Articles de revues sur le sujet « Xu Kun »

Correction for ‘Rational design of a “dual lock-and-key” supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy’ by Kun-Xu Teng et al., Chem. Sci., 2020, 11, 9703–9711, DOI: 10.1039/D0SC01122C.

LetCbe a closed convex subset of a uniformly smooth Banach spaceE, andT:C→Ea nonexpansive nonself-mapping satisfying the weakly inwardness condition such thatF(T)≠∅, andf:C→Ca fixed contractive mapping. Fort∈(0,1), the implicit iterative sequence{xt}is defined byxt=P(tf(xt)+(1−t)Txt), the explicit iterative sequence{xn}is given byxn+1=P(αnf(xn)+(1−αn)Txn), whereαn∈(0,1)andPis a sunny nonexpansive retraction ofEontoC. We prove that{xt}strongly converges to a fixed point ofTast→0, and{xn}strongly converges to a fixed point ofTasαnsatisfying appropriate conditions. The results presented extend and improve the corresponding results of Hong-Kun Xu (2004) and Yisheng Song and Rudong Chen (2006).

Aristolochia Linnaeus (1753: 960) (Aristolochiaceae) comprises about 500 species. The genus has worldwide distribution (Wanke et al. 2006). Recent findings of Aristolochia (Phuphathanaphong 2006, Xu et al. 2011, Huong et al. 2014, Do et al. 2015, Wu et al. 2015), together with the previous treatments for the Flora of Thailand (Phuphathanaphong 1987), the Flora of Vietnam (Pham 2000) and the Flora of China (Huang et al. 2003) confirmed the Thai & Indo-Chinese floristic region as a center of diversity for Aristolochia, with currently about 90 species. A high degree of endemism is found for specific countries (Huang et al. 2003, Phuphathanaphong 2006). However, the delimitation and taxonomic status of some species are still unclear due to limited access to specimen databases, especially for the type specimens in those countries. Notably, recent studies have significantly revised the taxonomic status of several previously described Aristolochia species when herbarium materials from multiple countries in the region were consulted (Do et al. 2014, Do 2016, Zu et al. 2016). On the basis of the examination of the protologue, the type specimens, and recent collections from the herbaria BKF, C, GXMI, HITBC, IBSC, KUN, PE and PEM, we conclude that Aristolochia longeracemosa B. Hansen & Leena Phuphathanaphong (1999: 557), described from collections made in northern Thailand, is conspecific with A. chlamydophylla C.Y. Wu ex S. M. Hwang (1981: 223) from southern China. Hence, we here propose the former as a new synonym of the latter. A detailed comparison of the morphological characters and habitat of these two species is provided.

Abstract Epstein Barr Virus (EBV) latent infection is associated with multiple types of cancer. Several clinical studies have targeted EBV antigens as immune therapeutic targets with limited efficacy of EBV+ malignancies, suggesting additional targets might be important. BamHI-A rightward frame 1 (BARF1) is an EBV antigen that is highly expressed in EBV-associated gastric carcinoma (EBVaGC) and EBV+ nasopharyngeal carcinoma (NPC) and has not been evaluated as an antigen in the context of therapeutic immunization. Here, we developed a synthetic DNA-based expression cassette as immunotherapy targeting BARF1 (pBARF1). Immunization with pBARF1 induced potent antigen-specific humoral and polyfunctional effector T cell responses in vivo. We observed significant antigen-specific increases of IFN-γ+, IFN-γ+ TNF-α+, and IFN-γ+ TNF-α+ IL-2+ populations in CD8+ T cells from the pBARF1 immunized animals in both C57BL/6 and BALB/c mice. Novel BARF1 expressing carcinoma lines that grow in immune-competent animals were developed as surrogates for human EBV+ tumors. We confirmed that BARF1 expression in these new cancer cell lines, MC38-BARF1 and CT26-BARF1, was within the range of human EBV+ cancer cell lines, SNU719 and C666-1. Immunization with pBARF1 plasmid demonstrated impact of tumor progression through induction of CD8+ T cell in these BARF1+ carcinoma models. We also observed long-term antitumor immunity, at least up to 446 days, against BARF1 in a CT26-BARF1 rechallenge study. Using IVIS in vivo imaging, we observed that pBARF1 immunized animals rapidly controlled and cleared cancer cells. These studies demonstrate the potential for pBARF1 immunity to induce antigen-specific immune responses impacting tumor progression. Further study of this immune target and these EBV+ tumor models is likely important as part of therapeutic approaches for EBV+ malignancies. Citation Format: Xizhou Zhu, Alfredo Perales-Puchalt, Krzysztof Wojtak, Ziyang Xu, Kun Yun, Pratik S. Bhojnagarwala, Devivasha Bordoloi, Daniel H. Park, Kevin Liaw, Mamadou A. Bah, Paul M. Lieberman, Ebony N. Gary, Ami Patel, David B. Weiner. DNA immunotherapy targeting BARF1 demonstrates therapeutic impact in novel murine carcinoma models expressing EBV latent antigens [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 3573.

Data from a herd of 3,000 high-producing milking dairy cows under an intensive feeding system was analysed. The IVF laboratory at the farm uses a co-culture system (Vivanco-Mackie; page 30-48 in Proc. 2000 Australian Embryo Transfer Society) and transfers ∼1000 embryos per year. The semen used for IVF and for inseminations (AI) in the herd was female-sexed (F-sexed) and non-sexed (conventional). During the 4 years of evaluation (2016–2019) 1123 calves were born to AI with F-sexed semen and 6,456 to AI with conventional semen; the proportion of males born to AI with F-sexed semen was 9% (91% females), which was not different (P>0.05) from the expected ratio of 10% males and 90% females. The proportion of male calves born to AI with conventional semen was 53.2% (46.8% females), which agrees with the expected ratios for the population. During the same period of evaluation, 805 calves were born to IVF embryos transferred; 240 calves were born from embryos produced using F-sexed semen, of which 29.6% were males and 70.4% females, which was different (P<0.05) from the expected ratio of 10% males and 90% females. The proportion of male calves born from embryo transfer of IVF embryos produced with conventional semen was 82.7%, higher (P<0.05) than the expected 53.2% of males for the population; the proportion of females was 17.3%, significantly lower (P<0.05) than the expected 46.8% females for the population. For IVF, the proportion of males was significantly higher (P<0.05) than expected in all cases; for AI, there was no difference (P>0.05) between the observed sex proportion and the expected values. We conclude that the invitro embryo production process affects the sex ratio at birth in this population, and some factor in the IVF process is affecting the survival to calving of female embryos and consequently increasing the proportion of male calves born from invitro-produced embryos. Gutierrez et al. (2001 Reprod. Fertil. Dev. 13, 361–365) found a similar effect in dairy cattle and linked it to glucose imbalance in the media. Larson et al. (2001 PNAS 98, 9677-9682) found that female cattle embryos had a lower ability to progress in development in glucose-rich media, but the mechanism is not yet fully understood. Xu et al. (1992Mol. Reprod. Dev. 31, 249-252) and others indicate that invitro-produced male bovine embryos predominate among blastocysts, expanded and hatched stages. Meanwhile, embryos lagging in development are predominantly female. Kun Tan et al. (2016 Reproduction 151, 443-543) found that IVF in mice favours the birth of males because of dysregulated expression of representative dimorphic genes. Further studies in cattle are necessary to determine the cause of the increased proportion of males born from invitro embryos and to find ways to control it.

Data from a herd of 3,000 high-producing milking dairy cows under an intensive feeding system was analysed. The IVF laboratory at the farm uses a co-culture system (Vivanco-Mackie; page 30-48 in Proc. 2000 Australian Embryo Transfer Society) and transfers ∼1000 embryos per year. The semen used for IVF and for inseminations (AI) in the herd was female-sexed (F-sexed) and non-sexed (conventional). During the 4 years of evaluation (2016–2019) 1123 calves were born to AI with F-sexed semen and 6,456 to AI with conventional semen; the proportion of males born to AI with F-sexed semen was 9% (91% females), which was not different (P>0.05) from the expected ratio of 10% males and 90% females. The proportion of male calves born to AI with conventional semen was 53.2% (46.8% females), which agrees with the expected ratios for the population. During the same period of evaluation, 805 calves were born to IVF embryos transferred; 240 calves were born from embryos produced using F-sexed semen, of which 29.6% were males and 70.4% females, which was different (P<0.05) from the expected ratio of 10% males and 90% females. The proportion of male calves born from embryo transfer of IVF embryos produced with conventional semen was 82.7%, higher (P<0.05) than the expected 53.2% of males for the population; the proportion of females was 17.3%, significantly lower (P<0.05) than the expected 46.8% females for the population. For IVF, the proportion of males was significantly higher (P<0.05) than expected in all cases; for AI, there was no difference (P>0.05) between the observed sex proportion and the expected values. We conclude that the invitro embryo production process affects the sex ratio at birth in this population, and some factor in the IVF process is affecting the survival to calving of female embryos and consequently increasing the proportion of male calves born from invitro-produced embryos. Gutierrez et al. (2001 Reprod. Fertil. Dev. 13, 361–365) found a similar effect in dairy cattle and linked it to glucose imbalance in the media. Larson et al. (2001 PNAS 98, 9677-9682) found that female cattle embryos had a lower ability to progress in development in glucose-rich media, but the mechanism is not yet fully understood. Xu et al. (1992Mol. Reprod. Dev. 31, 249-252) and others indicate that invitro-produced male bovine embryos predominate among blastocysts, expanded and hatched stages. Meanwhile, embryos lagging in development are predominantly female. Kun Tan et al. (2016 Reproduction 151, 443-543) found that IVF in mice favours the birth of males because of dysregulated expression of representative dimorphic genes. Further studies in cattle are necessary to determine the cause of the increased proportion of males born from invitro embryos and to find ways to control it.

Abstract Background: KRAS G12C oncogenic mutations occur in ~13% of non-small cell lung cancers (NSCLCs) and up to 4% of other solid tumors. JDQ443 is a selective, covalent, orally bioavailable, investigational KRASG12C inhibitor that irreversibly traps KRASG12C in the inactive, GDP-bound state. JDQ443 is structurally unique and forms novel interactions with KRAS in the switch II pocket. Methods: KontRASt-01 (NCT04699188) is a Phase Ib/II, open-label, multicenter, dose-escalation and dose-expansion trial of JDQ443 as monotherapy or in combination with TNO155 (SHP2 inhibitor) and/or tislelizumab (anti-PD-1 monoclonal antibody). Primary objectives of dose escalation are to assess safety and tolerability, and identify the maximum tolerated doses (MTDs) and/or recommended doses (RDs) and regimens for future studies. The primary objective of dose expansion is to assess efficacy. Key inclusion criteria: advanced, KRAS G12C-mutated solid tumors; previous standard-of-care treatment; age ≥18 yrs; ECOG PS 0-1. Key exclusion criteria for the JDQ443 monotherapy arm: active brain metastases, prior KRASG12C inhibitor treatment. Here, we present preliminary results for JDQ443 monotherapy dose escalation. Results: As of Nov 3, 2021, 39 pts were treated with JDQ443 PO continuously across 4 dose levels: 200 mg once daily (QD) (n=10), 400 mg QD (n=11), 200 mg twice daily (BID) (n=11), and 300 mg BID (n=7). Median age was 60 yrs (range 26-76), median prior lines of therapy was 3 (range 1-7), and indications included NSCLC (n=20) and colorectal cancer (CRC) (n=16). Median duration of exposure was 9.1 wks (range 0.9-21), with ongoing treatment in most pts (61.5%) at the time of cut-off. Treatment-related adverse events (TRAEs) occurred in 25 (64.1%) pts. Most TRAEs were Grade (Gr) 1-2. Four Gr 3 TRAEs occurred in 4 (10.3%) separate pts; there were no Gr 4-5 TRAEs. The most common TRAEs (occurring in ≥10% of pts) were fatigue (25.6%), nausea (15.4%), edema (12.8%), pruritus (10.3%), and vomiting (10.3%). There was one DLT (Gr 3 fatigue) and one treatment-related serious AE (Gr 3 photosensitivity reaction), each in separate pts treated at 300 mg BID. TRAEs led to dose reduction in 1 pt and discontinuation in 1 pt. A MTD was not reached. The RD was declared as 200 mg BID. At the RD, PK and PD modeling for JDQ443 predicted average KRASG12C target occupancy of >90% in >82% of pts. Using an efficacy cut-off date of Dec 13, 2021, for the 20 pts with NSCLC among the same 39 pts, the ORR (confirmed complete response or partial response) by RECIST 1.1 was 30.0% (6/20) across dose levels and 43.0% (3/7) at the RD. Additional data will be available at the time of presentation. Conclusions: JDQ443 demonstrates an acceptable safety and tolerability profile, with early signs of clinical activity in pts with NSCLC. Enrollment is ongoing to NSCLC and CRC dose-expansion groups for JDQ443 monotherapy at the RD, and to JDQ443 + TNO155 dose escalation. Citation Format: Daniel S. Tan, Toshio Shimizu, Benjamin Solomon, Rebecca S. Heist, Martin Schuler, Maria J. De Miguel Luken, Anas Gazzah, Martin Wermke, Christophe Dooms, Herbert H. Loong, Neeltje Steeghs, Enriqueta Felip, Conor E. Steuer, Eric van Cutsem, Ross A. Soo, Ashley C. Jaeger, Jaeyeon Kim, Kun Xu, Xueying Chen, Xiaoming Cui, Heather Burks, Anna Farago, Philippe A. Cassier. KontRASt-01: A phase Ib/II, dose-escalation study of JDQ443 in patients (pts) with advanced, KRAS G12C-mutated solid tumors [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 CT033.

Có một nhu cầu ngày càng tăng để hiểu mô hình và phát triển của các bề mặt không thấm ở các vùng nông thôn. Tuy nhiên, các nghiên cứu hiện nay thường tập trung nghiên cứu và thành lập bản đồ bề mặt không thấm khu vực đô thị, trong khi đó có rất ít nghiên cứu về sự thay đổi bề mặt không thấm nông thôn. Trong bài báo này, chúng tôi sử dụng 12 đặc trưng không gian (Feature Space)cơ bản để tách đối tượng bề mặt không thấm từ chuỗi ảnh Landsat TM và OLI, bao gồm 6 chỉ số: (NDBI), (SAVI), (SI), (RISI), (Brightness), Max.diff và 6 kênh phổ không bao gồm kênh nhiệt của ảnh vệ tinh Landsat. Các đặc trưng cơ bản trên được tiếp tục sử dụng để giải đoán sự có mặt của đối tượng bề mặt không thấm trên ảnh vệ tinh nhờ sự trợ giúp của thuật toán K-Nearest Neighbors (KNN). Kết quả của nghiên cứu cho thấy rằng thuật toán K-Nearest Neighbors áp dụng cho nhóm các đặc điểm được chọn của bề mặt không thấm (6 kênh phổ, 6 chỉ số)cho phép chiết xuất chính xác đối tượng bề mặt không thấm ở nông thôn. Đây là cơ sở để đánh giá xu hướng thay đổi bề mặt không thấm khu vực nghiên cứu theo không gian và thời gian.

Nghiên cứu này được thực hiện để làm sáng tỏ cơ chế cùng chung sống của các loài cây gỗ rừng lá rộng thường xanh tại Vườn Quốc gia Kon Ka Kinh, tỉnh Gia Lai. Tất cả các cây có đường kính ngang ngực (DBH) ≥ 2,5 cm trong 3 ô tiêu chuẩn 1 ha đã được lập bản đồ, xác định DBH và tên loài. Kết quả cho thấy mô hình không gian của 12/20 loài được phân tích là phân bố cụm ở quy mô nhỏ < 15 m, phân bố ngẫu nhiên và đều có xu hướng tăng lên ở quy mô lớn > 15 m. Quan hệ độc lập chiếm tỉ lệ cao (75-90%), quan hệ cạnh tranh và tương hỗ chiếm tỉ lệ thấp (10-25%), sự liên kết không gian của các loài chủ yếu là độc lập hoặc tách biệt ở quy mô lớn. Phát tán giới hạn, tính không đồng nhất của môi trường và tỷ lệ tử vong phụ thuộc vào mật độ là ba cơ chế điều chỉnh mô hình phân bố, quan hệ và các kiểu liên kết không gian của các loài cây gỗ tại khu vực nghiên cứu.

Rechargeable batteries are built on the foundation of redox-active compounds. Thus, understanding charge compensation mechanisms represents one of the most critical research directions in developing battery materials. Due to the compositional versatility of Li-containing layered cathode, i.e., LiNi1-x-yMnxCoyO2 (NMC), one can tune the TMs (transition metals) composition to satisfy various demands. As the Ni/Mn/Co stoichiometry moves across the compositional space, the charge compensation mechanism also gradually evolves due to the changing of TM 3d orbital energy levels. Thus, tailoring TMs stoichiometry has become effective to fine-tune battery performance. In a previous study, we found that NMCs with a highly heterogeneous TM distribution still exhibited a globally layered structure.1Another study on dopant distribution also suggests that the heterogeneous dopant can positively impact battery performance.2 Our previous studies show that the charge heterogeneity can result in local stress hotspots and exacerbate the chemomechanical breakdown of NMC particles.3 When the compositional heterogeneity prevails in individual NMC particles, charge distribution likely exhibits a heterogeneous pattern due to distinct redox reactions in domains with different TM stoichiometries. Thus, we believe that understanding the interplay between compositional heterogeneity and its impact on charge distribution may provide insights into engineering compositional heterogeneity to achieve desired charge distribution. Herein, in this work, we designed the compositionally heterogeneous NMC cathode with the ensemble-average layered structure as the platform to investigate the charge distribution with single-particle spectroscopic imaging measurements.4 We establish the relationship between charge distribution and local compositional heterogeneity at the single-particle level. The local Mn and Ni concentrations in individual NMC particles are positively and negatively correlated with the electrochemically induced Ni oxidation, respectively, whereas the Co concentration does not impose a clear effect on the Ni oxidation. The resulting material delivers excellent reversible capacity, rate capability, and cycle life at high operating voltages. Engineering Ni/Mn/Co distribution in NMC particles may provide a path toward controlling the charge distribution and thus chemomechanical properties of polycrystalline battery particles. Lin, F.; Nordlund, D.; Markus, I. M.; Weng, T.-C.; Xin, H. L.; Doeff, M. M., Profiling the nanoscale gradient in stoichiometric layered cathode particles for lithium-ion batteries. Energy & Environmental Science 2014, 7 (9), 3077-3085. Mu, L.; Zhang, R.; Kan, W. H.; Zhang, Y.; Li, L.; Kuai, C.; Zydlewski, B.; Rahman, M. M.; Sun, C.-J.; Sainio, S.; Avdeev, M.; Nordlund, D.; Xin, H. L.; Lin, F., Dopant Distribution in Co-Free High-Energy Layered Cathode Materials. Chemistry of Materials 2019, 31 (23), 9769-9776. Yang, Y.; Xu, R.; Zhang, K.; Lee, S.-J.; Mu, L.; Liu, P.; Waters, C. K.; Spence, S.; Xu, Z.; Wei, C.; Kautz, D. J.; Yuan, Q.; Dong, Y.; Yu, Y.-S.; Xiao, X.; Lee, H.-K.; Pianetta, P.; Cloetens, P.; Lee, J.-S.; Zhao, K.; Lin, F.; Liu, Y., Quantification of Heterogeneous Degradation in Li-Ion Batteries. Advanced Energy Materials 2019, 9 (25), 1900674. Mu, L.; Zhang, J.; Xu, Y.; Wei, C.; Rahman, M. M.; Nordlund, D.; Liu, Y.; Lin, F., Resolving Charge Distribution for Compositionally Heterogeneous Battery Cathode Materials. Nano Letters 2022, 22 (3), 1278-1286.

Abstract CRISPR-Cas9-based technologies have been developed to address a wide range of biological questions, including molecular recording of embryonic development, genetic screening, and tracking tumor evolution at the single-cell resolution. We developed a single-cell lineage tracking platform called native sgRNA Capture and sequencing (NSC-seq) to leverage CRISPR technology for clonal analysis of intestinal tumors in the ApcMin/+ mouse model. We combined CRISPR-induced mutations with spontaneously accumulating mitochondrial variants to enable highly efficient lineage-tracking of single cells. We generated lineage-tracked ApcMin/+ tumors and found that there are more than two independently arising clones within a tumor. We also found oligoclonal tumors within human colorectal specimens using this technology, supporting the oligoclonality of intestinal tumor development across species. Finally, we demonstrated the application of this technology in understanding the rate of loss-of-heterozygosity events in Apc as related to the cellular turnover rates of different intestinal regions. Overall, NSC-seq enables in vivo molecular recording of spontaneous intestinal tumor development at single-cell resolution. Citation Format: Mirazul Islam, Yilin Yang, Vishal M. Shah, Alan J. Simmons, Yanwen Xu, Robert J. Coffey, Ken S. Lau. Native sgRNA capture and sequencing (NSC-seq) reveals tumor formation in ApcMin/+ mice and in human colorectal cancer is an oligoclonal process [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B032.

Abstract Activating mutations in MYD88 alone or in coordination with BCR activating mutations transactivate Bruton's tyrosine kinase (BTK) in WM and ABC DLBCL cells (Yang et al, Blood 2013; Wilson WH et al, Nat Med 2015; Phelan JD, Nature 2018). Ibrutinib is a covalent inhibitor that binds to BTKCys481 and is active in MYD88 mutated WM and ABC-DLBCL (Treon et al, NEJM 2015; Wilson et al, Nat Med, 2015). Acquired resistance to ibrutinib is increasingly being recognized in WM, as well as other B-cell malignancies due to somatic mutations at BTKCys481 that abrogate BTK-ibrutinib binding (Xu et al, Blood 2017). BTKCys481 mutations are usually sub-clonal, but can drive ibrutinib resistance and protect BTK wild-type clones through a paracrine mechanism involving activation of ERK1/2 (Chen et al, Blood 2018). Hematopoietic cell kinase (HCK) which is aberrantly upregulated and transactivated by mutated MYD88, and triggers multiple pro-survival signaling cascades that include activation of BTK, as well as PI3K/AKT and MAPK/ERK1/2 (Yang G et al, Blood 2016). We therefore examined if inhibition of HCK could abrogate BTK activity and overcome ibrutinib resistance driven by BTKCys481 mutations in MYD88 mutated B-cell lymphomas. We performed a screen of 220 clinical and preclinical kinase inhibitors to identify compounds with potent HCK inhibition. Over 100 analogs of three series of promising compounds with HCK activity were synthesized and triaged. Target deconvolution was performed to clarify selectivity, and other important kinase targets. These efforts led to the selection of a lead compound identified as a type-II kinase inhibitor, KIN-8193, with a molecular weight around 600. Single-digit nanomolar (nM) biochemical and double-digit nM cellular potency was demonstrated, with high selectivity (S-score 0.07) in line with that observed with ibrutinib (S-score of 0.03). Live-cell target engagement for HCK was confirmed by competitive ATP-biotin binding assay. DMPK and PK studies showed very high levels of mouse, rat, and human microsomal stability (42.4, 60.2 and 79.3 minutes respectively), and oral bioavailability in mice (48%) and rats (79%). Cmax reached 2.0 µM, while T1/2 was 26.8 hours with 25 mg/kg single oral dosing in rats. Rats toxicology studies showed excellent tolerability in 28-days repeated oral dosing with 25 mg/kg/biw dosing schedule. No relevant inhibition was observed against a panel of 100 other receptor targets, including hERG. AMES was negative up to 100 uM, and Cyp inhibition studies showed acceptable inhibition up to 10 uM. KIN-8193 potently inhibited the phosphorylation of HCK(p-Y411) and its downstream target BTK(p-Y223) in both BTK wild-type and ibrutinib-resistant BTKCys481 mutated WM and ABC DLBCL cell lines driven by activating MYD88 mutations, and primary WM cells (Fig 1A). Target engagement studies showed HCK but not BTK direct binding. In vivo pharmacodynamic (PD) studies using luciferized BCWM.1 cells WM xenograft mouse model showed potent dose-dependent inhibition of HCK(p-Y411) and BTK(p-Y223) at 6 and 24 hours following single dose administration of KIN-8193. Importantly, KIN-8193 showed selective cytotoxicity against MYD88 mutated BTK wild-type and BTKCys481 mutated, ibrutinib-resistant WM and ABC DLBCL cell lines, and primary WM cells, but had no impact on healthy donor B- and T-cells at pharmacologically achievable levels (Fig. 1B). We therefore describe a novel, highly selective and potent HCK inhibitor that is well tolerated in long-term rat toxicology studies and shows selective killing of MYD88 mutated WM and ABC DLBCL cells. Inhibition of HCK by KIN-8193 blocks downstream wild-type BTK and Cys481 mutated BTK activity, and overcomes ibrutinib resistance induced by BTKCys481 mutations. Disclosures Hunter: Pharmacyclics: Consultancy. Castillo:Genentech: Consultancy; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Millennium: Research Funding. Gray:Syros, Soltego, Petra, C4 Therapeutics: Equity Ownership. Treon:Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Research Funding; Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses.

Abstract Background: Chemotherapy is the main treatment in patients with pre-treated endocrine-resistant HR+/HER2– metastatic breast cancer, but has limited efficacy and substantial toxicities. The antibody-drug conjugate Dato-DXd consists of a humanized IgG1 mAb targeting TROP2 attached via a stable cleavable linker to a topoisomerase I (TopI) inhibitor payload. Heavily pre-treated patients with metastatic triple-negative breast cancer in the TROPION-PanTumor01 (NCT03401385) study of Dato-DXd showed a manageable safety profile and highly encouraging objective response rates (ORR by blinded independent central review [BICR]: 34% in all patients; 52% in patients treatment-naïve to TopI inhibitor-based therapies). The metastatic HR+/HER2– breast cancer cohort of TROPION-PanTumor01 has completed enrollment (n=41); data are currently maturing. Trial design: TROPION-Breast01 (NCT05104866) is an ongoing, global, phase 3, open-label, randomized trial evaluating efficacy and safety of Dato-DXd vs investigators’ choice of chemotherapy (ICC) in patients with inoperable or metastatic HR+/HER2– breast cancer. Patients (n≈700) are randomized 1:1 to Dato-DXd 6 mg/kg IV Q3W or ICC (eribulin, capecitabine, vinorelbine, or gemcitabine) until progression. Adults with an ECOG performance status of 0–1, who experienced progression on or are unsuitable for endocrine therapy, and received 1–2 prior lines of standard-of-care chemotherapy in the inoperable or metastatic setting are eligible. Monotherapy treatment with inhibitors of mTOR, PD-[L]1, CDK4/6 and PARP do not count as prior chemotherapy lines. Patients must have ≥1 measurable lesion per RECIST 1.1 and an archival or fresh formalin-fixed and paraffin-embedded tumor sample. Clinically inactive brain metastases are permitted. Dual primary endpoints are progression-free survival (PFS) by BICR, and overall survival. Secondary endpoints include PFS per investigator, ORR, disease control rate, patient-reported outcomes, and Dato-DXd pharmacokinetics and immunogenicity. Exploratory endpoints include TROP2 expression and exposure–efficacy relationship. Patients are stratified by number of prior chemotherapy lines, prior CDK4/6 inhibitor use, and region. At the time of writing 236 patients have been enrolled across 19 countries. Citation Format: Aditya Bardia, Kevin Kalinsky, Junji Tsurutani, Erika Hamilton, Joo Hyuk Sohn, Kyong Hwa Park, Yeon Hee Park, Seock-Ah Im, Keun Seok Lee, Daisy Dastur, Vincent Haddad, Sabrina Khan, Binghe Xu, Barbara Pistilli, Hope Rugo. Datopotamab deruxtecan (Dato-DXd), a TROP2 antibody-drug conjugate, vs investigators’ choice of chemotherapy in previously-treated, inoperable or metastatic HR+/HER2– breast cancer: TROPION-Breast01 [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 OT1-03-04.

Abstract Background: Clinical response to therapy of patients diagnosed with high-grade serous ovarian carcinoma (HGSC) is highly variable. Mechanisms underlying response to treatment are not well understood. We previously performed bulk multi-omics analysis aimed at identifying biological differences between poor (PR) and excellent responders (ER) to neoadjuvant chemotherapy (NACT). Although differences were found, these were not as extensive as we had anticipated, suggesting that important molecular differences between such tumors may not be fully evident by bulk analyses. Thus, we carried out in-depth spatial analysis of HGSC to explore heterogeneity of disease and determine how the dynamic behavior between the tumor and the tumor microenvironment varies between PR and ER groups. Methods: We selected a cohort of patients with highly annotated HGSC samples categorized by response to NACT (PR and ER) and analyzed pre-treatment tumor tissues using bulk RNA sequencing (bRNASeq) and Visium Spatial Gene Expression. The definition of PR was stable or progressive disease after 3-4 cycles and/or suboptimal interval cytoreduction after NACT. ER was complete response or only microscopic disease left at the time of interval surgery. Results: To generate expression profiles, we used an unsupervised approach and identified nine distinct clusters, with at least 20 cell types. A comparison of the cell populations identified more stroma-dominated cell groups in the PR group. ER tumors contained more immune-related areas, with a high proportion of T, B and natural killer cells. This finding supports the established role of cytotoxic immune cells in strengthening chemotherapy response and better overall survival. In comparison with bRNASeq, we observed a blending phenomenon that hides deeper heterogeneity of the tumor. Some pathways, such as epithelial-mesenchymal transition (EMT), were statistically enriched in specific clusters of PR compared with the ER group, proving that deep characterization of tumor heterogeneity can be achieved only when exploring specific clusters of cells. The spatial distribution of the clusters showed that in the PR group, the clusters tended to be physically larger and distributed throughout the whole tissue. The ligand-receptor analysis revealed that co-expression of specific ligand-receptor pairing exists depending on their geographical localization, with closer interactions leading to stronger co-expression patterns. Conclusion: Two important findings emerged: importance of the stromal component as a potential driver of poor response to NACT; and identification of differential clusters (distribution and composition) in ER compared with PR tissues. Comparison of the in situ technique with bRNASeq allowed characterization of specific cell subpopulations that might be important determinants of lack of response to therapy, representing candidate therapeutic targets. Citation Format: Elaine Stur, Sara Corvigno, Mingchu Xu, Ken Chen, Sanghoon Lee, Jinsong Liu, Emilly Ricco, Nicole Fleming, Emine Bayraktar, Daniel Kraushaar, Jianhua Zhang, Anil K. Sood. Spatially resolved transcriptomics to understand mechanisms of response to neoadjuvant chemotherapy [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 1175.

Financial information is one of the important information in decision making. However, many cases of fraud committed by management so that the information in the financial statements cannot be relied upon in decision making. Therefore, the auditor's job is to ensure that the company's financial statements are represented correctly (faithful representation) so that financial statement information becomes more quality and useful in making decisions. So this study aims to examine the effect of audit fee on audit quality. In addition, this study also examines important determinants of audit costs, namely company size, profitability, audit risk, complexity, and firm size. By using the purposive sampling method, samples of the financial and manufacturing industry in 2010-2017 used are 39 firms per year. This sample is used to examine the effect of audit fee on audit quality and the determinant of audit fee using simple linear regression analysis and multiple linear regression analysis. 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Sodium-ion battery (NIB) system is an emerging technology and can be considered as a suitable alternative for lithium-ion batteries (LIBs) due to the large abundance and distribution of sodium on earth and similar working principles to LIB. Among those cathodes for NIBs, layered transition metal oxides (NaxMO2) receive more attention because of their higher capacity, appropriate operating potentials, higher ionic conductivity, and ease of synthesis [1]. According to the stacking sequence of oxygen layers and Na occupation sites, layered transition metal oxides are mainly classified as P2, O3, P3, and O2 structures. The letters P and O imply that the sodium occupies trigonal prismatic sites and octahedral sites, respectively. The numbers indicate the no. of oxygen stacking layers [2]. Among these, the P2 type layered transition metal oxides gained more recognition as cathode materials for NIBs due to their superior rate capability from the migration of sodium ions through the face-sharing trigonal prismatic sites [3]. However, the intercalation/de-intercalation of large sodium ions creates some structural deterioration and irreversibility. Designing multiphase materials is an effective strategy to improve the electrochemical performance of the material to avail the synergistic effects from each phase [3,4]. In this work, a cobalt-free layered-spinel composite was synthesized by sol-gel method as positive electrode material for NIBs. It is highly attractive, as it is cobalt-free and hence, cost-effective and environmentally benign. The layered phase provides a smoother diffusion pathway and the spinel phase could enhance the electronic conductivity [3,4]. The presence of layered and spinel phases was confirmed by the X-ray diffraction technique. Scanning electron microscopic investigations reveal particles of layered morphology with well-defined edges. The electrochemical investigations were done in Na-half cells in the voltage range of 1.5- 4.0 V vs. Na+/Na. The cyclic voltammogram of the layered-spinel composite in Na half-cell shows two sets of peaks corresponding to the redox activity of Mn and Ni. When the upper cut-off voltage was increased above 4 V, contributions from the Fe electrochemical activity were also observed. To investigate the sodium storage performance, galvanostatic charge-discharge studies were done. The material displayed an initial discharge capacity of 171 mAh g-1 and promising high-rate behavior. To investigate the electrochemical mechanism, in operando X-ray absorption spectroscopic studies were done and the results will be discussed in detail. Acknowledgement A.Bhaskar gratefully acknowledges financial support from “DST-IISc Energy Storage Platform on Supercapacitors and Power Dense Devices” through the MECSP-2K17 program under grant no. DST/TMD/MECSP/2K17/20”. D. Dixon acknowledges the financial support from SERB, New Delhi, India through Ramanujan Fellowship, under the grant number SB/S2/ RJN-162/2017. A. Thottungal is grateful to CSIR New Delhi for the CSIR SRF grant and AcSIR, Ghaziabad- 201002, India. DESY, Hamburg, Germany is acknowledged for the beamtime allocation at the P65 beamline at PETRA III and the beamline scientist Dr. Edmund Welter is acknowledged for his support. This work contributes to the research performed at CELEST, and was partially funded by the DFG under Project ID 390874152 (POLiS Cluster of Excellence). Reference D. Slater , D. Kim , E. Lee and C. S. Johnson , Adv. Funct. Mater., 2013, 23 , 947 —958 Delmas, C. Fouassier and P. Hagenmuller, Phys. B, 1980, 99, 81 Zheng, P. Yan, W. H. Kan, C. Wang and A. Manthiram, J. Electrochem. Soc., 2016, 163(3), A584 Hou , J. Yin , X. Lu , J. Li , Y. Zhao and X. Xu , Nanoscale, 2018, 10 , 6671 —6677

Abstract PURPOSE Triple negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer. Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) predicts better survival. Early prediction of the treatment response can potentially triage non-responding patients to alternative protocol treatments, spare them of the unneeded toxicity, and improve pCR. We evaluated the ability of radiomic textural analysis of intratumoral and peritumoral regions on the dynamic contrast enhanced (DCE) and diffusion-weighted imaging (DWI) MRI images obtained early during NAST to predict pCR. MATERIALS AND METHODS This IRB-approved prospective study (NCT02276443) included 182 patients with biopsy proven stage I-III TNBC who had multiparametric MRIs at baseline (BL), post 2 cycles (C2), and post 4 cycles (C4) of NAST before surgery. Tumors and peritumoral regions of 5 mm and 10 mm in thickness were segmented on the 2.5 minutes DCE subtraction images and on the b=800 DWI images. Ten histogram-based first order texture features including mean, minimum, maximum, standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentile, and 300 radiomic Grey Level Co-occurrence matrix (GLCM) features along with their absolute and relative differences between the 3 imaging time points were extracted from the tumors and from the peritumoral regions with an in-house Matlab toolbox. Treatment response at surgery (pCR vs non-pCR) was documented. The samples were divided into training and testing datasets by a 2:1 ratio. Area under the receiver operating characteristics curve (AUC ROC) was calculated for univariate analysis in predicting pCR. Logistic regression with elastic net regularization was performed for texture feature selection. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. RESULTS Of 182 TNBC patients, 88 (48%) had pCR and 94 (52%) did not achieve pCR. Eight multivariate models combining radiomic features from both DCE and DWI tumoral and peritumoral regions had AUC &gt; 0.8 (0.807-0.831) with p-value &lt; 0.001 in both training and testing sets. The highest AUC=0.831 was obtained from a model consisting of 15 radiomic features: tumor DWI (5 GLCM features) at C2, peritumoral region on DCE (skewness) at C2, tumor DCE (1st, 5th percentile) at C4, tumor DWI (3 GLCM features) at C4, peritumoral region DWI (1 GLCM feature) at C4, and the relative difference between C4/C2 on DCE (5th, 95th percentile and mean). CONCLUSION Multi-parametric MRI-based radiomics models from the tumor and the peritumoral regions showed high accuracy as potential early predictors of NAST response in TNBC patients. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Multi-Parametric MRI-Based Radiomics Models from Tumor and Peritumoral Regions as Potential Predictors of Treatment Response to Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [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 P6-01-06.

Abstract Background and Purpose Triple negative breast cancer (TNBC) is a biologically aggressive tumor and a refractory subtype of breast cancer due to the lack of therapeutic targets, such as estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. In this study, we investigated the accuracy of radiomic models based on the dynamic contrast enhanced (DCE) MRI images obtained after the completion of NAST as discriminators of treatment response in TNBC patients. Materials and Methods This IRB-approved prospective study (ARTEMIS trial, NCT02276443) included 181 patients with biopsy proven stage I-III TNBC who Had MRIs after completion of NAST and before surgery. Patients were classified as pathologic complete response (pCR) and non-pCR at the surgery. Tumors were segmented on the 2.5 minutes DCE subtraction images. Regions with necrosis or clip artifacts were excluded from the contour. If tumors were not visible, the tumor bed was contoured. Whole-tumor histogram-based first order texture features (p=10) including mean, minimum, maximum, Standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentiles, and radiomic (p=300) Grey Level Co-occurrence matrix (GLCM) features were extracted with an in-house Matlab toolbox. The samples were split into training and testing data sets by a 2:1 ratio. For univariate analysis area under the receiver operating characteristics curve (AUC ROC) was performed for pCR status prediction. For texture feature selection logistic regression with elastic net regularization was performed. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. A P-value less than 0.05 was considered statistically significant. Results Of the total 181 patients, 88 (49%) had pCR and 93 (51%) had non-pCR. Univariate analysis identified 7 statistically significant first order imaging features (Minimum, Maximum, Mean, 1st Percentile, 5th Percentile, 95th Percentile, and 99th Percentile) with AUC &gt;= 0.7 (p&lt; 0.001), in both training and testing data sets. Percentile 5 showed highest AUC = 0.78 (p&lt; 0.001). Two multivariate models were statistically significant at cross-validation with AUC&gt;=0.7. The first model combined 2 first order data (Percentile 1 and Percentile 5) with AUC = 0.73 (p&lt; 0.001). The second model combined 8 first order features (Percentile 1, 5, 95, 99, Mean, Minimum, Maximum, and Skewness) and 24 GLCM features with AUC = 0.7 (p=0.003). Conclusion DCE-MRI radiomic features from tumor and tumor bed regions in TNBC may be helpful imaging biomarkers for predicting treatment response after NAST. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Huiqin Chen, Jia Sun, Peng Wei, Jennifer K. Litton, Vicente Valero, Clinton Yam, Mark Pagel, Jingfei Ma, Gaiane Rauch. A Pre-operative Dynamic Contrast Enhanced MRI-Based Radiomics Models as Predictors of Treatment Response after Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [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 P6-01-35.

Abstract Background and Purpose Early prediction of neoadjuvant systemic therapy (NAST) response in triple negative breast cancer (TNBC) patients could potentially aid in the selection of alternative therapies and avoid unnecessary toxicity in patients unlikely to achieve pathologic complete response (pCR) with NAST. In this study, we investigated the radiomic features of the peritumoral and the tumoral regions from dynamic contrast enhanced (DCE) MRI acquired at different time points of NAST for early treatment response prediction in TNBC. Methods and Materials This study included 182 biopsy-confirmed stage I-III TNBC patients enrolled in an IRB approved prospective clinical trial (NCT02276433). All patients underwent DCE-MRI on a GE 3T MRI scanner at baseline (BL), after two (C2) and four (C4) cycles of doxorubicin/cyclophosphamide based chemotherapy and before surgery. The peritumoral and the tumoral regions were segmented manually by two fellowship-trained radiologists using early phase (2.5 min) DCE-MRI subtraction images. Ten first order radiomic features, 300 grey-level-co-occurrence matrix (GLCM) features along with their absolute and relative differences (C4/BL, C2/BL, C4/C2) between the 3 imaging time points were extracted from the peritumoral and the tumoral regions. Patients were randomly divided into training and testing sets in a 2:1 ratio. For univariate analysis, area under the receiver operating characteristics curve (AUC ROC) was measured to determine the features most predictive of pCR/non-pCR. Wilcoxon Rank Sum test was used to test the statistical significance of predictive performance. In multivariate analysis, radiomic models were established using logistic regression with elastic net regularization followed by 5-fold cross validation for performance assessment. Results Eighty-eight (48%) patients had pCR (59 training, 29 testing) and 94 (52%) patients had non-pCR (63 training, 31 testing). Twenty-five radiomic features (4 from peritumoral C4, 5 from tumoral C4, 4 from peritumoral C4/BL, 6 from tumoral C4/BL, 2 from peritumoral C4/C2 and 4 from tumoral C4/C2) were statistically significant with AUC ≥ 0.75 in both the training and the testing sets at the univariate analysis. The significant features at C4 had AUCs of 0.75-0.79 for the training set and 0.76-0.81 for the testing set. Changes measured between C4 and BL or C2 showed AUC of 0.76-0.84 in the training and 0.75-0.81 in the testing datasets. Eleven multivariate regression models comprised of radiomic features at BL, C2, C4 and their changes (C4/BL, C4/C2 and C2/BL) showed an AUC of 0.80-0.84 for cross validation and an AUC of 0.80-0.82 for independent testing. Conclusions Radiomic models using longitudinal DCE MRI parameters of peritumoral and tumoral regions during NAST have the potential to predict pCR in TNBC patients undergoing NAST. Citation Format: Bikash Panthi, Rania M. Mohamed, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Longitudinal DCE-MRI Radiomic Models for Early Prediction of Response to Neoadjuvant Systemic Therapy (NAST) in Triple Negative Breast Cancer (TNBC) Patients [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 P6-01-34.

This study aims to investigate the indigenous knowledge (IK) of three ethnic minority groups in the Northern Mountain Region (NMR) of Vietnam. The groups include (1) Tay people who live at lower elevations; (2) a Dao community who tend to live in the middle elevations and (3) Hmong farmers who mainly reside at higher elevations areas of the mountain. This research intends to identify climate change (CC) and its impact on agricultural cultivation and find out how these groups can adapt to CC by applying their IK in agriculture practices. Data was collected through focus group discussions (n=9), in-depth interviews (n=80), and participant observation. From the 80 respondents, 27 live in Bac Kan province, 23 in Yen Bai province and 30 in Son La province; those who had experience in agricultural production, elderly and village heads. The results show that the NMR weather has significant changes that negatively impact agriculture cultivation and local livelihood. Although the respondents are from different ethnic minorities, these farmers are highly aware of the CC risks, leading into adaptation practices. While the Tay people's major adaptation strategies include the use of a variety of native plants and changing planting calendars, the Dao and Hmong people apply intercropping and local techniques methods in terracing fields using local varieties of livestock. Our findings highlight the importance of using the IK of ethnic minorities in adaptation towards CC. A better targeting about the use of local resources in future national policies and projects is encouraged. Nghiên cứu này nhằm thu thập kiến thức bản địa (IK) của ba nhóm dân tộc thiểu số ở Miền núi phía Bắc (MNPB) của Việt Nam bao gồm (1) dân tộc Tày chủ yếu sống ở vùng thấp; (2) Người Dao có xu hướng sống ở các độ cao trung bình; và (3) người Hmông chủ yếu cư trú ở các khu vực đồi núi cao. Nghiên cứu này nhằm xác định tình hình biến đổi khí hậu (BĐKH) và tác động của nó đối với sản xuất nông nghiệp, đồng thời tìm hiểu cách thức các nhóm dân tộc thiểu số này có thể thích ứng với BĐKH bằng cách áp dụng các kiến thức bản địa của họ vào thực tiễn sản xuất nông nghiệp. Dữ liệu được thu thập thông qua thảo luận nhóm tập trung (n = 9), phỏng vấn sâu (n = 80) và quan sát người tham gia. Trong số 80 người được hỏi, có 27 người sống ở tỉnh Bắc Kạn; 23 người ở tỉnh Yên Bái và 30 người ở tỉnh Sơn La, là những người có kinh nghiệm sản xuất nông nghiệp, người cao tuổi và trưởng thôn. Kết quả cho thấy thời tiết ở khu vực MNPB đã có những thay đổi so với trước gây tác động xấu đến canh tác nông nghiệp và sinh kế của cộng đồng. Mặc dù những người được hỏi từ các dân tộc khác nhau nhưng họ đều nhận thức được sự thay đổi này của thời tiết, do đó họ đã có những thích ứng riêng. Trong khi người Tày sử dụng giống cây trồng địa phương và thay đổi lịch thời vụ thì người Dao và Hmong chọn phương pháp xen canh và áp dụng kỹ thuật bản địa trên đất ruộng bậc thang và sử dụng gióng vật nuôi bản địa. Các phát hiện của chúng tôi giúp hiểu được tầm quan trọng của việc sử dụng IK trong thích ứng với BĐKH của các dân tộc thiểu số, từ đó có thể hướng đến mục tiêu tốt hơn việc sử dụng các nguồn lực địa phương trong các chính sách và dự án quốc gia trong tương lai.

The use of non-precious catalysts (e.g., transition metal oxides) in electrochemical energy technologies in acid (e.g., proton exchange membrane fuel cells and electrolyzers) has been significantly hampered by the instability of such catalysts at low pHs. While first-row late transition metal oxides based on Fe, Co, and/or Ni have been reported with comparable or higher catalytic activity for the alkaline oxygen reduction and oxygen evolution reactions than their precious-metal-based counterparts (e.g., Pt and IrO2),[1] these oxide catalysts are not stable in acid.[2] Moreover, Mn-based oxides are more acid-stable than those based on late transition metals[1] and can be potentially stabilized by reaching dissolution-deposition equilibrium at moderately acidic pHs,[3] but they still corrode and deactivate in strong acid and after long operation.[4] To tackle this challenge, extensive efforts over the past decades have been focused on combining active, yet unstable metal oxides with corrosion-resistant oxides.[5-7] Nevertheless, having a higher fraction of corrosion-resistant elements results in more acid-stable, yet less active catalysts, indicating an activity-stability trade-off.[2,5,6] To design transition metal oxide catalysts (such as Mn-based oxides) with an optimal trade-off or bypass this limitation, it is critical to establish their stability descriptors in acid. These descriptors can offer a fundamental understanding of oxide dissolution and provide guiding principles to enhance their intrinsic stability. In this work, we employed a library of Mn-based oxides with diverse structures and Mn oxidation states to identify oxide stability descriptors in acid based on intrinsic electronic structure and energetic parameters. Using time-dependent dissolution experiments and density functional theory calculations, greater amounts and faster kinetics of oxide dissolution in acid were correlated with decreased Mn oxidation states, which are accompanied by lowered Mn-O covalency, weakened Mn-O bonds, and reduced barriers for key reaction steps (such as protonation, vacancy formation, and metal ion solvation). Such design principles were shown broadly with a computational screening across a vast chemical space of ~1,000 Mn-based oxides, where an Mn oxidation state of 4+ was found to give rise to the lowest energetic driving force for the dissolution of Mn-based oxides in acid. Moreover, limiting the percentage of ionic metal substituents in oxides and using more acidic substituents were shown to stabilize Mn-based oxides in acid. These findings can provide novel insights into designing acid-stable Mn-based oxides for renewable energy storage and conversion. References: [1] C. Wei, R. R. Rao, J. Peng, B. Huang, I. E. L. Stephens, M. Risch, Z. J. Xu, Y. Shao-Horn, Adv. Mater. 2019, 31, 1806296. [2] K. K. Rao, Y. Lai, L. Zhou, J. A. Haber, M. Bajdich, J. M. Gregoire, Chem. Mater. 2022, 34, 899. [3] M. Huynh, D. K. Bediako, D. G. Nocera, J. Am. Chem. Soc. 2014, 136, 6002. [4] A. Li, H. Ooka, N. Bonnet, T. Hayashi, Y. Sun, Q. Jiang, C. Li, H. Han, R. Nakamura, Angew. Chem. Int. Ed. 2019, 58, 5054. [5] R. Frydendal, E. A. Paoli, I. Chorkendorff, J. Rossmeisl, I. E. L. Stephens, Adv. Energy Mater. 2015, 5, 1500991. [6] L. Zhou, A. Shinde, J. H. Montoya, A. Singh, S. Gul, J. Yano, Y. Ye, E. J. Crumlin, M. H. Richter, J. K. Cooper, H. S. Stein, J. A. Haber, K. A. Persson, J. M. Gregoire, ACS Catal. 2018, 8, 10938. [7] L. Zhou, H. Li, Y. Lai, M. Richter, K. Kan, J. A. Haber, S. Kelly, Z. Wang, Y. Lu, R. S. Kim, X. Li, J. Yano, J. K. Nørskov, J. M. Gregoire, ACS Energy Lett. 2022, 7, 993. Figure 1

Lawyers use a reasoning process known as legal reasoning to solve legal problems. Legal expert systems could potentially help lawyers solve legal problems more quick and adequately, enable students to study law at school or at home more easily, and help legal scholars and professionals analyze the law and legal systems more clearly and precisely.In 1992, Hajime Yoshino of Meiji Gakuin University started a “Legal Expert Systems” project. This “Legal Expert” project is funded by the Japanese Ministry of Education, Science and Culture and is scheduled to run from May 1992 to March 1998. Yoshino organized over 30 lawyers and computer scientists to clarify legal knowledge and develop legal expert systems.This project covers a wide range of technologies such as the analysis of legal knowledge, the analysis of legal rules on international trade (United Nations Convention on Contracts for International Sale of Goods (CISG)), legal knowledge representation, legal inference models, utility programs to develop legal knowledge bases, and user interfaces. This project, which ends in March 1998, will focus on developing comprehensive legal expert systems as the final product. In this issue, we present 12 papers written by “Legal Expert” project members.In this number, Hajime Yoshino gives are overview of the legal expert systems project, explaining its aims, objectives, and organization. Six papers that follow his introduction include three on case-based reasoning. Legal rules are given by ambiguous predicates, making it difficult sometimes to determine whether conditions for rules are satisfied by the facts given of an event. In such cases, lawyers often refer to old cases and generate hypotheses through analogical reasoning.Kaoru Hirota, Hajime Yoshino and Ming Qiang Xu apply fuzzy theory to case-based reasoning. A number of related systems have been developed, but most focus on qualitative similarities between old cases and the current case, and cannot measure quantitative similarities. Hirota et al. treat quantitative similarity by applying fuzzy theory, explaining their method using CISG examples.Ken Satoh developed a way to compute an interpretation of undefined propositions in a legal rule using adversarial case-based reasoning. He translated old cases giving possible interpretations for a proposition into clauses in abductive logic programming and introduced abducibles to reason dynamically about important factors in an old case to the interpretation suiting the user’s purpose.Yoshiaki Okubo and Makoto Haraguchi formalized a way of attacking legal argument. Assume that an opponent has constructed a legal argument by applying a statute with an analogical interpretation. From the viewpoint of legal stability, the same statue for similar cases should be applied with the same interpretation. We thereby create a hypothetical case similar to the case in question and examine whether the statue can be interpreted analogically. Such a hypothetically similar case is created with the help of a goal-dependent abstraction framework. If a precedent in which a statue has been applied to a case with a different interpretation – particularly complete interpretation – can be found, the opponent’s argument is attacked by pointing out the incoherence of its interpretation of the statue.Takashi Kanai and Susumu Kunifuji proposed a legal reasoning system using abductive logic programming that deals with ambiguities in described facts and exceptions not described in articles. They examined the problems to be solved to develop legal knowledge bases through abductive logic programming, e.g., how to select ambiguities to be treated in abductive reasoning, how to describe time relationships, and how to describe an exception in terms of the application of abductive logic programming to legal reasoning.Toshiko Wakaki, Ken Satoh, and Katsumi Nitta presented an approach of reasoning about dynamic preferences in the framework of circumscription based on logic programming. To treat dynamic preferences correctly is required in legal reasoning to handle metarules such as lex posterior. This has become a hotly discussed topic in legal reasoning and more general nonmonotic reasoning. Comparisons of their method, Brewka’s approach, and Prakken and Sartor’s approach are discussed.Hiroyuki Matsumoto proposed a general legal reasoning model and a way of describing legal knowledge systematically. He applied his method to Japanese Maritime Traffic Law.Six more papers are to be presented in the next number

We are glad to introduce you that the 2021 4th International Conference on Mechanical, Electrical and Material Application (MEMA 2021) was successfully held on October 29-31, 2021. In light of worldwide travel restriction and the impact of COVID-19, MEMA 2021 was carried out in the form of virtual conference to avoid personnel gatherings. Because most participants were still highly enthusiastic about participating in this conference, we chose to carry out MEMA 2021 via online platform according to the original schedule instead of postponing it. MEMA 2021 is to bring together innovative academics and industrial experts in the field of Mechanical, Electrical and Material Application to a common forum. The primary goal of the conference is to promote research and developmental activities in Mechanical, Electrical and Material Application and another goal is to promote scientific information interchange between researchers, developers, engineers, students, and practitioners working all around the world. The conference will be held every year to make it an ideal platform for people to share views and experiences in Mechanical, Electrical and Material Application and related areas. We were greatly honored to invited Prof. Kun Li, from Chongqing University, China and Assoc. Prof. Wei Wei, from Xi’an University of Technology, China as our Conference Chairmen. This scientific event brings together more than 100 national and international researchers in mechanical, electrical and material application. During the conference, the conference model was divided into three sessions, including oral presentations, keynote speeches, and online Q&A discussion. In the first part, some scholars, whose submissions were selected as the excellent papers, were given about 5-10 minutes to perform their oral presentations one by one. Then in the second part, keynote speakers were each allocated 30-45 minutes to hold their speeches. We were pleased to invite four distinguished experts to present their insightful speeches. Our first keynote speaker, Prof. Shahid Hussain, Jiangsu University, China. His research interests include MOS-MOF-MXene Nanomaterials, Gas-Sensors, Electrochemical Supercapacitors, Li-S batteries. And then we had Prof. Jie Huang, from Southwest University, China. His research includes RF/Microwave circuits and sensors. Prof. Qiyan Xu, Anhui University of Technology, China. His main research directions are: New process and technology of low cost steel making, Direct reduction and melting reduction, Development of new metallurgical technology - comprehensive utilization of waste resources. Lastly, we were glad to invite Prof. Kun Li, Chongqing University, China. He mainly engaged in additive manufacturing, intelligent 3D net forming, high performance materials and phase transformation, material computing and other research. In the last part of the conference, all participants were invited to join in a WeChat group to discuss and explore the academic issues after the presentations. The online discussion was lasted for about 30-60 minutes. We are glad to share with you that we still received lots of submissions from the conference during this special period. Hence, we selected a bunch of high-quality papers and compiled them into the proceedings after rigorously reviewed them. These papers feature following topics but are not limited to: Mechanical Dynamics and its Applications, Material Physics, Electrical and Electronic Systems and other related topics. All the papers have been through rigorous review and process to meet the requirements of International publication standard. Lastly, we would like to express our sincere gratitude to the Chairman, the distinguished keynote speakers, as well as all the participants. We also want to thank the publisher for publishing the proceedings. May the readers could enjoy the gain some valuable knowledge from the proceedings. We are expecting more and more experts and scholars from all over the world to join this international event next year. The Committee of MEMA 2021 List of Committee member is available in this pdf.

The paper aims to improve the multi-label classification performance using the feature reduction technique. According to the determination of the dependency among features based on fuzzy rough relation, features with the highest dependency score will be retained in the reduction set. The set is subsequently applied to enhance the performance of the multi-label classifier. We investigate the effectiveness of the proposed model againts the baseline via time complexity. Keywords: Fuzzy rough relation, label-specific feature, feature reduction set References [1] Richard Jensen, Chris Cornelis, Fuzzy-Rough Nearest Neighbor Classification and Prediction. Proceedings of the 6th International Conference on Rough Sets and Current Trends in Computing, 2011, 310-319. [2] Y.H. Qian, Q. Wang, H.H. Cheng, J.Y. Liang, C.Y. Dang, Fuzzy-Rough feature selection accelerator, Fuzzy Sets Syst. 258 (2014) 61-78. [3] Quang-Thuy Ha, Thi-Ngan Pham, Van-Quang Nguyen, Minh-Chau Nguyen, Thanh-Huyen Pham, Tri-Thanh Nguyen, A New Text Semi-supervised Multi-label Learning Model Based on Using the Label-Feature Relations, International Conference on Computational Collective Intelligence, LNAI 11055, Springer, 2018, pp. 403-413. [4] Daniel Kostrzewa, Robert Brzeski, The data Dimensionality Reduction and Feature Weighting in the Classification Process Using Forest Optimization Algorithm, ACIIDS, 2019, pp. 97-108. [5] Nele Verbiest, Fuzzy Rough and Evolutionary Approaches to Instance Selection, PhD Thesis, Ghent University, 2014. [6] Y. Yu, W. Pedrycz, D.Q. Miao, Multi-label classification by exploiting label correlations, Expert syst, Appl. 41 (2014) 2989-3004. [7] M.L. Zhang, LIFT: Multi-label learning with label-specific features, IEEE Trans, Pattern Anal, Mach, Intell 37 (2015) 107-120. [8] Suping Xu, Xibei Yang, Hualong Yu, Dong-Jun Yu, Jingyu Yang, Eric CC Tsang, Multi-label learning with label-specific feature reduction, Knowledge-Based Systems 104 (2016) 52-61. https://doi.org/10.1080/24751839.2017.1364925. [9] Thi-Ngan Pham, Van-Quang Nguyen, Van-Hien Tran, Tri-Thanh Nguyen, Quang-Thuy Ha, A Semi-supervised multi-label classification framework with feature reduction and enrichment, Journal of Information and Telecommunication 1(4) (2017) 305-318. [10] M. Ghaemi, M.R. Feizi-Derakhshi, Feature selection using forest optimization algorithm, Pattern Recognition 60 (2016) 121-129. [11] M.L. Zhang, Z.H. Zhou, ML-KNN: A lazy learning approach to multi-label learning, Pattern Recognition 40 (2007) 2038-2048. [12] M.Z. Ahmad, M.K. Hasan, A New Approach for Computing Zadeh's Extension Principle, MATEMATIKA. 26(1) (2010) 71-81. [13] Richard Jensen, Neil Mac Parthaláin and Qiang Shen. Fuzzy-rough data mining (using the Weka data mining suite), A Tutorial, IEEE WCCI 2014, Beijing, China, July 6, 2014. [14] D. Dubois, H. Prade, Rough fuzzy sets and fuzzy rough sets, Int. J. Gen. Syst. 17 (1990) 191-209.

Abstract The Society gratefully acknowledges the time and effort of the following individuals who served as reviewers of abstracts for this meeting: ASH ABSTRACTS COORDINATING REVIEWERS Blanche P. Alter Stephen M. Ansell Ralph B. Arlinghaus Scott Armstrong Asad Bashey Philip Bierman Neil Blumberg Chiara Bonini Dominique Bonnet Jacqueline Boultwood Rena Buckstein John C. Byrd Marc Carrier Lucio H. Castilla Selina Chen-Kiang Nicholas Chiorazzi Jorge Cortes-Franco Claire E. Dearden Mary C. Dinauer Harry Paul Erba Carolyn A. Felix Pierre Fenaux Debra L. Friedman Irene M. Ghobrial Jason R. Gotlib Brandon Hayes-Lattin Cheryl A. Hillery Achille Iolascon Jean-Pierre J. Issa Sundar Jagannath Diane F. Jelinek H. Phillip Koeffler John Koreth Robert J. Kreitman Robert B. Levy David Lillicrap Richard Lottenberg John D. McMannis Mark D. Minden Charles G. Mullighan Arnon Nagler Peter J. Newman Robert Z. Orlowski Antonio Palumbo Julie A. Panepinto Warren S. Pear Sibrand Poppema Barbara Pro Ching-Hon Pui A. Koneti Rao Aaron P. Rapoport Pieter H. Reitsma Douglas D. Ross J. Eric Russell Barbara Savoldo Kirk R. Schultz Radek C. Skoda Marilyn L. Slovak Susan Smyth Hugo ten Cate Herve Tilly John M. Timmerman Ivo Touw Amy J. Wagers Russell E. Ware Catherine J. Wu Virginia M. Zaleskas ASH ABSTRACTS REVIEWERS Camille Abboud Omar Abdel-Wahab Jeremy Abramson Suneet Agarwal Sikander Ailawadhi Onder Alpdogan Andrew Aprikyan Mary Armanios Aneel Ashrani Norio Asou Aglaia Athanassiadou Eyal Attar Mohammad Azam Maria Baer Jorg Baesecke Sarah Ball Karen Ballen Frederic Baron Shannon Bates Minoo Battiwalla Marie Bene Charles Bennett James Berenson Steven Bernstein Francesco Bertoni Monica Bessler Wolfgang Bethge Kapil Bhalla Deepa Bhojwani James Bieker Bruce R. Blazar Annemarie Block David Bodine Catherine Bollard Antonio Bonati Eric Bouhassira Benjamin Braun Christopher Bredeson Patrick Brown Ross Brown Jan Burger Dario Campana Jose Cancelas Paul Carpenter Andrew Carroll James Casella Rebecca Chan Roy Chemaly Benny Chen Jerry Cheng Linzhao Cheng Bruce Cheson Mark Chiang Athar Chishti Hearn Cho Magdalena Chrzanowska-Wodnicka Richard E. Clark Joseph Connors Kenneth Cooke Miguel Cruz Adam Cuker Sandeep Dave Janice Davis Sproul Lucia De Franceschi Philip De Groot Rodney DeKoter Richard Delarue Stephen Devereux Steven Devine Paola Jorge Di Don Diamond Meletios Dimopoulos John DiPersio Angela Dispenzieri Benjamin Djulbegovic Jing-fei Dong James Downing William Drobyski Rafael Duarte Charles Dumontet Kieron Dunleavy Brian Durie Dimitar Efremov Elizabeth Eklund Jonas Emsley Patricia Ernst Andrew Evens Chris Fegan Andrew Feldman Giuliana Ferrari Willem Fibbe Adele Fielding Thoas Fioretos Robert Flaumenhaft Rafael Fonseca James Foran Joseph Frank Janet Franklin Paul Frenette Alan Friedman Terry Fry Saghi Gaffari Naomi Galili Patrick Gallagher Anne Galy David Garcia Randy Gascoyne Cristina Gasparetto Norbert Gattermann Tobias Gedde-Dahl Alan Gewirtz Francis Giles Robert Godal Lucy Godley Ivana Gojo Norbert Gorin Andre Goy Eric Grabowski Steven Grant Timothy Graubert Elizabeth Griffiths H. Leighton Grimes Claudia Haferlach Corinne Haioun Parameswaran Hari Christine Harrison Robert Hasserjian Nyla Heerema Shelly Heimfeld Roland Herzog Elizabeth Hexner Teru Hideshima William H. Hildebrand Gerhard Hildebrandt Devendra Hiwase Karin Hoffmeister Donna Hogge Scott Howard Brian Huntly Hiroto Inaba Baba Inusa Shai Izraeli Suresh Jhanwar Amy Johnson Craig Jordan Joseph Jurcic Nina Kadan-Lottick Lawrence Kaplan Jonathan Kaufman Neil Kay Michelle Kelliher Craig Kessler H. Jean Khoury Allison King Joseph Kiss Issay Kitabayashi Robert Klaassen Christoph Klein Yoshihisa Kodera Alexander Kohlmann Barbara Konkle Michael Kovacs Robert Kralovics Amrita Krishnan Nicolaus Kroger Ashish Kumar Ralf Küppers Jeffery Kutok Ann LaCasce Raymond Lai David Lane Peter Lane Richard Larson Michelle Le Beau Gregoire Le Gal Ollivier Legrand Suzanne Lentzsch John Leonard John Levine Ross Levine Linheng Li Renhao Li Zhenyu Li Wendy Lim Charles Linker Jeffrey Lipton Per Ljungman John Lollar Philip Low David Lucas Selina Luger Leo Luznik Gary Lyman Jaroslaw Maciejewski Elizabeth MacIntyre Nigel Mackman Luca Malcovati Guido Marcucci Tomer Mark Susan Maroney Giovanni Martinelli Peter Maslak Alan Mast Grant McArthur Philip McCarthy Michael McDevitt Peter McLaughlin Bruno Medeiros Jules P.P. Meijerink Junia Melo Thomas Mercher Bradley Messmer Marco Mielcarek Ken Mills Shin Mineishi Arturo Molina Silvia Montoto Marie Joelle Mozziconacci Auayporn Nademanee Vesna Najfeld Eneida Nemecek Ellis Neufeld Peter Newburger Heyu Ni Charlotte Marie Niemeyer Yago Nieto Anne Novak Paul O\'Donnell Vivian Oehler Fritz Offner Johannes Oldenburg Rebecca Olin Richard J. O'Reilly Thomas Ortel Keiya Ozawa Rose Ann Padua Sung-Yun Pai James Palis Derwood Pamphilon Animesh Pardanani Farzana Pashankar Andrea Pellagatti Catherine Pellat-Deceunynck Louis Pelus Chris Pepper Melanie Percy Andrew Perkins Luke Peterson Andrew Pettitt Javier Pinilla-Ibarz Kimmo Porkka David Porter Amy Powers Claude Preudhomme Frederick Racke Margaret Ragni Thomas Raife Alessandro Rambaldi Mariusz Ratajczak Pavan Reddy Mary Relling Tannishtha Reya Lisa Rimsza Stefano Rivella Isabelle Riviere Pamela Robey Gail Roboz Aldo Roccaro Maria Alma Rodriguez Frank Rosenbauer Laura Rosinol Alan Rosmarin Giuseppe Saglio Jonathan Said Valeria Santini Ravindra Sarode Yogenthiran Saunthararajah Bipin Savani Alan Schechter Charles Schiffer Robert Schlossman Laurie Sehn Rita Selby Orhan Sezer Sadhna Shankar John Shaughnessy Jordan Shavit Kevin Sheehan Shalini Shenoy Colin Sieff Paul Simmons Seema Singhal Sonali Smith Gerard Socie Pieter Sonneveld Simona Soverini David Spaner Steven Spitalnik Kostas Stamatopoulos David Steensma Richard Stone Toshio Suda Perumal Thiagarajan Courtney Thornburg Rodger Tiedemann David Traver Guido Tricot Darrell Triulzi Suzanne Trudel Christel Van Geet Karin Vanderkerken David Varon Amit Verma Srdan Verstovsek Ravi Vij Dan Vogl Loren Walensky Edmund Waller George Weiner Daniel Weisdorf Karl Welte Peter Westervelt Adrian Wiestner P.W. Wijermans John Wingard Anne Woolfrey Mingjiang Xu Qing Yi Anas Younes Ryan Zarychanski Arthur Zelent Clive Zent Dong-Er Zhang Xianzheng Zhou James Zimring

“What is the point of stories in such a moment”, asks author and critic James Bradley, writing about climate extinction: Bradley emphasises that “climatologist James Hansen once said being a climate scientist was like screaming at people from behind a soundproof glass wall; being a writer concerned with these questions often feels frighteningly similar” (“Writing”). If the impact of climate change asks humans to think differently, to imagine differently, then surely writing—and reading—must change too? According to writer and geographer Samuel Miller-McDonald, “if you’re a writer, then you have to write about this”. But how are we to do that? Where might it be done already? Perhaps not in traditional (or even post-) Modernist modes. In the era of the Anthropocene I find myself turning to non-traditional, un-real models to write the slow violence and read the deep time that is where we can see our current climate catastrophe.At a “Writing in the Age of Extinction” workshop earlier this year Bradley and Jane Rawson advocated changing the language of “climate change”—rejecting such neutral terms—in the same way that I see the stories discussed here pushing against Modernity’s great narrative of progress.My research—as a reader and writer, is in the fantastic realm of speculative fiction; I have written in The Conversation about how this genre seems to be gaining literary popularity. There is no doubt that our current climate crisis has a part to play. As Margaret Atwood writes: “it’s not climate change, it’s everything change” (“Climate”). This “everything” must include literature. Kim Stanley Robinson is not the only one who sees “the models modern literary fiction has are so depleted, what they’re turning to now is our guys in disguise”. I am interested in two recent examples, which both use the strongly genre-associated time-travel trope, to consider how science-fiction concepts might work to re-imagine our “deranged” world (Ghosh), whether applied by genre writers or “our guys in disguise”. Can stories such as The Heavens by Sandra Newman and “Anxiety is the Dizziness of Freedom” by Ted Chiang—which apply time travel, whether as an expression of fatalism or free will—help us conceive the current collapse: understand how it has come to pass, and imagine ways we might move through it?The Popularity of Time TravelIt seems to me that time as a notion and the narrative device, is key to any idea of writing through climate change. “Through” as in via, if the highly contested “cli-fi” category is considered a theme; and “through” as entering into and coming out the other side of this ecological end-game. Might time travel offer readers more than the realist perspective of sweeping multi-generational sagas? Time-travel books pose puzzles; they are well suited to “wicked” problems. Time-travel tales are designed to analyse the world in a way that it is not usually analysed—in accordance with Tim Parks’s criterion for great novels (Walton), and in keeping with Darko Suvin’s conception of science fiction as a literature of “cognitive estrangement”. To read, and write, a character who travels in “spacetime” asks something more of us than the emotional engagement of many Modernist tales of interiority—whether they belong to the new “literary middlebrow’” (Driscoll), or China Miéville’s Booker Prize–winning realist “litfic” (Crown).Sometimes, it is true, they ask too much, and do not answer enough. But what resolution is possible is realistic, in the context of this literally existential threat?There are many recent and recommended time-travel novels: Kate Atkinson’s 2013 Life after Life and Jenny Erpenbeck’s 2014 End of Days have main characters who are continually “reset”, exploring the idea of righting history—the more literary experiment concluding less optimistically. For Erpenbeck “only the inevitable is possible”. In her New York Times review Francine Prose likens Life after Life to writing itself: “Atkinson sharpens our awareness of the apparently limitless choices and decisions that a novelist must make on every page, and of what is gained and lost when the consequences of these choices are, like life, singular and final”. Andrew Sean Greer’s 2013 The Impossible Lives of Greta Wells also centres on the WorldWar(s), a natural-enough site to imagine divergent timelines, though he draws a different parallel. In Elan Mastai’s 2017 debut All Our Wrong Todays the reality that is remembered—though ultimately not missed, is more dystopic than our own time, as is also the way with Joyce Carol Oates’s 2018 The Hazards of Time Travel. Oates’s rather slight contribution to the subgenre still makes a clear point: “America is founded upon amnesia” (Oates, Hazards). So, too, is our current environment. We are living in a time created by a previous generation; the environmental consequence of our own actions will not be felt until after we are gone. What better way to write such a riddle than through the loop of time travel?The Purpose of Thought ExperimentsThis list is not meant to be comprehensive. It is an indication of the increasing literary application of the “elaborate thought experiment” of time travel (Oates, “Science Fiction”). These fictional explorations, their political and philosophical considerations, are currently popular and potentially productive in a context where action is essential, and yet practically impossible. What can I do? What could possibly be the point? As well as characters that travel backwards, or forwards in time, these titles introduce visionaries who tell of other worlds. They re-present “not-exactly places, which are anywhere but nowhere, and which are both mappable locations and states of mind”: Margaret Atwood’s “Ustopias” (Atwood, “Road”). Incorporating both utopian and dystopian aspects, they (re)present our own time, in all its contradictory (un)reality.The once-novel, now-generic “novum” of time travel has become a metaphor—the best possible metaphor, I believe, for the climatic consequence of our in/action—in line with Joanna Russ’s wonderful conception of “The Wearing out of Genre Materials”. The new marvel first introduced by popular writers has been assimilated, adopted or “stolen” by the dominant mode. In this case, literary fiction. Angela Carter is not the only one to hope “the pressure of the new wine makes the old bottles explode”. This must be what Robinson expects: that Ken Gelder’s “big L” literature will be unable to contain the wine of “our guys”—even if it isn’t new. In the act of re-use, the time-travel cliché is remade anew.Two Cases to ConsiderTwo texts today seem to me to realise—in both senses of that word—the possibilities of the currently popular, but actually ancient, time-travel conceit. At the Melbourne Writers Festival last year Ted Chiang identified the oracle in The Odyssey as the first time traveller: they—the blind prophet Tiresias was transformed into a woman for seven years—have seen the future and report back in the form of prophecy. Chiang’s most recent short story, “Anxiety is the Dizziness of Freedom”, and Newman’s novel The Heavens, both of which came out this year, are original variations on this re-newed theme. Rather than a coherent, consistent, central character who travels and returns to their own time, these stories’ protagonists appear diversified in/between alternate worlds. These texts provide readers not with only one possible alternative but—via their creative application of the idea of temporal divergence—myriad alternatives within the same story. These works use the “characteristic gesture” of science fiction (Le Guin, “Le Guin Talks”), to inspire different, subversive, ways of thinking and seeing our own one-world experiment. The existential speculation of time-travel tropes is, today, more relevant than ever: how should we act when our actions may have no—or no positive, only negative—effect?Time and space travel are classic science fiction concerns. Chiang’s lecture unpacked how the philosophy of time travel speaks uniquely to questions of free will. A number of his stories explore this theme, including “The Alchemist’s Gate” (which the lecture was named after), where he makes his thinking clear: “past and future are the same, and we cannot change either, only know them more fully” (Chiang, Exhalation). In “Story of Your Life”, the novella that the film Arrival is based on, Chiang’s main character-narrator embraces a future that could be seen as dystopic while her partner walks away from it—and her, and his daughter—despite the happiness they will offer. Gary cannot accept the inevitable unhappiness that must accompany them. The suggestion is that if he had had Louise’s foreknowledge he might, like the free-willing protagonist in Looper, have taken steps to ensure that that life—that his daughter’s life itself—never eventuated. Whether he would have been successful is suspect: according to Chiang free will cannot foil fate.If the future cannot be changed, what is the role of free will? Louise wonders: “what if the experience of knowing the future changed a person? What if it evoked a sense of urgency, a sense of obligation to act precisely as she knew she would?” In his “story notes” Chiang says inspiration came from variational principles in physics (Chiang, Stories); I see the influence of climate calamity. Knowing the future must change us—how can it not evoke “a sense of urgency, a sense of obligation”? Even if events play out precisely as we know they will. In his talk Chiang differentiated between time-travel films which favour free will, like Looper, and those that conclude fatalistically, such as Twelve Monkeys. “Story of Your Life” explores the idea that these categories are not mutually exclusive: exercising free will might not change fate; fatalism may not preclude acts of free will.Utopic Free Will vs. Dystopic Fate?Newman’s latest novel is more obviously dystopic: the world in The Heavens is worse each time Kate wakes from her dreams of the past. In the end it has become positively post-apocalyptic. The overwhelming sadness of this book is one of its most unusual aspects, going far beyond that of The Time Traveler’s Wife—2003’s popular tale of love and loss. The Heavens feels fatalistic, even though its future is—unfortunately, in this instance—not set but continually altered by the main character’s attempts to “fix” it (in each sense of the word). Where Twelve Monkeys, Looper, and The Odyssey present every action as a foregone conclusion, The Heavens navigates the nightmare that—against our will—everything we do might have an adverse consequence. As in A Christmas Carol, where the vision of a possible future prompts the protagonist to change his ways and so prevent its coming to pass, it is Kate’s foresight—of our future—which inspires her to act. History doesn’t respond well to Kate’s interventions; she is unable to “correct” events and left more and more isolated by her own unique version of a tortuous Cassandra complex.These largely inexplicable consequences provide a direct connection between Newman’s latest work and James Tiptree Jr.’s 1972 “Forever to a Hudson Bay Blanket”. That tale’s conclusion makes no “real” sense either—when Dovy dies Loolie’s father’s advisers can only say that (time) paradoxes are proliferating—but The Heavens is not the intellectual play of Tiptree’s classic science fiction: the wine of time-travel has been poured into the “depleted” vessel of “big L” literature. The sorrow that seeps through this novel is profound; Newman apologises for it in her acknowledgements, linking it to the death of an ex-partner. I read it as a potent expression of “solastalgia”: nostalgia for a place that once provided solace, but doesn’t any more—a term coined by Australian philosopher Glen Albrecht to express the “psychic or existential distress caused by environmental change” (Albrecht et al.). It is Kate’s grief, for a world (she has) destroyed that drives her mad: “deranged”.The Serious Side of SpeculationIn The Great Derangement Ghosh laments the “smaller shadow” cast by climate change in the landscape of literary fiction. He echoes Miéville: “fiction that deals with climate change is almost by definition not the kind that is taken seriously by serious literary journals; the mere mention of the subject is often enough to relegate a novel or short story to the genre of science fiction” (Ghosh). Time-travel tales that pose the kind of questions handled by theologians before the Enlightenment and “big L” literature after—what does it mean to exist in time? How should we live? Who deserves to be happy?—may be a way for literary fiction to take climate change “seriously”: to write through it. Out-of-time narratives such as Chiang and Newman’s pose existential speculations that, rather than locating us in time, may help us imagine time itself differently. How are we to act if the future has already come to pass?“When we are faced with a world whose problems all seem ‘wicked’ and intractable, what is it that fiction can do?” (Uhlmann). At the very least, should writers not be working with “sombre realism”? Science fiction has a long and established tradition of exposing the background narratives of the political—and ecological—landscapes in which we work: the master narratives of Modernism. What Anthony Uhlmann describes here, as the “distancing technique” of fiction becomes outright “estrangement” in speculative hands. Stories such as Newman and Chiang’s reflect (on) what readers might be avoiding: that even though our future is fixed, we must act. We must behave as though our decisions matter, despite knowing the ways in which they do not.These works challenge Modernist concerns despite—or perhaps via—satisfying genre conventions, in direct contradiction to Roy Scranton’s conviction that “Narrative in the Anthropocene Is the Enemy”. In doing so they fit Miéville’s description of a “literature of estrangement” while also exemplifying a new, Anthropocene “literature of recognition” (Crown). These, then, are the stories of our life.What Is Not ExpectedChiang’s 2018 lecture was actually a PowerPoint presentation on how time travel could or would “really” work. His medium, as much as his message, clearly showed the author’s cross-disciplinary affiliations, which are relevant to this discussion of literary fiction’s “depleted” models. In August this year Xu Xi concluded a lecture on speculative fiction for the Vermont College of Fine Arts by encouraging attendees to read—and write—“other” languages, whether foreign forms or alien disciplines. She cited Chiang as someone who successfully raids the riches of non-literary traditions, to produce a new kind of literature. Writing that deals in physics, as much as characters, in philosophy, as much as narrative, presents new, “post-natural” (Bradley, “End”) retro-speculations that (in un- and super-natural generic traditions) offer a real alternative to Modernism’s narrative of inevitable—and inevitably positive—progress.In “What’s Expected of Us” Chiang imagines the possible consequence of comprehending that our actions, and not just their consequence, are predetermined. In what Oates describes as his distinctive, pared-back, “unironic” style (Oates, “Science Fiction”), Chiang concludes: “reality isn’t important: what’s important is your belief, and believing the lie is the only way to avoid a waking coma. Civilisation now depends on self-deception. Perhaps it always has”. The self-deception we need is not America’s amnesia, but the belief that what we do matters.ConclusionThe visions of her “paraself” that Nat sees in “Anxiety Is the Dizziness of Freedom” encourage her to change her behaviour. The “prism” that enables this perception—a kind of time-tripped iPad that “skypes” alternate temporal realities, activated by people acting in different ways at a crucial moment in their lives—does not always reflect the butterfly effect the protagonist, or reader, might expect. Some actions have dramatic consequences while others have minimal impact. While Nat does not see her future, what she spies inspires her to take the first steps towards becoming a different—read “better”—person. We expect this will lead to more positive outcomes for her self in the story’s “first” world. The device, and Chiang’s tale, illustrates both that our paths are predetermined and that they are not: “our inability to predict the consequences of our own predetermined actions offers a kind of freedom”. The freedom to act, freedom from the coma of inaction.“What’s the use of art on a dying planet? What’s the point, when humanity itself is facing an existential threat?” Alison Croggon asks, and answers herself: “it searches for the complex truth … . It can help us to see the world we have more clearly, and help us to imagine a better one”. In literary thought experiments like Newman and Chiang’s artful time-travel fictions we read complex, metaphoric truths that cannot be put into real(ist) words. In the time-honoured tradition of (speculative) fiction, Chiang and Newman deal in, and with, “what cannot be said in words … in words” (Le Guin, “Introduction”). These most recent time-slip speculations tell unpredictable stories about what is predicted, what is predictable, but what we must (still) believe may not necessarily be—if we are to be free.ReferencesArrival. Dir. Dennis Villeneuve. Paramount Pictures, 2016.Albrecht, Glenn, et al. “Solastalgia: The Distress Caused by Environmental Change.” Australasian Psychiatry (Feb. 2007): 41–55. Atwood, Margaret. “The Road to Ustopia.” The Guardian 15 Oct. 2011 <https://www.theguardian.com/books/2011/oct/14/margaret-atwood-road-to-ustopia>.———. “It’s Not Climate Change, It’s Everything Change.” Medium 27 July 2015. <https://medium.com/matter/it-s-not-climate-change-it-s-everything-change-8fd9aa671804>.Bradley, James. “Writing on the Precipice: On Literature and Change.” City of Tongues. 16 Mar. 2017 <https://cityoftongues.com/2017/03/16/writing-on-the-precipice-on-literature-and-climate-change/>.———. “The End of Nature and Post-Naturalism: Fiction and the Anthropocene.” City of Tongues 30 Dec. 2015 <https://cityoftongues.com/2015/12/30/the-end-of-nature-and-post-naturalism-fiction-and-the-anthropocene/>.Bradley, James, and Jane Rawson. “Writing in the Age of Extinction.” Detached Performance and Project Space, The Old Mercury Building, Hobart. 27 July 2019.Chiang, Ted. Stories of Your Life and Others. New York: Tor, 2002.———. Exhalation: Stories. 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Le Guin Talks to Michael Cunningham about Genres, Gender, and Broadening Fiction.” Electric Literature 1 Apr. 2016. <https://electricliterature.com/ursula-k-le-guin-talks-to-michael- cunningham-about-genres-gender-and-broadening-fiction-57d9c967b9c>.Miller-McDonald, Samuel. “What Must We Do to Live?” The Trouble 14 Oct. 2018. <https://www.the-trouble.com/content/2018/10/14/what-must-we-do-to-live>.Oates, Joyce Carol. Hazards of Time Travel. New York: Ecco Press, 2018.———. "Science Fiction Doesn't Have to be Dystopian." The New Yorker 13 May 2019. <https://www.newyorker.com/magazine/2019/05/13/science-fiction-doesnt-have-to-be-dystopian>.Prose, Francine. “Subject to Revision.” New York Times 26 Apr. 2003. <https://www.nytimes.com/2013/04/28/books/review/life-after-life-by-kate-atkinson.html>.Robinson, Kim Stanley. “Kim Stanley Robinson and the Drowning of New York.” The Coode Street Podcast 305 (2017). <http://www.jonathanstrahan.com.au/wp/the-coode-street-podcast/>.Russ, Joanna. “The Wearing Out of Genre Materials.” College English 33.1 (1971): 46–54.Scranton, Roy. “Narrative in the Anthropocene Is the Enemy.” Lithub.com 18 Sep. 2019. <https://lithub.com/roy-scranton-narrative-in-the-anthropocene-is-the-enemy/>.Suvin, Darko. Metamorphoses of Science Fiction: On the Poetics and History of a Literary Genre. New Haven: Yale UP, 1979. Walton, James. “Fascinating, Fearless, and Distinctly Odd.” The New York Review of Books 9 Jan. 2014: 63–64.Uhlmann, Anthony. “The Other Way, the Other Truth, the Other Life: Simpson Returns.” Sydney Review of Books. 2 Sep. 2019 <https://sydneyreviewofbooks.com/macauley-simpson-returns/>. Xu, Xi. “Speculative Fiction.” Presented at the International MFA in Creative Writing and Literary Translation, Vermont College of Fine Arts, Vermont, 15 Aug. 2019.