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Kimberly M Cirelli, Diane G Carnathan, Bartek Nogal, Jacob T Martin, Oscar L Rodriguez, Amit A Upadhyay, Chiamaka A Enemuo, Etse H Gebru, Yury Choe, Federico Viviano, Catherine Nakao, Matthias G Pauthner, Samantha Reiss, Christopher A Cottrell, Melissa L Smith, Raiza Bastidas, William Gibson, Amber N Wolabaugh, Mariane B Melo, Benjamin Cossette, Venkatesh Kumar, Nirav B Patel, Talar Tokatlian, Sergey Menis, Daniel W Kulp, Dennis R Burton, Ben Murrell, William R Schief, Steven E Bosinger, Andrew B Ward, Corey T Watson, Guido Silvestri, Darrell J Irvine, Shane Crotty
Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (TFH ) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates...
May 9, 2019: Cell
Jason H Yang, Sarah N Wright, Meagan Hamblin, Douglas McCloskey, Miguel A Alcantar, Lars Schrübbers, Allison J Lopatkin, Sangeeta Satish, Amir Nili, Bernhard O Palsson, Graham C Walker, James J Collins
Current machine learning techniques enable robust association of biological signals with measured phenotypes, but these approaches are incapable of identifying causal relationships. Here, we develop an integrated "white-box" biochemical screening, network modeling, and machine learning approach for revealing causal mechanisms and apply this approach to understanding antibiotic efficacy. We counter-screen diverse metabolites against bactericidal antibiotics in Escherichia coli and simulate their corresponding metabolic states using a genome-scale metabolic network model...
May 7, 2019: Cell
Shayan Shamipour, Roland Kardos, Shi-Lei Xue, Björn Hof, Edouard Hannezo, Carl-Philipp Heisenberg
Segregation of maternal determinants within the oocyte constitutes the first step in embryo patterning. In zebrafish oocytes, extensive ooplasmic streaming leads to the segregation of ooplasm from yolk granules along the animal-vegetal axis of the oocyte. Here, we show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the oocyte. This wave functions in segregation by both pulling ooplasm animally and pushing yolk granules vegetally...
May 7, 2019: Cell
Masatoshi Inoue, Atsuya Takeuchi, Satoshi Manita, Shin-Ichiro Horigane, Masayuki Sakamoto, Ryosuke Kawakami, Kazushi Yamaguchi, Kouhei Otomo, Hiroyuki Yokoyama, Ryang Kim, Tatsushi Yokoyama, Sayaka Takemoto-Kimura, Manabu Abe, Michiko Okamura, Yayoi Kondo, Sean Quirin, Charu Ramakrishnan, Takeshi Imamura, Kenji Sakimura, Tomomi Nemoto, Masanobu Kano, Hajime Fujii, Karl Deisseroth, Kazuo Kitamura, Haruhiko Bito
To decipher dynamic brain information processing, current genetically encoded calcium indicators (GECIs) are limited in single action potential (AP) detection speed, combinatorial spectral compatibility, and two-photon imaging depth. To address this, here, we rationally engineered a next-generation quadricolor GECI suite, XCaMPs. Single AP detection was achieved within 3-10 ms of spike onset, enabling measurements of fast-spike trains in parvalbumin (PV)-positive interneurons in the barrel cortex in vivo and recording three distinct (two inhibitory and one excitatory) ensembles during pre-motion activity in freely moving mice...
May 6, 2019: Cell
Katherine Basore, Arthur S Kim, Christopher A Nelson, Rong Zhang, Brittany K Smith, Carla Uranga, Lo Vang, Ming Cheng, Michael L Gross, Jonathan Smith, Michael S Diamond, Daved H Fremont
Mxra8 is a receptor for multiple arthritogenic alphaviruses that cause debilitating acute and chronic musculoskeletal disease in humans. Herein, we present a 2.2 Å resolution X-ray crystal structure of Mxra8 and 4 to 5 Å resolution cryo-electron microscopy reconstructions of Mxra8 bound to chikungunya (CHIKV) virus-like particles and infectious virus. The Mxra8 ectodomain contains two strand-swapped Ig-like domains oriented in a unique disulfide-linked head-to-head arrangement. Mxra8 binds by wedging into a cleft created by two adjacent CHIKV E2-E1 heterodimers in one trimeric spike and engaging a neighboring spike...
May 6, 2019: Cell
Ryoma Hattori, Bethanny Danskin, Zeljana Babic, Nicole Mlynaryk, Takaki Komiyama
Decision making is often driven by the subjective value of available options, a value which is formed through experience. To support this fundamental behavior, the brain must encode and maintain the subjective value. To investigate the area specificity and plasticity of value coding, we trained mice in a value-based decision task and imaged neural activity in 6 cortical areas with cellular resolution. History- and value-related signals were widespread across areas, but their strength and temporal patterns differed...
April 30, 2019: Cell
Jae Yeon Hwang, Nadja Mannowetz, Yongdeng Zhang, Robert A Everley, Steven P Gygi, Joerg Bewersdorf, Polina V Lishko, Jean-Ju Chung
Varying pH of luminal fluid along the female reproductive tract is a physiological cue that modulates sperm motility. CatSper is a sperm-specific, pH-sensitive calcium channel essential for hyperactivated motility and male fertility. Multi-subunit CatSper channel complexes organize linear Ca2+ signaling nanodomains along the sperm tail. Here, we identify EF-hand calcium-binding domain-containing protein 9 (EFCAB9) as a bifunctional, cytoplasmic machine modulating the channel activity and the domain organization of CatSper...
April 30, 2019: Cell
Carolyn R Shurer, Joe Chin-Hun Kuo, LaDeidra Monét Roberts, Jay G Gandhi, Marshall J Colville, Thais A Enoki, Hao Pan, Jin Su, Jade M Noble, Michael J Hollander, John P O'Donnell, Rose Yin, Kayvon Pedram, Leonhard Möckl, Lena F Kourkoutis, W E Moerner, Carolyn R Bertozzi, Gerald W Feigenson, Heidi L Reesink, Matthew J Paszek
Cells bend their plasma membranes into highly curved forms to interact with the local environment, but how shape generation is regulated is not fully resolved. Here, we report a synergy between shape-generating processes in the cell interior and the external organization and composition of the cell-surface glycocalyx. Mucin biopolymers and long-chain polysaccharides within the glycocalyx can generate entropic forces that favor or disfavor the projection of spherical and finger-like extensions from the cell surface...
April 30, 2019: Cell
Xiangyu Liu, Xinyu Xu, Daniel Hilger, Philipp Aschauer, Johanna K S Tiemann, Yang Du, Hongtao Liu, Kunio Hirata, Xiaoou Sun, Ramon Guixà-González, Jesper M Mathiesen, Peter W Hildebrand, Brian K Kobilka
The crystal structure of the β2-adrenergic receptor (β2AR) bound to the G protein adenylyl cyclase stimulatory G protein (Gs) captured the complex in a nucleotide-free state (β2AR-Gsempty ). Unfortunately, the β2AR-Gsempty complex does not provide a clear explanation for G protein coupling specificity. Evidence from several sources suggests the existence of a transient complex between the β2AR and GDP-bound Gs protein (β2AR-GsGDP ) that may represent an intermediate on the way to the formation of β2AR-Gsempty and may contribute to coupling specificity...
April 28, 2019: Cell
Yang Du, Nguyen Minh Duc, Søren G F Rasmussen, Daniel Hilger, Xavier Kubiak, Liwen Wang, Jennifer Bohon, Hee Ryung Kim, Marcin Wegrecki, Awuri Asuru, Kyung Min Jeong, Jeongmi Lee, Mark R Chance, David T Lodowski, Brian K Kobilka, Ka Young Chung
The activation of G proteins by G protein-coupled receptors (GPCRs) underlies the majority of transmembrane signaling by hormones and neurotransmitters. Recent structures of GPCR-G protein complexes obtained by crystallography and cryoelectron microscopy (cryo-EM) reveal similar interactions between GPCRs and the alpha subunit of different G protein isoforms. While some G protein subtype-specific differences are observed, there is no clear structural explanation for G protein subtype-selectivity. All of these complexes are stabilized in the nucleotide-free state, a condition that does not exist in living cells...
April 28, 2019: Cell
Hao Song, Zhennan Zhao, Yan Chai, Xiyue Jin, Changyao Li, Fei Yuan, Sheng Liu, Zhengrong Gao, Haiyuan Wang, Jian Song, Leonardo Vazquez, Yanfang Zhang, Shuguang Tan, Carlos M Morel, Jinghua Yan, Yi Shi, Jianxun Qi, Feng Gao, George F Gao
Arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), cause severe and debilitating rheumatic diseases worldwide, resulting in severe morbidity and economic costs. Recently, MXRA8 was reported as an entry receptor. Here, we present the crystal structures of the mouse MXRA8, human MXRA8 in complex with the CHIKV E protein, and the cryo-electron microscopy structure of human MXRA8 and CHIKV virus-like particle. MXRA8 has two Ig-like domains with unique structural topologies. This receptor binds in the "canyon" between two protomers of the E spike on the surface of the virion...
April 26, 2019: Cell
Ishraq Alim, Joseph T Caulfield, Yingxin Chen, Vivek Swarup, Daniel H Geschwind, Elena Ivanova, Javier Seravalli, Youxi Ai, Lauren H Sansing, Emma J Ste Marie, Robert J Hondal, Sushmita Mukherjee, John W Cave, Botir T Sagdullaev, Saravanan S Karuppagounder, Rajiv R Ratan
Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons...
April 26, 2019: Cell
Antoine Fages, Kristian Hanghøj, Naveed Khan, Charleen Gaunitz, Andaine Seguin-Orlando, Michela Leonardi, Christian McCrory Constantz, Cristina Gamba, Khaled A S Al-Rasheid, Silvia Albizuri, Ahmed H Alfarhan, Morten Allentoft, Saleh Alquraishi, David Anthony, Nurbol Baimukhanov, James H Barrett, Jamsranjav Bayarsaikhan, Norbert Benecke, Eloísa Bernáldez-Sánchez, Luis Berrocal-Rangel, Fereidoun Biglari, Sanne Boessenkool, Bazartseren Boldgiv, Gottfried Brem, Dorcas Brown, Joachim Burger, Eric Crubézy, Linas Daugnora, Hossein Davoudi, Peter de Barros Damgaard, María de Los Ángeles de Chorro Y de Villa-Ceballos, Sabine Deschler-Erb, Cleia Detry, Nadine Dill, Maria do Mar Oom, Anna Dohr, Sturla Ellingvåg, Diimaajav Erdenebaatar, Homa Fathi, Sabine Felkel, Carlos Fernández-Rodríguez, Esteban García-Viñas, Mietje Germonpré, José D Granado, Jón H Hallsson, Helmut Hemmer, Michael Hofreiter, Aleksei Kasparov, Mutalib Khasanov, Roya Khazaeli, Pavel Kosintsev, Kristian Kristiansen, Tabaldiev Kubatbek, Lukas Kuderna, Pavel Kuznetsov, Haeedeh Laleh, Jennifer A Leonard, Johanna Lhuillier, Corina Liesau von Lettow-Vorbeck, Andrey Logvin, Lembi Lõugas, Arne Ludwig, Cristina Luis, Ana Margarida Arruda, Tomas Marques-Bonet, Raquel Matoso Silva, Victor Merz, Enkhbayar Mijiddorj, Bryan K Miller, Oleg Mochlov, Fatemeh A Mohaseb, Arturo Morales, Ariadna Nieto-Espinet, Heidi Nistelberger, Vedat Onar, Albína H Pálsdóttir, Vladimir Pitulko, Konstantin Pitskhelauri, Mélanie Pruvost, Petra Rajic Sikanjic, Anita Rapan Papeša, Natalia Roslyakova, Alireza Sardari, Eberhard Sauer, Renate Schafberg, Amelie Scheu, Jörg Schibler, Angela Schlumbaum, Nathalie Serrand, Aitor Serres-Armero, Beth Shapiro, Shiva Sheikhi Seno, Irina Shevnina, Sonia Shidrang, John Southon, Bastiaan Star, Naomi Sykes, Kamal Taheri, William Taylor, Wolf-Rüdiger Teegen, Tajana Trbojević Vukičević, Simon Trixl, Dashzeveg Tumen, Sainbileg Undrakhbold, Emma Usmanova, Ali Vahdati, Silvia Valenzuela-Lamas, Catarina Viegas, Barbara Wallner, Jaco Weinstock, Victor Zaibert, Benoit Clavel, Sébastien Lepetz, Marjan Mashkour, Agnar Helgason, Kári Stefánsson, Eric Barrey, Eske Willerslev, Alan K Outram, Pablo Librado, Ludovic Orlando
Horse domestication revolutionized warfare and accelerated travel, trade, and the geographic expansion of languages. Here, we present the largest DNA time series for a non-human organism to date, including genome-scale data from 149 ancient animals and 129 ancient genomes (≥1-fold coverage), 87 of which are new. This extensive dataset allows us to assess the modern legacy of past equestrian civilizations. We find that two extinct horse lineages existed during early domestication, one at the far western (Iberia) and the other at the far eastern range (Siberia) of Eurasia...
April 26, 2019: Cell
Suhas Vasaikar, Chen Huang, Xiaojing Wang, Vladislav A Petyuk, Sara R Savage, Bo Wen, Yongchao Dou, Yun Zhang, Zhiao Shi, Osama A Arshad, Marina A Gritsenko, Lisa J Zimmerman, Jason E McDermott, Therese R Clauss, Ronald J Moore, Rui Zhao, Matthew E Monroe, Yi-Ting Wang, Matthew C Chambers, Robbert J C Slebos, Ken S Lau, Qianxing Mo, Li Ding, Matthew Ellis, Mathangi Thiagarajan, Christopher R Kinsinger, Henry Rodriguez, Richard D Smith, Karin D Rodland, Daniel C Liebler, Tao Liu, Bing Zhang
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings...
April 25, 2019: Cell
Tslil Ast, Joshua D Meisel, Shachin Patra, Hong Wang, Robert M H Grange, Sharon H Kim, Sarah E Calvo, Lauren L Orefice, Fumiaki Nagashima, Fumito Ichinose, Warren M Zapol, Gary Ruvkun, David P Barondeau, Vamsi K Mootha
Friedreich's ataxia (FRDA) is a devastating, multisystemic disorder caused by recessive mutations in the mitochondrial protein frataxin (FXN). FXN participates in the biosynthesis of Fe-S clusters and is considered to be essential for viability. Here we report that when grown in 1% ambient O2 , FXN null yeast, human cells, and nematodes are fully viable. In human cells, hypoxia restores steady-state levels of Fe-S clusters and normalizes ATF4, NRF2, and IRP2 signaling events associated with FRDA. Cellular studies and in vitro reconstitution indicate that hypoxia acts through HIF-independent mechanisms that increase bioavailable iron as well as directly activate Fe-S synthesis...
April 23, 2019: Cell
Yan Wang, Nam X Nguyen, Ji She, Weizhong Zeng, Yi Yang, Xiao-Chen Bai, Youxing Jiang
Mitochondrial calcium uptake is crucial to the regulation of eukaryotic Ca2+ homeostasis and is mediated by the mitochondrial calcium uniporter (MCU). While MCU alone can transport Ca2+ in primitive eukaryotes, metazoans require an essential single membrane-spanning auxiliary component called EMRE to form functional channels; however, the molecular mechanism of EMRE regulation remains elusive. Here, we present the cryo-EM structure of the human MCU-EMRE complex, which defines the interactions between MCU and EMRE as well as pinpoints the juxtamembrane loop of MCU and extended linker of EMRE as the crucial elements in the EMRE-dependent gating mechanism among metazoan MCUs...
April 22, 2019: Cell
Yuxuan Miao, Hanseul Yang, John Levorse, Shaopeng Yuan, Lisa Polak, Megan Sribour, Bhuvanesh Singh, Michael Rosenblum, Elaine Fuchs
Our bodies are equipped with powerful immune surveillance to clear cancerous cells as they emerge. How tumor-initiating stem cells (tSCs) that form and propagate cancers equip themselves to overcome this barrier remains poorly understood. To tackle this problem, we designed a skin cancer model for squamous cell carcinoma (SCC) that can be effectively challenged by adoptive cytotoxic T cell transfer (ACT)-based immunotherapy. Using single-cell RNA sequencing (RNA-seq) and lineage tracing, we found that transforming growth factor β (TGF-β)-responding tSCs are superior at resisting ACT and form the root of tumor relapse...
April 22, 2019: Cell
Zhe Zhang, Peng Zhong, Fei Hu, Zeke Barger, Yulan Ren, Xinlu Ding, Shangzhong Li, Franz Weber, Shinjae Chung, Richard D Palmiter, Yang Dan
The perioculomotor (pIII) region of the midbrain was postulated as a sleep-regulating center in the 1890s but largely neglected in subsequent studies. Using activity-dependent labeling and gene expression profiling, we identified pIII neurons that promote non-rapid eye movement (NREM) sleep. Optrode recording showed that pIII glutamatergic neurons expressing calcitonin gene-related peptide alpha (CALCA) are NREM-sleep active; optogenetic and chemogenetic activation/inactivation showed that they strongly promote NREM sleep...
April 22, 2019: Cell
Chuan Yan, Dalton C Brunson, Qin Tang, Daniel Do, Nicolae A Iftimia, John C Moore, Madeline N Hayes, Alessandra M Welker, Elaine G Garcia, Taronish D Dubash, Xin Hong, Benjamin J Drapkin, David T Myers, Sarah Phat, Angela Volorio, Dieuwke L Marvin, Matteo Ligorio, Lyle Dershowitz, Karin M McCarthy, Murat N Karabacak, Jonathan A Fletcher, Dennis C Sgroi, John A Iafrate, Shyamala Maheswaran, Nick J Dyson, Daniel A Haber, John F Rawls, David M Langenau
Xenograft cell transplantation into immunodeficient mice has become the gold standard for assessing pre-clinical efficacy of cancer drugs, yet direct visualization of single-cell phenotypes is difficult. Here, we report an optically-clear prkdc-/- , il2rga-/- zebrafish that lacks adaptive and natural killer immune cells, can engraft a wide array of human cancers at 37°C, and permits the dynamic visualization of single engrafted cells. For example, photoconversion cell-lineage tracing identified migratory and proliferative cell states in human rhabdomyosarcoma, a pediatric cancer of muscle...
April 22, 2019: Cell
Natalie Romanov, Michael Kuhn, Ruedi Aebersold, Alessandro Ori, Martin Beck, Peer Bork
Proteotypes, like genotypes, have been found to vary between individuals in several studies, but consistent molecular functional traits across studies remain to be quantified. In a meta-analysis of 11 proteomics datasets from humans and mice, we use co-variation of proteins in known functional modules across datasets and individuals to obtain a consensus landscape of proteotype variation. We find that individuals differ considerably in both protein complex abundances and stoichiometry. We disentangle genetic and environmental factors impacting these metrics, with genetic sex and specific diets together explaining 13...
April 19, 2019: Cell
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