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作者：Aderounmu, Adedeji M.; Maus-Conn, Josephine; Consalvo, Claudia D.; Shen, Peter S.; Bass, Brenda L.
作者单位：Utah System of Higher Education; University of Utah
摘要：A fully functional Dicer helicase, present in the modern arthropod, uses energy from ATP hydrolysis to power translocation on bound dsRNA, enabling the processive dsRNA cleavage required for efficient antiviral defense. However, modern Dicer orthologs exhibit divergent helicase functions that affect their ability to contribute to antiviral defense. Moreover, mechanisms that couple ATP hydrolysis to Dicer helicase movement on dsRNA remain enigmatic. We used biochemical and structural analyses o...
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作者：Ota, Naruhisa; Davies, Christopher W.; Kang, Jing; Yan, Donghong; Scherl, Alexis; Wong, Anne; Cook, Ryan; Tao, Xun; Dunlap, Debra; Klabunde, Sha; Mantik, Priscilla; Mohanan, Vishnu; Lin, WeiYu; McBride, Jacqueline; Sadekar, Shraddha; Storek, Kelly M.; Lupardus, Patrick; Ye, Zhengmao; Wallweber, Heidi Ackerly; Kiefer, James R.; Xu, Min; Chan, Pamela; Nagapudi, Karthik; Xi, Tangshen; Koerber, James T.
作者单位：Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech
摘要：Interleukin (IL)- 23 is a validated therapeutic target in inflammatory bowel disease. While antibodies targeting IL23 demonstrate clinical efficacy, they face challenges such as high costs, safety risks, and the necessity of parenteral administration. Here, we present a workflow to simultaneously enhance the affinity and protease stability of an anti- IL23R VHH employs both CDR and framework residues to achieve picomolar affinity for IL23R. The engineered VHH remains stable for over 8 h in int...
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作者：Sella, Yehonatan; Bergman, Aviv
作者单位：Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; The Santa Fe Institute
摘要：This study investigates the intricate interplay among neutral landscape structure, mutation rate, recombination rate, and population dynamics in shaping evolutionary robustness. We provide a comprehensive framework that elucidates how different evolutionary forces interact to influence genotypic robustness and localization within haploid and diploid populations. We demonstrate that in haploid populations, high mutation rates relative to recombination typically drive the population toward regio...
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作者：White, William L.; Yirdaw, Hailemikael K.; Ben-Sasson, Ariel J.; Groves, Jay T.; Baker, David; Kueh, Hao Yuan
作者单位：University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of California System; University of California Berkeley; Nanyang Technological University; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; University of Washington; University of Washington Seattle
摘要：T cells display the remarkable ability to detect single foreign peptides displayed on target cells, while ignoring highly abundant self-peptides. This selectivity has been explained by kinetic proofreading in the T cell receptor (TCR) signaling pathway, which prevents responses to short-lived binding events regardless of their abundance. However, the biochemical mechanisms that drive kinetic proofreading have remained unclear. Here, using computational modeling, we show that these key signalin...
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作者：Zhang, Sitao; Megarioti, Amalia H.; Hendricks, Joseph M.; Zhou, Junshu; Sun, Qingxiang; Jia, Da; Olzmann, James A.
作者单位：Sichuan University; University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of Electronic Science & Technology of China; Sichuan Provincial People's Hospital
摘要：FSP1 is an FAD-dependent oxidoreductase that uses NAD(P)H to regenerate the reduced forms of lipophilic quinone antioxidants, such as coenzyme Q10 and vitamin K. These quinone antioxidants function as radical scavenging agents that prevent the propagation of lipid peroxidation and the induction of ferroptosis. Although several small-molecule inhibitors of FSP1 have been developed and found to sensitize cancer cells to ferroptosis, our understanding of their molecular mechanisms remains limited...
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作者：Cheong, Mi Cheong; Mackowiak, Bryan; Kim, Hyung Bum; Hernandez, Genaro; Nandu, Tulip; Vale, Kevin; Zhang, Yuan; Zacharias, Lauren G.; Mathews, Thomas P.; Gao, Bin; Kraus, W. Lee; Kliewer, Steven A.; Mangelsdorf, David J.
作者单位：University of Texas System; University of Texas Southwestern Medical Center; National Institutes of Health (NIH) - USA; NIH National Institute on Alcohol Abuse & Alcoholism (NIAAA); University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute
摘要：Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, this induction of FGF21 occurs at the level of gene transcription and is regulated by two byproducts of ethanol metabolism, glycerol-3-phosphate (G3P) and acetyl-CoA. Using cell-based reporter and thermal shift binding assays, we show that G3P binds to a conserved domain and activates the transcripti...
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作者：Li, Shufen; Li, Hao; Zhou, Zhenxing; Ye, Meidi; Wang, Yifei; Li, Wenqin; Guan, Zhenqiong; Guan, Zihan; Zhang, Chongtao; Zhang, Yulan; Liu, Wei; Peng, Ke
作者单位：Chinese Academy of Sciences; Wuhan Institute of Virology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Academy of Military Medical Sciences - China
摘要：Necroptosis is an inflammatory programmed cell death pathway triggered by RIPK3 activation through one of the upstream RHIM-domain-containing proteins including RIPK1, TRIF, and ZBP1. Whether necroptosis can be activated independent of the upstream signaling pathways leading to inflammatory pathogenesis remains ambiguous. Here, we revealed a mechanism in which a viral protein mediates direct RIPK3 activation resulting in severe inflammatory pathogenesis in patients. The nonstructural protein N...
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作者：He, Zhangping; Zuo, Peiyao; Xu, Peiliu; Yuan, Haozhi; Bhave, Madhura; Wei, Xiangying; Yang, Ziyan; Han, Lu; Schmid, Sandra L.; Chen, Zhiming
作者单位：University of South China; University of South China; University of Texas System; University of Texas Southwestern Medical Center; Chan Zuckerberg Initiative (CZI); Minjiang University
摘要：Clathrin-mediated endocytosis (CME) begins with the assembly of clathrin onto the plasma membrane. These structures grow and stabilize to form clathrin-coated pits (CCPs), which invaginate and accumulate cargo. Finally, through membrane fission, CCPs detach to form clathrin-coated vesicles (CCVs). Mechanisms governing the transition of CCPs from flat-to-curved structures have been a matter of debate. GAK and its chaperone protein, Hsc70, are well known to mediate clathrin release from CCVs, an...
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作者：Tian, Limin; Long, Guangyu; Zhu, Siqi; Wang, Yuelong; Xu, Pengcheng; Liu, Lifeng; Yao, Hong; Fang, Shentong; Chen, Shuqing; Li, Suxin
作者单位：China Pharmaceutical University; Inner Mongolia Medical University; China Pharmaceutical University; China Pharmaceutical University; Huazhong University of Science & Technology
摘要：Imbalanced production and clearance of amyloid-n (An) is a hallmark pathological feature of Alzheimer's disease (AD). While several monoclonal antibodies targeting An have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and An, as well as the...
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作者：Bonetti, Pietro M.; Christos, Maine; Sachdev, Subir
