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

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• Manifold fitting reveals metabolomic heterogeneity and disease associations in UK Biobank populations AI翻译
  作者：Li, Bingjie; Lin, Runyu; Yau, Shing-Tung; Yao, Zhigang
  作者单位：National University of Singapore; Tsinghua University
  摘要：NMR-based metabolic biomarkers provide comprehensive insights into human metabolism; however, extracting biologically meaningful patterns from such highdimensional data remains a significant challenge. In this study, we propose a manifold-fitting-based framework to analyze metabolic heterogeneity within the UK participants. Initially, our method clusters these biomarkers into seven distinct metabolic categories that reflect the modular organization of human metabolism. Subsequent manifold fitt...
• Mechanisms of photoreceptor protection upon targeting the Nrl-Nr2e3 pathway AI翻译
  作者：Murphy, Daniel P.; V. Kolesnikov, Alexander; Montana, Cynthia L.; Khaja, Zaid M.; Liu, Yu; Kefalov, Vladimir J.; Corbo, Joseph C.
  作者单位：Washington University (WUSTL); University of California System; University of California Irvine; Washington University (WUSTL); Saint Louis University; University of California System; University of California Irvine
  摘要：Acute knockout of the rod photoreceptor transcription factor Nrl delays retinal degeneration in multiple mouse models of blindness, but the downstream transcriptomic changes that mediate these therapeutic effects are unknown. Here, we show that acute Nrl knockout causes upregulation of a subset of cone genes in rods as well as downregulation of rod genes, including the rod-specific transcriptional repressor Nr2e3. We hypothesized that Nr2e3 downregulation might mediate some of the therapeutic ...
• Reply to Liu et al.: Visualization of cerebral perivascular spaces following administration of intrathecal contrast AI翻译
  作者：Piantino, Juan
  作者单位：Oregon Health & Science University
• Pattern formation along signaling gradients driven by active droplet behavior of cell swarms AI翻译
  作者：Ford, Hugh Z.; Celora, Giulia L.; Westbrook, Elizabeth R.; Dalwadi, Mohit P.; Walker, Benjamin J.; Baumann, Hella; Weijer, Cornelis J.; Pearce, Philip; Chubb, Jonathan R.
  作者单位：University of London; University College London; University of London; University College London; University of London; University College London; University of Bath; University of Dundee
  摘要：Gradients of extracellular signals organize cells in tissues. Although there are several models for how gradients can pattern cell behavior, it is not clear how cells react to gradients when the population is undergoing 3D morphogenesis, in which cell-cell and cell-signal interactions are continually changing. Dictyostelium cells follow gradients of their nutritional source to feed and maintain their undifferentiated state. Using lightsheet imaging to simultaneously monitor signaling, single-c...
• Discovery of an LSD1 PROTAC degrader AI翻译
  作者：Hosseini, Amir; Qiu, Xing; Xiong, Yan; Chiang, Ki Him Nicholas; Catlett, Jerrel; Kaltheuner, Ines; Deng, Zhijie; Ghosh, Sudipta; Shi, Yang; Jin, Jian
  作者单位：Ludwig Institute for Cancer Research; University of Oxford; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai
  摘要：Aberrant expression of lysine-specific demethylase 1 (LSD1) has been implicated in various cancers, including acute myeloid leukemia (AML). Recent studies have revealed both catalytic and noncatalytic oncogenic functions of LSD1, which cannot be effectively addressed by traditional small-molecule inhibitors. Therefore, to remove LSD1 and mitigate its oncogenic activity, we utilized the proteolysis-targeting chimera (PROTAC) approach and developed an LSD1 PROTAC degrader MS9117, which recruits ...
• Synergistic regulation of metal-organic cage architectures via temperature- and solvent-driven atropisomerism AI翻译
  作者：Liang, Jiaqi; Peng, Li-Jun; Zhu, Ke-Lin; Li, Zhi-Ao; Chen, Xu-Lang; Yang, Yu-Dong; Li, Qian; Bi, Qian-Nan; Cui, Jie; Guan, Ai-Jiao; Liang, Tong-Ling; Hao, Xiang; Wang, Heng; Li, Xiaopeng; Gong, Han-Yuan
  作者单位：Beijing Normal University; Hubei Normal University; University of Texas System; University of Texas Austin; Shenzhen University; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Shanghai Institute of Organic Chemistry, CAS
  摘要：Regulating multistimulus responses in artificial systems remains a challenge in smart material development. We present a versatile chemical switching system that precisely controls the self-assembly of metal-organic cages via temperature and solvent changes. The key component, cyclo[2](1,3-(4,6-dimethyl)benzene) (4-pyridine)[6](1,3-(4,6-dimethyl)benzene) (CP2), was generated as three atropisomers (1, 2, and 3) with Cs, C1, and C2v symmetries. Thermally, metastable isomers (1 and 2) convert int...
• Cyclic peptide inhibitors function as molecular glues to stabilize Gq/ 11 heterotrimers AI翻译
  作者：Muhle, Jonas; Alenfelder, Judith; Rodrigues, Matthew J.; Juergenliemke, Lars; Guixa-Gonzalez, Ramon; Graetz, Lukas; Andres, Fabio; Bacchin, Arianna; Hennig, Michael; Schihada, Hannes; Cruesemann, Max; Koenig, Gabriele M.; Schertler, Gebhard; Kostenis, Evi; Deupi, Xavier
  作者单位：University of Bonn; University of Bonn; Swiss Institute of Bioinformatics; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Investigacion y Desarrollo Pascual Vila (CID-CSIC); CSIC - Instituto de Quimica Avanzada de Cataluna (IQAC); Philipps University Marburg; University of Bonn; Goethe University Frankfurt
  摘要：Heterotrimeric G alpha:Gfa gamma G proteins function as molecular switches downstream of G protein-coupled receptors (GPCRs). They alternate between a heterotrimeric GDP- bound OFF- state and a GTP- bound ON- state in which G alpha GTP is separated from the Gfa gamma dimer. Consequently, pharmacological tools to securely prevent the OFF- ON transition are of utmost importance to investigate their molecular switch function, specific contribution to GPCR signal transduction, and potential as dru...
• Unbiased mechanical cloaks AI翻译
  作者：Senhora, Fernando Vasconcelos; Sanders, Emily D.; Paulino, Glaucio H.
  作者单位：University System of Georgia; Georgia Institute of Technology; University System of Georgia; Georgia Institute of Technology; Princeton University; Princeton University
  摘要：The distinction between reinforcement and cloaking has been overlooked in optimization-based design of devices intended to conceal a defect in an elastic medium. In the former, a so-called cloak is severely biased toward one or a few specific elastic disturbances, whereas in the latter, an unbiased cloak is effective under any elastic disturbance. We propose a two-stage approach for optimization-based design of elastostatic cloaks that targets true, unbiased cloaks. First, we perform load-case...
• Activity and structure of human (d)CTP deaminase CDADC1 AI翻译
  作者：Slyvka, Anton; Rathore, Ishan; Yang, Renbin; Gewartowska, Olga; Kanai, Tapan; Lountos, George T.; Skowronek, Krzysztof; Czarnocki-Cieciura, Mariusz; Wlodawer, Alexander; Bochtler, Matthias
  作者单位：Miedzynarodowy Instytut Biologii Molekularnej i Komorkowej; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Miedzynarodowy Instytut Biologii Molekularnej i Komorkowej; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Miedzynarodowy Instytut Biologii Molekularnej i Komorkowej; Miedzynarodowy Instytut Biologii Molekularnej i Komorkowej; Polish Academy of Sciences; Institute of Biochemistry & Biophysics - Polish Academy of Sciences
  摘要：Vertebrates have evolved an understudied protein termed CDADC1 (NYD-SP15) that contains an inactive N-terminal and active C-terminal DCTD-like domain. Here, we show that human CDADC1 is a (d)CTP-specific deaminase, with a roughly 2-fold in vitro preference for dCTP over CTP. We determined high-resolution cryo-EM structures of CDADC1 in the absence of substrate and in complex with dCTP and 5-methyl-dCTP. The structures show that CDADC1 forms trimers and dimers of trimers in solution. The (d)CTP...
• Interferon- induced activation of dendritic cells and monocytes by yellow fever vaccination correlates with early antibody responses AI翻译
  作者：Winheim, Elena; Santos-Peral, Antonio; Ehm, Tamara; Rinke, Linus; Riemer, Sandra; Zaucha, Magdalena; Goresch, Sebastian; Lehmann, Lisa; Eisenaecher, Katharina; Pritsch, Michael; Barba-Spaeth, Giovanna; Straub, Tobias; Rothenfusser, Simon; Krug, Anne B.
  作者单位：University of Munich; University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Munich; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; University of Munich
  摘要：Yellow fever vaccination provides long- lasting protection and is a unique model for studying the immune response to an acute RNA virus infection in humans. To elucidate the early innate immune events preceding the rapid generation of protective immunity, we performed transcriptome analysis of human blood dendritic cell (DC) and monocyte subpopulations before and 3, 7, 14, and 28 d after vaccination. We detected temporary upregulation of IFN- stimulated genes (ISG) in all DC and monocyte subse...