Ankur Sharma, Justine Jia Wen Seow, Charles-Antoine Dutertre, Rhea Pai, Camille Blériot, Archita Mishra, Regina Men Men Wong, Gurmit Singh Naranjan Singh, Samydurai Sudhagar, Shabnam Khalilnezhad, Sergio Erdal, Hui Min Teo, Ahad Khalilnezhad, Svetoslav Chakarov, Tony Kiat Hon Lim, Alexander Chung Yaw Fui, Alfred Kow Wei Chieh, Cheow Peng Chung, Glenn Kunnath Bonney, Brian Goh Kim Poh, Jerry K Y Chan, Pierce K H Chow, Florent Ginhoux, Ramanuj DasGupta
We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of ∼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages...
September 24, 2020: Cell
Mirkko Flecken, Huping Wang, Leonhard Popilka, F Ulrich Hartl, Andreas Bracher, Manajit Hayer-Hartl
Rubisco, the key enzyme of CO2 fixation in photosynthesis, is prone to inactivation by inhibitory sugar phosphates. Inhibited Rubisco undergoes conformational repair by the hexameric AAA+ chaperone Rubisco activase (Rca) in a process that is not well understood. Here, we performed a structural and mechanistic analysis of cyanobacterial Rca, a close homolog of plant Rca. In the Rca:Rubisco complex, Rca is positioned over the Rubisco catalytic site under repair and pulls the N-terminal tail of the large Rubisco subunit (RbcL) into the hexamer pore...
September 23, 2020: Cell
Tom Misteli
Genomes have complex three-dimensional architectures. The recent convergence of genetic, biochemical, biophysical, and cell biological methods has uncovered several fundamental principles of genome organization. They highlight that genome function is a major driver of genome architecture and that structural features of chromatin act as modulators, rather than binary determinants, of genome activity. The interplay of these principles in the context of self-organization can account for the emergence of structural chromatin features, the diversity and single-cell heterogeneity of nuclear architecture in cell types and tissues, and explains evolutionarily conserved functional features of genomes, including plasticity and robustness...
September 20, 2020: Cell
Aleksandra S Chikina, Francesca Nadalin, Mathieu Maurin, Mabel San-Roman, Thibault Thomas-Bonafos, Xin V Li, Sonia Lameiras, Sylvain Baulande, Sandrine Henri, Bernard Malissen, Livia Lacerda Mariano, Jorge Barbazan, J Magarian Blander, Iliyan D Iliev, Danijela Matic Vignjevic, Ana-Maria Lennon-Duménil
The colon is primarily responsible for absorbing fluids. It contains a large number of microorganisms including fungi, which are enriched in its distal segment. The colonic mucosa must therefore tightly regulate fluid influx to control absorption of fungal metabolites, which can be toxic to epithelial cells and lead to barrier dysfunction. How this is achieved remains unknown. Here, we describe a mechanism by which the innate immune system allows rapid quality check of absorbed fluids to avoid intoxication of colonocytes...
September 17, 2020: Cell
Brian D Brown, Andrew M Leader, Jan Vilcek, Miriam Merad
The U.S. government has sought to restrict immigration under the "America First" doctrine. These policies severely harm American science by stripping it of talent and eliminating a major driver of its innovation engine. We urge scientists to work to reverse these policies and forcefully condemn anti-immigrant sentiments.
September 16, 2020: Cell
Anita Reddy, Luiz H M Bozi, Omar K Yaghi, Evanna L Mills, Haopeng Xiao, Hilary E Nicholson, Margherita Paschini, Joao A Paulo, Ryan Garrity, Dina Laznik-Bogoslavski, Julio C B Ferreira, Christian S Carl, Kim A Sjøberg, Jørgen F P Wojtaszewski, Jacob F Jeppesen, Bente Kiens, Steven P Gygi, Erik A Richter, Diane Mathis, Edward T Chouchani
In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release...
September 15, 2020: Cell
Helen C Barron, Hayley M Reeve, Renée S Koolschijn, Pavel V Perestenko, Anna Shpektor, Hamed Nili, Roman Rothaermel, Natalia Campo-Urriza, Jill X O'Reilly, David M Bannerman, Timothy E J Behrens, David Dupret
Every day we make decisions critical for adaptation and survival. We repeat actions with known consequences. But we also draw on loosely related events to infer and imagine the outcome of entirely novel choices. These inferential decisions are thought to engage a number of brain regions; however, the underlying neuronal computation remains unknown. Here, we use a multi-day cross-species approach in humans and mice to report the functional anatomy and neuronal computation underlying inferential decisions. We show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally structured learned associations...
September 15, 2020: Cell
Shuo Du, Yunlong Cao, Qinyu Zhu, Pin Yu, Feifei Qi, Guopeng Wang, Xiaoxia Du, Linlin Bao, Wei Deng, Hua Zhu, Jiangning Liu, Jianhui Nie, Yinghui Zheng, Haoyu Liang, Ruixue Liu, Shuran Gong, Hua Xu, Ayijiang Yisimayi, Qi Lv, Bo Wang, Runsheng He, Yunlin Han, Wenjie Zhao, Yali Bai, Yajin Qu, Xiang Gao, Chenggong Ji, Qisheng Wang, Ning Gao, Weijin Huang, Youchun Wang, X Sunney Xie, Xiao-Dong Su, Junyu Xiao, Chuan Qin
Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their "up" or "down" conformations...
September 14, 2020: Cell
Thomas Mandel Clausen, Daniel R Sandoval, Charlotte B Spliid, Jessica Pihl, Hailee R Perrett, Chelsea D Painter, Anoop Narayanan, Sydney A Majowicz, Elizabeth M Kwong, Rachael N McVicar, Bryan E Thacker, Charles A Glass, Zhang Yang, Jonathan L Torres, Gregory J Golden, Phillip L Bartels, Ryan N Porell, Aaron F Garretson, Logan Laubach, Jared Feldman, Xin Yin, Yuan Pu, Blake M Hauser, Timothy M Caradonna, Benjamin P Kellman, Cameron Martino, Philip L S M Gordts, Sumit K Chanda, Aaron G Schmidt, Kamil Godula, Sandra L Leibel, Joyce Jose, Kevin D Corbett, Andrew B Ward, Aaron F Carlin, Jeffrey D Esko
We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2...
September 14, 2020: Cell
Kevin R Parker, Denis Migliorini, Eric Perkey, Kathryn E Yost, Aparna Bhaduri, Puneet Bagga, Mohammad Haris, Neil E Wilson, Fang Liu, Khatuna Gabunia, John Scholler, Thomas J Montine, Vijay G Bhoj, Ravinder Reddy, Suyash Mohan, Ivan Maillard, Arnold R Kriegstein, Carl H June, Howard Y Chang, Avery D Posey, Ansuman T Satpathy
CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level...
September 11, 2020: Cell
Andrew G Manford, Fernando Rodríguez-Pérez, Karen Y Shih, Zhuo Shi, Charles A Berdan, Mangyu Choe, Denis V Titov, Daniel K Nomura, Michael Rape
Metazoan organisms rely on conserved stress response pathways to alleviate adverse conditions and preserve cellular integrity. Stress responses are particularly important in stem cells that provide lifetime support for tissue formation and repair, but how these protective systems are integrated into developmental programs is poorly understood. Here we used myoblast differentiation to identify the E3 ligase CUL2FEM1B and its substrate FNIP1 as core components of the reductive stress response. Reductive stress, as caused by prolonged antioxidant signaling or mitochondrial inactivity, reverts the oxidation of invariant Cys residues in FNIP1 and allows CUL2FEM1B to recognize its target...
September 10, 2020: Cell
Xiong Xiao, Hanfei Deng, Alessandro Furlan, Tao Yang, Xian Zhang, Ga-Ram Hwang, Jason Tucciarone, Priscilla Wu, Miao He, Ramesh Palaniswamy, Charu Ramakrishnan, Kimberly Ritola, Adam Hantman, Karl Deisseroth, Pavel Osten, Z Josh Huang, Bo Li
The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs...
September 10, 2020: Cell
Ruben A T Mars, Yi Yang, Tonya Ward, Mo Houtti, Sambhawa Priya, Heather R Lekatz, Xiaojia Tang, Zhifu Sun, Krishna R Kalari, Tal Korem, Yogesh Bhattarai, Tenghao Zheng, Noam Bar, Gary Frost, Abigail J Johnson, Will van Treuren, Shuo Han, Tamas Ordog, Madhusudan Grover, Justin Sonnenburg, Mauro D'Amato, Michael Camilleri, Eran Elinav, Eran Segal, Ran Blekhman, Gianrico Farrugia, Jonathan R Swann, Dan Knights, Purna C Kashyap
The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function...
September 10, 2020: Cell
Alexandra Serris, Robert Stass, Eduardo A Bignon, Nicolás A Muena, Jean-Claude Manuguerra, Rohit K Jangra, Sai Li, Kartik Chandran, Nicole D Tischler, Juha T Huiskonen, Felix A Rey, Pablo Guardado-Calvo
Hantaviruses are rodent-borne viruses causing serious zoonotic outbreaks worldwide for which no treatment is available. Hantavirus particles are pleomorphic and display a characteristic square surface lattice. The envelope glycoproteins Gn and Gc form heterodimers that further assemble into tetrameric spikes, the lattice building blocks. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Here we describe the high-resolution X-ray structures of the heterodimer of Gc and the Gn head and of the homotetrameric Gn base...
September 9, 2020: Cell
José A Nicolás-Ávila, Ana V Lechuga-Vieco, Lorena Esteban-Martínez, María Sánchez-Díaz, Elena Díaz-García, Demetrio J Santiago, Andrea Rubio-Ponce, Jackson LiangYao Li, Akhila Balachander, Juan A Quintana, Raquel Martínez-de-Mena, Beatriz Castejón-Vega, Andrés Pun-García, Paqui G Través, Elena Bonzón-Kulichenko, Fernando García-Marqués, Lorena Cussó, Noelia A-González, Andrés González-Guerra, Marta Roche-Molina, Sandra Martin-Salamanca, Georgiana Crainiciuc, Gabriela Guzmán, Jagoba Larrazabal, Elías Herrero-Galán, Jorge Alegre-Cebollada, Greg Lemke, Carla V Rothlin, Luis Jesús Jimenez-Borreguero, Guillermo Reyes, Antonio Castrillo, Manuel Desco, Pura Muñoz-Cánoves, Borja Ibáñez, Miguel Torres, Lai Guan Ng, Silvia G Priori, Héctor Bueno, Jesús Vázquez, Mario D Cordero, Juan A Bernal, José A Enríquez, Andrés Hidalgo
Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress...
September 9, 2020: Cell
Mònica Santiveri, Aritz Roa-Eguiara, Caroline Kühne, Navish Wadhwa, Haidai Hu, Howard C Berg, Marc Erhardt, Nicholas M I Taylor
Many bacteria use the flagellum for locomotion and chemotaxis. Its bidirectional rotation is driven by a membrane-embedded motor, which uses energy from the transmembrane ion gradient to generate torque at the interface between stator units and rotor. The structural organization of the stator unit (MotAB), its conformational changes upon ion transport, and how these changes power rotation of the flagellum remain unknown. Here, we present ~3 Å-resolution cryoelectron microscopy reconstructions of the stator unit in different functional states...
September 7, 2020: Cell
Hangping Yao, Yutong Song, Yong Chen, Nanping Wu, Jialu Xu, Chujie Sun, Jiaxing Zhang, Tianhao Weng, Zheyuan Zhang, Zhigang Wu, Linfang Cheng, Danrong Shi, Xiangyun Lu, Jianlin Lei, Max Crispin, Yigong Shi, Lanjuan Li, Sai Li
SARS-CoV-2 is an enveloped virus responsible for the COVID-19 pandemic. Despite recent advances in the structural elucidation of SARS-CoV-2 proteins, the detailed architecture of the intact virus remains to be unveiled. Here we report the molecular assembly of the authentic SARS-CoV-2 virus using cryoelectron tomography (cryo-ET) and subtomogram averaging (STA). Native structures of the S proteins in pre- and postfusion conformations were determined to average resolutions of 8.7-11 Å. Compositions of the N-linked glycans from the native spikes were analyzed by mass spectrometry, which revealed overall processing states of the native glycans highly similar to that of the recombinant glycoprotein glycans...
September 6, 2020: Cell
Camila Rosat Consiglio, Nicola Cotugno, Fabian Sardh, Christian Pou, Donato Amodio, Lucie Rodriguez, Ziyang Tan, Sonia Zicari, Alessandra Ruggiero, Giuseppe Rubens Pascucci, Veronica Santilli, Tessa Campbell, Yenan Bryceson, Daniel Eriksson, Jun Wang, Alessandra Marchesi, Tadepally Lakshmikanth, Andrea Campana, Alberto Villani, Paolo Rossi, Nils Landegren, Paolo Palma, Petter Brodin
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C...
September 6, 2020: Cell
Qiyi Zhao, Jiayu Liu, Hong Deng, Ruiying Ma, Jian-You Liao, Huixin Liang, Jingxiong Hu, Jiaqian Li, Zhiyong Guo, Junchao Cai, Xiaoding Xu, Zhiliang Gao, Shicheng Su
Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation...
September 5, 2020: Cell
Lihua Jiang, Meng Wang, Shin Lin, Ruiqi Jian, Xiao Li, Joanne Chan, Guanlan Dong, Huaying Fang, Aaron E Robinson, Michael P Snyder
Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from over 12,000 genes across 32 normal human tissues. Tissue-specific or tissue-enriched proteins were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode tissue-specific proteins. Discordance of RNA and protein enrichment revealed potential sites of synthesis and action of secreted proteins...
September 5, 2020: Cell
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