Journal articles on the topic 'Wu Ming 2'

This paper relies on the dataset “Historical Social Network of Chinese Buddhism” (Ver. 2021-06). The focus is on the period between c. 1570 and 1700 CE. We argue that the actor who was most influential for institutional Buddhism in the 17th century was not one of the “four great monks of the late Ming” but rather Miyun Yuanwu 密雲圓悟 (1566–1642). The network illustrates how Miyun’s Tiantong branch 天童派 of the Linji School became the dominant Chan lineage in China and beyond. The main results of this study are: (1) the data corroborate the assumption that (at least) monastic Buddhism declined between c. 1420 and 1570. (2) The network view de-emphasizes the importance of the ‘four famous late Ming eminent monks’ for the development of 17th-century Buddhist monasticism. (3) The data align well with a suggestion by Jiang Wu to distinguish two different stages in the development of late Ming Buddhism. The first is characterized by the “late Ming revival,” led by figures such as Yunqi Zhuhong, Zibo Zhenke, and Hanshan Deqing; the second phase is the organization of orthopraxy around the Chan lineage discourse dominated by Miyun Yuanwu and his students. (4) For the 17th century, the network data clearly shows the centrality of Miyun Yuanwu and his network.

L’articolo esamina il romanzo Timira, scritto da Antar Mohamed Marincola e Wu Ming 2 e pubblicato nel 2012. Ci concentriamo su due macrotemi: la marginalità spaziale e culturale rappresentata nel libro o percepita dai personaggi (la città, la periferia, la controcultura, e l’attivismo politico), e come razzismo, sessismo e colonialismo plasmino non solo l’identità della protagonista Isabella Marincola ma anche le sue esperienze nel mondo artistico e cinematografico. Il saggio è frutto di un esperimento di scrittura collettiva, nella convinzione che questa pratica dovrebbe essere più diffusa nelle scienze umane, e che un romanzo complesso e stratificato come Timira possa essere affrontato a più voci e da punti di vista diversi.

Abstract While China's almost flawless space endeavours—such as its space lab Tiangong-2, launched last year, and the 2012 mission that sent a rover to the surface of the Moon—have long impressed the world, space-science missions were not among its priorities until recently. The situation improved in 2011 when the Chinese Academy of Sciences won government support for a 10-year Strategic Pioneering Programme on Space Science—with a total budget of nearly 1 billion dollars. Since then, China has launched satellites to probe dark matter, detect black holes and conduct quantum experiments from space. This year will see the launch of an astronomy satellite and a highly anticipated mission to bring back rocks from the Moon. In a forum chaired by National Science Review's Executive Associate Editor Mu-ming Poo, space scientists discussed different types of Chinese space programmes, the science missions already launched or in development, the importance and challenges of international collaboration, and the uncertain future of the country's space-science development. Chunlai Li Deputy Director, National Astronomical Observatories, Chinese Academy of Sciences, Beijing Ji Wu Director, National Centre of Space Science, Chinese Academy of Sciences, Beijing Jianyu Wang Deputy Director, Chinese Academy of Sciences Shanghai Branch Shuangnan Zhang Institute of High-Energy Physics, Chinese Academy of Sciences, Beijing Yifang Wang Director, Institute of High-Energy Physics, Chinese Academy of Sciences, Beijing Mu-ming Poo (Chair) Director, Institute of Neuroscience, Institute of High-Energy Physics, Chinese Academy of Sciences, Shanghai

Abstract Background Camrelizumab and nab-paclitaxel demonstrated promising anti-tumour activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC) in FUTURE trial. Anti-angiogenic agents have been reported to facilitate immune infiltration. Famitinib is a tyrosine kinase inhibitor targeting VEGFR-2, PDGFR and c-kit. The FUTURE-C-PLUS trial (NCT04129996) which added famitinib to camrelizumab and nab-paclitaxel is a single-arm, phase 2 trial evaluating this novel triplet combinatorial strategy in patients with advanced immunomodulatory TNBC. Study design and the primary endpoint ORR has been reported previously (Zhi-ming Shao, et al. ASCO 2021, Abstract 1007). Here, we reported the updated results of this trial. Method Briefly, this study enrolled women aged 18-70 years, with previously untreated, histologically confirmed, unresectable, locally advanced, recurrent or metastatic immunomodulatory TNBC. Immunomodulatory TNBC was defined as CD8 expression on at least 10% of cells using immunohistochemistry analysis. Eligible patients received the triple therapy. Study design has been reported previously in ASCO 2021. Results Between Oct 2019 and Oct 2020, 48 patients were enrolled and treated. 39 (81.3%, 95% CI 70.2-92.3) patients had a confirmed objective response which has been reported in ASCO 2021. At this updating data cutoff (June 30, 2021), the median progression-free survival was 11.9 months (95% CI, 7.3-16.5) with the median follow-up was 14.0 months. While overall survival data were not mature yet, a promising overall survival rate was observed at 12 months (84•2%, 95% CI 73.4-95.0) and 18 months (73.6%, 95% CI 52.0-95.2). In the 39 responders, median duration of response was also not mature. The disease control rate was 95.8% (46/48). The most common treatment-related grade 3 or 4 adverse events were neutropenia (16 [33.3%]), anemia (5 [10.4%]), febrile neutropenia (5 [10.4%]), and thrombocytopenia (4 [8.3%]). No treatment-related deaths were reported. Conclusions These data, combined with those from our previous reports, provide further evidence for the triplet combination of famitinib, camrelizumab and nab-paclitaxel as an active therapy in advanced Immunomodulatory TNBC. To our knowledge, this is the best objective response rate reached in first-line treatment of advanced TNBC. A randomized controlled FUTURE-Super trial (NCT04395989) is keeping recruiting patients to further validate those findings. Citation Format: Li Chen, Yi-Zhou Jiang, Songyang Wu, Jiong Wu, Genhong Di, Guangyu Liu, Keda Yu, Lei Fan, Junjie Li, Yifeng Hou, Zhen Hu, Canming Chen, Xiaoyan Huang, Ayong Cao, Xin Hu, Shen Zhao, Xiaoyan Ma, Xiaoyu Zhu, Jianjun Zou, Wentao Yang, Zhonghua Wang, Zhi-ming Shao. Updated data from FUTURE-C-PLUS: Combination of famitinib with camrelizumab plus nab-paclitaxel as first-line treatment for advanced, immunomodulatory triple-negative breast cancer, an open-label, single-arm, phase 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-04.

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes (luminal androgen receptor [LAR], immunomodulatory [IM], basal-like immune-suppressed [BLIS], mesenchymal-like [MES]) with distinct molecular features. We aimed to assess the efficacy and safety of molecular subtype-derived precision treatment in patients with heavily pretreated metastatic TNBC. Methods: This open-label, phase 2, umbrella trial included patients from four centers in China. Participants were women (aged ≥18 years) with histologically confirmed metastatic TNBC with disease progression after multiple lines of standard chemotherapy. Patients were enrolled into seven parallel arms according to their molecular subtypes: LAR with or without ERBB2 somatic mutation/amplification assigned to arm A (pyrotinib with capecitabine) and arm B (androgen inhibitor included therapy); IM assigned to arm C (anti-PD-1 antibody with nab-paclitaxel); BLIS with or without BRCA1/2 germline mutation assigned to arms D (PARP inhibitor included therapy) and E (anti-VEGFR included therapy); MES without or with PI3K-AKT mutation assigned to arms F (anti-VEGFR included therapy) and G (everolimus with nab-paclitaxel). Bayesian predictive probability was adopted to monitor each arm, which can be terminated independently according to a prespecified futility or efficacy boundary. This trial is registered with ClinicalTrials.gov, NCT03805399. Findings: Between October 18, 2018, and February 11, 2022, we enrolled 141 patients. All patients were heavily pretreated and resistant to six categories of the most common chemotherapeutic agents used in breast cancer treatment, with a median of 3 previous lines of therapies in the metastatic setting (Table 1 and 2). The median follow-up was 18.3 months (IQR 11.7-27.7). A confirmed objective response was achieved in 42 (29.8%, 95% CI 22.4-38.1) of the 141 patients. The median PFS was 3.4 months (95% CI 2.7-4.2), and the median OS was 10.7 months (95% CI 9.0-12.3) (Table 3). Arms A, C, E and G achieved efficacy boundaries, with 3 (75.0%) out of 4 patients in arm A, 20 (43.5%) out of 46 patients in arm C, 13 (28.3%) out of 46 patients in arm E, and 3 (33.3%) out of 9 patients in arm G achieving objective responses. Potential predictive biomarkers of efficacy in each arm were explored. Safety data were consistent with the known safety profiles of relevant drugs. Interpretation: We demonstrate the feasibility and clinical utility of a subtyping-based, genomic sequencing-guided strategy which allows the majority of heavily pretreated metastatic TNBCs to benefit from precision treatment. Most arms exhibit promising efficacy and manageable toxicities, providing subtyping schema to optimize personalized treatment. Table 1. The FUTURE trial schema. Patients are stratified into seven arms using the FUSCC 484-gene NGS panel testing and IHC subtyping. Abbreviations: mTNBC, metastatic triple-negative breast cancer; NGS, next-generation sequencing; IHC, immunohistochemistry; FUSCC, Fudan University Shanghai Cancer Center; LAR, luminal androgen receptor; IM, immunomodulatory; BLIS, basal-like immune-suppressed; MES, mesenchymal-like; n, number; AR, androgen receptor; PD-1, programmed cell death-1; PARPi, poly ADP-ribose polymerase inhibitor; VEGF, vascular endothelial growth factor; mTORi, mammalian target of rapamycin inhibitors. Table 2. Patient characteristics in the FUTURE trial. Table 3. Summary of treatment efficacy of TNBC in the FUTURE trial Citation Format: Zhi-Ming Shao, Zhong-Hua Wang, Yi-Zhou Jiang, Yin Liu, Xiu-Zhi Zhu, Yi Xiao, Song-Yang Wu, Wen-Jia Zuo, Qiang Yu, A-Yong Cao, Jun-Jie Li, Ke-Da Yu, Guang-Yu Liu, Jiong Wu, Tao Sun, Jiuwei Cui, Zheng Lv, Hui-Ping Li, Xiao-Yu Zhu. Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: a multicenter, phase 2, umbrella, FUTURE trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-27-01.

Abstract Background: FCN-437c is a second-generation CDK4/6 inhibitor. Phase 1b clinical results indicated improved antitumor activity in patients (pts) with HR+, HER2– advanced breast cancer (ABC), treated with FCN-437c + letrozole. Methods: This Phase 2, multicenter, open-label clinical study evaluated the antitumor activity, pharmacokinetics (PK), and safety of FCN-437c + fulvestrant in post-menopausal pts (Cohort 1, treatment-naïve or 2L), FCN-437c + letrozole + goserelin in pre-menopausal pts (Cohort 2, treatment-naïve). Pts received FCN-437c (200 mg QD) in a 21-day-on and 7-day-off schedule either in combination with fulvestrant (500 mg D1) or letrozole (2.5 mg QD) + goserelin (3.6 mg once per cycle) in 28-day cycles. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), PK, and safety. Results: At study cutoff (Feb 7, 2022), 36 pts were enrolled in Cohort 1 and 31 pts were in Cohort 2; 42 (62.7%) pts had visceral metastases and 9 (13.4%) pts had bone-only metastases. In Cohort 1, 18 pts were treatment-naïve, 15 pts had received 1L treatment, and 3 pts had received ≥2L treatment. In Cohort 2, 25 pts were treatment-naïve and 6 pts had received 1L treatment. Overall, 27 pts in the per-protocol set achieved partial response (PR), resulting in an ORR of 40.9% (95% CI, 29.0-53.7). Median follow-up was 12.8 months, and median PFS (mPFS), OS, and DOR were not reached. However, at 12 months, the PFS rate was 67.7% (95% CI, 53.2-78.6) and the OS rate was 95.9% (95% CI, 84.5-99.0); the 6-month DOR rate was 96.0% (95% CI, 74.8-99.4). In Cohort 1 (n=35), 11 pts achieved PR: the ORR was 31.4% (16.9-49.3%) and mPFS was 12.9 months (95% CI, 9.2-NR); the 6-month DOR rate was 100%. In Cohort 2 (n=31), 16 pts achieved PR: the ORR was 51.6% (95% CI, 33.1-69.9%). mPFS, OS, and DOR were not reached; the 6-month DOR rate was 92.9% (95% CI, 59.08-98.96) (Table). Treatment-emergent adverse events (TEAEs) were observed in all pts. Majority of AE were G1 or 2 except for hematological TEAE. 58 (86.6%) pts reported grade ≥3 TEAEs, mainly neutropenia (74.6%), leukopenia (49.3%), hypertriglyceridemia (6.0%), lymphocyte count decrease (4.5%), and γ-glutamyltransferase increase (3.0%): most were reversed through dose interruption and symptomatic therapy. Steady-state PK parameters were analyzed after 15-21 days of QD administration: Cohort 1: median Tmax was 3 h, geomean T1/2 was 44.6 h, geomean Cmax was 1650.7 ng/mL, and geomean AUC0-24h was 29,148.08 h*ng/mL; the geomean accumulation ratios of AUC0-24h and RCmax were 2.18 and 1.74, respectively, compared with first dose. Cohort 2: median Tmax was 4 h, geomean T1/2 was 35.7 h, geomean Cmax was 1314.34 ng/mL, and geomean AUC0-24h was 22,889.96 h*ng/mL; the geomean accumulation ratios of AUC0-24h and RCmax were 1.95 and 1.63, respectively, compared with first dose. Conclusion: FCN-437c in combination with fulvestrant or letrozole + goserelin demonstrates antitumor activity and safety and is well tolerated in pts with HR+, HER2– ABC. This combination therapy will be further investigated in 2 ongoing Phase 3 trials (NCT05438810 and NCT05439499). Clinical trial number: NCT05004142. Research Sponsor: Avanc Pharmaceutical Co., Ltd Table. Clinical outcomes for patients in the per-protocol set. Citation Format: JiaJie Shi, Wei Li, Zhongsheng Tong, Aimin Zang, Xiaohua Zeng, Shui Wang, Tao Huang, Ying Wang, Yanqiu Song, Lihua Kang, Zheng Lv, Yehui Shi, Hua Yang, Jing Wu, Yongmei Yin, Yan Liang, Jie Tan, Jie Ming, Yaping Yang, Simin Luo, Xiujuan Gui, Ai-Min Hui, Zhuli Wu, Ling Tian, Yuchen Yang, Lei Diao, Wenjing Zhang, Yongjiao Zhang, Yunjiang Liu. Phase 2 Study of the CDK4/6 Inhibitor FCN-437c in Combination With Fulvestrant or Letrozole and Goserelin in Patients With HR+, HER2– Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-21.

Abstract Background: With more endocrine therapies- (ET) based treatment (tx) available, genomic markers that could assist in the prediction of tx outcome is critical. The role of ctDNA mutations in ER+/HER2- metastatic breast cancer (MBC) after prior ET is based on retrospective study results. Methods: ER+/HER2- MBC patients (pts) starting ET-based salvage tx were eligible (NCT04212702). Cell-free DNA (cfDNA) was extracted from plasma before tx, and prepared for next-generation sequencing (NGS) analysis. The targeted NGS for ctDNA included regions of the ESR1 ligand-binding domain, PIK3CA hotspot mutations, and TP53 DNA-bonding domain mutations. 96% of the samples were sequenced at an average depths >10000x using the Ion Torrent platform. Progression-free survival (PFS) was defined from the start of the salvage tx to the date of progression. Results: From 2015/08 to 2020/05, a total of 163 pts treated with ET-based tx were prospectively enrolled. The median age was 60 (32-92). 13%, 15%, 48%, and 17% of pts received ET only, ET + CDK4/6 inhibitor, ET + everolimus, and ET + metronomic chemotherapy, respectively. Only 14 patients received fulvestrant as ET. The median level of recovered cfDNA was 38.5 ng (range 4.4-1935) and the level of cfDNA was significantly and inversely correlated with PFS (p = 0.0032). With mutation ctDNA ≥ 0.5% as a threshold for positive calling, 100 (61.3%), 41 (25.1%), and 25 (15.3) pts have at least one ESR1, PIK3CA, and TP53 mutation, respectively and 61 (37.4%) pts had >1 ESR1 mutation genotypes. The median PFS of the cohort (n=163) was 8.3 mos (95% CI 5.7 – 11.1 mos). PIK3CA mutation (MT) in ctDNA was associated with a worse outcome in all patients (HR 1.91, 95% CI 1.20 to 3.04, p = 0.0064) and the subgroups of ET + everolimus (HR 2.20, 95% CI 1.10 – 4.39, p = 0.025) and ET + metronomic chemotherapy (HR 5.34, 95% CI 1.63- 17.54, p = 0.006). The presence of TP53 MT ctDNA was also associated with worse PFS (HR 1.81, p = 0.043, n = 163) but also exerted a poor prognostic impact in pts with wild type (WT) PIK3CA (HR 3.28, 95% CI 1.44 – 7.48, p = 0.0048). However, the variant allelic frequency (VAF) of PIK3CA MT (p = 0.0421), but not TP53 MT (p = 0.7723), had a inverse linear correlation with PFS. Surprisingly, pts with ESR1 MT had a better PFS as compared to ESR1 WT pts (HR 0.68 95% CI 0.46 – 0.99, p = 0.049). However, if the threshold for. variant calling was raised to 2%, then ESR1 MT (n= 52, 31.9%) vs WT pts had similar PFS (median PFS 8.6 vs 7.8 mos, HR 0.92, 95% CI 0.62-1.37, p = 0.69), suggesting that defining different VAF threshold of MT ESR1 may have divergent PFS impact. How ERS1 MT ctDNA affected PFS was dependent on PIK3CA/TP53 status. When either PIK3CA or TP53 MT ctDNA was present, the ESR1 MT ctDNA did not have any impact on PFS, regardless of VAF. In pts with WT PIK3CA/TP53, pts with ESR1 MT ctDNA VAF 0.5 – 2.0% had a significant better PFS as compared with triple WT pts (HR 1.9, p = 0.0035). Conclusion: Using a 3-gene panel for ctDNA testing with MT ctDNA ≥ 0.5% as a threshold for positive calling in ER+/HER2- MBC pts treated with ET-based tx, the presence of PIK3CA and TP53 mut in ctDNA conferred a worse prognosis. The positive prognostic impact of ESR1 was only noticeable in pts with PIK3CA and TP53 WT ctDNA, and the presence of a low VAF ESR1 MT ctDNA, which may suggest an ER denpendency, was significantly correlated with a better outcome. Table 1.Median PFS of pts with and without PIK3CA, TP53 and ESR in ctDNAPopulation (n)Genotype(s)Median PFS (mos)Hazard Ratiop-valueAll (163)PIK3CA MT (41) vs. WT (122)(VAF ≥ 0.5%)5.4 vs. 10.31.910.0064TP53 MT (25) vs. WT (143)(VAF ≥ 0.5%)4.1 vs. 8.91.810.0439ESR1 MT vs. WT(VAF ≥ 0.5%)9.8 vs. 5.80.680.0493ET + everolimus (82)PIK3CA MT vs. WT(VAF ≥ 0.5%)2.8 vs. 5.92.200.0254PIK3CA and TP53 WT (106)WT vs ESR1 MT (VAF ≥ 0.5% - < 2%)6 vs 15.61.910.0035WT vs ESR1 MT (VAF ≥ 2%)6 vs 121.360.355 Citation Format: Tom Wei-Wu Chen, Wen Hsiao, Ming-Shen Dai, Ching-Hung Lin, Dwang-Ying Chang, I-Chun Chen, Ming-Yang Wang, Ling-Yi Huang, Shu-Han Chang, Shu-Min Huang, Ann-Lii Cheng, Kien Thiam Tan, Yen-Shen Lu. Clinical impact of ESR1 mutation ctDNA on survival outcome is dependent on PI3KCA/TP53 ctDNA mutation status [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-09.

Finger millet has gained considerable attention worldwide due to its nutritional and health benefits. Being a rainfed crop of semiarid and arid regions, drought is one of the major constraints to its yield stabilisation. To address this, a set of 38 accessions of finger millet were evaluated in both field and mini-lysimeters under both well-watered (WW) and water-stressed (WS) conditions. The objectives of the study were to identify the range of variations for yield components, water-use (WU) and transpiration efficiency (TE) and to examine the potential of the mini-lysimeter system in assessing the genotypic performance in the field conditions. Approximately 2-fold variations in shoot biomass and ~9-fold variations in grain yield under WS conditions were observed. Reproductive growth was more sensitive to WS than the vegetative growth. Our results indicate that in addition to yield potential under WW conditions, WU followed by TE were the other two major contributors toward shoot biomass, whereas, HI followed by TE were the major contributors toward grain yield under WS. The close association between the yield components recorded in the field and in mini-lysimeters suggests that the lysimetric system has the great potential to reflect the genotypic performance under field conditions. Regression analyses suggest that HI explained almost all the variations in grain yield under WW conditions, whereas under WS treatment, next to HI, both TE and WU had also contributed significantly to grain yield. The absence of interrelationship between WU and TE suggests that both these components contribute independently toward the yield components under WW or WS conditions. The accessions with higher shoot biomass and grain yield extract much more water during the post-anthesis stages than the poor performers under WS. Results also suggests that higher WU contributed more towards shoot biomass and higher TE contributed more towards grain yield by improving the harvest index.

Abstract Background: CID occurs in up to 80% of patients with breast cancer who receive trastuzumab (H), pertuzumab (P), and a taxane, with grade 3 experienced by 8-12% of patients. Crofelemer is an extract of the Croton lechleri tree that inhibits luminal chloride efflux, implicated in the HP-related CID. We hypothesized crofelemer would prevent diarrhea in patients with HER2+ breast cancer receiving HP and docetaxel or paclitaxel, with/without carboplatin (THP or TCHP) in the neoadjuvant, adjuvant, or metastatic setting. Clinical trial information: NCT02910219. Methods: Adult patients with HER2+ any stage breast cancer, scheduled to receive at least 3 consecutive cycles of TCHP (docetaxel, carboplatin, trastuzumab and pertuzumab) or THP (trastuzumab and pertuzumab with paclitaxel or docetaxel), normal organ function, PS 0-2, who provided written informed consent were randomized 1:1 to receive crofelemer 125 mg PO 2x/day during cycles 1 and 2 of chemotherapy or no scheduled prophylactic medication. Randomization was stratified according to chemotherapy regimen. The primary endpoint was the incidence of CID of any grade for ≥2 consecutive days assessed by NCI CTCAE v4.0. Provider reported outcomes were collected during clinic visits and prospectively documented in clinical notes. Patient reported outcomes (PRO) were collected from patient diaries. Secondary endpoints were incidence of all grades and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; frequency of break through anti-diarrheal medications use; and FACIT-D total score. Fisher’s exact test was used for comparing binary and categorical variables and summary statistics and Wilcoxon test for ordinal grade variables. The trial was designed to detect a 40% absolute decrease in incidence of CID (from 60% to 20%), two-sided significance level of 0.10. Results: A total of 53 patients were enrolled between 02/21/2017- 08/25/2020 on crofelemer (n=27) or control (n=26) arms. One patient withdrew consent prior to starting protocol procedures and was substituted. Early treatment discontinuation occurred in 7 cases: complications of diarrhea (n=1, control group), chemotherapy regimen changed for other cause than diarrhea (n=4) and non-compliance with trial procedures (n=2). 29 patients had early stage disease treated with TCHP; 23 patients had metastatic disease treated with THP (16 with paclitaxel and 7 with docetaxel). The primary endpoint was not statistically different between the two groups. The incidence of Grade 2 or greater diarrhea was 20.9% vs 26.4% of patients receiving crofelemer or placebo respectively in cycle 1, and 9.5% vs 41.1% in cycle 2 (Table). Results were consistent between provider assessments and patient reported outcomes (PRO). Detailed description of pooled cycle 1-2 data using correlated ordinal model and the additional secondary endpoints will be presented. Conclusions: Although there was no significant difference between crofelemer and control for diarrhea for 2 or more consecutive days in both cycles, there was a clinically meaningful difference between the crofelemer and control groups in maximum within-cycle diarrhea ordinal CTCAE grade diarrhea. These data are supportive for further testing of crofelemer in the ongoing randomized Phase 3 trial OnTARGET (NCT04538625). CycleCTCAE bCrofelemerControlPDiarrhea >= 2 consecutive days a168.069.6NS d265.272.2Maximum diarrhea grade a1Grade 0 c33.321.1NS eGrade 145.852.6Grade 216.721.1Grade 34.25.3Grade 40.00.02Grade 0 c38.117.60.0261 eGrade 152.441.2Grade 29.523.5Grade 30.017.6Grade 40.00.0Maximum diarrhea grade PRO f1Grade 0 c4.08.7NS eGrade 172.039.1Grade 216.043.5Grade 38.08.7Grade 40.00.02Grade 0 c9.10.00.0361 eGrade 181.866.7Grade 24.522.2Grade 34.511.1Grade 40.00.0aProvider assessedbCTCAE: NCI Common Terminology Criteria for Adverse Events v4.0cGrade 0: no diarrheadFisher''s exact testeWilcoxon rank sum testfPRO: Patient reported outcomes Citation Format: Paula R Pohlmann, Deena Graham, Tianmin Wu, Yvonne Ottaviano, Mahsa Mohebtash, Shweta Kurian, Donna McNamara, Filipa Lynce, Robert Warren, Asma Dilawari, Suman Rao, Candace Mainor, Nicole Swanson, Ming Tan, Claudine Isaacs, Sandra M. Swain. Halt-d: A randomized open label phase 2 study of crofelemer for the prevention of chemotherapy induced diarrhea (cid) in patients with breast cancer receiving trastuzumab, pertuzumab, and a taxane [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-09.

Background:With multiple disease domains affected in PsA, clinical and patient-reported outcome (PRO) measures are important to assess disease improvement following treatment. Rapid, meaningful improvements in disease activity are a priority for physicians and patients (pts). Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Higher proportions of pts achieved responses in PROs and clinical measures when treated with tofacitinib for 3 months vs placebo (PBO).1-5Proportions of responders were also similar between tofacitinib and adalimumab (ADA) after 3, 6 and 12 months.2,3,5Objectives:To determine the time to initial response using responder definitions for selected PROs and clinical endpoints in pts with active PsA treated with tofacitinib, ADA or PBO switching to tofacitinib.Methods:In this post hoc analysis, data were collected from two Phase 3 studies (OPAL Broaden [12 months;NCT01877668]; OPAL Beyond [6 months;NCT01882439]).3,4Pts receiving tofacitinib 5 or 10 mg twice daily (BID), subcutaneous ADA 40 mg once every two weeks (Q2W; OPAL Broaden only), or PBO switching to tofacitinib 5 or 10 mg BID at Month (M)3, were included. Responder definitions included: HAQ-DI ≥0.35-point improvement from baseline (BL), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score ≥4-point improvement from BL, minimal disease activity (MDA) yes/no composite response (meeting at least 5 of 7 criteria) and PsA Disease Activity Score (PASDAS) post-BL score of ≤3.2 and >1.6-point improvement from BL. First post-BL data were collected at Week 2 (eg for HAQ-DI) or M1. Time-to-event analyses were performed using the Kaplan-Meier (KM) method, with pts censored at the last observed visit. Log-rank tests compared time to initial response across treatment groups.Results:KM analyses show days to initial response (Figure 1, Figure 2). Time to initial HAQ-DI response was significantly different between treatment groups in OPAL Broaden (p<0.01): faster response in pts receiving tofacitinib 5 mg BID, tofacitinib 10 mg BID and ADA 40 mg Q2W vs pts who switched from PBO to tofacitinib at M3 (Figure 1a). A similar, but not significant (ns), trend was observed for HAQ-DI responses in OPAL Beyond (Figure 1b). Generally, initial FACIT-F responses were achieved faster (ns) in pts receiving tofacitinib 5 mg BID vs other treatment in both studies (Figure 1c, Figure 1d). Times to initial MDA and PASDAS responses were similar between tofacitinib and ADA treatment groups (Figure 2).Conclusion:Times to initial response in functional ability and disease activity were similar in pts treated with either tofacitinib or ADA. Time to initial response prior to first post-BL observation (Week 2 or M1) was not estimable in this analysis. These results may help physicians better understand the time frame for a meaningful response in pts receiving tofacitinib.References:[1]Strand et al. RMD Open 2019;5:e000808.[2]Strand et al. RMD Open 2019;5:e000806.[3]Mease et al. NEJM 2017;377:1537-50.[4]Gladman et al. NEJM 2017;377:1525-36.[5]Helliwell et al. Arthritis Res Ther 2018;20:242.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Eric Comeau of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Laura C Coates: None declared, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Elizabeth Bacci Employee of: Evidera, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Philip Helliwell: None declared

Abstract Given that CD38 is a clinically validated target for NK cell mediated cytotoxicity in multiple myeloma, we sought to leverage our FLEX NKTrademark platform to create a NK engager antibody targeting CD38. FLEX NKTrademark is a proprietary platform for production of tetravalent multifunctional NK engager antibodies with a novel FLEX linker to allow for simultaneous binding of both the targeted cancer cells and NK cells. NK engagement and activation is mediated through a binder directed against the natural cytotoxicity receptor NKp46. With the FLEX NKTrademark scaffold, we created two novel tetravalent NK cell engagers targeting CD38, one with a wild type (WT) Fc and one with a mutant null Fc. Both CD38 NKp46 engagers showed dose dependent binding to CD38 expressing multiple myeloma cell lines MM1S and KMS11 and no binding to a CD38 knock out MM.1S cell line. Both engagers also bound multiple myeloma cell lines with ~ 2-fold higher mean fluorescence intensity than anti-CD38 monoclonal antibody (mAb)or daratumumab alone. Epitope mapping studies for our anti-CD38 mAb using alanine scanning mutagenesis showed that amino acid S274 on CD38, critical for binding to daratumumab, is not important for our anti-CD38 antibody binding to CD38, suggesting a distinct epitope detected by our antibody. Interestingly, the NKp46 monoclonal antibody alone without a functional Fc induced peripheral blood NK cell cytolysis of the multiple myeloma cells, consistent with a prior report that NKp46 plays a key role in NK-cell mediated killing of myeloma cells. Both CD38 NKp46 engagers showed further enhanced dose dependent NK cell redirected cytolysis and degranulation against multiple myeloma cells compared to anti-NKp46 monoclonal antibody. The CD38 NKp46 engagers demonstrated higher cytotoxicity than the anti-CD38 binder mAb or daratumumab alone. The CD38 NKp46 engager with the WT Fc is more potent in induction of TNF-α and IFN-ɣ production compared to daratumumab and the engager with the mutant Fc. No IL-1β or IL-6 was induced by the engagers or daratumumab. Daratumumab treatment resulted in NK cell fratricide, while no fratricide was observed with the CD38-NKp46 NK engager with the mutant Fc. In peripheral blood mononuclear cell hemato-toxicity studies depletion of monocytes and NK cells were observed with daratumumab but no depletion was observed with the CD38 NKp46 engager with the mutant Fc. These results suggest that the CD38 NKp46 engagers have a favorable NK cell engager profile for targeting CD38 expressing multiple myeloma that’s distinct from daratumumab. Citation Format: Liang Lin, Hao-Ming Chang, Cecilia Nakid, Stanley Frankel, Dennis Wu, Jean Kadouche, Daniel Teper, Ofer Mandelboim, Jean-Christophe Bories, Antonio Arulanandam, Wei Li. Novel multifunctional tetravalent CD38 NKp46 FLEX NK࣪ engagers actively target and kill multiple myeloma cells [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 3436.

Background:Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease, usually involving multiple systems of the whole body (1). A variety of factors can affect SLE, such as genetic, environmental, immunoregulatory, hormonal and epigenetic (2). Long non-coding RNA is a type of RNA greater than 200 nucleotides that does not encode proteins. With the development of research, lncRNA gradually becomes the key regulator of gene expression in the immune system (3). Studies have shown that several lncRNAs, such as NEAT1 and GAS5 are dysregulated in SLE and are involved in the pathogenesis of SLE (4,5). These results suggest that lncRNA can be used as a potential biomarker for disease diagnosis and treatment. However, our current understanding of SLE related lncRNAS is still limited.Objectives:The purpose of this study was to find new lncRNAs in peripheral blood monouclear cells of SLE patients by transcriptome sequencing and explore their potential as biomarkers and their correlation with clinical features.Methods:Transcriptome sequencing was used to screen differentially expressed lncRNAs (DELs) and mRNAs (DEMs). DAVID and WebGestalt were used to perform enrichment analysis. Cytoscape was used to constructed protein-protein network, co-expression network and competitive endogenous RNA network to reveal the regulatory mechanism of lncRNAs in transcriptome level. The expression of these selected lncRNAs in SLE patients and healthy controls were verified by qPCR.Results:A toal of 1737 DELs and 4078 DEMs were identified between 5 SLE patients and 5 healthy controls. Most of upregulated genes were enriched in defense and immune response, while downregulated genes were mainly enriched in SLE related pathways. Topology network analysis reveal the regulatory mechanism of lncRNAs in transcriptome level including directly acting on mRNA or indirectly affecting gene expression after acting on miRNA. Ten lncRNAs and eight genes was verified by qPCR in bigger samples including 77 SLE patients and 25 healthy controls. LncRNA NONHSAT101022.2 was significantly downregulated in SLE patients (p=0.001) and the expression of NONHSAT101022.2 showed a significant negative correlation with SLE disease activity index (SLEDAI, r=-0.3592, p=0.0013).Conclusion:In this work, we identified a large number of mRNAs and novel lncRNAs by transcriptome sequence. The function and regulatory mechanism of these lncRNAs were analyzed by bioinformatics methods. LncRNA NONHSAT101022.2 is significantly downregulated in SLE patients and significantly related to the activity and severity of disease. Additionally, we put forward that NONHSAT101022.2 may enhance the signal transduction of β2-AR by cis-regulating its target gene, LMBRD2, which induces NK cells to produce high levels of IFN-γ, thereby exacerbating SLE.References:[1]Carter EE, Barr SG, Clarke AE. The global burden of SLE: prevalence, health disparities and socioeconomic impact. Nat Rev Rheumatol. 2016;12(10):605-20.[2]Han EC. Systemic lupus erythematosus. N Engl J Med. 2012;366(6):573-4; author reply.[3]Chen YG, Satpathy AT, Chang HY. Gene regulation in the immune system by long noncoding RNAs. Nat Immunol. 2017;18(9):962-72.[4]Zhang F, Wu L, Qian J, Qu B, Xia S, La T, et al. Identification of the long noncoding RNA NEAT1 as a novel inflammatory regulator acting through MAPK pathway in human lupus. Journal of autoimmunity. 2016;75:96-104.[5]Liu Q, Deng Y, Li C, Xie H, Liu Q, Ming S, et al. LncRNA GAS5 suppresses CD4(+) T cell activation by upregulating E4BP4 via inhibiting miR-92a-3p in systemic lupus erythematosus. Immunol Lett. 2020;227:41-7.Disclosure of Interests:None declared

Abstract Claudin 18.2 (CLDN18.2) is a surface protein overexpressed in gastric and pancreatic tumors and has been demonstrated to be a clinically validated target for developing mAb and CAR-T therapies for these tumors. CD47 is a well-established “don’t eat me” signal and commonly overexpressed by many types of tumor cells as a mechanism for evading the innate immune system. It has been demonstrated in clinic that blocking CD47 from interacting with its ligand SIRPα leads to reduced growth of certain hematological tumors, presumably by activating the innate immune system against tumor cells. Here we present a therapeutic strategy for targeting both CLDN18.2 and CD47 with a bispecific antibody to achieve cancer killing by two mechanisms: (1) Blocking the CD47-SIRPα interaction and stimulating phagocytosis of tumor cells by macrophages. (2) Delivering robust effector effect (ADCC by NK cells and ADPC by macrophages) mediated by the functional Fc of the bispecific antibody. We report a native IgG-like anti-CLDN18.2/anti-CD47 bispecific antibody, PT886, that was generated using our newly developed PACbody™ and SPECpair™ technology platforms. The PACbody™ and SPECpair™ technologies are designed to allow assembled bispecific antibodies to have excellent biophysical properties and to be manufactured by a conventional three-step platform process commonly used for mAbs. PT886 has high affinity monovalent binding to cell surface CLDN18.2 and low affinity monovalent binding to cell surface CD47. This combination allows for the preferential binding of PT886 to tumor cells which overexpress both CLDN18.2 and CD47, but reduced binding to normal cells that only express CD47. Consequently, PT886 exhibits higher activity toward CLDN18.2-expressing tumor cells and lower to no activity to normal cells that do not express CLDN18.2. This was demonstrated in a phagocytosis assay where PT886 stimulates stronger phagocytosis in the presence of CLDN18.2 binding in vitro. In addition to targeting both CLDN18.2 and CD47, PT886 has a fully functional Fc to directly recruit the tumor cell killing activities of NK cells and macrophages. The potent anti-tumor activity of PT886 was demonstrated in vivo in a pancreatic cancer xenograft model, where PT886 treatment resulted in a complete tumor clearance at doses as low as 1 mg/kg. PT886 also demonstrated a good safety profile in NHP studies and exhibited regular mAb-like manufacturability in process development and CMC. These data support the proof of concept of the PACbody™ and SPECpair™ technology platforms and demonstrate the unique profile of our anti-CD47 arm that’s suitable for the bispecific antibody approach. PT886 is a first-in-class anti-CLDN18.2/anti-CD47 bispecific antibody with native IgG-like structure and phase 1 clinical trial is planned for the first quarter of 2022. Citation Format: Jack Li, Haiqun Jia, Erin Ramsey, Huiwen Wu, Yang Long, Kelan Chen, Albert Lam, Ming Wang, Hui Zou. PT886, an anti-claudin18.2/anti-CD47 bispecific antibody constructed with the PACbody࣪ and SPECpair࣪ technology platforms, exhibits robust anti-tumor activity in a pancreatic cancer xenograft model [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 4260.

Abstract Background: Anti-PD1 immune checkpoint blockade (ICB) has largely failed as a monotherapy for metastatic prostate cancer likely due to inadequate tumor neoantigen load and inadequate T cell filtration (TILs). Strategies to increase TILs that can be tested in novel syngeneic mouse models are needed in order to fulfill this critical medical need. CDK7 is a major regulator of the cell cycle that is under investigation as a novel therapeutic target. CDK7 inhibition can trigger robust anti-tumor immunity by causing genomic instability and DNA damage in lung cancer mouse models. Herein, we characterize our novel syngeneic mouse models and report on the anti-tumor activity of CDK7 alone and in combination with anti-PD1 ICB as an immunotherapeutic strategy. Methods: We generated two models of prostate cancer organoids and syngeneic mouse models. APC and PTEN are tumor suppressor genes commonly lost in metastatic prostate cancer and are emerging as a putative mechanism of resistance to immunotherapy. The MPA and MPP models were established by ex-vivo Lenti-Cas9-sgRNA knock-out of APC or PTEN from the prostate organoids grown in 3D cultures established from the prostate of a MYCT/TP53-/- GEMM. Results: Organoids from the MPA and MPP models form orthotopic high grade prostate adenocarcinoma from 2 to 3 weeks post-implantation and spontaneously develop lung metastases 10-12 weeks after orthotopic implantation. In addition, the MPA model developed immediate castration resistance and neuroendocrine transformation following hormone deprivation in vivo. By contrast, the MPP tumors significantly regressed after in vivo androgen deprivation. Baseline immunoprofiling of the MPA and MPP orthotopic tumors showed increased infiltration from monocytic MDSCs and expression of T cell exhaustion markers. Treatment of the MPA and MPP orthotopic models with YKL-5-124, a CDK7 inhibitor, led to substantial in vivo tumor growth inhibition, which was further augmented by the addition of anti-PD-1 ICB. Immunoprofiling of tumors treated with combined YKL-5-124 and PD-1 blockade showed activation of CD4+ and CD8+ T cells, and a decrease in the Treg, B cell and NK cell population. Conclusions: The MPA and MPP orthotopic models recapitulate the biology and immune suppressive microenvironment of advanced prostate cancer and provide useful tools for immunotherapy drug development. Combination of CDK7 inhibition with anti-PD-1 blockade profoundly inhibited in vivo orthotopic tumor growth in both MPA and MPP model, providing a rationale for exploring CDK7 in combination with PD-1 checkpoint immunotherapy as a novel therapeutical strategy for advanced prostate cancer. Funding Acknowledgements: DRW is funded through 2018YI2295 Prostate Cancer Foundation Young Investigator Award and PC160944 Department of Defense Physician Research Career Development Award. Citation Format: David Wise, Luiza Doro Pereira, Jiansheng Wu, Victor R. Adorno Febles, Jonathan Melamed, Fang-Ming Deng, Hua Zhang, Kwok-Kin Wong. Profound anti-tumor efficacy of dual CDK7 and PD1 blockade in novel syngeneic prostate cancer models [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 2297.

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Abstract Background: The emergence of anti-HER2 antibody–drug conjugates (ADCs) gave rise to the concept of HER2-low breast cancer (BC). HER2-low BC, which refers to a subgroup of HER2-negative BC with relatively higher HER2 expression (defined as 1+ or 2+ by immunohistochemistry (IHC) staining, without ERBB2 amplification), represents a rather large part of all BCs. However, the molecular nature and internal heterogeneity of HER2-low breast cancer remain obscure, and little is known about the ethnic differences of HER2-low BC. These limitations prevent us from a more precise patient selection and better drug combination strategies in the era of ADCs. To provide a comprehensive and intensive landscape of HER2-low BCs, we characterized HER2-low BCs both clinically and molecularly, which may help clinicians to achieve a more precise clinical management of these patients. Patients and methods: We established a HER2-low BC cohort (N=441) in early-stage Chinese patients and included HER2-0 (N=114) and HER2-positive (N=181) tumors as auxiliary cohorts to characterize HER2-low breast cancers both clinically and molecularly. Whole-exome sequencing, copy number variation assays, RNA sequencing and isobaric quantitative proteomics were conducted to obtain multiomics data. We compared the clinicopathological and molecular features between HER2-low tumors and other HER2 status subgroups stratified and not stratified hormone receptor (HR) status to clarify the distinctness of HER2-low BCs. And we analyzed the internal heterogeneity and ethnic difference of HER2-low BCs by characterizing a distinct subgroup of patients with unique driving mechanisms. Results: HER2-low BCs showed different molecular manifestations from HER2-0 BCs in different HR subgroups. In the HR-negative subgroup, HER2-low BCs consisted of more non-basal-like subtypes than HER2-0 tumors (40.0% vs. 9.1%, P = 0.002), which was an East Asian-specific phenomenon absent in Western cohorts. Also, HR-negative HER2-low BCs showed significant internal molecular heterogeneity, of which basal-like tumors closely mimicked HER2-0 BCs, whereas non-basal-like tumors were similar to HER2-positive BCs. These non-basal-like tumors were mostly categorized as HER2-enriched and luminal androgen receptor (LAR) subtypes. These molecularly distinct tumors might be driven by frequent mutation in PIK3CA and overexpression of FGFR4 and PTK6, which may also serve as therapeutic targets. These results have also been proved in a triple negative breast cancer cohort we reported previously. In contrast, in the HR-positive subgroup, HER2-low BCs showed no large-scale molecular difference from HER2-0 BCs or internal heterogeneity. However, HER2-low patients showed significantly better distant metastasis-free survival than HER2-0 patients (P = 0.029), which might be attributed to the lower loss/deletion levels of 17q11.12 and 17q21.31 in HER2-low breast cancers, in which genes including NF1 and BRCA1 are located. Conclusions: We reported the largest single-center multiomics HER2-low BC cohort in East Asian hitherto, and revealed its molecular nature, internal heterogeneity and ethnic difference. Compared with HR-positive diseases, HER2-low BCs in the HR-negative subgroup were more likely to be a molecularly distinct entity from HER2-0 tumors. Furthermore, HR-negative HER2-low BC also accommodates higher internal heterogeneity, which was ethnicity-specific in our East Asian cohort and may infer a different treatment response. Our work emphasized the need of a more precise stratification within HER2-low BCs and across ethnic groups, which has also been inferred by the results in the subgroup analysis of DESTINY-Breast04 trial. Citation Format: Lei-Jie Dai, Ding Ma, Yi Xiao, Xi Jin, Song-Yang Wu, Ya-Xin Zhao, Han Wang, Wen-Tao Yang, Yi-Zhou Jiang, Zhi-Ming Shao. HER2-09 Multiomics Profiling Characterizes Distinct HER2-low Breast Cancer Subgroups in the East Asian Population [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-09.

Abstract Background: In the past 20 years, the efficacy and prognosis of HER2-positive breast cancer have significantly improved. However, nearly 50% of patients still have residual invasive tumors after chemotherapy combined with dual-targeted neoadjuvant therapy, especially for those with disease progression during treatment. A lack of effective therapeutic regimens results from the failure of targeted therapy, whose heterogeneity is especially worthy of our attention. The aim of this study was to look for efficacy markers and investigate new drug-resistance mechanisms. Methods: Firstly, the high-throughput sequencing data from 81 patients who received neoadjuvant chemotherapy TCbH (paclitaxel + carboplatin + trastuzumab) was analyzed by the efficacy outcomes. They were divided into 8 patients with stable or progressive disease (SD/PD), 35 with partial response (PR), and 38 with pathological complete remission (pCR). Then, UBE2E3 was chosen from the different expression genes between SD/PD and pCR based on efficacy results and the weighted gene co-expression network (WGCNA). UBE2E3 clinical correlations were investigated using publicly available data from The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and UBE2E3 was validated using immunohistochemistry (IHC) on 200 HER2-positive breast cancer tissue chips. Further, the UBE2E3 knockdown and overexpression stable transfer cell lines were constructed, and the effects of UBE2E3 on cell proliferation, clone formation, and drug sensitivity were verified by live cell imaging, the CCK8 assay, plate cloning, and IC50 assays, respectively. The tumor growth of UBE2E3 in vivo was investigated by an in situ transplantation tumor assay in nude mice. Meanwhile, the p-RB assay of mouse tissues by IHC was used to explore the effect of UBE2E3 on cell proliferation. RNA-seq was used to screen the downstream molecules of UBE2E3. Western blotting was used to verify the results of bioinformatics analysis and to explore the downstream key molecules. The protease inhibitor MG132 and actinomycin CHX were used to look at the effect on the stability of the target protein. Immunoprecipitation and silver staining assays were used to find interacting proteins with the UBE2E3. Results: Ten hub-genes which were efficacy-related were identified by WGCNA analysis, in which UBE2E3 was highly expressed in the SD/PD group (p &lt; 0.05). In HER2-positive breast cancer, high expression of UBE2E3 was associated with poor prognosis and decreased disease-free survival both in public data and Fudan University Shanghai Cancer Center (FUSCC) data [HR 2. 36, (1.25–4.47), p &lt; 0.05]. The experimental results demonstrated that UBE2E3 promoted the proliferation of HER2-positive breast cancer cells, enhanced clone formation, and resisted lapatinib’s treatment in cellular phenotype; and that UBE2E3 promoted tumor growth in vivo and upregulated the expression of p-RB. The differentially expressed genes’ sets of the RNA-seq between overexpressed cell lines and control showed that overexpressing UBE2E3 activated the EGFR pathway. Further, an immunoblot assay confirmed that UBE2E3 positively regulated EGFR levels and activated the downstream MAPK pathway. The proteasome inhibitor MG132 and CHX assays showed that UBE2E3 could stabilize EGFR proteins. The co-immunoprecipitation and silver staining assays showed that UBE2E3 stabilized EGFR proteins by interacting with c-Cbl. Conclusion: UBE2E3 could negatively affect the efficacy of HER2-positive breast cancer therapy and is significantly associated with poor prognosis. UBE2E3 may serve as a potential marker of efficacy and prognosis for HER2-positive breast cancer in the future. Therapeutic efficacy is affected by UBE2E3, which binds to c-Cbl and causes upregulation of EGFR expression in vivo, which in turn causes the MAPK pathway to be activated and tumor growth to be pushed up. Citation Format: Pei Li, Wei-Ru Chi, Bingqiu Xiu, Qi Zhang, Liyi Zhang, Ming Chen, Jingyan Xue, Xiaoyan Huang, Yayun Chi, Jiong Wu. UBE2E3 promotes the progression of HER2-positive breast cancer and influences the efficacy of targeted therapy via EGFR stabilization [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-41.

Abstract Background: Female breast cancer has been the world’s leading cancer incidence among women. HER2-positive breast cancer accounts for about 15%~20% of all breast cancer, with a high degree of malignancy and easy metastasis and recurrence. With the development of medical technology and the continuous innovation of HER2 targeting drugs, patients with HER2-positive breast cancer have more treatment options and their prognosis had been greatly improved. However, there is still a lack of biomarkers for HER2-positive early breast cancer in clinical practice. Methods: This study prospectively collected single-center (Fudan University Shanghai Cancer Center, FUSCC) preoperative core needle biopsy samples of breast cancer patients from July 2017 to July 2018 who received neoadjuvant paclitaxel, carboplatin plus with trastuzumab (PCH). The patients were divided into pCR and non-PCR groups, and 81 patients were enrolled. The differential expression of genes was screened and validated by RNA-seq. The gene expression data for GSE181574 (this database has a total of 105 cases of breast cancer tissue samples were collected by core needle biopsy before neoadjuvant treatment. 52 cases underwent Ado-trastuzumab emtansine plus pertuzumab, 9 cases of paclitaxel plus trastuzumab, and 44 cases of paclitaxel plus trastuzumab and pertuzumab), GSE52707 (SK-BR-3 Lapatinib resistance cell group vs control group), and GSE15043 (BT474 Herceptin-resistant cell group vs control group), were downloaded from the Gene Expression Omnibus (GEO) database. Cell cloning formation, proliferation assay, and drug sensitivity experiments were conducted in MNX1 ectopic and knockdown cell lines. Co-IP assay, RNA-Seq, and ChIP-Seq analysis were used to explore the downstream pathways that MNX1 might be involved. Results: High-throughput sequencing results of core needle biopsy samples from 81 HER2-positive breast cancer patients were divided into pCR and non-pCR groups. Using DEseq2 packet analysis to screen differentially expressed genes, P-value &lt; 0.05, | log2FoldChange | &gt; 1 as the filter, there were 620 up-regulated genes and 715 down-regulated genes in the pCR group. The same method was used for the analysis of the GSE181574 data set. Combined the two datasets used P values and log2FoldChange (P-value &lt; 0.05, | log2FoldChange | &gt; 1.2) as selection criteria, we found the MNX1 and PNMT expressions were significantly higher in the pCR group. Subsequently, differential analysis of GSE52707 and GSE15043 datasets showed that MNX1 and PNMT expression levels were reduced in drug-resistant cell lines. Considering the P-value and | log2FoldChange |, we ultimately selected motor neuron and pancreatic homeobox 1(MNX1) gene as the target factors for follow-up studies. In the cloning formation and proliferation assay, overexpression of MNX1 inhibits proliferation and clonal formation of HER2-positive breast cancer cells. In the drug sensitivity experiments overexpression of MNX1 enhances the sensitivity of HER2-positive breast cancer cells to tyrosine kinase inhibitors (TKI) such as lapatinib and pyrotinib. MNX1 knockdown reduces the sensitivity of HER2-positive breast cancer cells to TKI. Through RNA-seq and ChIP-seq, we found that CD-M6PR might be a downstream target gene regulated by MNX1. Verification by Dual-Luciferase Reporter Assay MNX1 was found to positively regulate CD-M6PR transcription. By Co-IP assay, it was found that MNX1 interacted with EEF1D, and EEF1D stabilized MNX1. MNX1 and CD-M6PR affect the proliferation and drug sensitivity of breast cancer cells by down-regulating the PI3K-AKT-mTOR pathway. Conclusion: Overexpression of MNX1 increases the sensitivity of HER-2 positive cells to TKI. MNX1 binds to EEF1D and is stabilized by EEF1D. MNX1 positively regulates M6PR and affects the proliferation of breast cancer cells and the sensitivity of breast cancer cells to TKI through the PI3K-AKT-mTOR pathway. Citation Format: Wei-Ru Chi, Bingqiu Xiu, Min Xiong, Pei Li, Qi Zhang, Lun Li, Jianjing Hou, Xujie Zhou, Yuting Sang, Ming Chen, Liyi Zhang, Jingyan Xue, Yayun Chi, Jiong Wu. MNX1 promotes tumor sensitivity to HER2-targeted therapy in HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-04.

Background:Tofacitinib is an oral JAK inhibitor for the treatment of psoriatic arthritis (PsA).Objectives:To assess tofacitinib 5 mg BID as monotherapy after methotrexate (MTX) withdrawal vs with continued background MTX in patients (pts) with PsA.Methods:OPAL Balance (NCT01976364) was an open-label (OL) long-term extension (LTE) study of tofacitinib in pts with PsA who participated in Phase (P)3 studies (OPAL Broaden,NCT01877668; OPAL Beyond,NCT01882439). Pts who completed ≥24 months’ tofacitinib treatment in the LTE (stable 5 mg BID for ≥3 months) and were receiving oral MTX (7.5–20 mg/week; stable for ≥4 weeks) entered the multicentre, 12-month, double-blind, MTX withdrawal substudy. Pts remained on OL tofacitinib 5 mg BID and were randomised 1:1 to receive placebo (tofacitinib monotherapy, ie, blinded MTX withdrawal) or MTX (tofacitinib + MTX; same stable doses). Primary endpoints were changes from substudy baseline (Δ) in PASDAS and HAQ-DI at Month (M)6. Secondary efficacy endpoints were assessed at all time points. Safety was assessed throughout the substudy.Results:Of 180 pts randomised, 179 were treated (tofacitinib monotherapy n=90; tofacitinib + MTX n=89). Pt characteristics were similar between treatment arms. At M6, least squares mean (LSM) (standard error [SE]) ΔPASDAS was 0.229 (0.079) for tofacitinib monotherapy and 0.138 (0.081) for tofacitinib + MTX, and LSM (SE) ΔHAQ-DI was 0.043 (0.027) and 0.017 (0.028), respectively (Figure 1); no clinically meaningful differences were observed. Efficacy and pt-reported outcomes were generally similar between treatment arms at M6 and M12 (data not shown). Rates of pts achieving minimal disease activity, and maintaining an absence of enthesitis and dactylitis, were sustained to M12 in both treatment arms (Figure 2). Adverse event rates (Table) and laboratory parameters were comparable between treatment arms, but liver enzyme elevations were more common with tofacitinib + MTX.Conclusion:No clinically meaningful differences in efficacy and safety were observed in PsA pts who received OL tofacitinib 5 mg BID as monotherapy after MTX withdrawal vs with continued MTX. Safety was consistent with previous P3 studies. The substudy was an estimation study and not powered for hypothesis testing.Table.Safety outcomes to Month 12Pts with events, n (%) AEs of special interestTofacitinib monotherapy N=90Tofacitinib + MTXN=89AE43 (47.8)41 (46.1)Serious AE4 (4.4)3 (3.4)Discontinuations due to AE3 (3.3)4 (4.5)Death00 Herpes zoster (serious/non-serious)1 (1.1)2 (2.2) Serious infection02 (2.2) Opportunistic infectiona01 (1.1) Malignancy (excl. NMSC)a1 (1.1)1 (1.1) NMSCa00 Major adverse cardiovascular eventa00 Venous thromboembolismc00 Arterial thromboembolismc1 (1.1)0 Gastrointestinal perforationa00 Interstitial lung diseaseb00Laboratory parametersdALT ≥3×ULN05 (5.6) ALT (IU/L), mean (SE)-2.7 (1.6)2.5 (1.3)AST ≥3×ULN03 (3.4) AST (IU/L), mean (SE)-1.5 (1.2)1.7 (0.8)Reviewed by independentaexternal/binternal adjudication committeecPer Standardised MedDRA Query termsdWithout regard to baseline abnormalityALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normalAcknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Laura C Coates: None declared, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, James Cheng-Chung Wei Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB Pharma, Dona Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ana Belen Romero Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Keith Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

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При оценке подвижности тяжелых металлов в системе «вода – донные отложения» важно не только понимать условия и особенности фазовых переходов, но и иметь надежные критерии для их оценки и интерпретации. Среди факторов иммобилизации металлов в донных отложениях обычно рассматривают присутствие в них органического вещества и тонкодисперсных фракций и pH среды. Целью исследования явилось построение репрезентативных моделей такой взаимосвязи. Список литературы Бреховских В.Ф. Тяжёлые металлы в донных отложениях Нижней Волги и дельты реки // Вода: химия и экология. 2010. №2. С. 2‒10. Даувальтер В.А. Геоэкология донных отложений озер. Мурманск: МГТУ, 2012. 242 с. Добровольский В.В. Роль гуминовых кислот в формировании миграционных массопотоков тяжелых металлов // Почвоведение. 2004. №1. С. 32‒39. Садчиков А.П. Структурные показатели бактерий и детрита в пресных водоемах (методические аспекты) // Материалы по флоре и фауне Республики Башкортостан / Сборник статей. Вып. XII. 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Background:In the absence of evidence-based treatment guidelines, medication use in SLE is highly variable. Low rates of remission and lupus low disease activity state (LLDAS) suggest that suboptimal responses to standard medications, which include glucocorticoids (GC), anti-malarial (AM) drugs and immunosuppressive (IS) agents, are common. Understanding the utility of current medications will facilitate the selection of patients for advanced therapies as they emerge.Objectives:To examine medication use patterns in a large multicentre SLE cohort.Methods:We used 2013-18 data from the Asia Pacific Lupus Collaboration (APLC) cohort in which disease activity (SLEDAI-2K) and medication details were captured at every visit. LLDAS was defined as in Golderet al., 2019 (1). We examined the use of medication (med) categories (GC &/or AM &/or IS) by SLE disease activity and LLDAS at the visit level. Additionally, we performed Cox regression analyses to determine the time-to-discontinuation of meds stratified by SLE disease activity, ranked by time-adjusted mean SLEDAI-2K, and by percent-time spent in LLDAS.Results:We analysed data from 19,804 visits of 2,860 patients. We observed 8 med categories: no meds; GC, AM or IS only; GC+AM; GC+IS; AM+IS and GC+AM+IS (triple therapy). Triple therapy was the most frequent med pattern (32%); single agents were used in 21% of visits and biologicals in only 3%. Among visits where SLEDAI-2K was ≥10, triple therapy was used in 46%, with median [IQR] GC dose 10 [6, 24] mg/day; in contrast, among visits with SLEDAI-2K≤4 triple therapy was used in 28% (p<0.01). Patients in LLDAS received less combination therapy than those who were not in LLDAS.Med persistence (survival analysis) varied widely, with lowest survivals for IS. Patients with time-adjusted mean SLEDAI-2K ≥10 had lower discontinuation of GC and higher discontinuation of IS including azathioprine, leflunomide and cyclosporine (Table 1). In contrast, increased time in LLDAS was associated with reduced discontinuation of AM and azathioprine.GCAMISMPhMPhAAZAMTXCyALEFOverall med survival, days to 25% discontinuation (95%CI)1048(938, 1197)1267(1113, 1428)175(175, 182)387(252, 756)409(350, 476)525(219, 686)268(182, 350)329(190, 524)Univariable associations,HR (95% CI) p-valueDisease activity≤41.001.001.001.001.001.001.001.00>4 & <100.69 (0.56,0.84)p<0.0011.15 (0.92,1.44)0.20.92 (0.80,1.05)0.21.37 (0.78,2.42)0.31.16 (0.97,1.39)0.111.11 (0.72,1.71)0.61.26 (0.90,1.77) 0.181.88 (1.07,3.30) 0.03≥100.65 (0.35,1.21) 0.181.56 (0.94,2.59) 0.080.84 (0.45,1.57)0.61.92 (0.80,4.63)0.142.69 (1.86,3.91) p<0.0011.85 (0.92,3.71) 0.082.66 (1.36,5.21) 0.0041.62 (1.13,2.32)0.009LLDAS<50%1.001.001.001.001.001.001.001.00≥50%1.30 (1.09, 1.55)0.0030.67 (0.54, 0.84)<0.0011.22 (1.08, 1.40)0.0020.83 (0.44,1.57)0.60.83 (0.69, 1.00)0.0540.70 (0.46, 1.07)0.101.29 (0.92, 1.83)0.140.43 (1.5, 1.25)0.12Conclusion:In a large multicentre SLE cohort, most patients were receiving combination treatment. AM treatment survival was high and associated with low disease activity, GC survival was high and associated with high disease activity, while IS survival was low. Patients with high disease activity received more medication combinations but had reduced IS survival. These data suggest ongoing unmet need for improved medications for treatment of SLE.Reference:Golder, V., et al Lancet Rheum. 2019 1(2):e95-102Disclosure of Interests:Rangi Kandane-Rathnayake Grant/research support from: The APLC has received financial (non-restricted educational) grants from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen, EMD Serono, Eli Lilly and UCB for the LLDAS Validation Study., Worawit Louthrenoo: None declared, Shue Fen Luo: None declared, Yeong-Jian Wu Consultant of: Pfizer, Lilly, Novartis, Abbvie, Roche, Speakers bureau: Lilly, Novartis, Yi-Hsing Chen Grant/research support from: Taiwan Ministry of Science and Technology, Taiwan Department of Health, Taichung Veterans General Hospital, National Yang-Ming University, GSK, Pfizer, BMS., Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Paid instructor for: Pfizer, Novartis, Johnson & Johnson, Roche, Lilly, Astra& Zeneca, Sanofi, Astellas, Agnitio Science Technology, United Biopharma., Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Vera Golder: None declared, Aisha Lateef: None declared, Jiacai Cho: None declared, Sandra Navarra Speakers bureau: Astellas, Novartis, Pfizer, Johnson & Johnson, Abbvie, Leonid Zamora: None declared, Laniyati Hamijoyo Speakers bureau: Pfizer, Novartis, Tanabe, Abbot, Dexa Medica, Roche, Sargunan Sockalingam: None declared, Yuan An: None declared, Zhanguo Li: None declared, Yasuhiro Katsumata: None declared, masayoshi harigai Grant/research support from: AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd. MH has received speaker’s fee from 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., Oxford Immuotec, Pfizer Japan Inc., and Teijin Pharma Ltd. MH is a consultant for AbbVie, Boehringer-ingelheim, Kissei Pharmaceutical Co., Ltd. and Teijin Pharma., Yanjie Hao: None declared, Zhuoli Zhang: None declared, Madelynn Chan: None declared, Jun Kikuchi: None declared, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., Fiona Goldblatt: None declared, Sean O’Neill: None declared, Chetan Karyekar Shareholder of: Johnson & Johnson, Consultant of: Janssen, Employee of: Janssen Global Services, LLC. Previously, Novartis, Bristol-Myers Squibb, and Abbott Labs., Jennifer H. Lofland Employee of: Janssen, Sang-Cheol Bae: None declared, Chak Sing Lau: None declared, Alberta Hoi: None declared, Mandana Nikpour: None declared, Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca

The paper presents research findings with 56 Roma children from Macedonia and Serbia between the ages of 3-6 years. The children’s knowledge of Romani as their mother tongue was assessed with a specially designed test. The test measures the children’s comprehension and production of different types of grammatical knowledge such as wh–questions, wh-complements, passive verbs, possessives, tense, aspect, the ability of the children to learn new nouns and new adjectives, and repetition of sentences. In addition, two pictured narratives about Theory of Mind were given to the children. The hypothesis of the authors was that knowledge of the complex grammatical categories by children will help them to understand better the Theory of Mind stories. The results show that Roma children by the age of 5 know most of the grammatical categories in their mother tongue and most of them understand Theory of Mind. References Bakalar, P. (2004). The IQ of Gypsies in Central Europe. 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Patients both male and female with diagnosis of Acute Coronary Syndrome (ACS) present with chest pain as presenting complaint. Lichtman JH et al. in his study with ACS showed that 93% of women presented with chest pain or discomfort.1 As compared to men women experience more associated symptoms as primary complaint. The associated symptoms are fatigue, dyspnea, backache, flue like symptoms, indigestion, palpitations and most common is anxiety & feeling scarry.2 Keeping these scenarios in mind one should inquire this associated presentation along with chest pain or discomfort in evaluating ACS in women. In continuation with symptoms there is quite a debate on pathophysiology of Acute Myocardial infraction in men and women regarding coronary pathologic features.3 Type 1 plaque rupture most common in both genders with plaque erosion most common in women in non-obstructive coronary artery disease.4 Spontaneous coronary artery dissection (SCAD) having high mortality exists in the absence of risk factor of ACS.5 It was found in women up to 35% of patients with mean age of 42 to 53 years with a MACE (Major acute coronary event) of 47.4% and 10 years mortality rate of 7.7%2 SCAD seen in peripartum cases, oral contraception use, lack of exercise, connective tissue disorders and vasculidites. It is important for the physician to have in mind these disorders to avoid complications of coronary interventions. In a scientific statement from AHA, Mehte LS et al. showed a lower prevalence of atheroscrotic CAD in women.3 These are certain scoring system,6 that under present women because of vague symptoms and presentation. These scoring systems lead to decrease hospital admission and less noninvasive cardiac testing. For risk satisfaction of chest pain female gender should not be taken as sole criteria for presence or absence of coronary events in presence of other multiple factors. The last but not the least is the psychosocial stress more in women than in men. It has been found that young women who present with early onset myocardial infarction have more psychosocial risk factors in comparison to men of similar age,3 probably having high rates of poverty and trauma exposure during childhood because of various reasons.7 Different studies are endorsing relationship between depression and ischemic heart disease as prognostic factor after ACS.7 In our population where there is lack of education, poverty, awareness of disease especially in women the physician should ponder on different factors mentioned above i.e. presentation perceptions, prevalence, pathophysiology and psychosocial stress for evaluation and management of chest pain. References Lichtman JH, Leifheit-Limson EC, Watanabe E, Allen NB, Garavalia B, Garavalia LS, et al. Symptom recognition and healthcare experiences of young women with acute myocardial infarction. Circ Cardiovasc Qual Outcomes. 2015;8:S31-8. Vargas K, Messman A, Levy PD. Nuances in Evaluation of Chest Pain in women. JACC Case Rep. 2021;3(17):1793-7. Mehta LS, Beckie TM, DeVon HA, Grines CL, Krumholz HM, Johnson MN, et al. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation. 2016;133:916-47. Mukherjee D. Myocardial infarction with nonobstructive coronary arteries: a call for individualized treatment. J Am Heart 2019;8(14):e013361. Hayes SN, Kim ESH, Saw J, Adlam D, Arslanian-Engoren C, Economy KE, et al. Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association. Circulation. 2018;137:e523-e557. Preciado SM, Sharp AL, Sun BC, Baecker A, Wu YL, Lee MS, et al. Evaluating sex disparities in the emergency department management of patients with suspected acute coronary syndrome. Ann Emerg 2021;77(4):416-24. Lichtman JH, Froelicher ES, Blumenthal JA, Carney RM, Doering LV, Frasure-Smith N, et al. Depression as a risk factor for poor prognosis among patients with acute coronary syndrome: systematic review and recommendations: a scientific statement from the American Heart Association. Circulation. 2014;129:1350-69.

1. Nature has its own logic, which does not follow the human will. Nature is itself; it exists, moves, changes, and evolves according to its own intrinsic ways. Human and human society, as a product of a specific stage of natural development, can only be a concrete manifestation of the logic of nature. 2. In the broad sense, nature refers to all, both phenomena and processes, in the universe. It includes human society spiritual phenomena. In a narrow sense, nature refers to the world outside the society and opposed to society as well, or refers to the research objects of natural sciences 3. The narrow natural philosophy is in the intermediary position between the natural sciences and the overall philosophy (the supreme philosophy, an advocation of Kun Wu’s philosophy of information. For further detail, please refer to the subscript in the following.). Furthermore, it is an independent sub-level philosophical discipline; the broad natural philosophy is a meta-philosophy or supreme philosophy, stipulating the entire world from the dimensions of nature itself. 4. Natural philosophy reveals the laws of nature’s own existence, movement, change, and evolution. This determines that the way of expressing natural philosophy is necessarily natural ontology. The construction of the theoretical system of natural philosophy is inevitably a process of abandoning cognitive mediums of human beings through reflection. It is necessary for us to conclude that natural philosophy is the stipulation of nature itself, which comes out of the nature itself. So, we must explain the nature from the standpoint of the nature itself. 5. The true philosophy should move from the human world to the nature, finding back Husserl’s suspended things, and establish a brand-new philosophy in which man and nature, substance, information, and spirit are united. This kind of philosophy is able to provide contemporary ecological civilization with a reasonable philosophical foundation, rebuilding natural philosophy in a new era, which is a very urgent task for contemporary philosophers. 6. The unity of philosophy and science cannot be seen merely as an external convergence, but also as an intrinsic fusion; a true philosophy should have a scientific character, and science itself must have a philosophical basis. The unity of such an intrinsic fusion of science and philosophy can be fully demonstrated by the practical relationship of development between human philosophy and science. 7. In addition to the narrow path along epistemology, linguistics, and phenomenology, the development of human philosophy has another path. This is the development of philosophy itself that has been nurtured and demonstrated during the development of general science: On the one hand, the construction of scientific rationality requires philosophical thinking and exploration; On the other hand, the progress of science opens the way for the development of philosophy. 8. In the real process of the development of human knowledge, science and philosophy are regulated, contained, and merged with each other in the process of interaction. The two are inlaid together internally to form an interactive dynamic feedback loop. The unified relationship of mutual influence, regulation, promotion and transformation presented in the intrinsic interplay of interaction between science and philosophy profoundly breeds and demonstrates the general way of human knowledge development: the philosophicalization (a term used in Kun Wu’s philosophy of information. For more details please see in Kun Wu, 2016, The Interaction and Convergence of the Philosophy and Science of Information, https://doi.org/10.3390/philosophies1030228) of science and scientification (a term used in Kun Wu’s philosophy of information. For more detail, please see in Kun Wu, 2016, The Interaction and Convergence of the Philosophy and Science of Information, https://doi.org/10.3390/philosophies1030228) of philosophy. 9. We face two types of dogmatism: one is the dogmatism of naturalism, and the other is the dogmatism of the philosophy of consciousness. One of the best ways to overcome these tendencies of dogmatism is to unite natural ontology, and epistemic constructivism. The crisis of contemporary philosophy induced by the western consciousness philosophy seems like belonging to the field of epistemology, but the root of this crisis is deeply buried in the ontology. The key to solving the crisis of contemporary philosophy lies precisely in the reconstruction of the doctrine of natural philosophy centering to the nature itself and excluding God. The task to be accomplished by this new natural philosophy is how to regain the natural foundation of human consciousness after the God has left the field. 10. Since the 1980s, the philosophy of information established and developed in China has proposed a theory of objective information, as well as the dual existence and dual evolution of matter and information (a key advocation in the ontological theory of Kun Wu’s philosophy of information). It is this theory that has made up for the vacancy existing between matter and mind, which apparently exists in Cartesian dualism, after the withdrawal of the God’s from the field. Philosophy of information in China is first and foremost a natural philosophy that adheres to naturalistic attitudes. Second, this natural philosophy explains the human, human mind and human society in the interpretation of the process and mechanism of natural evolution. In this connection, philosophy of information (a key advocation of Kun Wu’s philosophy of information) in China is a system of meta-philosophy or supreme philosophy. This system undoubtedly has the nature of a new natural philosophy. At the same time, this philosophy can better reflect the philosophical spirit of the information age.

This study aims to develop an activity-based science learning model with an inquiry learning approach for early childhood that can be used to increase the sense of curiosity and scientific thinking in children aged 5-6 years. This research was conducted with research and development / R & D research methods. Data was collected through interviews, observations, questionnaires, pre-test and post-test for children. Data analysis using paired t-test. The results showed that children were interested and enthusiastic in the learning process by using a science-based learning model with the inquiry approach, Sig. (2-tailed) showing results of 0.000, so the value of 0.000 <0.05 was different from before and after the use of learning models. The results showed that: children can understand the material given by the teacher, the child is more confident and has the initiative to find answers to the teacher's questions about science material, the child's curiosity increases to examine the information provided by the teacher, the child's understanding of work processes and procedures from science learning with the inquiry approach getting better. It was concluded that an activity-based science learning model with an inquiry approach for children aged 5-6 years used an activity model with an inquiry learning approach based on children's interests and children's needs so that children's curiosity would emerge and continue to be optimally stimulated. Keywords: Inquiry approach, Learning model, Science Learning References Abdi, A. (2014). The Effect of Inquiry-based Learning Method on Students’ Academic Achievement in Science Course. Universal Journal of Educational Research, 2(1), 37–41. https://doi.org/10.13189/ujer.2014.020104 Anderson, R. D. (2002). Reforming science teaching: What research says about inquiry. Journal of Science Teacher Education, 13(1), 11–12. Bell, R. L., Smetana, L., & Binns, I. (2005). Simplifying inquiry instruction: Assessing the inquiry level of classroom activities. The Science Teacher, 72(7), 30–33. Borowske, K. (2005). Curiosity and Motivation-to-Learn (hal. 346–350). Bransford, J. D., Brown, A. L., & Cocking, R. R. (2000). How people learn: Brain, mind, experience, and school. Washington D.C.: National Academy Press. Buday, S. K., Stake, J. E., & Peterson, Z. D. (2012). Gender and The Choice of a Science Career: The Impact of Social Support and Possible Selves. Sex Roles. Diambil dari https://doi.org/10.1007/s11199-011-0015-4 Bustamance, S. A., White, J. L., & Grienfield, B. daryl. (2018). Approaches to learning and science education in Head Start: Examining bidirectionality. Early Childhood Science Quarterly. Caballero Garcia, P. A., & Diaz Rana, P. (2018). Inquiry-Based Learning: an Innovative Proposal for Early Childhood Education. Journal of Learning Styles, 11(22), 50–81. Cridge, B. J., & Cridhe, A. G. (2011). Evaluating How Universities Engage School Student with The Science: a Model Based on Analysis of The Literature. Australian University Review. Darmadi. (2017). Pengembangan Model dan Metode Pembelajaran dalam Dinamika Belajar Siswa. Yogyakarta: Deepublish. Doǧru, M., & Şeker, F. (2012). The effect of science activities on concept acquisition of age 5-6 children groups. Kuram ve Uygulamada Egitim Bilimleri, 12(SUPPL. 4), 3011–3024. Duran, M., & Dökme, I. (2016). The effect of the inquiry-based learning approach on student’s critical-thinking skills. Eurasia Journal of Mathematics, Science and Technology Education, 12(12), 2887–2908. https://doi.org/10.12973/eurasia.2016.02311a Falloon, G. (2019). 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(2015). Exploring Preschool Children’s Science Content Knowledge. Early Education and Development, 26(1), 125–146. https://doi.org/10.1080/10409289.2015.968240 Halim, L., Abd Rahman, N., Zamri, R., & Mohtar, L. (2018). The roles of parents in cultivating children’s interest towards science learning and careers. Kasetsart Journal of Social Sciences, 39(2), 190–196. https://doi.org/10.1016/j.kjss.2017.05.001 Jirout, J. J. (2011). Curiosity and the Development of Question Generation Skills, (1994), 27–30. Justice, L. M., & Kaderavek, J. (2004). Embedded-explicit emergent literacy I: Background and description of approach. Language, Speech, and Hearing Services in Schools, 35, 201–211. Lind, K. K. (1998). Science in Early Childhood: Developing and Acquring Fundamental Concepts and Skills. Retrieved from ERIC (ED418777), 85. Diambil dari http://files.eric.ed.gov/fulltext/ED418777.pdf Lind, K. K. (2005). Exploring science in early childhood. (4 ed.). New York: Thomson Delmar Learning. Lindholm, M. (2018). Promoting Curiosity ? Possibilities and Pitfalls in Science Education, (1), 987–1002. Lu, S., & Liu, Y. (2017). Integrating augmented reality technology to enhance children ’ s learning in marine education, 4622(November), 525–541. https://doi.org/10.1080/13504622.2014.911247 Lukas, M. (2015). Parental Involvement of Occupational Education for Their Children. International Multidicilinary Scientific Cocerence on Social Science and Arts. Maltese, A. V, & Tai, R. H. (2011). Pipeline Persistence; Examining The Association of Educational with Earn Degrees i STEM Among US Students. Science Education. Nugent, G., Barker, B., Welsch, G., Grandgenett, N., Wu, C., & Nelson, C. (2015). A Model of Factors Contributing to STEM Learning and Career Orientation. International Journal of Science Education. Pluck, G., & Johnson, H. L. (2011). Stimulating curiosity to enhance learning. Reiser, B. J. (2004). Scaffolding complex learning: The mechanisms of structuring and problematizing student work. Journal of the Learning Sciences, 13(3), 273–304. Sackes, M., Trundle, K. C., & Flevares, L. M. (2009). Using children’s literature to teach standard-based science concepts in early years. Early Childhood Education Journal, 36(5), 415–422. https://doi.org/10.1007/s10643-009-0304-5 Walin, H., & Grady, S. O. (2016). Curiosity and Its Influence on Children ’ s Memory, 872–876. Wang, F., Kinzie, M. B., McGuire, P., & Pan, E. (2010). Applying technology to inquiry-based learning in early childhood education. Early Childhood Education Journal, 37(5), 381–389. https://doi.org/10.1007/s10643-009-0364-6 Wu, S. C., & Lin, F. L. (2016). Inquiry-based mathematics curriculum design for young children-teaching experiment and reflection. Eurasia Journal of Mathematics, Science and Technology Education, 12(4), 843–860. https://doi.org/10.12973/eurasia.2016.1233a Yahya, A., & Ismail, N. (2011). Factor in Choosing Courses and Learning Problems in Influencing The Academic Achievment of Student`s Technical Courses in Three Secondary School in The State of Negei Sembilan. Journal of Technical, Vocational & Eginereing Education. Youngquist, J., & Pataray-Ching, J. (2004). Revisiting ‘“play”’: Analyzing and articulating acts of inquiry. Early Childhood Education Journal, 31(3), 171–178.

This paper presents some results of rainfall forecast in the monsoon onset period in South Vietnam, with the use of ensemble Kalman filter to assimilate observation data into the initial field of the model. The study of rainfall forecasts are experimented at the time of Southern monsoon outbreaks for 3 years (2005, 2008 and 2009), corresponding to 18 cases. In each case, there are five trials, including satellite wind data assimilation, upper-air sounding data assimilation, mixed data (satellite wind+upper-air sounding data) assimilation and two controlled trials (one single predictive test and one multi-physical ensemble prediction), which is equivalent to 85 forecasts for one trial. Based on the statistical evaluation of 36 samples (18 meteorological stations and 18 trials), the results show that Kalman filter assimilates satellite wind data to forecast well rainfall at 48 hours and 72 hours ranges. With 24 hour forecasting period, upper-air sounding data assimilation and mixed data assimilation experiments predicted better rainfall than non-assimilation tests. The results of the assessment based on the phase prediction indicators also show that the ensemble Kalman filter assimilating satellite wind data and mixed data sets improve the rain forecasting capability of the model at 48 hours and 72 hour ranges, while the upper-air sounding data assimilation test produces satisfactory results at the 72 hour forecast range, and the multi-physical ensemble test predicted good rainfall at 24 hour and 48 hour forecasts. The results of this research initially lead to a new research approach, Kalman Filter Application that assimilates the existing observation data into input data of the model that can improve the quality of rainfall forecast in Southern Vietnam and overall country in general.References Bui Minh Tuan, Nguyen Minh Truong, 2013. 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In this paper, seismic activity characteristics in the East Sea area was analyzed by authors on the base of the unified earthquake catalog (1900-2017), including 131505 events with magnitude 3 ≤ Mw ≤ 8.4. The seismic intensity in the East Sea during the period 1900-2017 is characterized by the earthquake representative level Mw = 4.7. The strong earthquake activity in the East Sea area clearly shows the regularity in each stage. In the period from 1900 to 2017, the East Sea area has four periods of strong earthquake activity, each stage is nearly 30 years with particular characteristics. The distribution of the maximum earthquake quantities by years has a cyclicity in all four periods. In each stage there are 1-2 strong earthquakes with Mmax ≥ 8.0. The strong earthquakes with Mmax ≥ 7.5 have occurred by a repeatable rule of 3-5 years in all four stages. This allows the prediction of the maximum earthquake repeat cycle of Mmax ≥ 7.5 in the study area is 3-5 years. In other hand, the maximum magnitude values for the East Sea region has assessed by GEV method with several different predict periods (20, 40, 60, 80, 100 years), with predicted probability 80%. We concluded that it is possible that earthquake have Mmax = 8.7 will occur in next 100 years.ReferencesBautista C.B., Bautista M.L.P., Oike K., Wu F.T., Punongbayan R.S., 2001. A new insight on the geometry of subducting slabs in northern Luzon, Philippines. Tectonophysics, 339, 279-310.Bui Cong Que, et al., 2010. Seismic and tsunamis hazard in coastal Viet Nam. Natural Science and Technology Publishing House, 311p.Bui Van Duan, Nguyen Cong Thang, Nguyen Van Vuong, Pham Dinh Nguyen, 2013. The magnitude of the largest possible earthquake in the Muong La-Bac Yen fault zone. J. Sci. of the Earth, 35, 53-59 (in Vietnamese).Cao Dinh Trieu, Pham Nam Hung, 2008. Deep-seated fault zone presents the risk of strong earthquakes in the East and South Vietnam Sea. Scientific Report of the First National Conference on Marine Geology, Ha Long, October, 9-10, 491-497.Hsu Ya-Ju, Yu Shui Ben, Song Teh.-Ru Alex, Bacolcol Teresito, 2012. Plate coupling along the Manila subduction zone between Taiwan and northern Luzon. J. Asian Earth Sci., 51, 98-108.http://www.ioc-tsunami.org/index.php?option=com_oe&task=viewDocumentRecord&docID=16478.http://www.jcomm.info/index.php?option=com_oevàtask=viewDocumentRecordvafdocID=16484.Kirby S., Geist E., Lee W.H., Scholl D., Blakely, R., October 2005. 660 Tsunami source characterization for western Pacific subduction 661 zones: a perliminary report. Report, USGS Tsunami Subduction 662 Source Working Group.Le Duc Anh, Nguyen Hoang., Shakirov RB., Tran T.H., 2017. Geochemistry of late miocene-pleistocene basalts in the Phu Quy island area (East Vietnam Sea): Implication for mantle source feature and melt generation, Vietnam J. Earth Sci., 39, 270-288.Le Huy Minh, Frederic Masson, Alain Bourdiilon, Patrick Lassudrie Duchesne, Rolland Fleury, Jyr-ching Hu, Vu Tuan Hung, Le Truong Thanh, Nguyen Chien Thang, Nguyen Ha Thanh, 2014. GPS data continuously in Vietnam and Southeast Asia. J. Sci. of the Earth, 36, 1-13.Le Van De, 1986. Outline of tectonics of the East Vietnam sea and adjacent areas. Proc. 1st Conf. Geol. Indoch., Ho Chi Minh City, 397-404, Hanoi.Ngo T.L., Tran V.P., 2013. Development of a new algorithm for the separation of seismic and anemone groups from the earthquake list to ensure the independence of events. Journal of Marine Science and Technology, Hanoi, 13(3A), 79-85.Nguyen Dinh Xuyen., et al., 2007. Report on the implementation of the task "Earthquake scenarios for tsunamis in the South China Sea". Institute of Meteorology and Hydrology.Nguyen Hong Phuong, 2015. Estimation of seismic hazard parameters for potential tsunami genic sources in the South China Sea region.Nguyen Hong Phuong, 2001. Probabilistic Seismic Hazard Assessment Along the Southeastern Coast of Vietnam, Natural Hazards, 24, 53-74.Nguyen Hong Phuong, 2004. Earthquake risk map of Vietnam and East Sea. J. Sci. of the Earth, 26, 97-111.Nguyen Hong Phuong, Bui Cong Que, 2012. Investigation of earthquake tsunami sources, capable of affecting Vietnamese coast, Nat Hazards, 64, 311-327.Nguyen Hong Phuong, Pham The Truyen, 2014. Probabilistic Seismic Hazard Assessment for the South Central Vietnam. J. Sci. of the Earth, 36, 451-461.Nguyen Hong Phuong, Pham The Truyen, Nguyen Ta Nam, 2017. Probabilistic Seismic Hazard Assessment for the Tranh River hydropower plant No2 site, Quang nam province, Vietnam J. Earth Sci., 38(2), 188-201.Nguyen Van Luong, Bui Cong Que, Nguyen Van Duong, 2008. Tectonic stresses and modern movements in the crust of the Earth in the East Sea area, Journal of Marine Science and Technology, 46-52.Nguyen Van Luong, Duong Quoc Hung, Bui Thi Thanh and Tong Duy Cuong, 2003. Characteristics of fault systems in the East Sea area. J. Sci. of the Earth., 25, 1-8 (in Vietnamese).Nguyen Van Luong, et al., 2002. Result of establishment of the list of earthquake dynamics in the East Sea area, studies on geology and marine geophysics, VII, Hanoi.Nguyen Van Luong, et al., 2008. Tectonic seismic and geodynamic features of the South China Sea, Proceedings of the 1st National Conference on Marine Geology and Sustainable Development, 9-10, Ha Long, 498-509.Pham Van Thuc and Nguyen Thi Kim Thanh, 2004. Earthquake zone in the South China Sea and coastal areas. Journal of Geology, A series, 285, 11-12.Pham Van Thuc, 2001, Characteristics of tsunamis in the East Sea region of Vietnam. TC and CNN, TI, 2, 52-64.Phan Trong Trinh, Ngo Van Liem, Vy Quoc Hai, John Beavan, Nguyen Van Huong, Hoang Quang Vinh, Bui Van Thom, Nguyen Quang Xuyen, Nguyen Dang Tuc, Dinh Van Thuan, Nguyen Trong Tan, Nguyen Viet Thuan, Le Huy Minh, Bui Thi Thao. Nguyen Huy Thinh, Dinh Van The, Le Minh Tung, Tran Quoc Hung, Nguyen Viet Tien, 2010b. Modern tectonic movement in the East Sea and surrounding areas. Journal of Geology. Series A, 320, 9-10, Hanoi.Phan Trong Trinh, 2006. The Tsunami and December 26, 2004 in the Indian Ocean: A Warning to Vietnam. Journal of Geology, Series A, 293, Hanoi.Phan Trong Trinh, et al., 2010a. Research on the tectonic activity, modern tectonics and geodynamics of the South China Sea as a scientific basis for forecasting the types of catastrophe involved and proposed solutions prevent. KC.09.11/06-10. Institute of Geology, 446p.Phan Trong Trinh, Nguyen Van Huong, Ngo Van Liem, Tran Dinh To, Vy Quoc Hai, Hoang Quang Vinh, Bui Van Thom, Nguyen Quang Xuyen, Nguyen Viet Thuan, Bui Thi Thao, 2011. Geological and geological hazards in Vietnam's sea and nearby. J. Sci. of the Earth, 33, 443-456.Pisarenko V.F., Sornette A., Sornette D. and Rodkin M.V, 2008. New approach to the Characterization of Mmax and of the Tail of the Distribution of Earthquake Magnitudes. Pure and Applied Geophysics, 165, 847-888.Pisarenko V.F, Sornette D. and Rodkin M.V., 2010. Distribution of maximum Earthquake magnitudes in future time intervals: application to the seismicity of Japan (1923-2007). EPS (Earth, Planets and Space), 62, 567-578.Pisarenko V.F., Rodkin M.V, and Rukavishnikova T.A., 2014. Estimation of the Probability of Strongest Seismic Disasters Based on the Extreme Value Theory. Physics of the Solid Earth, 50(3), 311-324.Pisarenko V.F., Rodkin M.V. and et al., 2012. New general quantile approach to the seismic rick assessment application to the Vietnam region. //Proceedings of the International Conference on "Geophysics - Cooperation and Sustainable Development." Science and Technology Publishing House. Hanoi, 161-167.Vu Thanh Ca, 2008. Report on the project to build a map of tsunami warning for coastal areas of Vietnam. Institute of Hydrometeorology and Environment - Ministry of Natural Resources and Environment.Yingchun Liu, Angela Santos, Shuo M. Wang, Yaolin Sh, Hailing Liu, David A. Yuen, 2007. Tsunami hazards along Chinese coast from potential earthquakes in the South China Sea. Phys. Earth Planet. Interiors, 163, 233-244.Zhiguo Xu, 2015. Seismicity and Focal mechanisms in the South China Sea Region and its Tectonic Significances.

The global goal to combat climate change is growing year by year, as for example indicated by the latest climate conference by the United Nations, COP26. Hereby, one of the main goals concerns the transition from fossil fuels to more renewable energy means. In doing so, the importance of highly efficient energy storage technologies, such as supercapacitors, Li-ion batteries and/or redox flow batteries that both store and release energy on a short-, mid- and long-term scale, grows alongside it1. Among storage technologies, redox flow batteries (RFBs) are considered as promising candidates for mid-term storage (daily discharge for 2-12 h) due to their unique characteristic of a decoupled energy storage and power output2. To enable the incorporation of these systems into society further and thus smoothen the transition towards renewable energy technologies, highly efficient and low cost membranes in terms of efficiency and durability are needed, that will simultaneously improve the efficiency and reduce the cost of energy storage. One of the membrane types for vanadium redox flow battery (VRFB) applications that gained the interest of industry and the scientific community are of the polybenzimidazole (PBI) type. Although these materials possess excellent chemical stability and vanadium barrier properties, they suffer from a poor proton conductivity compared to commercial standards such as Nafion® 212. Several strategies were proposed to tackle this issue, ranging from the preparation of composite membranes with a thin PBI skin layer3, alkaline pretreatments that improve the swelling characteristics of the PBI film4 and chemical modifications to attach ionic conducting groups on the polymer backbone, thus directly improving the conductivity5. This latter approach showed that a highly conductive PBI membrane could be obtained by the addition of sidechains containing charged moieties such as sulfonic acid5. However, this improved conductivity comes at a price, specifically, a decrease in its vanadium barrier properties due to a significant crossover of vanadium ions, thus losing one of the main benefits of PBI type membranes5. The work presented herein describes the preparation of multiple PBI derivatives containing small and readily available non-charged sidechains, such as alkylated or benzylated PBI. Herein, it was envisaged that the addition of non-charged sidechains to the PBI backbone could increase the free volume of the membrane and thus enable the incorporation of electrolyte into the film without significantly affecting its repelling effect for vanadium ions. With this in mind, the influence of these non-charged sidechains on the ex-situ properties under VRFB conditions was studied in terms of dimensional swelling, acid uptake, vanadium barrier properties and mechanical strength. Hereby, key differences in the behavior of the membranes were observed between each individual type of functionalization, such as swelling, uptake and composition in acidic media. Subsequently, the correlation between the ex-situ properties of the PBI derivatives and in-situ VRFB cycling performance was studied to further understand their significance. Through this process, valuable knowledge was obtained that showed a clear correlation between the ex-situ properties and the observed in-situ area specific resistance, energy efficiency and capacity fading of the various materials, with the best material outperforming Nafion® 212 in terms of energy efficiency by 1% at a current density of 200 mA∙cm2, a current density regime that is normally dominated by cation exchange membranes due to their low resistance. Thereby proving that even a small modification of the PBI backbone can have a significant influence on the performance in a VRFB cell. Yuan, Z.; Duan, Y.; Zhang, H.; Li, X.; Zhang, H.; Vankelecom, I., Advanced porous membranes with ultra-high selectivity and stability for vanadium flow batteries. Energy & Environmental Science 2016, 9 (2), 441-447. Chae, I. S.; Luo, T.; Moon, G. H.; Ogieglo, W.; Kang, Y. S.; Wessling, M., Ultra-High Proton/Vanadium Selectivity for Hydrophobic Polymer Membranes with Intrinsic Nanopores for Redox Flow Battery. Advanced Energy Materials 2016, 6 (16), 1600517. Gubler, L.; Vonlanthen, D.; Schneider, A.; Oldenburg, F. J., Composite Membranes Containing a Porous Separator and a Polybenzimidazole Thin Film for Vanadium Redox Flow Batteries. Journal of The Electrochemical Society 2020, 167 (10), 100502. Noh, C.; Serhiichuk, D.; Malikah, N.; Kwon, Y.; Henkensmeier, D., Optimizing the performance of meta-polybenzimidazole membranes in vanadium redox flow batteries by adding an alkaline pre-swelling step. Chemical Engineering Journal 2020, 126574. Yan, X.; Dong, Z.; Di, M.; Hu, L.; Zhang, C.; Pan, Y.; Zhang, N.; Jiang, X.; Wu, X.; Wang, J.; He, G., A highly proton-conductive and vanadium-rejected long-side-chain sulfonated polybenzimidazole membrane for redox flow battery. Journal of Membrane Science 2020, 596, 117616.

Одним из перспективных направлений альтернативной энергетики является использование возобновляемой энергии биомассы, в первую очередь отходов агропромышленного комплекса, с получением биогаза. Биогаз представляет собой климатически нейтральный возобновляемый источник энергии, который имеет ряд преимуществ с точки зрения вклада в декарбонизацию по сравнению с другими видами «зеленой» энергетики. Последние десятилетия одним из признанных лидеров в области развития биогазовой технологии и биоэнергетики является Европа. История развития этой отрасли альтернативной энергии переживала периоды бурного роста, интенсивного развития и завоевания европейского рынка, однако в последние годы отрасль испытывает серьезные проблемы, описанные на примере Германии. С учетом этих проблем анаэробные технологии очистки сточных вод, также получающие биогаз в качестве вторичного продукта, выглядят предпочтительной альтернативой технологиям переработки органических отходов сельского хозяйства и энергетической биомассы, поскольку лишены присутствия вторичного спутника метаногенного сбраживания отходов – органической фракции, создающей основные экологические проблемы и снижающей экономическую эффективность процесса. Республика Татарстан является одним из лидеров в Российской Федерации по переработке молока, а этот процесс вызывает образование большого количества концентрированных сточных вод. В связи с этим представляло интерес оценить эколого-экономическую эффективность технологии биологической анаэробно-аэробной очистки сточных вод молокоперерабатывающего предприятия, работающего на территории Республики Татарстан. Представлена методика и исходные данные для расчета. Показано, что при очистке по усовершенствованной анаэробно-аэробной технологии годовой эколого-экономический эффект на действующем предприятии может составить 147 тысяч рублей. Представлены результаты расчета количества альтернативного климатически нейтрального источника энергии – биогаза. При внедрении усовершенствованной анаэробно-аэробной очистки сточных вод на действующем предприятии объем биогаза может составить до 104 тыс. м3 условного газообразного топлива, а в масштабах Республики Татарстан – до 8.3 млн. м3 условного топлива в год. Расчет коэффициента воспроизводства энергии показал его достаточно высокое значение (около 18.4) при реализации разработанных усовершенствований, что указывает на экономическую привлекательность анаэробно-аэробной очистки сточных вод предприятия по переработке молока с получением биогаза. Библиографические ссылки 1. Баланов П.Е., Смотраева И.В., Иванченко О.Б., Хабибуллин Р.Э. Биотехнология и биоэнергетика в решении вопросов экологии // Вестник Казанского технологического университета. 2015. Т. 18, № 5. C. 229‒232.2. Будущее биогаза в Европе. Часть 1. Декарбонизация htpps://blog.nordicecocentre.com/2020/04/15/будущее-биогаза-в-европе-часть-1-декар (дата обращения 20.02.2022).3. Временная методика определения предотвращенного экологического ущерба. М., 1999. 41 с.4. Гоголева Н.А., Белькова С.В. Анализ использования биогаза в качестве альтернативного топлива на предприятии пищевой промышленности // Актуальные вопросы энергетики. 2020. Т. 2, №1. С. 126‒131. doi: 10.25206/2686-6935-2020-2-1-126-1315. Методика определения предотвращенного экологического ущерба. М., 1999. 32 с.6. Реестр перерабатывающих предприятий Республики Татарстан. https://www.dairynews.ru/news/v-top-100-zavodov-po-kolichestvu-lidiruet-tatarsta.html (дата обращения 20.02.2022).7. Рекус И.Г., Шорина О.С. Основы экологии и рационального природопользования. М.: Изд-во МГУП, 2001. 146 с.8. Фиапшев А.Г., Темукуев Т.Б., Кильчукова О.Х., Хамоков М.М. Энергетическое обоснование использования биогаза // Известия Горского государственного аграрного университета. 2014. Т. 51, № 4. С. 207‒211.9. Хабибуллин Р.Э., Петров А.М., Князев И.В. Анализ энергетической эффективности анаэробно-аэробной технологии очистки сточных вод молочного производства // Вестник Казанского технологического университета. 2014. Т. 17,№1. С. 232‒234.10. Хабибуллин Р.Э., Петров А.М., Князев И.В., Крапивина Н.Ю. Влияние разделения фаз на эффективность процесса очистки сточных вод молочного производства // Георесурсы. 2011. Т. 41, №5. С. 22‒26.11. Хабибуллин Р.Э., Князев И.В., Хасанова Э.Ф., Петров А.М. Энергетический потенциал сточных вод пищевых производств Республики Татарстан в процессе их анаэробной очистки // ЕвразияБио-2010 / Сборник трудов II международного конгресса. М., 2010. С. 201‒203.12. Ahmad T., Aadil R.M., Ahmed H., Rahman U., Soares B.C.V., Souza S.L.Q., Cruz A.G. Treatment and utilization of dairy industrial waste: A review // Trends in food scienceand technology. 2019. Vol. 88. P. 361‒372. doi:10.1016/j.tifs.2019.04.00313. Demirel B., Yenigun O., Onay T.T. Anaerobic treatment of dairy wastewaters: A review // Process biochemistry. 2005. Vol. 40, №8. P. 2583‒2595. doi:10.1016/j.procbio.2004.12.01514. Demuynck M. Biogas plants in Europe: A practical handbook. Springer, 2007. 361 p.15. Göblös S., Portöro P., Bordás D., Kálmán M., Kiss I. Comparison of the effectivities of two-phase and single-phase anaerobic sequencing batch reactors during dairy wastewater treatment // Renewable energy. 2008. Vol. 33, №5. P. 960‒965.doi: 10.1016/j.renene.2007.06.00616. Slavov A.K. General characteristics and treatment possibilities of dairy wastewaters – a review // Food technology and biotechnology. 2017. Vol. 55, №1. P. 14‒28. doi: 10.17113/ftb.55.01.17.452017. Rajeshwari K.V., Balakrishnan M., Kansal A., Lata K., Kishore V.V.N. State-of-the-art of anaerobic digestion technology for industrial wastewater treatment // renewable and sustainable energy reviews. 2000. Vol. 4, №2. P. 135‒156. https://doi.org/10.1016/S1364-0321(99)00014-318. Tocchi C., Federici E., Scargetta S., D’Annibale A., Petruccioli M. Dairy wastewater polluting load and treatment performances of an industrial three-cascade-reactor plant // Process biochemistry. 2013. Vol. 48, №5‒6. P. 941-944. doi:10.1016/j.procbio.2013.04.00919. Weiland P. Production and energetic use of biogas from energy crops and wastes in Germany // Applied biochemistry and biotechnology. 2003. Vol. 109, №1‒3. P. 263‒274. doi: 10.1385/abab:109:1-3:263.20. Zhao K., Wu Y.W., Young S., Chen X.J. Biological treatment of dairy wastewater: A mini review // Journal of environmental informatics letters. 2020. Vol. 4. P. 22‒31. doi:10.3808/jeil.202000036

The pandemic of COVID-19 has afflicted every individual and has initiated a cascade of directly or indirectly involved events in precipitating mental health issues. The human species is a wanderer and hunter-gatherer by nature, and physical social distancing and nationwide lockdown have confined an individual to physical isolation. The present review article was conceived to address psychosocial and other issues and their aetiology related to the current pandemic of COVID-19. The elderly age group has most suffered the wrath of SARS-CoV-2, and social isolation as a preventive measure may further induce mental health issues. Animal model studies have demonstrated an inappropriate interacting endogenous neurotransmitter milieu of dopamine, serotonin, glutamate, and opioids, induced by social isolation that could probably lead to observable phenomena of deviant psychosocial behavior. Conflicting and manipulated information related to COVID-19 on social media has also been recognized as a global threat. Psychological stress during the current pandemic in frontline health care workers, migrant workers, children, and adolescents is also a serious concern. Mental health issues in the current situation could also be induced by being quarantined, uncertainty in business, jobs, economy, hampered academic activities, increased screen time on social media, and domestic violence incidences. The gravity of mental health issues associated with the pandemic of COVID-19 should be identified at the earliest. Mental health organization dedicated to current and future pandemics should be established along with Government policies addressing psychological issues to prevent and treat mental health issues need to be developed. References World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard. 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A quitosana, polissacarídeo linear obtido a partir do exoesqueleto de crustáceos e artrópodes, tem sido pesquisada em Odontologia por suas diversas propriedades terapêuticas. O objetivo do presente estudo foi realizar uma revisão da literatura sobre as aplicações atuais e as possibilidades terapêuticas da quitosana na odontologia. A busca foi realizada através do banco de dados eletrônico do Pubmed, utilizando os descritores Quitosana, Odontologia e Biomateriais. Foram incluídas pesquisas científicas utilizando quitosana em diversas áreas da odontologia e excluídas revisões de literatura e estudos não odontológicos, sendo selecionados 13 artigos. A quitosana induz resposta transcricional e anti-inflamatória em fibroblastos gengivais sobre citocinas inflamatórias, fatores transformadores do crescimento (TGF -β) e fatores de crescimento tumoral (TNF-α) que estão diretamente relacionados à atividade patológica periodontal. Nas infecções endodônticas persistentes, a substância atua criando ligações de hidrogênio e liberação de íons cálcio, o que potencializa a ação dos irrigadores intracanal, além de causar menos estresse oxidativo. Para a odontologia restauradora, a quitosana demonstrou eficácia como auxiliar no condicionamento da dentina e mostrou potencial para induzir a migração de odontoblastos na proteção do complexo dentino-pulpar. A substância atua como uma cura de feridas orais devido à sua capacidade de estimular a formação de fibroblastos e novos vasos sanguíneos, além de células anti-inflamatórias. Descritores: Biopolímeros; Biomateriais; Biotecnologia. Referências Zhao X, Li P, Guo B, Ma PX. Antibacterial and conductive injectable hydrogels based on quaternized chitosan-graft-polyaniline/oxidized dextran for tissue engineering. Acta Biomater. 2015;26:236-48. Tomihata K, Ikada Y. In vitro and in vivo degradation of films of chitin and its deacetylated derivatives. Biomaterials. 1997;18(7):567-75 Citgez B, Cengiz AN, Akgun I, Uludag M, Yetkin G, Bahat N, Ozcan O, Polat N, Akcakaya A, Karatepe O. Effects of chitosan on healing and strength of colonic anastomosis in rats. Acta Cir Bras. 2012;27(10):707-12. Azevedo VVC, Chaves SA, Bezerra DC, Lia Fook MV, Costa ACFM. Quitina e Quitosana: aplicações como biomateriais. Rev Eletr Mater Proc. 2007;2(3):27-34. Tavaria FK, Costa EM, Pina-Vaz I, Carvalho MF, Pintado MM. A quitosana como biomaterial odontológico: estado da arte. Rev Bras Eng Bioméd. 2013;29(1):110-20. Ueno H, Nakamura F, Murakami M, Okumura M, Kadosawa T, Fujinag T. Evaluation effects of chitosan for the extracellular matrix production by fibroblasts and the growth factors production by macrophages. Biomaterials. 2001;22(15):2125-30. Shahid F, Abuzaytoun R. Chitin, chitosan, and co-products: chemistry, production, applications, and health effects. Adv Food Nutr Res. 2005;49(1):93-135. Croisier F, Jerome C. Chitosan-based biomaterials for tissue engineering. Eur Polym J. 2013;49(1):780-92. Giovino C, Ayensu I, Tetteh J, Boateng JS. An integrated buccal delivery system combining chitosan films impregnated with peptide loaded PEG-b-PLA nanoparticles. Colloids Surf B Biointerfaces. 2013;112(1):9-15. Wieckiewicz M, Boening KW, Grychowska N, Paradowska-Stolarz,U. Clinical Application of Chitosan in Dental Specialities. Mini Rev Med Chem. 2017;17(5):401-9. Ravi Kumar MNV. A análise dos pedidos de quitina e quitosana. R React Funct 2000;46(1):1-27. Chen CK, Chang NJ, Wu YT, Fu E, Shen EC, Feng CW, Wen ZH. Bone Formation Using Cross-Linked Chitosan Scaffolds in Rat Calvarial Defects. Implant Dent. 2018;27(1):15-21 Pavez L, Tobar N, Chacon C, Arancibia R, Martinez C, Tapia et al. Chitosan triclosan particles modulate inflammatory signaling in gingival fibroblasts. J Periodontal Res. 2017; 53(2):232-39. Moraes PC, Marques ICS, Basso FG, Rosseto HL, Pires de Sousa FCP, Costa CAS et al. Repair of Bone Defects with Chitosan- Collagen Biomembrane and Scaffold Containing Calcium Aluminate Cement. Braz Dent J. 2017;28(3):287-95. Aydin UZ, Akpinar KE, Hepokur C, Erdönmez D. Assessment of toxicity and oxidative DNA damage of sodium hypochlorite, chitosan and propolis on fibroblast cells. Braz Oral Res. 2018;32(1):1-8. Özdoğan AI, Ilarslan YD, Kösemehmetoğlu K, Acka G, Kutlu HB, Comerdov E et al. In Vivo Evaluation of Chitosan Based Local Delivery Systems for Atorvastatin in Treatment of Periodontitis. Int J Pharm. 2018;25(1):470-76. Paiola FG, Lopes FC, Mazzi-Chaves JF, Pereira RD, Oliveira HF, Queiroz AM et al. How to improve root canal filling in teeth subjected to radiation therapy for câncer. Braz Oral Res. 2018;32(1):1-9. Farhadian N, Godiny M, Moradi S, Hemati Azandaryani A, Shahlaei M. Chitosan/gelatin as a new nano-carrier system for calcium hydroxide delivery in endodontic applications: Development, characterization and process optimization. Mater Sci Eng C Mater Biol Appl. 2018;92:540-46. Subhi H, Reza F, Husein A, Al Shehadat SA, Nurul AA. Gypsum-Based Material for Dental Pulp Capping: Effect of Chitosan and BMP-2 on Physical, Mechanical, and Cellular Properties. Int J Biomater. 2018;2018:3804293. Soares DG, Anovazzi G, Bordini EAF, Zuta UO, Silva Leite MLA, Basso FG, Hebling J, de Souza Costa CA. Biological Analysis of Simvastatin-releasing Chitosan Scaffold as a Cell-free System for Pulp-dentin Regeneration. J Endod. 2018;44(6):971-76. Işılay Özdoğan A, Akca G, Şenel S. Development and in vitro evaluation of chitosan based system for local delivery of atorvastatin for treatment of periodontitis. Eur J Pharm Sci. 2018;124:208-16. Kesim B, Burak AK, Ustun Y, Delikan E, Gungor A. Effect of chitosan on sealer penetration into the dentinal tubules. Niger J Clin Pract. 2018;21(10):1284-90. Guo JM, Makvandi P, Wei CC, Chen JH, Xu HK, Breschi L, Pashley DH, Huang C, Niu LN, Tay FR. Polymer conjugation optimizes EDTA as a calcium-chelating agent that exclusively removes extrafibrillar minerals from mineralized collagen. Acta Biomater. 2019;90:424-40. Susanto A, Susanah S, Priosoeryanto BP, Satari MH, Komara I. The effect of the chitosan-collagen membrane on wound healing process in rat mandibular defect. J Indian Soc Periodontol. 2019;23(2):113-18.

This article provides the review of the medical use of pH- and temperature-sensitive polymer hydrogels. Such polymers are characterised by their thermal and pH sensitivity in aqueous solutions at the functioning temperature of living organisms and can react to the slightest changes in environmental conditions. Due to these properties, they are called stimuli-sensitive polymers. This response to an external stimulus occurs due to the amphiphilicity (diphilicity) of these (co)polymers. The term hydrogels includes several concepts of macrogels and microgels. Microgels, unlike macrogels, are polymer particles dispersed in a liquid and are nano- or micro-objects. The review presents studies reflecting the main methods of obtainingsuch polymeric materials, including precipitation polymerisation, as the main, simplest, and most accessible method for mini-emulsion polymerisation, microfluidics, and layer-by-layer adsorption of polyelectrolytes. Such systems will undoubtedly be promising for use in biotechnology and medicine due to the fact that they are liquid-swollen particles capable of binding and carrying various low to high molecular weight substances. It is also important that slight heating and cooling or a slight change in the pH of the medium shifts the system from a homogeneous to a heterogeneous state and vice versa. This providesthe opportunity to use these polymers as a means of targeted drug delivery, thereby reducing the negative effect of toxic substances used for treatment on the entire body and directing the action to a specific point. In addition, such polymers can be used to create smart coatings of implanted materials, as well as an artificial matrix for cell and tissue regeneration, contributing to a significant increase in the survival rate and regeneration rate of cells and tissues. References 1. Gisser K. R. C., Geselbracht M. J., Cappellari A.,Hunsberger L., Ellis A. B., Perepezko J., et al. 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Seven spot ladybird beetle, (Coccinella septempunctata) is a widely distributed natural enemy of soft-bodied insect pests especially aphids worldwide. Both the adult and larvae of this coccinellid beetle are voracious feeders and serve as a commercially available biological control agent around the globe. Different techniques are adopted to enhance the mass rearing and storage of this natural enemy by taking advantage of its natural ability to withstand under extremely low temperatures and entering diapause under unfavorable low temperature conditions. The key objective of this study was to develop a cost effective technique for enhancing the storage life and predatory potential of the larvae of C. septempunctata through cold storage in conjunction with the use of nuclear techniques, gamma radiations. Results showed that the host eating potential of larvae was enhanced as the cold storage duration was increased. Gamma irradiation further enhanced the feeding potential of larvae that were kept under cold storage. Different irradiation doses also affected the development time of C. septempuntata larvae significantly. Without cold storage, the lower radiation doses (10 and 25 GY) prolonged the developmental time as compared to un-irradiated larvae. Furthermore, the higher dose of radiation (50GY) increased the developmental time after removal from cold storage. This study first time paves the way to use radiation in conjunction with cold storage as an effective technique in implementation of different biological control approaches as a part of any IPM programs.Key wordGamma irradiations; cold storage, Coccinella septempunctata larvae; predatory potential; integrated pest management programme.INTRODUCTIONNuclear techniques such as gamma radiations have a vast application in different programmes of biological control including continuous supply of sterilized host and improved rearing techniques (Greany and Carpenter, 2000; Cai et al., 2017). Similarly irradiation can be used for sentinel-host eggs and larvae for monitoring survival and distribution of parasitoids (Jordão-paranhos et al., 2003; Hendrichs et al., 2009; Tunçbilek et al., 2009; Zapater et al., 2009; Van Lenteren, 2012). Also, at the production level, such technique may facilitate the management of host rearing, improve quality and expedite transport of product (Fatima et al., 2009; Hamed et al., 2009; Wang et al., 2009). Gamma irradiations can also be used to stop insect’s development to enhance host suitability for their use in different mass rearing programs (Celmer-Warda, 2004; Hendrichs et al., 2009; Seth et al., 2009). Development and survival of all insects have a direct connection with temperatures which in turn affect the physical, functional and behavioral adaptations (Ramløy, 2000). Many insects living in moderate regions can survive at low temperature by process of diapause. A temperature between 0 to 10oC may cause some insects to become sluggish and they only become active when the temperature is suitable. Such insects show greater adaptations to flexible temperature regimes for better survival. Many studies have reported this concept of cold-hardiness in insects in general (Bale, 2002; Danks, 2006) and specifically in coccinellid beetles over past years (Watanabe, 2002; Koch et al., 2004; Pervez and Omkar, 2006; Labrie et al., 2008; Berkvens et al., 2010). Using this cold hardiness phenomenon, many coccinellids have been studied for the effect of cold storage such as Coccinella undecimpunctata (Abdel‐Salam and Abdel‐Baky, 2000), Coleomegilla maculata (Gagné and Coderre, 2001) and Harmonia axyridis (Watanabe, 2002). This natural phenomenon, therefore, can be a helpful tool in developing low temperature stockpiling for improving mass-rearing procedures (Mousapour et al., 2014). It may provide a significant output in terms of providing natural enemies as and when required during pest infestation peaks (Venkatesan et al., 2000). Use of irradiation in conjunction with cold storage proves to be an effective technique in implementation of different biological control approaches as a part of any IPM programme. A study reported that the pupate of house fly, Musca domestica irradiated at dose of 500 Gy and can stored up to 2 months at 6°C for future use for a parasitoid wasp Spalangia endius rearing (Zapater et al., 2009). Similarly, when irradiated at 20 GY, parasitic wasps Cotesia flavipes were stored safely up to two months without deterioration of their parasitic potential (Fatima et al., 2009). Similarly, bio-control program of sugarcane shoot borer Chilo infescatellus proved successful through the use of irradiation combined with cold storage of its egg and larval parasitoids Trichogramma chilonis and C. flavipes (Fatima et al., 2009). Less mobile life stages such as larvae are of significance in any IPM strategy because they remain on target site for more time period as compared to adults. Therefore, use of predatory larvae is very promising in different biological control approaches because of their immediate attack on pests and more resistance to unfavorable environmental conditions than delicate egg stage. In addition, with their augmentation into fields, larval stage shows their presence for longer time than adult stage and their feeding potential is also satisfactory as that of adults. For the best utilization of these predators in the field and maximum impact of 3rd and 4th larval instars on prey, we should encourage late 2nd second instar larvae of predatory beetles in the fields as these instars have more feeding capacity due to increased size and ability to handle larger preys.In spite of higher significance, there is little information available about the effect of cold storage on the survival of larval instars of different ladybird beetles and its effect on their predatory potential. Very few studies report the use of cold storage for non-diapausing larval stage like for Semiadalia undecimnotata and only one study reported the short-term storage (up to two weeks) of 2nd and 3rd instar coccinellid, C. maculate, without any loss in feeding voracity of larvae after storage (Gagné and Coderre, 2001). The survival of 3rd and 4th larval instars of C. undecimpunctata for 7 days after storage at 5oC was reported in a study but the survival rate declined after 15-60 days of storage (Abdel‐Salam and Abdel‐Baky, 2000). As C. septempunctata is considered one of the voracious predators (Afroz, 2001; Jandial and Malik, 2006; Bilashini and Singh, 2009; Xia et al., 2018) and diapause is a prominent feature of this beetle and it may undergo facultative diapause under suitable laboratory conditions (Suleman, 2015). No information is available to date about the combined effect of cold storage and irradiation on the larval instars of this species.OBJECTIVES The objective of this study was to devise a cost effective technique for the cold storage and its effect on the subsequent predatory potential of the seven spotted ladybird beetle larvae in conjunction with the use of gamma radiations. Hypothesis of the study was that an optimum length of low temperature treatment for storage purpose would not affect the predation capacity of C. septempunctata larvae and their developmental parameters including survival and pupation will remain unaffected. Furthermore, use of gamma irradiation will have some additional effects on survival and feeding capacity of irradiated C. septempunctata larvae. Such techniques can be utilized in different biocontrol programs where short term storage is required. So these larvae can be successfully imparted in different IPM programs against sucking complex of insect pests as a component of biological control strategyMATERIALS AND METHODSPlant materials: Collection and rearing of C. septempunctata: Adult C. septempunctata were collected from the wheat crop (in NIAB vicinity and farm area) in the month of March during late winter and early in spring season 2016-2017. They were kept in plastic jars and were fed with brassica aphids. Under controlled laboratory conditions (25+2oC, 16h: 8h L:D and 65+5% R.H.), eggs of C. septempuctata were obtained and after hatching, larvae were also given brassica aphids as dietary source. Larvae of second instar were selected for this experiment (as the first instar is generally very weak and vulnerable to mortality under low temperatures). As the larvae approached second instar, they were separated for the experimentation. Irradiation of larvae at different doses: Irradiation of larvae was carried out by the irradiation source 137CS at Radiation laboratory, and the larvae were then brought back to the IPM laboratory, Plant Protection Division, Nuclear Institute for Agriculture and Biology (NIAB) Faisalabad. Radiation doses of 10 GY (Grey), 25 GY and 50 GY were used to treat the second instar larvae. There were three replicates for each treatment and five larvae per replicate were used. Control treatment was left un-irradiated.Cold storage of irradiated larvae: In present work, second instar C. septempunctata larvae were studied for storage at low temperature of 8oC. The larvae were kept at 8oC for 0, I and II weeks where week 0 depicts no cold treatment and this set of larvae was left under laboratory conditions for feeding and to complete their development. For larvae that were kept under cold storage for one week at 8°C, the term week I was devised. Similarly, week II denotes the larvae that remained under cold conditions (8°C) for two continuous weeks. Larvae were removed from cold storage in their respective week i.e., after week I and week II and were left under laboratory conditions to complete their development by feeding on aphids. Data collection: For recording the predatory potential of C. septempunctata larvae, 100 aphids were provided per larva per replicate on a daily basis until pupation as this number was more than their feeding capacity to make sure that they were not starved (personal observation). Observations were recorded for survival rate, developmental time and feeding potential. Data analysis: Data were statistically analysed by Statistical Software SPSS (Version 16.0). The data were subjected to normality check through the One-sample Kolmogorov-Smirnov test. Non normal data were transformed to normal data which were then used for all parametric variance tests. One-way and two-way analyses of variance were used. For comparison between variables, LSD test at α 0.05 was applied.RESULTSFeeding potential of irradiated larvae after removal from cold storage: Results showed an increase in the feeding potential of C. septempunctata larvae with increased cold storage duration. The feeding potential was significantly higher for the larvae that spent maximum length of time (week II) under cold storage conditions followed by week I and week 0. Gamma irradiations further enhanced the feeding potential of larvae that were kept under cold storage. When larvae were irradiated at 10 GY, the eating capacity of larvae increased significantly with the duration of cold storage. Similarly, larvae that were irradiated at 25 GY, showed increase in feeding potential on aphids as the time period of cold storage increased. The feeding potential of larvae that were irradiated at 50 GY, was again significantly increased with increase of cold storage duration. When different radiation doses were compared to week 0 of storage, there was a significant difference in feeding potential and larvae irradiated at 50 GY consumed the maximum numbers of aphids when no cold storage was done followed by larvae irradiated at 10 and 25 GY. With the other treatment, where larvae were kept under cold storage for one week (week I) the larvae irradiated at 50GY again showed the highest feeding potential. The feeding potential of irradiated larvae was again significantly higher than the un-irradiated larvae that were kept for two weeks (week II) under cold storage (table 1).Two-way ANOVA was performed to check the interaction between the different radiation doses and different lengths of storage durations for feeding potential of C. septempunctata larvae on aphids. The feeding potential of larvae irradiated at different doses and subjected to variable durations of cold storage were significantly different for both the radiation doses and cold storage intervals. Furthermore, the interaction between the radiation doses and storage duration was also significant meaning that the larvae irradiated at different doses with different length of cold storage were having significant variations in feeding levels (table 2).Developmental time of irradiated larvae after removal from cold storage: Significant difference was found in the development time of the larvae of C. septempunctata when irradiated at different doses at week 0 (without cold storage). The larvae irradiated at 10 GY took the maximum time for development and with the increase in irradiation dosage, from 25 to 50 GY, the time of development was shortened. The larvae irradiated at 50 GY had the same development time as the un-irradiated ones. When, the irradiated larvae were subjected to cold storage of one week duration (week I), their development time after removal from storage condition varied significantly. The larvae irradiated at 25 GY took the maximum time for development followed by larvae irradiated at 50 GY and 10 GY. There was an indication that the development time was extended for irradiated larvae as compared to un-irradiated larvae.Results also depicted a significant difference in the time taken by irradiated larvae to complete their development after taken out from cold storage of two weeks duration (week II). As the storage time of irradiated larvae increased, the development time was prolonged. Results showed that the larvae that were irradiated at 25 and 50 GY, took the maximum time to complete their development. With the prolonged duration of cold storage up to two weeks (week II), this difference of development time was less evident at lower doses (10 GY). The larvae irradiated at 10 GY showed a significant difference in their developmental duration after being taken out of cold storage conditions of the week 0, I and II. There was no difference in the developmental duration of larvae that were un-irradiated and subjected to different regimes of storage. Un-irradiated larvae were least affected by the duration of storage. With the increase in the storage time, a decrease in the developmental time was recorded. Larvae that were irradiated at 10 GY, took the maximum period to complete their development when no cold storage was done (week 0) followed by week I and II of cold storage. When the larvae irradiated at 25 GY were compared for their development time, there was again significant difference for week 0, I and II of storage duration. Maximum time was taken by the larvae for their complete development when removed from cold storage after one week (week I). With the increase in storage duration the time taken by larvae to complete their development after removal from cold storage reduced.When the larvae were removed after different lengths of cold storage duration i.e., week 0, week I and week II, there was a significant difference in the developmental time afterwards. Results have shown that the higher dose of radiation, increased the developmental time after removal from cold storage. The larvae irradiated at 50 GY took the longest time to complete their development after removal from cold storage (week I and week II) as compared the larvae that were not kept under cold storage conditions (week 0) (table 3).Interaction between the different radiation doses and different lengths of storage durations for development time of larvae were checked by two-way ANOVA. The development time of larvae irradiated at different doses and subjected to variable durations of cold storage were significantly different for both the doses and cold storage intervals. Furthermore, the interaction between the radiation doses and storage duration was also significant meaning that the larvae irradiated at different doses with different length of cold storage were having significant variations in development times (table 4). DISCUSSIONThe present research work indicates the possibility of keeping the larval instars of C. septempunctata under cold storage conditions of 8oC for a short duration of around 14 days without affecting its further development and feeding potential. Furthermore, irradiation can enhance the feeding potential and increase the development time of larval instars. This in turn could be a useful technique in mass rearing and field release programmes for biological control through larval instars. Usually temperature range of 8-10oC is an optimal selection of low temperature for storage as reported earlier for eggs two spotted ladybird beetle, Adalia bipunctata and the eggs of C. septempunctata (Hamalainen and Markkula, 1977), Trichogramma species (Jalali and Singh, 1992) and fairyfly, Gonatocerus ashmeadi (Hymenoptra; Mymaridae) (Leopold and Chen, 2007). However, a study reported more than 80% survival rate for the coccinellid beetle, Harmonia axyridis for up to 150 days at moderately low temperature of 3-6oC (Ruan et al., 2012). So there is great flexibility in coccinellid adults and larvae for tolerating low temperature conditions. After removal from cold storage, larvae showed better feeding potential with consumption of more aphids when compared to normal larvae that were not placed under low temperature conditions. This indicates that when the adult or immature insect stages are subjected to low temperature environment, they tend to reduce their metabolic activity for keeping them alive on the reserves of their body fats and sustain themselves for a substantial length of time under such cold environment. Hereafter, the larval instars that were in cold storage were behaving as if starved for a certain length of time and showed more hunger. This behavior of improved or higher feeding potential of stored larvae has been reported previously (Chapman, 1998). Hence, the feeding potential of C. septempunctata larvae significantly increased after cold storage. Gagné and Coderre (2001) reported higher predatory efficacy in larvae of C. maculata when stored at the same temperature as in the present study i.e., 8oC. Similarly, Ruan et al. (2012) showed that the multicolored Asian ladybug, H. axyridis, when stored under cold conditions, had more eating capacity towards aphids Aphis craccivora Koch than the individuals that were not stored. Such studies indicate that the higher feeding potential in insects after being subjected to low temperature environmental conditions could be due to the maintenance of their metabolism rate to a certain level while utilizing their energy reserves to the maximum extent (Watanabe, 2002).The individuals coming out from cold storage are therefore capable of consuming more pray as they were in a condition of starvation and they have to regain their energy loss through enhanced consumption. Furthermore, the starvation in C. septempunctata has previously been reported to affect their feeding potential (Suleman et al., 2017). In the present study, the larval development was delayed after returning to normal laboratory conditions. Cold storage affects the life cycle of many insects other than coccinellids. The cold storage of green bug aphid parasitoid, Lysiphlebus testaceipes Cresson (Hymenoptra; Braconidae) mummies increased the life cycle 3-4 times. Nevertheless, in current study the development process of stored larvae resumed quickly after taking them out and larvae completed their development up to adult stage. Similar kinds of results were reported for resumption of larval development after removal from cold storage conditions. Such studies only report satisfactory survival rates and development for a short duration of cold storage but as the length of storage is increased, it could become harmful to certain insects. Gagné and Coderre (2001) reported that cold storage for longer period (three weeks) proved fatal for almost 40% of larvae of C. maculata. Furthermore, in the same study, the feeding potential of C. maculata larvae was also affected beyond two weeks of cold storage due to the loss of mobility after a long storage period. Many studies have reported that longer durations of low temperature conditions can either damage the metabolic pathways of body cells or may increase the levels of toxins within the bodies of insects. Also, low temperature exposure for longer duration may cause specific interruptions in the insect body especially neuro-hormones responsible for insect development, which could be dangerous or even life threatening.Chen et al. (2004) also reported that the biological qualities of parasitized Bemisia tabaci pupae on population quality of Encarsia formosa were affected negatively with increase in cold storage duration. Similarly, the egg hatchability of green lacewing Chrysoperla carnea Stephen was lost completely beyond 18 days of cold storage (Sohail et al., 2019). However, in the present study the cold storage was done for maximum two weeks and it is to be regarded as a short term storage hence the survival rate was satisfactory. Longer periods of cold storage for larvae are not considered safe due to their vulnerable state as compared to adults which are hardier. Also 2nd instar larvae used in the present study for cold storage for being bigger in size and physical stronger than 1st instar. Abdel‐Salam and Abdel‐Baky (2000) reported that in C. undecimpunctata the cold storage of 3rd and 4th larval instars was higher and considered safer than early larval instars. The same study showed sharp decline in survival rate after two weeks and there was no survival beyond 30-60 days of cold storage. The present study showed that short term storage of the larvae of C. septempunctata could be done without any loss of their feeding potential or development so the quality of predator remained unaffected. Similar kind of work for many other insects had been reported previously where cold storage technique proved useful without deteriorating the fitness of stored insects. For example, the flight ability of reared codling moth Cydia pomonella Linnaeus remained unaffected after removal from cold storage (Matveev et al., 2017). Moreover, a sturdy reported that pupae of a parasitoid wasp Trichogramma nerudai (Hymenoptera; Trichogrammatidae) could be safely put in cold storage for above than 50 days (Tezze and Botto, 2004). Similarly, a technique of cold storage of non-diapausing eggs of black fly Simulium ornaturm Meigen was developed at 1oC. Another study reported safe storage of a predatory bug insidious flower bug Orius insidiosus for more than 10 days at 8°C (Bueno et al., 2014).In present study without cold storage, the lower doses of 10 and 25 GY prolonged the developmental time as compared to un-irradiated larvae and higher doses of irradiations in conjunction with cold storage again significantly prolonged the developmental time of larvae when returned to the laboratory conditions. Salem et al. (2014) also reported that Gamma irradiations significantly increased the duration of developmental stages (larvae and pupae) in cutworm, Agrotis ipsilon (Hufnagel). In another study, where endoparasitic wasps Glyptapanteles liparidis were evaluated with irradiated and non-irradiated gypsy moth Lymantria dispar larvae for oviposition, it was found that non-irradiated larvae had a shorter time to reach the adult stage as compared to irradiated larvae (Novotny et al., 2003). Both for higher doses with cold storage and lower doses without cold storage extended the larval duration of C. septempunctata. In another study when the parasitoid wasp Habrobracon hebetor was irradiated at the dose of 10 GY, it resulted in prolonged longevity (Genchev et al., 2008). In the same study, when another parasitoid Ventruria canescens was irradiated at lower doses of 4GY and 3 GY, it resulted in increased emergence from the host larvae, while gamma irradiations at the dose of 1 GY and 2 GY significantly stimulated the rate of parasitism (Genchev et al., 2008). The current study also indicated higher rates of predation in the form of increased feeding potential of larvae as a result of irradiations at lower doses.CONCLUSIONThe outcome of the current study shows that storage of 2nd instar C. septempunctata at low temperature of 8oC for a short duration of about 14 days is completely safe and could have broader application in different biocontrol programs. Such flexibility in storage duration can also assist in different mass rearing techniques and commercial uses. The combination of gamma radiation with low temperature cold storage could be a useful tool in developing different biological pest management programs against sucking insect pests. Incidence of periodic occurrence of both the target insect pests with their predatory ladybird beetles in synchrony is an important aspect that could be further strengthened by cold storage techniques. Therefore, short or long term bulk cold storage of useful commercial biocontrol agents and then reactivating them at appropriate time of pest infestation is a simple but an advantageous method in mass rearing programs. Increased feeding capacity of stored larvae is another edge and hence such larvae may prove more beneficial as compared to unstored larvae. Both cold storage and improved feeding of the C. septempuctata larvae can be utilized for implementation of IPM for many sucking insect pests of various crops, fruits and vegetables. Due to some constraints this study could not be continued beyond two weeks but for future directions, higher doses and longer duration periods could further elaborate the understanding and better application of such useful techniques in future IPM programmes on a wider scale. Also, some other predatory coccinellid beetle species can be tested with similar doses and cold storage treatments to see how effective this technique is on other species as well.ACKNOWLEDGMENTS We acknowledge the Sugarcane Research and Development Board for providing a research grant (No. SRDB/P/4/16) to carry out this research work. 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Use of irradiated musca domestica pupae to optimize mass rearing and commercial shipment of the parasitoid spalangia endius (Hymenoptera: Pteromalidae). Biocontrol science technology, 19(sup1): 261-270.

Review Targeting Inflammation to Control Tissue Fibrosis Weihua Song 1, Wu Sun 2, Zilong Wang 3, Kelvin Yi Chong Teo 2,4,5, Chui Ming Gemmy Cheung 2,4,5, and Xiaomeng Wang 4,5,6,* 1 Innoland Biosciences, 6 West Beijing Road, Taicang 215400, Jiangsu, China. 2 Singapore National Eye Center, 11 Third Hospital Ave 168751, Singapore. 3 Ocean University of China, 5 Yushan Rd, Shinan District, Qingdao 266005, Shandong, China. 4 Singapore Eye Research Institute, 20 College Road 169856, Singapore. 5 Duke-NUS Graduate Medical School, 20 College Road 169856, Singapore. 6 Insitute of Molecular and Cell Biology, 61 Biopolis Dr, Proteos 138673, Singapore. * Correspondence: xiaomeng.wang@duke-nus.edu.sg Received: 17 November 2022 Accepted: 19 November 2022 Published: 21 December 2022 Abstract: Remodeling of the extracellular matrix (ECM) is an essential process in host defense against pathogens and tissue repair following injury. However, aberrant inflammatory responses could disturb ECM homeostasis leading to progressive disruption in tissue architecture and organ function. Fibrosis is the common outcome of a wide range of diseases, especially chronic inflammatory disorders, and represents the leading cause of morbidity and mortality globally. This review provides the current understanding of the pathogenesis of fibrosis, with particular emphasis on the role of inflammation in this process and the translational potential of targeting inflammation as a strategy to control fibrotic progression.

Tanshinones are an important lipophilic, bioactive diterpenoid group of danshen roots with many pharmacological activities. In this study, tanshinones rich extract of danshen roots, a typically valuable product of danshen, was prepared through a two-step process of extraction and purification. In which, adsorptive (non-ionic) macroporous resins were exploited in the purification step to remove impurities and enrich tanshinones. The obtained refined extract was red brownish dry powder with the following characteristics: loss on drying of 4.04 ± 0.18%, tanshinone IIA and cryptotanshinone content of 10.55 ± 0.21% and 5.78 ± 0.64%, respectively (the results met the requirements of the Tanshinones monograph in The Chinese Pharmacopoeia 2015). The overall yield of the established extraction process was 2.21 ± 0.12%, calculated by the weight of dry extract. Keywords: Tanshinones, danshen, macroporous resins, tanshinone IIA, cryptotanshinone. References [1] X. Yan, Overview of Modern Research on Danshen, G. Du, J. Zhang, Danshen (Salvia Miltiorrhiza) in Medicine, Springer, Germany, Vol. 2, 2014, pp. 3-17.[2] C. Y. Su, Q. L. Ming, K. Rahman, H. Ting, L. P. Qin, Salvia miltiorrhiza: Traditional Medicinal Uses, Chemistry, and Pharmacology, Chinese Journal of Natural Medicines, Vol. 13, No. 3, 2015, pp. 163-182, https://doi.org/10.1016/S1875-5364(15)30002-9.[3] Y. Cui, B. Bhandary, A. Marahatta, G. H. Lee, B. Li, D. S. Kim, S. W. Chae, H. R. Kim, H. J. Chae, Characterization of Salvia Miltiorrhiza Ethanol Extract as An Anti-osteoporotic Agent, BMC complementary and alternative medicine, Vol. 11, No. 1, 2011, pp. 120-131, https://doi.org/10.1186/1472-6882-11-120.[4] J. Li, H. A. Chase, Development of Adsorptive (Non-ionic) Macroporous Resins and Their Uses in The Purification of Pharmacologically-Active Natural Products From Plant Sources, Natural product reports, Vol. 27, No. 10, 2010, pp. 1493-1510, https://doi.org/10.1039/c0np00015a.[5] Tanshinones, The Chinese Pharmacopoeia, China, 2015, pp. 398-399.[6] G. Tian, T. Zhang, Y. Zhang, Y. Ito, Separation of Tanshinones From Salvia miltiorrhiza Bunge by Multidimensional Counter-Current Chromatography, Journal of Chromatography A, Vol. 945, No. 1-2, 2002, pp. 281-285, https://doi.org/10.1016/S0021-9673(01)01495-9.[7] D. Wu, X. Jiang, S. Wu, Direct Purification of Tanshinones From Salvia miltiorrhiza Bunge by High‐speed Counter‐current Chromatography Without Presaturation of The Two‐phase Solvent Mixture, Journal of Separation Science, Vol. 33, No. 1, 2010, pp. 67-73, https://doi.org/10.1002/jssc.200900491.[8] M. Liu, X. H. Xia, Study on The Chemical Stability of Tanshinone IIA, Zhong Yao Cai, Vol. 33, No. 4, 2010, pp. 606-609, PMID: 20845791 (In Chinese).[9] X. Bi, X. Liu, L. Di, Q. Zu, Improved Oral Bioavailability Using a Solid Self-Microemulsifying Drug Delivery System Containing a Multicomponent Mixture Extracted from Salvia miltiorrhiza, Molecules, Vol. 21, No. 456, 2016, pp. 1-15. https://doi.org/10.3390/molecules21040456.

This article develops a combined solid phase extraction (SPE) and gas chromatography – mass spectrometry (GC-MS) procedure for determining amphetamine-type stimulants Amphetamine (AM) and Methamphetamine (MA) in human hair. Hair samples were incubated in methanol containing 1% hydrochloric acid in 18 hours and then subjected to SPE. The obtained extracts were evaporated to dryness, derivatized with heptafluorobutyric anhydride (HFBA) at 70 °C for 30 minutes prior to GC–MS analysis. Gas chromatography mass spectrometry was run on HP5-MS column (30 m × 0.25 mm × 0.25 µm) with detector MS 5975C. Experimentally, the proposed method proved sensitive, simple and time-saving, but quite accurate with a low limit of detection (LOD = 0.05ng/mg) and quantitation (LOQ = 0.15ng/mg). Keywords: SPE, GC – MS, hair samples, amphetamine, methamphetamine. References [1] Ming-Ren Fuh, Ti-Yu Wu and Tzuen-Yeuan Lin, Determination of amphetamine and methamphetamine in urine by solid phase extraction and ion-pair liquid chromatography–electrospray–tandem mass spectrometry Talanta, 68 (3) (2006), 987-991. https://doi.org/10.1016/j.talanta.2005.06.057[2] Naresh C. Jain, Thomas C. Sneath, and Robert D. Budd, Rapid Gas-Chomatographic Determination of Amphetamine and Methamphetamine in urine, Clinical Chemistry, 20 (11) (1974) 1460-1462. https://doi.org/10.1093/clinchem/20.11.1460.[3] Dong-liang Lin, Rea-Ming Yin, Ray H. Liu, Gas Chromatography-Mass Spectrometry (GC-MS) Analysis of Amphetamine, Methamphetamine, 3,4-Methylenedioxy- amphetamine and 3,4-Methylenedioxymethamphetamine in Human Hair and Hair Sections, Journal of Food and Drug Analysis, 13(2) (2005) 193-200. https://doi.org/10.38212/2224-6614.2526[4] María Jesús Tabernero, Maria Linda Felli, Ana María Bermejo, Marcello Chiarotti, Determination of ketamine and amphetamines in hair by LC/MS/MS, Anal Bioanal Chem, 395(2009), 2547–2557. https://doi.org/10.1007/s00216-009-3163-4.[5] D.V. Doan, D.Q. Huy, N.D. Hue, T.M. Tri, Determination of methamphetamine in urine samples by gas chromatography mass spectrometry combined with solid phase extraction technique, Journal of Science and Technology 47 (6) (2009) 53-58 (in Vietnamese).[6] Rodger L. Foltz, Allison F. Fentiman, Ruth B. Foltz, GC/MS Assays for Abused Drugs in Body Fluids, National Institute on Drug Abuse, Maryland, 1980.[7] AOAC, Appendix F: Guidelines for Standard Method Performance Requirements, AOAC official methods of analysis, Maryland, 2016.[8] Eunyoung Han, Martin P. Paulus, Marc Wittmann, Heesun Chung, Joon myong Song, Hair analysis and self-report of methamphetamine use by methamphetamine dependent individuals, Journal of Chromatography B, 879 (2011) 541–547. https://doi.org/10.1016/j.jchromb.2011.01.002.

Graphene-based composites have received a great deal of attention in recent year because the presence of graphene can enhance the conductivity, strength of bulk materials and help create composites with superior qualities. Moreover, the incorporation of metal oxide nanoparticles such as Fe3O4 can improve the catalytic efficiency of composite material. In this work, we have synthesized a composite material with the combination of reduced graphene oxide (rGO), and Fe3O4 modified tissue-paper (mGO-PP) via a simple hydrothermal method, which improved the removal efficiency of the of methylene blue (MB) in water. MB blue is used as the model of contaminant to evaluate the catalytic efficiency of synthesized material by using a Fenton-like reaction. The obtained materials were characterized by SEM, XRD. The removal of materials with methylene blue is investigated by UV-VIS spectroscopy, and the result shows that mGO-PP composite is the potential composite for the color removed which has the removal efficiency reaching 65% in acetate buffer pH = 3 with the optimal time is 7 h. Keywords Graphene-based composite, methylene blue, Fenton-like reaction. References [1] Ma Joshi, Rue Bansal, Reng Purwar, Colour removal from textile effluents, Indian Journal of Fibre & Textile Research, 29 (2004) 239-259 http://nopr.niscair.res.in/handle/123456789/24631.[2] Kannan Nagar, Sundaram Mariappan, Kinetics and mechanism of removal of methylene blue by adsorption on various carbons-a comparative study, Dyes and pigments, 51 (2001) 25-40 https://doi.org/10.1016/S0143-7208(01)00056-0.[3] K Rastogi, J. N Sahu, B. C Meikap, M. N Biswas, Removal of methylene blue from wastewater using fly ash as an adsorbent by hydrocyclone, Journal of hazardous materials, 158 (2008) 531-540.https://doi.org/10.1016/j.jhazmat.2008.01. 105.[4] Qin Qingdong, Ma Jun, Liu Ke, Adsorption of anionic dyes on ammonium-functionalized MCM-41, Journal of Hazardous Materials, 162 (2009) 133-139 https://doi.org/10.1016/j.jhazmat. 2008.05.016.[5] Mui Muruganandham, Rps Suri, Sh Jafari, Mao Sillanpää, Lee Gang-Juan, Jaj Wu, Muo Swaminathan, Recent developments in homogeneous advanced oxidation processes for water and wastewater treatment, International Journal of Photoenergy, 2014 (2014). http://dx. doi.org/10.1155/2014/821674.[6] Herney Ramirez, Vicente Miguel , Madeira Luis Heterogeneous photo-Fenton oxidation with pillared clay-based catalysts for wastewater treatment: a review, Applied Catalysis B: Environmental, 98 (2010) 10-26 https://doi.org/ 10.1016/j.apcatb.2010.05.004.[7] Guo Rong, Jiao Tifeng, Li Ruifei, Chen Yan, Guo Wanchun, Zhang Lexin, Zhou Jingxin, Zhang Qingrui, Peng Qiuming, Sandwiched Fe3O4/carboxylate graphene oxide nanostructures constructed by layer-by-layer assembly for highly efficient and magnetically recyclable dye removal, ACS Sustainable Chemistry & Engineering, 6 (2017) 1279-1288 https://doi.org/10.1021/acssuschemeng.7b03635.[8] Sun Chao, Yang Sheng-Tao, Gao Zhenjie, Yang Shengnan, Yilihamu Ailimire, Ma Qiang, Zhao Ru-Song, Xue Fumin, Fe3O4/TiO2/reduced graphene oxide composites as highly efficient Fenton-like catalyst for the decoloration of methylene blue, Materials Chemistry and Physics, 223 (2019) 751-757 https://doi.org/ 10.1016/j.matchemphys.2018.11.056.[9] Guo Hui, Ma Xinfeng, Wang Chubei, Zhou Jianwei, Huang Jianxin, Wang Zijin, Sulfhydryl-Functionalized Reduced Graphene Oxide and Adsorption of Methylene Blue, Environmental Engineering Science, 36 (2019) 81-89 https://doi. org/10.1089/ees.2018.0157.[10] Zhao Lianqin, Yang Sheng-Tao, Feng Shicheng, Ma Qiang, Peng Xiaoling, Wu Deyi, Preparation and application of carboxylated graphene oxide sponge in dye removal, International journal of environmental research and public health, 14 (2017) 1301 https://doi.org/10.3390/ijerph14111301.[11] Yu Dandan, Wang Hua, Yang Jie, Niu Zhiqiang, Lu Huiting, Yang Yun, Cheng Liwei, Guo Lin, Dye wastewater cleanup by graphene composite paper for tailorable supercapacitors, ACS applied materials & interfaces, 9 (2017) 21298-21306 https://doi.org/10.1021/acsami.7b05318.[12] Wang Hou, Yuan Xingzhong, Wu Yan, Huang Huajun, Peng Xin, Zeng Guangming, Zhong Hua, Liang Jie, Ren MiaoMiao, Graphene-based materials: fabrication, characterization and application for the decontamination of wastewater and wastegas and hydrogen storage/generation, Advances in Colloid and Interface Science, 195 (2013) 19-40 https://doi. org/10.1016/j.cis.2013.03.009.[13] Marcano Daniela C, Kosynkin Dmitry V, Berlin Jacob M, Sinitskii Alexander, Sun Zhengzong, Slesarev Alexander, Alemany Lawrence B, Lu Wei, Tour James M, Improved synthesis of graphene oxide, ACS nano, 4 (2010) 4806-4814 https://doi.org/10.1021/nn1006368.[14] Zhang Jiali, Yang Haijun, Shen Guangxia, Cheng Ping, Zhang Jingyan, Guo Shouwu, Reduction of graphene oxide via L-ascorbic acid, Chemical Communications, 46 (2010) 1112-1114 http://doi. org/10.1039/B917705A [15] Gong Ming, Zhou Wu, Tsai Mon-Che, Zhou Jigang, Guan Mingyun, Lin Meng-Chang, Zhang Bo, Hu Yongfeng, Wang Di-Yan, Yang Jiang, Nanoscale nickel oxide/nickel heterostructures for active hydrogen evolution electrocatalysis, Nature communications, 5 (2014) 4695 https:// doi.org/10.1038/ncomms5695.[16] Wu Zhong-Shuai, Yang Shubin, Sun Yi, Parvez Khaled, Feng Xinliang, Müllen Klaus, 3D nitrogen-doped graphene aerogel-supported Fe3O4 nanoparticles as efficient electrocatalysts for the oxygen reduction reaction, Journal of the American Chemical Society, 134 (2012) 9082-9085 https://doi.org/10.1021/ja3030565.[17] Nguyen Son Truong, Nguyen Hoa Tien, Rinaldi Ali, Nguyen Nam Van, Fan Zeng, Duong Hai Minh, Morphology control and thermal stability of binderless-graphene aerogels from graphite for energy storage applications, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 414 (2012) 352-358 https://doi.org/ 10.1016/j.colsurfa.2012.08.048.[18] Deng Yang, Englehardt James D, Treatment of landfill leachate by the Fenton process, Water research, 40 (2006) 3683-3694 https://doi.org/ 10.1016/j.watres.2006.08.009.

It is very important to unseal the closed coal mine fire zone safely. Although the fire source disappears in the closed fire zone, it is uncertain whether there are still have high-temperature ignition points, and there is a risk of fire or even explosion again after unsealing. To ensure that the closed fire zone can be unsealed successfully at one time, the study puts forward the method of oxygen augmentation observation to understand the combustion state of the closed fire zone in underground coal mine from the perspective of gas analysis technology. When the mine fire is detected to be extinguished, the method is to inject 8–12% oxygen into the fire area, and the fire area shall be monitored for 2 weeks to determine whether the fire area is completely extinguished. The accuracy and practicality of the method of oxygen augmentation observation are verified by comparing and analyzing the difference results generated by two oxygen augmentation observations in closed zone of Yuwu Coal Mine. In this paper, the use conditions of unsealing in fire zone, detailed methods and steps in the whole process of unsealing and emergency rescue plan are given. The research results can provide valuable reference for one-time safe unsealing of fire zone during the process of disaster relief.

The community Question Answering (cQA) problem requires the task that given a question it aims at selecting the most related question-answer tuples (a question and its answers) from the stored question-answer tuples data set. The core mission of this task is to measure the similarity (or relationship) between an input question and questions from the given question-answer data set. Under our observation, there are either various information sources as well as di erent measurement models which can provide complementary knowledge for indicating the relationship between questions and question-answer tuples. In this paper we address the problem of modeling and combining multiple knowledge sources for determining and ranking the most related question-answer tuples given an input question for cQA problem. Our proposed model will generate di erent features based on di erent representations of the data as well as on di erent methods and then integrate this information into the BERT model for similarity measurement in cQA problem. We evaluate our proposed model on the SemEval 2016 data set and achieve the state-of-the-art result. Keywords Community question answering, Multi knowledge sources, Deep learning, The BERT model References [1] C. Alberto, D. Bonadiman, G. D. S. Martino, Answer and Question Selection for Question Answering on Arabic and English Fora, in Proceedings of SemEval-2016, 2016, pp. 896-903. [2] Filice, D. Croce, A. Moschitti, R. Basili, Learning Semantic Relations between Questions and Answers, in Proceedings of SemEval-2016, 2016, pp. 1116-1123. [3] Wang, Z. Ming, T. S. Chua, A Syntactic Tree Matching Approach to Finding Similar Questions in Community-based qa Services, in SIGIR, 2009, pp. 187-194. [4] Pengfei, Q. Xipeng, C. Jifan, H. Xuanjing, Deep Fusion lstms for Text Semantic Matching, in Proceedings of the 54th Annual Meeting of the Association for Computational Linguistics, Vol. 1, 2016, pp. 1034-1043, https://doi.org/ 10.18653/v1/P16-1098. [5] Jonas, T. Aditya, Siamese Recurrent Architectures for Learning Sentence Similarity, in Proceedings of the Thirtieth AAAI Conference on Artificial Intelligence (AAAI-16), 2016, pp. 2786-2792. [6] Jacob, C. M. Wei, L. Kenton, T. Kristina, Bert: Pre-training of Deep Bidirectional Transformers for Language Understanding, in Proceedings of the 2019 Conference of the North American Chapter of the Association for Computational Linguistics: Human Language Technologies, 2019, pp. 4171-4186. [7] Wissam, B. Fady, H. Hazem, Arabert: Transformer-based Model for Arabic Language Understanding, in Proceedings of the 4th Workshop on Open-Source Arabic Corpora and Processing Tools, with a Shared Task on O ensive Language Detection, 2020, pp. 9-15. [8] Lukovnikov, A. Fischer, J. Lehmann, Pretrained Transformers for Simple Question Answering Over Knowledge Graphs, ArXiv, abs/2001.11985, 2019. [9] V. Aken, B. Winter, A. Loser, F. Gers, How Does BERT Answer Questions?: A Layer-Wise Analysis of Transformer Representations, in Proceedings of the 28th ACM International Conference on Information and Knowledge Management, 2019. [10] Chan, Y. Fan, A Recurrent BERT-based Model for Question Generation, in Proceedings of the Second Workshop on Machine Reading for Question Answering, 2019, pp. 154-162. [11] Lan, M. Chen, S. Goodman, K. Gimpel, P. Sharma, R. Soricut, ALBERT: A Lite BERT for Self-supervised Learning of Language Representations, ArXiv, abs/1909.11942, 2020. [12] Ngai, Y. Park, J. Chen, M. Parsapoor, Transformer-Based Models for Question Answering on COVID19, ArXiv, abs/2101.11432, 2021. [13] Yu, L. Wu, Y. Deng, R. Mahindru, Q. Zeng, S. Guven, M. Jiang, A Technical Question Answering System with Transfer Learning, in Proceedings of the 2020 EMNLP (Systems Demonstrations), 2020, pp. 92-99. [14] S. McCarley, R. Chakravarti, A. Sil, Structured Pruning of a BERT-based Question Answering Model, arXiv: Computation and Language, 2019. [15] Almiman, N. Osman, M. Torki, Deep Neural Network Approach for Arabic Community Question Answering, Alexandria Engineering Journal, Vol. 59, 2020, pp. 4427-4434. [16] Vaswani, N. Shazeer, N. Parmar, J. Uszkoreit, L. Jones, A. N. Gomez, I. Polosukhin, Attention is all you Need, in Advances in Neural Information Processing Systems, 2017, pp. 5998-6008. [17] T. Nguyen, A. C. Le, H. N. Nguyen, A Model of Convolutional Neural Network Combined with External Knowledge to Measure the Question Similarity for Community Question Answering Systems, International Journal of Machine Learning and Computing, Vol. 11, No. 3, 2021, pp. 194-201, https://doi.org/ 10.18178/ijmlc.2021.11.3.1035.

Cowpea (Vigna unguiculata L. Walp) is one of the important legume crops of Nepal, which is consumed as a green vegetable or a dried pulse. In recent years, virus diseases have caused significant yield and quality losses in cowpea. In September 2019, five cowpea plants showing virus-like symptoms of mosaic, yellow mosaic, vein clearing, chlorotic spots, (Fig. S1) were collected in Chitwan, Nepal. The incidence of symptomatic plants in the three kitchen gardens was about 10-20%. To identify the viruses associated with the disease, a pooled sample from all five plants was screened initially by next generation sequencing (NGS). Total RNA was extracted from the symptomatic leaves using RNeasy Plant Mini Kit (Qiagen, Germany) and a transcriptome library was generated using the TruSeq Stranded Total RNA LT Sample Prep kit (Illumina, San Diego, CA) according to the standard protocol. NGS was performed using an Illumina NovaSeq 6000 system (Macrogen Inc. Korea). A total of 324,807 contigs in the range of 201-14,645 nucleotides (nt) were obtained and analyzed against the viral reference genome database in GenBank by BLASTn and BLASTx search. Among the analyzed contigs, two large contigs showed homologies to cowpea polerovirus 2 (CPPV2) and southern cowpea mosaic virus (SCPMV. The CPPV2 contig (361,121 mapped reads, mean read coverage of 9,206.4 times) had a nearly complete genome sequence of 5,923 nt and showed 96% identity (99% coverage) with CPPV2 isolate BE179 (GenBank Acc. No. KY364847) isolaed from cowpea in Burkina Faso (Palanga et al. 2017). The SCPMV contig (10,612 mapped reads, mean read coverage of 384.1 times) had a nearly complete genome sequence of 4,172 nt and showed 90% identity (100% coverage) with SCPMV isolate C (GenBank Acc. No. M23021) isolated from cowpea in the USA (Wu et al. 1987). Additionally, mungbean yellow mosaic India virus (MYMIV, genus Begomovirus) and bean common mosaic virus (BCMV, genus Potyvirus) were detected at very low read depths. To confirm the presence of these viruses, total RNA was extracted from individual leaf samples, and reverse transcription PCR (RT-PCR) was performed using specific primers for each virus (Table S1). Three of five cowpea samples were positive for CPPV2, and they were co-infected with one other virus; SCPMV, MYMIV, or BCMV (Fig. S1). One cowpea sample was positive for the remaining one with symptom of overall chlorosis was negative for all four viruses. The amplified products of 1,205 bp for CPPV2 isolates, CPPV2-NP10, -NP12, and -NP24 were sequenced and deposited in GenBank under accession nos. MZ318692-93. These Sanger sequences shared 99% nt identity with the NGS-derived sequence. The amplified product of 1,394 bp for SCPMV isolate SCPMV-NP12 (GenBank acc. no. MZ355623) shared 100% nt identity with the NGS-derived sequence. CPPV2 is a member of the genus Polerovirus and it was first identified and characterized by molecular assays in Burkina Faso (Palanga et al. 2016; 2017). SCPMV is a member of the genus Sobemovirus and it has been reported in the USA, China, and Burkina Faso (Hull et al. 2000; Lee et al. 2001; Wu et al. 1987). In Nepal, MYMIV has been reported in legumes, such as kidney bean, black gram, and mungbean, and BCMV in common bean (Acharya and Regmi 2020). To our knowledge, this is the first report of CPPV2 and SCPMV in cowpea in Nepal. Further work is required to determine the distribution, pathological properties, and economic impact of these two viruses.

The genus Piper has about 1.500 species mainly distributed in tropical, there were 43 Piper species recorded in Vietnam. In this paper, we reported Piper minutistigmum C. DC. newly recorded for the flora of Vietnam. Voucher specimens were collected in Thanh Hoa province (Ben En National park), Nghe An province (Pu Mat National Park: Khe Kem), Ha Tinh province (Vu Quang National park: Doc De) deposited in the Herbarium of the Faculty of Biology, Vinh University and Herbarium of the Institute of Ecology and Biological Resources (HN) Ha Noi, Vietnam. Woody clember, 3-12 m high. Petiole 3-8 mm, glabrous or sometimes sparsely pubescent; leaf simple, alternate, ovate, 6-11 × 3-7 cm, leaf blade toward apex aute, glabrous or sometimes sparsely pubescent, base oblique, 1 side rounded, other side tapered and acute, bilateral difference 3-4 mm, apex acute to long acuminate; veins 3-4, usually 1 more lateral vein on wider side, apical pair arising along midvein. Male spikes is smilar to female spikes, 5-10 x 1-1,5 cm., peduncle 1-1,2 cm, bracts 1-1,5 cm. Fruit a drupe, globose, 1-2 mm, often red. Keywords Piper minutistigmum, Piperaceae, Ben En, Pu Mat, Vu Quang, National Park References [1] Chaveerach A., P.Mokkamul, R. Sudmoon, T. Tanee (2006), Ethnobotany of the genus Piper (Piperaceae) in Thailand, Ethnobotany Research & Applications, 4: 223-231.[2] Chaveerach A., R. Sudmoon T. Tanee, P. Mokkamul (2006), Three new species of Piperaceae from Thaila[3] nd, Acta Phytotaxonomica Sinica, 44: 447-453. [4] Cheng Y., N. Xia & M.G. Gilbert (1999), Piperaceae, Pp 110-129 in Flora of China Vol. 4. Edited by Z. Wu & P.H. Raven. Missouri Botanical Garden, St.Louis, Missouri.[5] Lê Thị Hương, Lê Đông Hiếu, Trần Minh Hợi, Đỗ Ngọc Đài (2018), Piperboehmeriaefolium (Piperaceae) loài bổ sung cho hệ thực vật Việt Nam, Báo cáo Khoa học về Nghiên cứu và Giảng dạy Sinh học ở Việt Nam, Hội nghị Khoa học Quốc gia lần thứ 3, Nxb Nông nghiệp Hà Nội, Quy Nhơn, 20/5/2018; 529-531[6] Nguyễn Kim Đào (2003), Họ Piperaceae trong Nguyễn Tiến Bân (Chủ biên), Danh lục các loài thực vật Việt Nam, tập 2, Nxb. Nông nghiệp, Hà Nội, 115-122.[7] Lê Đông Hiếu, Đỗ Ngọc Đài, Trần Minh Hợi (2017), Đa dạng họ Hồ tiêu (Piperaceae) ở Bắc Trung Bộ, Tạp chí Nông nghiệp và Phát triển Nông thôn, [8] Phạm Hoàng Hộ (1999), Piperaceae - Họ Hồ tiêu, Cây cỏ Việt Nam, 1: 228-301. Nxb Trẻ, Tp Hồ Chí Minh.

LANGUAGE NOTE | Document text in Chinese; abstract also in English. 《老子》中有三個最重要的概念：道、無、有。要言之，道是真理，無與有表示道這真理的形上性格。但無一概念的內容非常豐富，經筆者細心研究，發現無一概念起碼有六面意思。一、指本體的道。道是客觀的實體，是實際存在的，且是天地萬物成立和滋長的超越依據。無亦是這個意思。二、是本體的道的描述語。無表示道以沖虚為體，由此可產生無窮妙用，包括創生萬物在內。三、表示道的虚無為用。虛無狀態之能有用，由於“反”的義理。四、表示工夫修行。要撤除一切的障礙，化解人生的挫折。五、表示處事方法或態度。這便是無為和無不為。無為是不妄為，不刻意做些干擾人的本性的事。能如此，則一切都能辦得妥當，這便是無不為。六、指主觀的實踐境界。即在主觀的心上實現客觀的道而成的一種沖虛的精神境界。 貫串無的這六面意義的，是虛無的狀態。這是客觀的道的性格，也是主觀的心境。 老子是《老子》或《道德經》一書的作者。他的哲學有三個最重要的概念，這便是道、無、有。如下文所表述那樣，道是老子心目中的真理，無與有是道這真理的形而上性格，老子又視道為無，而無與有又有相對相關的密切關係。故無似乎介於道與有之間，是老子哲學的一個關鍵概念。了解了無，老子哲學的整個輪廓與根本精神，便能把握得到。故本文即以“老子哲學的無的概念之探究”為題，闡述與探討老子的哲學。 很多研究老子哲學的學者，都不會忽視他的無的概念。他們通常認為這無的意義有兩個層次：其一是指作為客觀實體的道，另一則是一般的意思，指不存在，是有無的無。這樣理解自然是對的，不過，筆者認為並不足夠，不夠全面，也不夠具體。筆者以為，老子的無有以下多面的意思：它指本體的道，是本體的道的代語：它也指道的虛無為用，也涵有工夫修行及處事方法或態度的意思：另外，它也指一種主觀的實踐境界。這樣理解，自然包含上面的兩個層次的意思。以下我們即就無的這些方面的意思來進行探討。在探討中，我們會廣泛地參考現代學者研究老子哲學的成果，並把重要的説法也推介出來。There are three important concepts in Lao-tzu’s philosophy, namely, Tao, Nothing and Being. Tao is the Truth, whereas Nothing and Being represent the metaphysical nature of this Truth. The content of the concept of Nothing is, indeed, very abundant. It consists of at least six meanings. 1. It denotes the metaphysical Tao which does exist, serving as the transcendental ground of all entities. 2. It describes the essence of Tao as voidness. Numerous wondrous functions originate from this voidness, including giving birth to all entities. 3. It denotes the various functions based on Tao’s voidness. That voidness can induce functions is due to its implication of “return”. 4. It involves the implication of cultivation which is achieved in the eradication of all kinds of hindrance and the dissolution of all difficulties. 5. It denotes the methods or attitudes of dealing with daily matters, namely wu-wei and wu pu-wei. Wu-wei means one does not initiate unnecessary actions that will hamper human nature. If one can do so, there is nothing that cannot be done well. This is Wu pu-wei. 6. It denotes a subjective state achieved through practice. That is, one realizes the objective Tao in one’s mind, attaining a spiritual state of emptiness. This empty state is Nothing. These six meanings are not separated from each other. They are co¬related through the implication of voidness, which denotes, objectively, the nature of Tao, and subjectively, a state of the mind.

Abstract: The genus Alpinia Roxb. is a large genus in the ginger family (Zingiberaceae) with about 250 species in the world, mainly distributed in tropical and subtropical Asia, a small number distributed in Australia and Pacific islands. In the Vietnam, more than 30 species of galangal have been published, in of which many new species for science and new record to the Vietnamese flora have been discovered in recent years. One species of galangal in northern Vietnam (Lang Son province and Bac Giang province) has been identified as Alpinia calcarata (Haw) Rosc. Extract from crushed rhizomes (tubers) of this plant is used in the production of sausage, has the effect of creating color and preserving for long time. The specimens are preserved in the Vietnam Museum National (VNMN) and Hanoi College of Pharmacy (HNIP). Keywords: Alpinia calcarata, Rieng hoa cua, Lang Son, Bac Giang. References [1] Phạm Hoàng Hộ, Cây cỏ Việt Nam, Nhà xuất bản Trẻ Tp. Hồ Chí Minh, 2003, Tập 3: pp. 432-461.[2] http://www.theplantlist.org/1.1/browse/A/Zingiberaceae[3] Lê Thị Hương, Trần Thế Bách, Nguyễn Quốc Bình, Lý Ngọc Sâm, Bổ sung loài Riềng nhiều hoa (Alpinia polyantha D.Fang) (Zingiberaceae) cho hệ thực vật Việt Nam, Tạp chí Khoa học ĐHQGHN: Khoa học Tự nhiên và Công nghệ 31(4S) (2015) 154-157. [4] Lê Thị Hương, Đỗ Ngọc Đài, Nguyễn Quốc Bình, Nguyễn Trung Thành, Alpinia rugosa S.J.Chen & Z.Y.Chen (Zingiberaceae) loài bổ sung cho hệ thực vật Việt Nam, Tạp chí Khoa học ĐHQGHN: Khoa học Tự nhiên và Công nghệ 33(1) (2017) 101-104. [5] Ly Ngoc Sam, Alpinia newmanii sp. nov. (Zingiberaceae) from central Vietnam, Nordic Journal of Botany, 35(2), (2017) 176-181. https:// doi.org/10.1111/njb.01429[6] W. Delin and K. Larsen, Zingiberaceae, In: Z.Y. Wu, P.H. Raven, D.Y. Hong (eds), Flora of China, (Flagellariaceae through Marantaceae), Science Press, Beijing and Missouri Botanical Garden Press, St. Louis, 24, 2000, pp. 322-377.[7] R.M. Smith, Alpinia (Zingiberaceae): A proposed new infrageneric classification, Notes from the Royal Botanic Garden Edinburgh 47(1) (1990) 1-175.

The curtain rose. The howling of desert wind filled the performance hall in the Shanghai Grand Theatre. Into the center stage, where a scenic construction of a mountain cliff and a desert landscape was dimly lit, entered the character of the Daoist priest Wang Yuanlu (1849–1931), performed by Chen Yizong. Dressed in a worn and dusty outfit of dark blue cotton, characteristic of Daoist priests, Wang began to sweep the floor. After a few moments, he discovered a hidden chambre sealed inside one of the rock sanctuaries carved into the cliff.Signaled by the quick, crystalline, stirring wave of sound from the chimes, a melodious Chinese ocarina solo joined in slowly from the background. Astonished by thousands of Buddhist sūtra scrolls, wall paintings, and sculptures he had just accidentally discovered in the caves, Priest Wang set his broom aside and began to examine these treasures. Dawn had not yet arrived, and the desert sky was pitch-black. Priest Wang held his oil lamp high, strode rhythmically in excitement, sat crossed-legged in a meditative pose, and unfolded a scroll. The sound of the ocarina became fuller and richer and the texture of the music more complex, as several other instruments joined in.Below is the opening scene of the award-winning, theatrical dance-drama Dunhuang, My Dreamland, created by China’s state-sponsored Lanzhou Song and Dance Theatre in 2000. Figure 1a: Poster Side A of Dunhuang, My Dreamland Figure 1b: Poster Side B of Dunhuang, My DreamlandThe scene locates the dance-drama in the rock sanctuaries that today are known as the Dunhuang Mogao Caves, housing Buddhist art accumulated over a period of a thousand years, one of the best well-known UNESCO heritages on the Silk Road. Historically a frontier metropolis, Dunhuang was a strategic site along the Silk Road in northwestern China, a crossroads of trade, and a locus for religious, cultural, and intellectual influences since the Han dynasty (206 B.C.E.–220 C.E.). Travellers, especially Buddhist monks from India and central Asia, passing through Dunhuang on their way to Chang’an (present day Xi’an), China’s ancient capital, would stop to meditate in the Mogao Caves and consult manuscripts in the monastery's library. At the same time, Chinese pilgrims would travel by foot from China through central Asia to Pakistan, India, Nepal, Bangladesh, and Sri Lanka, playing a key role in the exchanges between ancient China and the outside world. Travellers from China would stop to acquire provisions at Dunhuang before crossing the Gobi Desert to continue on their long journey abroad. Figure 2: Dunhuang Mogao CavesThis article approaches the idea of “abroad” by examining the present-day imagination of journeys along the Silk Road—specifically, staged performances of the various Silk Road journey-themed dance-dramas sponsored by the Chinese state for enhancing its cultural and foreign policies since the 1970s (Kuang).As ethnomusicologists have demonstrated, musicians, choreographers, and playwrights often utilise historical materials in their performances to construct connections between the past and the present (Bohlman; Herzfeld; Lam; Rees; Shelemay; Tuohy; Wade; Yung: Rawski; Watson). The ancient Silk Road, which linked the Mediterranean coast with central China and beyond, via oasis towns such as Samarkand, has long been associated with the concept of “journeying abroad.” Journeys to distant, foreign lands and encounters of unknown, mysterious cultures along the Silk Road have been documented in historical records, such as A Record of Buddhist Kingdoms (Faxian) and The Great Tang Records on the Western Regions (Xuanzang), and illustrated in classical literature, such as The Travels of Marco Polo (Polo) and the 16th century Chinese novel Journey to the West (Wu). These journeys—coming and going from multiple directions and to different destinations—have inspired contemporary staged performance for audiences around the globe.Home and Abroad: Dunhuang and the Silk RoadDunhuang, My Dreamland (2000), the contemporary dance-drama, staged the journey of a young pilgrim painter travelling from Chang’an to a land of the unfamiliar and beyond borders, in search for the arts that have inspired him. Figure 3: A scene from Dunhuang, My Dreamland showing the young pilgrim painter in the Gobi Desert on the ancient Silk RoadFar from his home, he ended his journey in Dunhuang, historically considered the northwestern periphery of China, well beyond Yangguan and Yumenguan, the bordering passes that separate China and foreign lands. Later scenes in Dunhuang, My Dreamland, portrayed through multiethnic music and dances, the dynamic interactions among merchants, cultural and religious envoys, warriors, and politicians that were making their own journey from abroad to China. The theatrical dance-drama presents a historically inspired, re-imagined vision of both “home” and “abroad” to its audiences as they watch the young painter travel along the Silk Road, across the Gobi Desert, arriving at his own ideal, artistic “homeland”, the Dunhuang Mogao Caves. Since his journey is ultimately a spiritual one, the conceptualisation of travelling “abroad” could also be perceived as “a journey home.”Staged more than four hundred times since it premiered in Beijing in April 2000, Dunhuang, My Dreamland is one of the top ten titles in China’s National Stage Project and one of the most successful theatrical dance-dramas ever produced in China. With revenue of more than thirty million renminbi (RMB), it ranks as the most profitable theatrical dance-drama ever produced in China, with a preproduction cost of six million RMB. The production team receives financial support from China’s Ministry of Culture for its “distinctive ethnic features,” and its “aim to promote traditional Chinese culture,” according to Xu Rong, an official in the Cultural Industry Department of the Ministry. Labeled an outstanding dance-drama of the Chinese nation, it aims to present domestic and international audiences with a vision of China as a historically multifaceted and cosmopolitan nation that has been in close contact with the outside world through the ancient Silk Road. Its production company has been on tour in selected cities throughout China and in countries abroad, including Austria, Spain, and France, literarily making the young pilgrim painter’s “journey along the Silk Road” a new journey abroad, off stage and in reality.Dunhuang, My Dreamland was not the first, nor is it the last, staged performances that portrays the Chinese re-imagination of “journeying abroad” along the ancient Silk Road. It was created as one of many versions of Dunhuang bihua yuewu, a genre of music, dance, and dramatic performances created in the early twentieth century and based primarily on artifacts excavated from the Mogao Caves (Kuang). “The Mogao Caves are the greatest repository of early Chinese art,” states Mimi Gates, who works to increase public awareness of the UNESCO site and raise funds toward its conservation. “Located on the Chinese end of the Silk Road, it also is the place where many cultures of the world intersected with one another, so you have Greek and Roman, Persian and Middle Eastern, Indian and Chinese cultures, all interacting. Given the nature of our world today, it is all very relevant” (Pollack). As an expressive art form, this genre has been thriving since the late 1970s contributing to the global imagination of China’s “Silk Road journeys abroad” long before Dunhuang, My Dreamland achieved its domestic and international fame. For instance, in 2004, The Thousand-Handed and Thousand-Eyed Avalokiteśvara—one of the most representative (and well-known) Dunhuang bihua yuewu programs—was staged as a part of the cultural program during the Paralympic Games in Athens, Greece. This performance, as well as other Dunhuang bihua yuewu dance programs was the perfect embodiment of a foreign religion that arrived in China from abroad and became Sinicized (Kuang). Figure 4: Mural from Dunhuang Mogao Cave No. 45A Brief History of Staging the Silk Road JourneysThe staging of the Silk Road journeys abroad began in the late 1970s. Historically, the Silk Road signifies a multiethnic, cosmopolitan frontier, which underwent incessant conflicts between Chinese sovereigns and nomadic peoples (as well as between other groups), but was strongly imbued with the customs and institutions of central China (Duan, Mair, Shi, Sima). In the twentieth century, when China was no longer an empire, but had become what the early 20th-century reformer Liang Qichao (1873–1929) called “a nation among nations,” the long history of the Silk Road and the colourful, legendary journeys abroad became instrumental in the formation of a modern Chinese nation of unified diversity rooted in an ancient cosmopolitan past. The staged Silk Road theme dance-dramas thus participate in this formation of the Chinese imagination of “nation” and “abroad,” as they aestheticise Chinese history and geography. History and geography—aspects commonly considered constituents of a nation as well as our conceptualisations of “abroad”—are “invariably aestheticized to a certain degree” (Bakhtin 208). Diverse historical and cultural elements from along the Silk Road come together in this performance genre, which can be considered the most representative of various possible stagings of the history and culture of the Silk Road journeys.In 1979, the Chinese state officials in Gansu Province commissioned the benchmark dance-drama Rain of Flowers along the Silk Road, a spectacular theatrical dance-drama praising the pure and noble friendship which existed between the peoples of China and other countries in the Tang dynasty (618-907 C.E.). While its plot also revolves around the Dunhuang Caves and the life of a painter, staged at one of the most critical turning points in modern Chinese history, the work as a whole aims to present the state’s intention of re-establishing diplomatic ties with the outside world after the Cultural Revolution. Unlike Dunhuang, My Dreamland, it presents a nation’s journey abroad and home. To accomplish this goal, Rain of Flowers along the Silk Road introduces the fictional character Yunus, a wealthy Persian merchant who provides the audiences a vision of the historical figure of Peroz III, the last Sassanian prince, who after the Arab conquest of Iran in 651 C.E., found refuge in China. By incorporating scenes of ethnic and folk dances, the drama then stages the journey of painter Zhang’s daughter Yingniang to Persia (present-day Iran) and later, Yunus’s journey abroad to the Tang dynasty imperial court as the Persian Empire’s envoy.Rain of Flowers along the Silk Road, since its debut at Beijing’s Great Hall of the People on the first of October 1979 and shortly after at the Theatre La Scala in Milan, has been staged in more than twenty countries and districts, including France, Italy, Japan, Thailand, Russia, Latvia, Hong Kong, Macao, Taiwan, and recently, in 2013, at the Lincoln Center for the Performing Arts in New York.“The Road”: Staging the Journey TodayWithin the contemporary context of global interdependencies, performing arts have been used as strategic devices for social mobilisation and as a means to represent and perform modern national histories and foreign policies (Davis, Rees, Tian, Tuohy, Wong, David Y. H. Wu). The Silk Road has been chosen as the basis for these state-sponsored, extravagantly produced, and internationally staged contemporary dance programs. In 2008, the welcoming ceremony and artistic presentation at the Olympic Games in Beijing featured twenty apsara dancers and a Dunhuang bihua yuewu dancer with long ribbons, whose body was suspended in mid-air on a rectangular LED extension held by hundreds of performers; on the giant LED screen was a depiction of the ancient Silk Road.In March 2013, Chinese president Xi Jinping introduced the initiatives “Silk Road Economic Belt” and “21st Century Maritime Silk Road” during his journeys abroad in Kazakhstan and Indonesia. These initiatives are now referred to as “One Belt, One Road.” The State Council lists in details the policies and implementation plans for this initiative on its official web page, www.gov.cn. In April 2013, the China Institute in New York launched a yearlong celebration, starting with "Dunhuang: Buddhist Art and the Gateway of the Silk Road" with a re-creation of one of the caves and a selection of artifacts from the site. In March 2015, the National Development and Reform Commission (NDRC), China’s top economic planning agency, released a new action plan outlining key details of the “One Belt, One Road” initiative. Xi Jinping has made the program a centrepiece of both his foreign and domestic economic policies. One of the central economic strategies is to promote cultural industry that could enhance trades along the Silk Road.Encouraged by the “One Belt, One Road” policies, in March 2016, The Silk Princess premiered in Xi’an and was staged at the National Centre for the Performing Arts in Beijing the following July. While Dunhuang, My Dreamland and Rain of Flowers along the Silk Road were inspired by the Buddhist art found in Dunhuang, The Silk Princess, based on a story about a princess bringing silk and silkworm-breeding skills to the western regions of China in the Tang Dynasty (618-907) has a different historical origin. The princess's story was portrayed in a woodblock from the Tang Dynasty discovered by Sir Marc Aurel Stein, a British archaeologist during his expedition to Xinjiang (now Xinjiang Uygur autonomous region) in the early 19th century, and in a temple mural discovered during a 2002 Chinese-Japanese expedition in the Dandanwulike region. Figure 5: Poster of The Silk PrincessIn January 2016, the Shannxi Provincial Song and Dance Troupe staged The Silk Road, a new theatrical dance-drama. Unlike Dunhuang, My Dreamland, the newly staged dance-drama “centers around the ‘road’ and the deepening relationship merchants and travellers developed with it as they traveled along its course,” said Director Yang Wei during an interview with the author. According to her, the show uses seven archetypes—a traveler, a guard, a messenger, and so on—to present the stories that took place along this historic route. Unbounded by specific space or time, each of these archetypes embodies the foreign-travel experience of a different group of individuals, in a manner that may well be related to the social actors of globalised culture and of transnationalism today. Figure 6: Poster of The Silk RoadConclusionAs seen in Rain of Flowers along the Silk Road and Dunhuang, My Dreamland, staging the processes of Silk Road journeys has become a way of connecting the Chinese imagination of “home” with the Chinese imagination of “abroad.” Staging a nation’s heritage abroad on contemporary stages invites a new imagination of homeland, borders, and transnationalism. Once aestheticised through staged performances, such as that of the Dunhuang bihua yuewu, the historical and topological landscape of Dunhuang becomes a performed narrative, embodying the national heritage.The staging of Silk Road journeys continues, and is being developed into various forms, from theatrical dance-drama to digital exhibitions such as the Smithsonian’s Pure Land: Inside the Mogao Grottes at Dunhuang (Stromberg) and the Getty’s Cave Temples of Dunhuang: Buddhist Art on China's Silk Road (Sivak and Hood). 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