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Toufic Mayassi, Kristin Ladell, Herman Gudjonson, James E McLaren, Dustin G Shaw, Mai T Tran, Jagoda J Rokicka, Ian Lawrence, Jean-Christophe Grenier, Vincent van Unen, Cezary Ciszewski, Matthew Dimaano, Hoda E Sayegh, Vinod Kumar, Cisca Wijmenga, Peter H R Green, Ranjana Gokhale, Hilary Jericho, Carol E Semrad, Stefano Guandalini, Aaron R Dinner, Sonia S Kupfer, Hugh H Reid, Luis B Barreiro, Jamie Rossjohn, David A Price, Bana Jabri
Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+ /Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+ /Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8...
February 5, 2019: Cell
Javier Gallego-Bartolomé, Wanlu Liu, Peggy Hsuanyu Kuo, Suhua Feng, Basudev Ghoshal, Jason Gardiner, Jenny Miao-Chi Zhao, Soo Young Park, Joanne Chory, Steven E Jacobsen
The RNA-directed DNA methylation (RdDM) pathway in plants controls gene expression via cytosine DNA methylation. The ability to manipulate RdDM would shed light on the mechanisms and applications of DNA methylation to control gene expression. Here, we identified diverse RdDM proteins that are capable of targeting methylation and silencing in Arabidopsis when tethered to an artificial zinc finger (ZF-RdDM). We studied their order of action within the RdDM pathway by testing their ability to target methylation in different mutants...
January 31, 2019: Cell
Gabriel E Neurohr, Rachel L Terry, Jette Lengefeld, Megan Bonney, Gregory P Brittingham, Fabien Moretto, Teemu P Miettinen, Laura Pontano Vaites, Luis M Soares, Joao A Paulo, J Wade Harper, Stephen Buratowski, Scott Manalis, Folkert J van Werven, Liam J Holt, Angelika Amon
Cell size varies greatly between cell types, yet within a specific cell type and growth condition, cell size is narrowly distributed. Why maintenance of a cell-type specific cell size is important remains poorly understood. Here we show that growing budding yeast and primary mammalian cells beyond a certain size impairs gene induction, cell-cycle progression, and cell signaling. These defects are due to the inability of large cells to scale nucleic acid and protein biosynthesis in accordance with cell volume increase, which effectively leads to cytoplasm dilution...
January 29, 2019: Cell
Mariela D Petkova, Gašper Tkačik, William Bialek, Eric F Wieschaus, Thomas Gregor
In developing organisms, spatially prescribed cell identities are thought to be determined by the expression levels of multiple genes. Quantitative tests of this idea, however, require a theoretical framework capable of exposing the rules and precision of cell specification over developmental time. We use the gap gene network in the early fly embryo as an example to show how expression levels of the four gap genes can be jointly decoded into an optimal specification of position with 1% accuracy. The decoder correctly predicts, with no free parameters, the dynamics of pair-rule expression patterns at different developmental time points and in various mutant backgrounds...
January 29, 2019: Cell
Yi-Rong Peng, Karthik Shekhar, Wenjun Yan, Dustin Herrmann, Anna Sappington, Gregory S Bryman, Tavé van Zyl, Michael Tri H Do, Aviv Regev, Joshua R Sanes
High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences...
January 28, 2019: Cell
Geoffrey Schiebinger, Jian Shu, Marcin Tabaka, Brian Cleary, Vidya Subramanian, Aryeh Solomon, Joshua Gould, Siyan Liu, Stacie Lin, Peter Berube, Lia Lee, Jenny Chen, Justin Brumbaugh, Philippe Rigollet, Konrad Hochedlinger, Rudolf Jaenisch, Aviv Regev, Eric S Lander
Understanding the molecular programs that guide differentiation during development is a major challenge. Here, we introduce Waddington-OT, an approach for studying developmental time courses to infer ancestor-descendant fates and model the regulatory programs that underlie them. We apply the method to reconstruct the landscape of reprogramming from 315,000 single-cell RNA sequencing (scRNA-seq) profiles, collected at half-day intervals across 18 days. The results reveal a wider range of developmental programs than previously characterized...
January 28, 2019: Cell
Chengcheng Jin, Georgia K Lagoudas, Chen Zhao, Susan Bullman, Arjun Bhutkar, Bo Hu, Samuel Ameh, Demi Sandel, Xu Sue Liang, Sarah Mazzilli, Mark T Whary, Matthew Meyerson, Ronald Germain, Paul C Blainey, James G Fox, Tyler Jacks
Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells. Germ-free or antibiotic-treated mice were significantly protected from lung cancer development induced by Kras mutation and p53 loss...
January 25, 2019: Cell
Tetsuro Kobayashi, Benjamin Voisin, Do Young Kim, Elizabeth A Kennedy, Jay-Hyun Jo, Han-Yu Shih, Amanda Truong, Thomas Doebel, Keiko Sakamoto, Chang-Yi Cui, David Schlessinger, Kazuyo Moro, Susumu Nakae, Keisuke Horiuchi, Jinfang Zhu, Warren J Leonard, Heidi H Kong, Keisuke Nagao
Immune cells and epithelium form sophisticated barrier systems in symbiotic relationships with microbiota. Evidence suggests that immune cells can sense microbes through intact barriers, but regulation of microbial commensalism remain largely unexplored. Here, we uncovered spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORγt+ ILCs residing within hair follicles in close proximity to sebaceous glands. Their persistence in skin required IL-7 and thymic stromal lymphopoietin, and localization was dependent on the chemokine receptor CCR6...
January 25, 2019: Cell
Shreya Endapally, Donna Frias, Magdalena Grzemska, Austin Gay, Diana R Tomchick, Arun Radhakrishnan
Sphingomyelin and cholesterol are essential lipids that are enriched in plasma membranes of animal cells, where they interact to regulate membrane properties and many intracellular signaling processes. Despite intense study, the interaction between these lipids in membranes is not well understood. Here, structural and biochemical analyses of ostreolysin A (OlyA), a protein that binds to membranes only when they contain both sphingomyelin and cholesterol, reveal that sphingomyelin adopts two distinct conformations in membranes when cholesterol is present...
January 25, 2019: Cell
Alexander J Davies, Hyoung Woo Kim, Rafael Gonzalez-Cano, Jahyang Choi, Seung Keun Back, Seung Eon Roh, Errin Johnson, Melanie Gabriac, Mi-Sun Kim, Jaehee Lee, Jeong Eun Lee, Yun Sook Kim, Yong Chul Bae, Sang Jeong Kim, Kyung-Mi Lee, Heung Sik Na, Priscilla Riva, Alban Latremoliere, Simon Rinaldi, Sophie Ugolini, Michael Costigan, Seog Bae Oh
Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury...
January 25, 2019: Cell
Helmuth Gehart, Johan H van Es, Karien Hamer, Joep Beumer, Kai Kretzschmar, Johanna F Dekkers, Anne Rios, Hans Clevers
Homeostatic regulation of the intestinal enteroendocrine lineage hierarchy is a poorly understood process. We resolved transcriptional changes during enteroendocrine differentiation in real time at single-cell level using a novel knockin allele of Neurog3, the master regulator gene briefly expressed at the onset of enteroendocrine specification. A bi-fluorescent reporter, Neurog3Chrono, measures time from the onset of enteroendocrine differentiation and enables precise positioning of single-cell transcriptomes along an absolute time axis...
January 25, 2019: Cell
Daniel W Bayless, Taehong Yang, Matthew M Mason, Albert A T Susanto, Alexandra Lobdell, Nirao M Shah
Sexually naive animals have to distinguish between the sexes because they show species-typical interactions with males and females without meaningful prior experience. However, central neural pathways in naive mammals that recognize sex of other individuals remain poorly characterized. We examined the role of the principal component of the bed nucleus of stria terminalis (BNSTpr), a limbic center, in social interactions in mice. We find that activity of aromatase-expressing BNSTpr (AB) neurons appears to encode sex of other animals and subsequent displays of mating in sexually naive males...
January 24, 2019: Cell
Chengqian Yin, Bo Zhu, Ting Zhang, Tongzheng Liu, Shuyang Chen, Yu Liu, Xin Li, Xiao Miao, Shanshan Li, Xia Mi, Jie Zhang, Li Li, Guo Wei, Zhi-Xiang Xu, Xiumei Gao, Canhua Huang, Zhi Wei, Colin R Goding, Peng Wang, Xianming Deng, Rutao Cui
Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation...
January 24, 2019: Cell
Alexandra C Walls, Xiaoli Xiong, Young-Jun Park, M Alejandra Tortorici, Joost Snijder, Joel Quispe, Elisabetta Cameroni, Robin Gopal, Mian Dai, Antonio Lanzavecchia, Maria Zambon, Félix A Rey, Davide Corti, David Veesler
Recent outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome, along with the threat of a future coronavirus-mediated pandemic, underscore the importance of finding ways to combat these viruses. The trimeric spike transmembrane glycoprotein S mediates entry into host cells and is the major target of neutralizing antibodies. To understand the humoral immune response elicited upon natural infections with coronaviruses, we structurally characterized the SARS-CoV and MERS-CoV S glycoproteins in complex with neutralizing antibodies isolated from human survivors...
January 23, 2019: Cell
Abhishek Bhattacharya, Ulkar Aghayeva, Emily G Berghoff, Oliver Hobert
The specific patterns and functional properties of electrical synapses of a nervous system are defined by the neuron-specific complement of electrical synapse constituents. We systematically examined the molecular composition of the electrical connectome of the nematode C. elegans through a genome- and nervous-system-wide analysis of the expression patterns of the invertebrate electrical synapse constituents, the innexins. We observe highly complex combinatorial expression patterns throughout the nervous system and found that these patterns change in a strikingly neuron-type-specific manner throughout the nervous system when animals enter an insulin-controlled diapause arrest stage under harsh environmental conditions, the dauer stage...
January 21, 2019: Cell
Mirella Georgouli, Cecilia Herraiz, Eva Crosas-Molist, Bruce Fanshawe, Oscar Maiques, Anna Perdrix, Pahini Pandya, Irene Rodriguez-Hernandez, Kristina M Ilieva, Gaia Cantelli, Panagiotis Karagiannis, Silvia Mele, Hoyin Lam, Debra H Josephs, Xavier Matias-Guiu, Rosa M Marti, Frank O Nestle, Jose L Orgaz, Ilaria Malanchi, Gilbert O Fruhwirth, Sophia N Karagiannis, Victoria Sanz-Moreno
ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+ CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages...
January 18, 2019: Cell
Yimu Zhao, Naimeh Rafatian, Nicole T Feric, Brian J Cox, Roozbeh Aschar-Sobbi, Erika Yan Wang, Praful Aggarwal, Boyang Zhang, Genevieve Conant, Kacey Ronaldson-Bouchard, Aric Pahnke, Stephanie Protze, Jee Hoon Lee, Locke Davenport Huyer, Danica Jekic, Anastasia Wickeler, Hani E Naguib, Gordon M Keller, Gordana Vunjak-Novakovic, Ulrich Broeckel, Peter H Backx, Milica Radisic
Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity...
January 18, 2019: Cell
Soumyashree Das, Andrew B Goldstone, Hanjay Wang, Justin Farry, Gaetano D'Amato, Michael J Paulsen, Anahita Eskandari, Camille E Hironaka, Ragini Phansalkar, Bikram Sharma, Siyeon Rhee, Elya Ali Shamskhou, Dritan Agalliu, Vinicio de Jesus Perez, Y Joseph Woo, Kristy Red-Horse
Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly"...
January 17, 2019: Cell
Hideyuki Yoshida, Caleb A Lareau, Ricardo N Ramirez, Samuel A Rose, Barbara Maier, Aleksandra Wroblewska, Fiona Desland, Aleksey Chudnovskiy, Arthur Mortha, Claudia Dominguez, Julie Tellier, Edy Kim, Dan Dwyer, Susan Shinton, Tsukasa Nabekura, YiLin Qi, Bingfei Yu, Michelle Robinette, Ki-Wook Kim, Amy Wagers, Andrew Rhoads, Stephen L Nutt, Brian D Brown, Sara Mostafavi, Jason D Buenrostro, Christophe Benoist
A complete chart of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of differentiation and function of an organ system. We generated matched epigenome and transcriptome measurements in 86 primary cell types that span the mouse immune system and its differentiation cascades. This breadth of data enable variance components analysis that suggests that genes fall into two distinct classes, controlled by either enhancer- or promoter-driven logic, and multiple regression that connects genes to the enhancers that regulate them...
January 17, 2019: Cell
Hui Xu, Tianbo Li, Alexis Rohou, Christopher P Arthur, Foteini Tzakoniati, Evera Wong, Alberto Estevez, Christine Kugel, Yvonne Franke, Jun Chen, Claudio Ciferri, David H Hackos, Christopher M Koth, Jian Payandeh
Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel. Here, we visualize ProTx2 in complex with voltage-sensor domain II (VSD2) from Nav1.7 using X-ray crystallography and cryoelectron microscopy...
January 17, 2019: Cell
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