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

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• A bacteria-based search for drugs against avian and swine flu yields a potent and resistance-resilient channel blocker AI翻译
  作者：Lahiri, Hiya; Israeli, Eitan; Krugliak, Miriam; Basu, Kingshuk; Britan-Rosich, Yelena; Yaish, Tamar Ravins; Arkin, Isaiah T.
  作者单位：Hebrew University of Jerusalem; Hebrew University of Jerusalem; Hebrew University of Jerusalem; City University of Hong Kong; City University of Hong Kong
  摘要：Influenza represents a significant threat with seasonal epidemics that can transition to global pandemics, and cross-species infection presenting a continuous challenge. While vaccines and several antiviral drugs are available, constant genetic changes vitiate these prevention and treatment options. Consequently, we decided to search for inhibitors against one of the virus's validated drug targets, its M2 channel that is blocked by aminoadamantanes. Regrettably, widespread mutations in M2 abol...
• In situ cryo- ET visualization of mitochondrial depolarization and mitophagic engulfment AI翻译
  作者：Rose, Kevin; Herrmann, Eric; Kakudji, Eve; Lizarrondo, Javier; Celebi, A. Yasemin; Wilfling, Florian; Lewis, Samantha C.; Hurley, James H.
  作者单位：University of California System; University of California Berkeley; University of California System; University of California Berkeley; Max Planck Society; University of California System; University of California Berkeley
  摘要：Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN. Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like ...
• Micro magnetic resonance spectroscopy for noninvasive metabolic screening of mammalian embryos and oocytes AI翻译
  作者：Sivelli, Giulia; Barakat, Arthur; Marable, Kathryn B.; Gruet, Guillaume; Bitetti, Serena L.; Behr, Barry; Lodde, Valentina; Luciano, Alberto Maria; Herrera, Carolina; Blom, Michelle; Grisi, Marco
  作者单位：Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Stanford University; Stanford University; University of Milan; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV)
  摘要：Analyzing cellular health and metabolism without compromising cell integrity is a major challenge. We present a noninvasive technique using micro magnetic resonance spectroscopy (micro MRS) for nondestructive metabolic fingerprinting at the single-cell scale. This is an application of micro MRS to bovine preimplantation embryos (similar to 8 cells) and oocytes (single cell), with measurements performed on a total of over 150 samples. Among various applications, this method holds significant po...
• Combining MicroED and native mass spectrometry for structural discovery of enzyme-small molecule complexes AI翻译
  作者：Vlahakis, Niko W.; Flowers, Cameron W.; Liu, Mengting; Agdanowski, Matthew P.; Johnson, Samuel; Summers, Jacob A.; Jacobs, Lian M. C.; Keyser, Catherine; Russell, Phoebe; Rose, Samuel L.; Orlans, Julien; Adhami, Nima; Chen, Yu; Sawaya, Michael R.; Basu, Shibom; de Sanctis, Daniele; Chen, Yu; Wakatsuki, Soichi; Nelson, Hosea M.; Loo, Joseph A.; Tang, Yi; Rodriguez, Jose A.
  作者单位：University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; National Science Foundation (NSF); NSF - Science and Technology Centers (STCs); University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; California Institute of Technology; Stanford University; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; State University System of Florida; University of South Florida; European Molecular Biology Laboratory (EMBL)
  摘要：With the goal of accelerating the discovery of small molecule-protein complexes, we leverage fast, low-dose, event-based electron counting microcrystal electron diffraction (MicroED) data collection and native mass spectrometry. This approach, which we term electron diffraction with native mass spectrometry (ED-MS), allows assignment of protein target structures bound to ligands with data obtained from crystal slurries soaked with mixtures of known inhibitors and crude biosynthetic reactions. ...
• Mesozoic atmospheric CO2 concentrations reconstructed from dinosaur tooth enamel AI翻译
  作者：Feng, Dingsu; Tuetken, Thomas; Griebeler, Eva Maria; Herwartz, Daniel; Pack, Andreas
  作者单位：University of Gottingen; Ruhr University Bochum; Johannes Gutenberg University of Mainz; Johannes Gutenberg University of Mainz
  摘要：Air-breathing vertebrates incorporate a fraction of isotopically anomalous air O2 in their body water. The 17O isotope anomaly of air O2 (expressed as 0'17Oair) is related to atmospheric CO2 concentrations (pCO2) and gross primary production (GPP). Tooth enamel records the 0'17O of body water and can thus preserve such paleo-pCO2 or paleo-GPP information over geological time periods. Here, we demonstrate the potential of respective reconstructions of atmosphericpCO2 or GPP from the triple oxyg...
• Nucleation at solid-liquid interfaces is accompanied by the reconfiguration of electrical double layers AI翻译
  作者：Ai, Qian; Bonagiri, Lalith Krishna Samanth; Panse, Kaustubh S.; Kim, Jaehyeon; Zhou, Shan; Zhang, Yingjie; Cui, Yi
  作者单位：University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Urbana-Champaign
  摘要：In electrochemical systems, the structure of electrical double layers (EDLs) near electrode surfaces is crucial for energy conversion and storage functions. While the electrodes in real-world systems are usually heterogeneous, to date the investigation of EDLs is mainly limited to planar, homogeneous substrates. To bridge this gap, here we image the EDL structure of an ionic liquid/graphite battery anode system in the initial stage of interfacial nucleation and growth using our recently develo...
• eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer AI翻译
  作者：Boyer, Jacob A.; Rosen, Ezra Y.; Sharma, Malvika; Dorso, Madeline A.; Mai, Nicholas; Amor, Corina; Reiter, Jason M.; Kannan, Ram; Gadal, Sunyana; Xu, Jianing; Miele, Matthew; Li, Zhuoning; Chen, Xiaoping; Chang, Qing; Pareja, Fresia; Worland, Stephan; Warner, Douglas; Sperry, Sam; Chiang, Gary G.; Thompson, Peggy A.; Yang, Guangli; Ouerfelli, Ouathek; Drilon, Alexander; de Stanchina, Elisa; Wendel, Hans- Guido; Chandarlapaty, Sarat; Rosen, Neal
  作者单位：Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Ludwig Institute for Cancer Research; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine
  摘要：Most breast cancers depend on hormone-stimulated estrogen receptor alpha (ER) activity and are sensitive to ER inhibition. Resistance can arise from activating mutations in the gene encoding ER (ESR1) or from reactivation of downstream targets. Newer ER antagonists occasionally show efficacy but are largely ineffective as single agents in the long term. Here, we show that ER translation is eIF4E/cap-independent yet sensitive to inhibitors of the translation initiation factor eIF4A. EIF4A inhib...
• Training and retraining liquid crystal elastomer metamaterials for pluripotent functionality AI翻译
  作者：Gowen, Savannah D.; Ghimire, Elina; Lindberg, Charlie A.; Appen, Ingrid S.; Rowan, Stuart J.; Nagel, Sidney R.
  作者单位：University of Chicago; University of Chicago; University of Chicago; University of Chicago
  摘要：Training has emerged as a promising materials design technique in which function can be achieved through repeated physical modification of an existing material rather than by direct chemical functionalization, cutting, or reprocessing. This work investigates both the ability to train for function and then to erase that function on-demand in macroscopic metamaterials made from liquid crystal elastomers. We first show that the Poisson's ratio of these disordered arrays can be tuned via directed ...
• Neutron and time- resolved X- ray crystallography reveal the substrate recognition and catalytic mechanism of human Nudix hydrolase MTH1 AI翻译
  作者：Hirata, Keisuke; Fujimiya, Kana; Ostermann, Andreas; Schrader, Tobias E.; Hiromoto, Takeshi; Goto, Masataka; Arimori, Takao; Hirano, Yu; Kusaka, Katsuhiro; Tamada, Taro; Nakamura, Teruya
  作者单位：Kumamoto University; Kumamoto University; Technical University of Munich; Helmholtz Association; Research Center Julich; National Institutes for Quantum Science & Technology; University of Osaka; Chiba University; Comprehensive Research Organisation for Science & Society
  摘要：Human MTH1, a Nudix enzyme, hydrolyzes several oxidized nucleotides such as 8-oxo-dGTP and 2-oxo-dATP, owing to its broad substrate specificity. MTH1 has also attracted attention as an anticancer target, and its substrate recognition is of biological and medical interest. Previous studies have suggested that MTH1 exhibits broad substrate specificity by changing the protonation states of Asp119 and Asp120 with high pKa. However, the recognition mechanism remains unclear, owing to the difficulty...
• Diverse and dynamic influences of saccades on visual representations in the mouse superior colliculus AI翻译
  作者：Hunt, Joshua B.; Buteau, Anna; Barreto, Joe; Hanson, Spencer; Scholl, Benjamin; Poleg-Polsky, Alon; Felsen, Gidon
  作者单位：University of Colorado System; University of Colorado Anschutz Medical Campus; University of Colorado System; University of Colorado Anschutz Medical Campus
  摘要：How do sensory systems account for stimuli generated by natural behavior? We addressed this question by examining how an ethologically relevant class of saccades modulates visual representations in the mouse superior colliculus (SC), a key region for sensorimotor integration. Leveraging the conserved natural tendency to make saccades that reset the eye-head angle to a default position via the optokinetic reflex, we developed an efficient and unbiased white noise approach to study the modulatio...