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Clair Crewe, Nolwenn Joffin, Joseph M Rutkowski, Min Kim, Fang Zhang, Dwight A Towler, Ruth Gordillo, Philipp E Scherer
We have uncovered the existence of extracellular vesicle (EV)-mediated signaling between cell types within the adipose tissue (AT) proper. This phenomenon became evident in our attempts at generating an adipocyte-specific knockout of caveolin 1 (cav1) protein. Although we effectively ablated the CAV1 gene in adipocytes, cav1 protein remained abundant. With the use of newly generated mouse models, we show that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs...
October 3, 2018: Cell
Yi Gu, Sam Lewallen, Amina A Kinkhabwala, Cristina Domnisoru, Kijung Yoon, Jeffrey L Gauthier, Ila R Fiete, David W Tank
How the topography of neural circuits relates to their function remains unclear. Although topographic maps exist for sensory and motor variables, they are rarely observed for cognitive variables. Using calcium imaging during virtual navigation, we investigated the relationship between the anatomical organization and functional properties of grid cells, which represent a cognitive code for location during navigation. We found a substantial degree of grid cell micro-organization in mouse medial entorhinal cortex: grid cells and modules all clustered anatomically...
September 27, 2018: Cell
Anju Sreelatha, Samantha S Yee, Victor A Lopez, Brenden C Park, Lisa N Kinch, Sylwia Pilch, Kelly A Servage, Junmei Zhang, Jenny Jiou, Monika Karasiewicz-Urbańska, Małgorzata Łobocka, Nick V Grishin, Kim Orth, Roza Kucharczyk, Krzysztof Pawłowski, Diana R Tomchick, Vincent S Tagliabracci
Approximately 10% of human protein kinases are believed to be inactive and named pseudokinases because they lack residues required for catalysis. Here, we show that the highly conserved pseudokinase selenoprotein-O (SelO) transfers AMP from ATP to Ser, Thr, and Tyr residues on protein substrates (AMPylation), uncovering a previously unrecognized activity for a member of the protein kinase superfamily. The crystal structure of a SelO homolog reveals a protein kinase-like fold with ATP flipped in the active site, thus providing a structural basis for catalysis...
September 25, 2018: Cell
Andreas E Moor, Yotam Harnik, Shani Ben-Moshe, Efi E Massasa, Milena Rozenberg, Raya Eilam, Keren Bahar Halpern, Shalev Itzkovitz
The intestinal epithelium is a highly structured tissue composed of repeating crypt-villus units. Enterocytes perform the diverse tasks of absorbing a wide range of nutrients while protecting the body from the harsh bacterium-rich environment. It is unknown whether these tasks are spatially zonated along the villus axis. Here, we extracted a large panel of landmark genes characterized by transcriptomics of laser capture microdissected villus segments and utilized it for single-cell spatial reconstruction, uncovering broad zonation of enterocyte function along the villus...
September 20, 2018: Cell
Yun Xia, Yonghua Xie, Zhengsen Yu, Hongying Xiao, Guimei Jiang, Xiaoying Zhou, Yunyun Yang, Xin Li, Meng Zhao, Liping Li, Mingke Zheng, Shuai Han, Zhaoyun Zong, Xianbin Meng, Haiteng Deng, Huahu Ye, Yunzhi Fa, Haitao Wu, Eric Oldfield, Xiaoyu Hu, Wanli Liu, Yan Shi, Yonghui Zhang
Motivated by the clinical observation that interruption of the mevalonate pathway stimulates immune responses, we hypothesized that this pathway may function as a druggable target for vaccine adjuvant discovery. We found that lipophilic statin drugs and rationally designed bisphosphonates that target three distinct enzymes in the mevalonate pathway have potent adjuvant activities in mice and cynomolgus monkeys. These inhibitors function independently of conventional "danger sensing." Instead, they inhibit the geranylgeranylation of small GTPases, including Rab5 in antigen-presenting cells, resulting in arrested endosomal maturation, prolonged antigen retention, enhanced antigen presentation, and T cell activation...
September 20, 2018: Cell
Wenfei Han, Luis A Tellez, Matthew H Perkins, Isaac O Perez, Taoran Qu, Jozelia Ferreira, Tatiana L Ferreira, Daniele Quinn, Zhong-Wu Liu, Xiao-Bing Gao, Melanie M Kaelberer, Diego V Bohórquez, Sara J Shammah-Lagnado, Guillaume de Lartigue, Ivan E de Araujo
The gut is now recognized as a major regulator of motivational and emotional states. However, the relevant gut-brain neuronal circuitry remains unknown. We show that optical activation of gut-innervating vagal sensory neurons recapitulates the hallmark effects of stimulating brain reward neurons. Specifically, right, but not left, vagal sensory ganglion activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia nigra. Cell-specific transneuronal tracing revealed asymmetric ascending pathways of vagal origin throughout the CNS...
September 18, 2018: Cell
James P White, Shanshan Xiong, Nicole P Malvin, William Khoury-Hanold, Robert O Heuckeroth, Thaddeus S Stappenbeck, Michael S Diamond
Although chronic gastrointestinal dysmotility syndromes are a common worldwide health problem, underlying causes for these disorders are poorly understood. We show that flavivirus infection of enteric neurons leads to acute neuronal injury and cell death, inflammation, bowel dilation, and slowing of intestinal transit in mice. Flavivirus-primed CD8+ T cells promote these phenotypes, as their absence diminished enteric neuron injury and intestinal transit delays, and their adoptive transfer reestablished dysmotility after flavivirus infection...
September 17, 2018: Cell
Zheng Jiang, Wendy W S Yue, Lujing Chen, Yanghui Sheng, King-Wai Yau
Non-image-forming vision in mammals is mediated primarily by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). In mouse M1-ipRGCs, by far the best-studied subtype, melanopsin activates PLCβ4 (phospholipase C-β4) to open TRPC6,7 channels, mechanistically similar to phototransduction in fly rhabdomeric (microvillous) photoreceptors. We report here that, surprisingly, mouse M4-ipRGCs rely on a different and hitherto undescribed melanopsin-driven, ciliary phototransduction mechanism involving cyclic nucleotide as the second messenger and HCN channels rather than CNG channels as the ion channel for phototransduction...
September 13, 2018: Cell
Johannes Felsenberg, Pedro F Jacob, Thomas Walker, Oliver Barnstedt, Amelia J Edmondson-Stait, Markus W Pleijzier, Nils Otto, Philipp Schlegel, Nadiya Sharifi, Emmanuel Perisse, Carlas S Smith, J Scott Lauritzen, Marta Costa, Gregory S X E Jefferis, Davi D Bock, Scott Waddell
Accurately predicting an outcome requires that animals learn supporting and conflicting evidence from sequential experience. In mammals and invertebrates, learned fear responses can be suppressed by experiencing predictive cues without punishment, a process called memory extinction. Here, we show that extinction of aversive memories in Drosophila requires specific dopaminergic neurons, which indicate that omission of punishment is remembered as a positive experience. Functional imaging revealed co-existence of intracellular calcium traces in different places in the mushroom body output neuron network for both the original aversive memory and a new appetitive extinction memory...
September 6, 2018: Cell
Nao Nitta, Takeaki Sugimura, Akihiro Isozaki, Hideharu Mikami, Kei Hiraki, Shinya Sakuma, Takanori Iino, Fumihito Arai, Taichiro Endo, Yasuhiro Fujiwaki, Hideya Fukuzawa, Misa Hase, Takeshi Hayakawa, Kotaro Hiramatsu, Yu Hoshino, Mary Inaba, Takuro Ito, Hiroshi Karakawa, Yusuke Kasai, Kenichi Koizumi, SangWook Lee, Cheng Lei, Ming Li, Takanori Maeno, Satoshi Matsusaka, Daichi Murakami, Atsuhiro Nakagawa, Yusuke Oguchi, Minoru Oikawa, Tadataka Ota, Kiyotaka Shiba, Hirofumi Shintaku, Yoshitaka Shirasaki, Kanako Suga, Yuta Suzuki, Nobutake Suzuki, Yo Tanaka, Hiroshi Tezuka, Chihana Toyokawa, Yaxiaer Yalikun, Makoto Yamada, Mai Yamagishi, Takashi Yamano, Atsushi Yasumoto, Yutaka Yatomi, Masayuki Yazawa, Dino Di Carlo, Yoichiroh Hosokawa, Sotaro Uemura, Yasuyuki Ozeki, Keisuke Goda
A fundamental challenge of biology is to understand the vast heterogeneity of cells, particularly how cellular composition, structure, and morphology are linked to cellular physiology. Unfortunately, conventional technologies are limited in uncovering these relations. We present a machine-intelligence technology based on a radically different architecture that realizes real-time image-based intelligent cell sorting at an unprecedented rate. This technology, which we refer to as intelligent image-activated cell sorting, integrates high-throughput cell microscopy, focusing, and sorting on a hybrid software-hardware data-management infrastructure, enabling real-time automated operation for data acquisition, data processing, decision-making, and actuation...
August 23, 2018: Cell
Waleed Minzel, Avanthika Venkatachalam, Avner Fink, Eric Hung, Guy Brachya, Ido Burstain, Maya Shaham, Amitai Rivlin, Itay Omer, Adar Zinger, Shlomo Elias, Eitan Winter, Paul E Erdman, Robert W Sullivan, Leah Fung, Frank Mercurio, Dansu Li, Joseph Vacca, Nathali Kaushansky, Liran Shlush, Moshe Oren, Ross Levine, Eli Pikarsky, Irit Snir-Alkalay, Yinon Ben-Neriah
CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes...
August 20, 2018: Cell
Karina K Sanchez, Grischa Y Chen, Alexandria M Palaferri Schieber, Samuel E Redford, Maxim N Shokhirev, Mathias Leblanc, Yujung M Lee, Janelle S Ayres
Pathogen virulence exists on a continuum. The strategies that drive symptomatic or asymptomatic infections remain largely unknown. We took advantage of the concept of lethal dose 50 (LD50) to ask which component of individual non-genetic variation between hosts defines whether they survive or succumb to infection. Using the enteric pathogen Citrobacter, we found no difference in pathogen burdens between healthy and symptomatic populations. Iron metabolism-related genes were induced in asymptomatic hosts compared to symptomatic or naive mice...
July 31, 2018: Cell
Paul D Carlson, Molly E Evans, Angela M Yu, Eric J Strobel, Julius B Lucks
Chemical probing coupled to high-throughput sequencing offers a flexible approach to uncover many aspects of RNA structure relevant to its cellular function. With a wide variety of chemical probes available that each report on different features of RNA molecules, a broad toolkit exists for investigating in vivo and in vitro RNA structure and interactions with other molecules.
October 4, 2018: Cell
Samuel A Lambert, Arttu Jolma, Laura F Campitelli, Pratyush K Das, Yimeng Yin, Mihai Albu, Xiaoting Chen, Jussi Taipale, Timothy R Hughes, Matthew T Weirauch
No abstract text is available yet for this article.
October 4, 2018: Cell
Shicheng Su, Jinghua Zhao, Yue Xing, Xiaoqian Zhang, Jiang Liu, Qian Ouyang, Jianing Chen, Fengxi Su, Qiang Liu, Erwei Song
Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression...
October 4, 2018: Cell
David Enard, Dmitri A Petrov
Neanderthals and modern humans interbred at least twice in the past 100,000 years. While there is evidence that most introgressed DNA segments from Neanderthals to modern humans were removed by purifying selection, less is known about the adaptive nature of introgressed sequences that were retained. We hypothesized that interbreeding between Neanderthals and modern humans led to (1) the exposure of each species to novel viruses and (2) the exchange of adaptive alleles that provided resistance against these viruses...
October 4, 2018: Cell
Siyang Liu, Shujia Huang, Fang Chen, Lijian Zhao, Yuying Yuan, Stephen Starko Francis, Lin Fang, Zilong Li, Long Lin, Rong Liu, Yong Zhang, Huixin Xu, Shengkang Li, Yuwen Zhou, Robert W Davies, Qiang Liu, Robin G Walters, Kuang Lin, Jia Ju, Thorfinn Korneliussen, Melinda A Yang, Qiaomei Fu, Jun Wang, Lijun Zhou, Anders Krogh, Hongyun Zhang, Wei Wang, Zhengming Chen, Zhiming Cai, Ye Yin, Huanming Yang, Mao Mao, Jay Shendure, Jian Wang, Anders Albrechtsen, Xin Jin, Rasmus Nielsen, Xun Xu
We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1...
October 4, 2018: Cell
Peter W Reddien
Regeneration is one of the great mysteries of biology. Planarians are flatworms capable of dramatic feats of regeneration, which have been studied for over 2 centuries. Recent findings identify key cellular and molecular principles underlying these feats. A stem cell population (neoblasts) generates new cells and is comprised of pluripotent stem cells (cNeoblasts) and fate-specified cells (specialized neoblasts). Positional information is constitutively active and harbored primarily in muscle, where it acts to guide stem cell-mediated tissue turnover and regeneration...
October 4, 2018: Cell
Miguel F Sanmamed, Lieping Chen
Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This "immune enhancement" strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs...
October 4, 2018: Cell
Dennis H Kim
Siderophores are small molecules produced by bacteria that bind ferric iron in the surrounding environment with extraordinary affinity. A new study provides evidence that a simple animal host, Caenorhabditis elegans, co-opts siderophores to promote its own iron acquisition and growth.
October 4, 2018: Cell
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