in a safe place. Then We have fashioned the nutfa into an ‘alaqa (clinging clot or cell cluster), then We developed the ‘alaqa into mudgha (a lump of flesh), and We made mudgha into bones, and clothed the bones with flesh, then We brought it into being as a new creation. So Blessed is Allah, the Best of Creators.”[52] Many scholars of Islam estimate the time of soul installment, marked by the angel breathing in the soul to bring the individual into creation, as 120 days from conception.[53] Personhood begins at this point, and the value of life would prohibit research or experimentation that could harm the individual. If the fetus is more than 120 days old, the time ensoulment is interpreted to occur according to Islamic law, abortion is no longer permissible.[54] There are a few opposing opinions about early embryos in Islamic traditions. According to some Islamic theologians, there is no ensoulment of the early embryo, which is the source of stem cells for ESC research.[55] In Buddhism, the stance on stem cell research is not settled. The main tenets, the prohibition against harming or destroying others (ahimsa) and the pursuit of knowledge (prajña) and compassion (karuna), leave Buddhist scholars and communities divided.[56] Some scholars argue stem cell research is in accordance with the Buddhist tenet of seeking knowledge and ending human suffering. Others feel it violates the principle of not harming others. Finding the balance between these two points relies on the karmic burden of Buddhist morality. In trying to prevent ahimsa towards the embryo, Buddhist scholars suggest that to comply with Buddhist tenets, research cannot be done as the embryo has personhood at the moment of conception and would reincarnate immediately, harming the individual's ability to build their karmic burden.[57] On the other hand, the Bodhisattvas, those considered to be on the path to enlightenment or Nirvana, have given organs and flesh to others to help alleviate grieving and to benefit all.[58] Acceptance varies on applied beliefs and interpretations. Catholicism does not support embryonic stem cell research, as it entails creation or destruction of human embryos. This destruction conflicts with the belief in the sanctity of life. For example, in the Old Testament, Genesis describes humanity as being created in God’s image and multiplying on the Earth, referencing the sacred rights to human conception and the purpose of development and life. In the Ten Commandments, the tenet that one should not kill has numerous interpretations where killing could mean murder or shedding of the sanctity of life, demonstrating the high value of human personhood. In other books, the theological conception of when life begins is interpreted as in utero,[59] highlighting the inviolability of life and its formation in vivo to make a religious point for accepting such research as relatively limited, if at all.[60] The Vatican has released ethical directives to help apply a theological basis to modern-day conflicts. The Magisterium of the Church states that “unless there is a moral certainty of not causing harm,” experimentation on fetuses, fertilized cells, stem cells, or embryos constitutes a crime.[61] Such procedures would not respect the human person who exists at these stages, according to Catholicism. Damages to the embryo are considered gravely immoral and illicit.[62] Although the Catholic Church officially opposes abortion, surveys demonstrate that many Catholic people hold pro-choice views, whether due to the context of conception, stage of pregnancy, threat to the mother’s life, or for other reasons, demonstrating that practicing members can also accept some but not all tenets.[63] Some major Jewish denominations, such as the Reform, Conservative, and Reconstructionist movements, are open to supporting ESC use or research as long as it is for saving a life.[64] Within Judaism, the Talmud, or study, gives personhood to the child at birth and emphasizes that life does not begin at conception:[65] “If she is found pregnant, until the fortieth day it is mere fluid,”[66] Whereas most religions prioritize the status of human embryos, the Halakah (Jewish religious law) states that to save one life, most other religious laws can be ignored because it is in pursuit of preservation.[67] Stem cell research is accepted due to application of these religious laws. We recognize that all religions contain subsets and sects. The variety of environmental and cultural differences within religious groups requires further analysis to respect the flexibility of religious thoughts and practices. We make no presumptions that all cultures require notions of autonomy or morality as under the common morality theory, which asserts a set of universal moral norms that all individuals share provides moral reasoning and guides ethical decisions.[68] We only wish to show that the interaction with morality varies between cultures and countries. III. A Flexible Ethical Approach The plurality of different moral approaches described above demonstrates that there can be no universally acceptable uniform law for ESC on a global scale. Instead of developing one standard, flexible ethical applications must be continued. We recommend local guidelines that incorporate important cultural and ethical priorities. While the Declaration of Helsinki is more relevant to people in clinical trials receiving ESC products, in keeping with the tradition of protections for research subjects, consent of the donor is an ethical requirement for ESC donation in many jurisdictions including the US, Canada, and Europe.[69] The Declaration of Helsinki provides a reference point for regulatory standards and could potentially be used as a universal baseline for obtaining consent prior to gamete or embryo donation. For instance, in Columbia University’s egg donor program for stem cell research, donors followed standard screening protocols and “underwent counseling sessions that included information as to the purpose of oocyte donation for research, what the oocytes would be used for, the risks and benefits of donation, and process of oocyte stimulation” to ensure transparency for consent.[70] The program helped advance stem cell research and provided clear and safe research methods with paid participants. Though paid participation or covering costs of incidental expenses may not be socially acceptable in every culture or context,[71] and creating embryos for ESC research is illegal in many jurisdictions, Columbia’s program was effective because of the clear and honest communications with donors, IRBs, and related stakeholders. This example demonstrates that cultural acceptance of scientific research and of the idea that an egg or embryo does not have personhood is likely behind societal acceptance of donating eggs for ESC research. As noted, many countries do not permit the creation of embryos for research. Proper communication and education regarding the process and purpose of stem cell research may bolster comprehension and garner more acceptance. “Given the sensitive subject material, a complete consent process can support voluntary participation through trust, understanding, and ethical norms from the cultures and morals participants value. This can be hard for researchers entering countries of different socioeconomic stability, with different languages and different societal values.[72] An adequate moral foundation in medical ethics is derived from the cultural and religious basis that informs knowledge and actions.[73] Understanding local cultural and religious values and their impact on research could help researchers develop humility and promote inclusion. IV. Concerns Some may argue that if researchers all adhere to one ethics standard, protection will be satisfied across all borders, and the global public will trust researchers. However, defining what needs to be protected and how to define such research standards is very specific to the people to which standards are applied. We suggest that applying one uniform guide cannot accurately protect each individual because we all possess our own perceptions and interpretations of social values.[74] Therefore, the issue of not adjusting to the moral pluralism between peoples in applying one standard of ethics can be resolved by building out ethics models that can be adapted to different cultures and religions. Other concerns include medical tourism, which may promote health inequities.[75] Some countries may develop and approve products derived from ESC research before others, compromising research ethics or drug approval processes. There are also concerns about the sale of unauthorized stem cell treatments, for example, those without FDA approval in the United States. Countries with robust research infrastructures may be tempted to attract medical tourists, and some customers will have false hopes based on aggressive publicity of unproven treatments.[76] For example, in China, stem cell clinics can market to foreign clients who are not protected under the regulatory regimes. Companies employ a marketing strategy of “ethically friendly” therapies. Specifically, in the case of Beike, China’s leading stem cell tourism company and sprouting network, ethical oversight of administrators or health bureaus at one site has “the unintended consequence of shifting questionable activities to another node in Beike's diffuse network.”[77] In contrast, Jordan is aware of stem cell research’s potential abuse and its own status as a “health-care hub.” Jordan’s expanded regulations include preserving the interests of individuals in clinical trials and banning private companies from ESC research to preserve transparency and the integrity of research practices.[78] The social priorities of the community are also a concern. The ISSCR explicitly states that guidelines “should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities.”[79] The adaptable ethics model extends this consideration further by addressing whether research is warranted given the varying degrees of socioeconomic conditions, political stability, and healthcare accessibilities and limitations. An ethical approach would require discussion about resource allocation and appropriate distribution of funds.[80] CONCLUSION While some religions emphasize the sanctity of life from conception, which may lead to public opposition to ESC research, others encourage ESC research due to its potential for healing and alleviating human pain. Many countries have special regulations that balance local views on embryonic personhood, the benefits of research as individual or societal goods, and the protection of human research subjects. To foster understanding and constructive dialogue, global policy frameworks should prioritize the protection of universal human rights, transparency, and informed consent. In addition to these foundational global policies, we recommend tailoring local guidelines to reflect the diverse cultural and religious perspectives of the populations they govern. Ethics models should be adapted to local populations to effectively establish research protections, growth, and possibilities of stem cell research. For example, in countries with strong beliefs in the moral sanctity of embryos or heavy religious restrictions, an adaptive model can allow for discussion instead of immediate rejection. In countries with limited individual rights and voice in science policy, an adaptive model ensures cultural, moral, and religious views are taken into consideration, thereby building social inclusion. While this ethical consideration by the government may not give a complete voice to every individual, it will help balance policies and maintain the diverse perspectives of those it affects. Embracing an adaptive ethics model of ESC research promotes open-minded dialogue and respect for the importance of human belief and tradition. By actively engaging with cultural and religious values, researchers can better handle disagreements and promote ethical research practices that benefit each society. This brief exploration of the religious and cultural differences that impact ESC research reveals the nuances of relative ethics and highlights a need for local policymakers to apply a more intense adaptive model. - [1] Poliwoda, S., Noor, N., Downs, E., Schaaf, A., Cantwell, A., Ganti, L., Kaye, A. D., Mosel, L. I., Carroll, C. B., Viswanath, O., & Urits, I. (2022). Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice. 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International Society for Stem Cell Research. https://www.isscr.org/guidelines/blog-post-title-one-ed2td-6fcdk [5] Concerning the moral philosophies of stem cell research, our paper does not posit a personal moral stance nor delve into the “when” of human life begins. To read further about the philosophical debate, consider the following sources: Sandel M. J. (2004). Embryo ethics--the moral logic of stem-cell research. The New England journal of medicine, 351(3), 207–209. https://doi.org/10.1056/NEJMp048145; George, R. P., & Lee, P. (2020, September 26). Acorns and Embryos. The New Atlantis. https://www.thenewatlantis.com/publications/acorns-and-embryos; Sagan, A., & Singer, P. (2007). The moral status of stem cells. Metaphilosophy, 38(2/3), 264–284. http://www.jstor.org/stable/24439776; McHugh P. R. (2004). Zygote and "clonote"--the ethical use of embryonic stem cells. 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[14] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics, 22(2), 112–122. https://doi.org/10.1111/dewb.12324 [15] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics, 22(2), 112–122. https://doi.org/10.1111/dewb.12324 [16] Jackson, C.S., Pepper, M.S. Opportunities and barriers to establishing a cell therapy programme in South Africa. Stem Cell Res Ther 4, 54 (2013). https://doi.org/10.1186/scrt204; Pew Research Center. (2014, May 1). Public health a major priority in African nations. Pew Research Center’s Global Attitudes Project. https://www.pewresearch.org/global/2014/05/01/public-health-a-major-priority-in-african-nations/ [17] Department of Health Republic of South Africa. (2021). Health Research Priorities (revised) for South Africa 2021-2024. National Health Research Strategy. https://www.health.gov.za/wp-content/uploads/2022/05/National-Health-Research-Priorities-2021-2024.pdf [18] Oosthuizen, H. (2013). Legal and Ethical Issues in Stem Cell Research in South Africa. In: Beran, R. (eds) Legal and Forensic Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32338-6_80, see also: Gaobotse G (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142 [19] United States Bureau of Citizenship and Immigration Services. (1998). Tunisia: Information on the status of Christian conversions in Tunisia. UNHCR Web Archive. https://webarchive.archive.unhcr.org/20230522142618/https://www.refworld.org/docid/3df0be9a2.html [20] Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142 [21] Kooli, C. Review of assisted reproduction techniques, laws, and regulations in Muslim countries. Middle East Fertil Soc J 24, 8 (2020). https://doi.org/10.1186/s43043-019-0011-0; Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142 [22] Pang M. C. (1999). Protective truthfulness: the Chinese way of safeguarding patients in informed treatment decisions. Journal of medical ethics, 25(3), 247–253. https://doi.org/10.1136/jme.25.3.247 [23] Wang, L., Wang, F., & Zhang, W. (2021). Bioethics in China’s biosecurity law: Forms, effects, and unsettled issues. Journal of law and the biosciences, 8(1). https://doi.org/10.1093/jlb/lsab019 https://academic.oup.com/jlb/article/8/1/lsab019/6299199 [24] Wang, Y., Xue, Y., & Guo, H. D. (2022). Intervention effects of traditional Chinese medicine on stem cell therapy of myocardial infarction. Frontiers in pharmacology, 13, 1013740. https://doi.org/10.3389/fphar.2022.1013740 [25] Li, X.-T., & Zhao, J. (2012). Chapter 4: An Approach to the Nature of Qi in TCM- Qi and Bioenergy. In Recent Advances in Theories and Practice of Chinese Medicine (p. 79). InTech. [26] Luo, D., Xu, Z., Wang, Z., & Ran, W. (2021). China's Stem Cell Research and Knowledge Levels of Medical Practitioners and Students. Stem cells international, 2021, 6667743. https://doi.org/10.1155/2021/6667743 [27] Luo, D., Xu, Z., Wang, Z., & Ran, W. (2021). China's Stem Cell Research and Knowledge Levels of Medical Practitioners and Students. Stem cells international, 2021, 6667743. https://doi.org/10.1155/2021/6667743 [28] Zhang, J. Y. (2017). Lost in translation? accountability and governance of Clinical Stem Cell Research in China. Regenerative Medicine, 12(6), 647–656. https://doi.org/10.2217/rme-2017-0035 [29] Wang, L., Wang, F., & Zhang, W. (2021). Bioethics in China’s biosecurity law: Forms, effects, and unsettled issues. Journal of law and the biosciences, 8(1). https://doi.org/10.1093/jlb/lsab019 https://academic.oup.com/jlb/article/8/1/lsab019/6299199 [30] Chen, H., Wei, T., Wang, H. et al. Association of China’s two-child policy with changes in number of births and birth defects rate, 2008–2017. BMC Public Health 22, 434 (2022). https://doi.org/10.1186/s12889-022-12839-0 [31] Azuma, K. Regulatory Landscape of Regenerative Medicine in Japan. Curr Stem Cell Rep 1, 118–128 (2015). https://doi.org/10.1007/s40778-015-0012-6 [32] Harris, R. (2005, May 19). Researchers Report Advance in Stem Cell Production. NPR. https://www.npr.org/2005/05/19/4658967/researchers-report-advance-in-stem-cell-production [33] Park, S. (2012). South Korea steps up stem-cell work. Nature. https://doi.org/10.1038/nature.2012.10565 [34] Resnik, D. B., Shamoo, A. E., & Krimsky, S. (2006). Fraudulent human embryonic stem cell research in South Korea: lessons learned. Accountability in research, 13(1), 101–109. https://doi.org/10.1080/08989620600634193. [35] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6 [36]Association for the Advancement of Blood and Biotherapies. https://www.aabb.org/regulatory-and-advocacy/regulatory-affairs/regulatory-for-cellular-therapies/international-competent-authorities/saudi-arabia [37] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6 [38] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6 Culturally, autonomy practices follow a relational autonomy approach based on a paternalistic deontological health care model. The adherence to strict international research policies and religious pillars within the regulatory environment is a great foundation for research ethics. However, there is a need to develop locally targeted ethics approaches for research (as called for in Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6), this decision-making approach may help advise a research decision model. For more on the clinical cultural autonomy approaches, see: Alabdullah, Y. Y., Alzaid, E., Alsaad, S., Alamri, T., Alolayan, S. W., Bah, S., & Aljoudi, A. S. (2022). Autonomy and paternalism in Shared decision‐making in a Saudi Arabian tertiary hospital: A cross‐sectional study. Developing World Bioethics, 23(3), 260–268. https://doi.org/10.1111/dewb.12355; Bukhari, A. A. (2017). Universal Principles of Bioethics and Patient Rights in Saudi Arabia (Doctoral dissertation, Duquesne University). https://dsc.duq.edu/etd/124; Ladha, S., Nakshawani, S. A., Alzaidy, A., & Tarab, B. (2023, October 26). Islam and Bioethics: What We All Need to Know. Columbia University School of Professional Studies. https://sps.columbia.edu/events/islam-and-bioethics-what-we-all-need-know [39] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics. Research Ethics, 17(2), 228-241. https://doi.org/10.1177/1747016120966779 [40] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics. Research Ethics, 17(2), 228-241. https://doi.org/10.1177/1747016120966779 [41] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East. Nature 510, 189. https://doi.org/10.1038/510189a [42] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East. Nature 510, 189. https://doi.org/10.1038/510189a [43] The EU’s definition of autonomy relates to the capacity for creating ideas, moral insight, decisions, and actions without constraint, personal responsibility, and informed consent. However, the EU views autonomy as not completely able to protect individuals and depends on other principles, such as dignity, which “expresses the intrinsic worth and fundamental equality of all human beings.” Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3 [44] Council of Europe. Convention for the protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No. 164) https://www.coe.int/en/web/conventions/full-list?module=treaty-detail&treatynum=164 (forbidding the creation of embryos for research purposes only, and suggests embryos in vitro have protections.); Also see Drabiak-Syed B. K. (2013). New President, New Human Embryonic Stem Cell Research Policy: Comparative International Perspectives and Embryonic Stem Cell Research Laws in France. Biotechnology Law Report, 32(6), 349–356. https://doi.org/10.1089/blr.2013.9865 [45] Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3 [46] Tomuschat, C., Currie, D. P., Kommers, D. P., & Kerr, R. (Trans.). (1949, May 23). Basic law for the Federal Republic of Germany. https://www.btg-bestellservice.de/pdf/80201000.pdf [47] Regulation of Stem Cell Research in Germany. Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-germany [48] Regulation of Stem Cell Research in Finland. Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-finland [49] Regulation of Stem Cell Research in Spain. Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-spain [50] Some sources to consider regarding ethics models or regulatory oversights of other cultures not covered: Kara MA. Applicability of the principle of respect for autonomy: the perspective of Turkey. J Med Ethics. 2007 Nov;33(11):627-30. doi: 10.1136/jme.2006.017400. PMID: 17971462; PMCID: PMC2598110. Ugarte, O. N., & Acioly, M. A. (2014). The principle of autonomy in Brazil: one needs to discuss it ... Revista do Colegio Brasileiro de Cirurgioes, 41(5), 374–377. https://doi.org/10.1590/0100-69912014005013 Bharadwaj, A., & Glasner, P. E. (2012). Local cells, global science: The rise of embryonic stem cell research in India. Routledge. For further research on specific European countries regarding ethical and regulatory framework, we recommend this database: Regulation of Stem Cell Research in Europe. Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-europe [51] Klitzman, R. (2006). Complications of culture in obtaining informed consent. The American Journal of Bioethics, 6(1), 20–21. https://doi.org/10.1080/15265160500394671 see also: Ekmekci, P. E., & Arda, B. (2017). Interculturalism and Informed Consent: Respecting Cultural Differences without Breaching Human Rights. Cultura (Iasi, Romania), 14(2), 159–172.; For why trust is important in research, see also: Gray, B., Hilder, J., Macdonald, L., Tester, R., Dowell, A., & Stubbe, M. (2017). Are research ethics guidelines culturally competent? Research Ethics, 13(1), 23-41. https://doi.org/10.1177/1747016116650235 [52] The Qur'an (M. Khattab, Trans.). (1965). Al-Mu’minun, 23: 12-14. https://quran.com/23 [53] Lenfest, Y. (2017, December 8). Islam and the beginning of human life. Bill of Health. https://blog.petrieflom.law.harvard.edu/2017/12/08/islam-and-the-beginning-of-human-life/ [54] Aksoy, S. (2005). Making regulations and drawing up legislation in Islamic countries under conditions of uncertainty, with special reference to embryonic stem cell research. Journal of Medical Ethics, 31:399-403.; see also: Mahmoud, Azza. "Islamic Bioethics: National Regulations and Guidelines of Human Stem Cell Research in the Muslim World." Master's thesis, Chapman University, 2022. https://doi.org/10.36837/ chapman.000386 [55] Rashid, R. (2022). When does Ensoulment occur in the Human Foetus. Journal of the British Islamic Medical Association, 12(4). ISSN 2634 8071. https://www.jbima.com/wp-content/uploads/2023/01/2-Ethics-3_-Ensoulment_Rafaqat.pdf. [56] Sivaraman, M. & Noor, S. (2017). Ethics of embryonic stem cell research according to Buddhist, Hindu, Catholic, and Islamic religions: perspective from Malaysia. Asian Biomedicine,8(1) 43-52. https://doi.org/10.5372/1905-7415.0801.260 [57] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.), Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues (pp. 79-94). Berkeley: University of California Press. https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005 [58] Lecso, P. A. (1991). The Bodhisattva Ideal and Organ Transplantation. Journal of Religion and Health, 30(1), 35–41. http://www.jstor.org/stable/27510629; Bodhisattva, S. (n.d.). The Key of Becoming a Bodhisattva. A Guide to the Bodhisattva Way of Life. http://www.buddhism.org/Sutras/2/BodhisattvaWay.htm [59] There is no explicit religious reference to when life begins or how to conduct research that interacts with the concept of life. However, these are relevant verses pertaining to how the fetus is viewed. ((King James Bible. (1999). Oxford University Press. (original work published 1769)) Jerimiah 1: 5 “Before I formed thee in the belly I knew thee; and before thou camest forth out of the womb I sanctified thee…” In prophet Jerimiah’s insight, God set him apart as a person known before childbirth, a theme carried within the Psalm of David. Psalm 139: 13-14 “…Thou hast covered me in my mother's womb. I will praise thee; for I am fearfully and wonderfully made…” These verses demonstrate David’s respect for God as an entity that would know of all man’s thoughts and doings even before birth. [60] It should be noted that abortion is not supported as well. [61] The Vatican. (1987, February 22). Instruction on Respect for Human Life in Its Origin and on the Dignity of Procreation Replies to Certain Questions of the Day. Congregation For the Doctrine of the Faith. https://www.vatican.va/roman_curia/congregations/cfaith/documents/rc_con_cfaith_doc_19870222_respect-for-human-life_en.html [62] The Vatican. (2000, August 25). 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