Proceedings of the National Academy of Sciences of the United States of America

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• Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases AI翻译
  作者：Gogte, Kalpshree; Mamashli, Fatemeh; Herrera, Maria Georgina; Kriegler, Simon; Bader, Verian; Kamps, Janine; Grover, Prerna; Winter, Roland; Winklhofer, Konstanze F.; Tatzelt, Joerg
  作者单位：Ruhr University Bochum; Ruhr University Bochum; Dortmund University of Technology; Ruhr University Bochum
  摘要：Protein misfolding and aggregation are a hallmark of various neurodegenerative disorders. However, the underlying mechanisms driving protein misfolding in the cellular context are incompletely understood. Here, we show that the two- dimensional confinement imposed by a membrane anchor stabilizes the native protein conformation and suppresses liquid-liquid phase separation (LLPS) and protein aggregation. Inherited prion diseases in humans and neurodegeneration in transgenic mice are linked to t...
• Tamsulosin ameliorates bone loss by inhibiting the release of Cl- through wedging into an allosteric site of TMEM16A AI翻译
  作者：Li, Shiliang; Sun, Weijia; Li, Shuang; Zhu, Lili; Guo, Shuai; He, Jiaqi; Li, Yuheng; Tian, Chaoquan; Zhao, Zhenjiang; Yu, Tao; Li, Jianwei; Zhang, Yiqing; Hai, Youlong; Wang, Jiawen; Zheng, Yongjun; Wang, Rui; Hu, Xiaoyong; Ling, Shukuan; Li, Honglin; Li, Yingxian
  作者单位：East China Normal University; East China University of Science & Technology; Fudan University; Beijing Institute of Technology; Hebei University; Shanghai Jiao Tong University; Oujiang Laboratory; Lingang Laboratory
  摘要：TMEM16A, a key calcium- activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high- resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.93 & Aring;. Tams...
• Learning the language of antibody hypervariability AI翻译
  作者：Singh, Rohit; Im, Chiho; Qiu, Yu; Mackness, Brian; Gupta, Abhinav; Joren, Taylor; Sledzieski, Samuel; Erlach, Lena; Wendt, Maria; Nanfack, Yves Fomekong; Bryson, Bryan; Berger, Bonnie
  作者单位：Massachusetts Institute of Technology (MIT); Sanofi-Aventis; Sanofi USA; Sanofi-Aventis; Sanofi USA; Swiss Federal Institutes of Technology Domain; ETH Zurich; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT)
  摘要：Protein language models (PLMs) have demonstrated impressive success in modeling proteins. However, general-purpose foundational PLMs have limited performance in modeling antibodies due to the latter's hypervariable regions, which do not conform to the evolutionary conservation principles that such models rely on. In this study, we propose a transfer learning framework called Antibody MutagenesisAugmented Processing (AbMAP), which fine-tunes foundational models for antibody- sequence inputs by ...
• Versatile Xenopus tropicalis model with targeted integration of human BRAFV600E AI翻译
  作者：Ran, Rensen; Li, Lanxin; Chen, Peng; Li, Shuai; Wang, Peng; Zhu, Zhenpeng; Wang, Xiran; Chen, Yonglong; Hang, Jing; Liang, Weizheng
  作者单位：Southern University of Science & Technology; Peking University; Xi'an Medical University; Guangdong Medical University; Hebei North University; Hebei North University
  摘要：Targeting exogenous gene integrations in animals often exhibits low efficiency, limiting the development of gene knock-in models. Theoretically, by screening founder generation individuals based on the cell phenotypes resulting from gene knock-ins and leveraging the high fecundity of animals, heritable descendants with targeted knock-ins can be efficiently generated. Therefore, we utilized the high fecundity of Xenopus tropicalis and easily observable pigment phenotypes to construct a BRAFV600...
• Dimerization propensity of the β1-adrenergic receptor in lipid nanodiscs probed by DEER and single-molecule spectroscopies AI翻译
  作者：Kubatova, Nina; Schmidt, Thomas; Wang, Quan; Clore, G. Marius
  作者单位：National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
  摘要：G protein-coupled receptors (GPCRs) comprise a large class of membrane proteins that mediate cellular responses to a wide range of external signals and as such constitute major drug targets. While oligomerization has been shown to play a well-established role in modulating signaling for class C GPCRs (e.g., the glutamate and GABA receptors), the functional relevance of oligomerization for class A receptors, such as the beta(1)-adrenergic receptor (beta(1)AR), remains unclear. Here, we have exa...
• Fracture of liquid crystal elastomers AI翻译
  作者：Zhou, Yu; Wei, Chen; Jin, Lihua
  作者单位：University of California System; University of California Los Angeles
  摘要：Liquid crystal elastomers (LCEs) are anisotropic, viscoelastic materials integrating polymer networks and liquid crystals. While their mechanical responses have been extensively studied, their fracture behavior remains largely unexplored. Specifically, the effect of the deformation-director coupling on LCE fracture paths is unknown, and fracture criteria for LCEs are not yet established. To address this gap, we combine experimental and theoretical approaches to investigate fracture propagation...
• Relationship dynamics and behavioral adaptations in the control of the 2022 mpox epidemic AI翻译
  作者：Hvid, Ulrik; Simonsen, Lone; Frisch, Morten; Sneppen, Kim
  作者单位：University of Copenhagen; Niels Bohr Institute; Roskilde University; Statens Serum Institut; Aalborg University
  摘要：We analyzed the patterns of transmission in the 2022 clade IIb mpox epidemic as it unfolded in the European population of men who have sex with men (MSM). We developed an agent-based model that simulates sexual pair formation, incorporating both brief and longer-term sexual relationships. The model implements survey data on the sexual behavior of MSM and accounts for the highly heterogeneous nature of the sexual contact network within this community. When simulating the mpox epidemic, the mode...
• Replication stress-induced nuclear hypertrophy alters chromatin topology and impacts cancer cell fitness AI翻译
  作者：Kim, Changgon; Hong, Semyeong; Ma, Soo Hyeon; Lee, Joochan; So, Hee; Kim, Jun Young; Shin, Eunbie; Lee, Kippeum; Choi, Sohee; Park, Juyeon; Park, YongKeun; Kim, You-Me; Kim, Ji Hun; Kim, Joon
  作者单位：Korea Advanced Institute of Science & Technology (KAIST); Korea University; Korea University Medicine (KU Medicine); Korea Advanced Institute of Science & Technology (KAIST); Korea Advanced Institute of Science & Technology (KAIST)
  摘要：Microscopic examination of biopsy tissues remains essential for cancer diagnosis, despite advancements in sequencing technologies. Alterations in nuclear size or the nuclear- to- cytoplasmic ratio are hallmark features of cancer cells and often correlate with disease progression. However, the mechanisms underlying nuclear size abnormalities and their impact on tumor progression remain unclear. In this study, we demonstrate that nuclear hypertrophy occurs in response to enhanced DNA replication...
• Structure of a polymorphic repeat at the CACNA1C locus AI翻译
  作者：Moya, Raquel; Wang, Xiaohan; Tsien, Richard W.; Maurano, Matthew T.
  作者单位：New York University; New York University; New York University; New York University
  摘要：Genetic variation within intron 3 of the CACNA1C calcium channel gene is associated with schizophrenia and other neuropsychiatric disorders, but analysis of the causal variants and their effect is complicated by a nearby variable- number tandem repeat (VNTR). Here, we explored the structure and population variability of the CACNA1C intron 3 VNTR using 155 long- read genome assemblies from 78 diverse individuals. Based on sequence differences among repeat units, we clustered individual sequence...
• Tumor-expressed GPNMB orchestrates Siglec-9+TAM polarization and EMT to promote metastasis in triple-negative breast cancer AI翻译
  作者：Cao, Thuy Linh Dang; Kawanishi, Kunio; Hashimoto, Sachie; Hengphasatporn, Kowit; Nagai-Okatani, Chiaki; Kimura, Takaharu; Abdelaziz, Mohammed; Shiratani, Rie; Poullikkas, Thanasis; Azmi, Nuriza Ulul; Baba, Masaki; Okita, Yukari; Watanabe, Yukihide; Bando, Hiroko; Yamazaki, Satoshi; Shigeta, Yasuteru; Kuno, Atsushi; Kato, Mitsuyasu
  作者单位：University of Tsukuba; Showa Medical University; University of Tsukuba; University of Tsukuba; National Institute of Advanced Industrial Science & Technology (AIST); University of Tsukuba; University of Tokyo; Egyptian Knowledge Bank (EKB); Sohag University; University of Tsukuba; Juntendo University; University of Tsukuba
  摘要：Metastasis remains the leading cause of cancer-related mortality, driven by complex interactions within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a pivotal role in metastatic progression, yet their molecular diversity and upstream regulators remain poorly defined. Glycoprotein nonmetastatic melanoma protein B (GPNMB), overexpressed in subsets of tumors including triple-negative breast cancer (TNBC), is implicated in epithelial-mesenchymal transition (EMT) and c...