ALBERT

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Gowri Nayak, Kevin X. Zhang, Shruti Vemaraju, Yoshinobu Odaka, Ethan D. Buhr, Amanda Holt-Jones, Stace Kernodle, April N. Smith, Brian A. Upton, Shane D’Souza, Jesse J. Zhan, Nicolás Diaz, Minh-Thanh Nguyen, Rajib Mukherjee, Shannon A. Gordon, Gang Wu, Robert Schmidt, Xue Mei, Nathan T. Petts, Matthew Batie〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Almost all life forms can detect and decode light information for adaptive advantage. Examples include the visual system, in which photoreceptor signals are processed into virtual images, and the circadian system, in which light entrains a physiological clock. Here we describe a light response pathway in mice that employs encephalopsin (OPN3, a 480 nm, blue-light-responsive opsin) to regulate the function of adipocytes. Germline null and adipocyte-specific conditional null mice show a light- and 〈em〉Opn3〈/em〉-dependent deficit in thermogenesis and become hypothermic upon cold exposure. We show that stimulating mouse adipocytes with blue light enhances the lipolysis response and, in particular, phosphorylation of hormone-sensitive lipase. This response is 〈em〉Opn3〈/em〉 dependent. These data establish a key mechanism in which light-dependent, local regulation of the lipolysis response in white adipocytes regulates energy metabolism.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317000-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Felix Horns, Cornelia L. Dekker, Stephen R. Quake〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Antibody memory protects humans from many diseases. Protective antibody memory responses require activation of transcriptional programs, cell proliferation, and production of antigen-specific antibodies, but how these aspects of the response are coordinated is poorly understood. We profile the molecular and cellular features of the antibody response to influenza vaccination by integrating single-cell transcriptomics, longitudinal antibody repertoire sequencing, and antibody binding measurements. Single-cell transcriptional profiling reveals a program of memory B cell activation characterized by 〈em〉CD11c〈/em〉 and 〈em〉T-bet〈/em〉 expression associated with clonal expansion and differentiation toward effector function. Vaccination elicits an antibody clone, which rapidly acquired broad high-affinity hemagglutinin binding during affinity maturation. Unexpectedly, many antibody clones elicited by vaccination do not bind vaccine, demonstrating non-specific activation of bystander antibodies by influenza vaccination. These results offer insight into how molecular recognition, transcriptional programs, and clonal proliferation are coordinated in the human B cell repertoire during memory recall.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317206-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Yi Liu, Ning Yin, Xue Wang, Andras Khoor, Vaishnavi Sambandam, Anwesha B. Ghosh, Zoe A. Fields, Nicole R. Murray, Verline Justilien, Alan P. Fields〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Lung squamous cell carcinoma (LSCC) is a prevalent form of lung cancer exhibiting distinctive histological and genetic characteristics. Chromosome 3q26 copy number gain (CNG) is a genetic hallmark of LSCC present in 〉90% of tumors. We report that 3q26 CNGs occur early in LSCC tumorigenesis, persist during tumor progression, and drive coordinate overexpression of 〈em〉PRKCI〈/em〉, 〈em〉SOX2〈/em〉, and 〈em〉ECT2〈/em〉. Overexpression of 〈em〉PRKCI〈/em〉, 〈em〉SOX2〈/em〉, and 〈em〉ECT2〈/em〉 in the context of 〈em〉Trp53〈/em〉 loss is sufficient to transform mouse lung basal stem cells into tumors with histological and genomic features of LSCC. Functionally, 〈em〉PRKCI〈/em〉 and 〈em〉SOX2〈/em〉 collaborate to activate an extensive transcriptional program that enforces a lineage-restricted LSCC phenotype, whereas 〈em〉PRKCI〈/em〉 and 〈em〉ECT2〈/em〉 collaborate to promote oncogenic growth. Gene signatures indicative of PKCι-SOX2 and PKCι-ECT2 signaling activity are enriched in the classical subtype of human LSCC and predict distinct therapeutic vulnerabilities. Thus, the 〈em〉PRKCI〈/em〉, 〈em〉SOX2〈/em〉, and 〈em〉ECT2〈/em〉 oncogenes represent a multigenic driver of LSCC.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317280-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Shira Yomtoubian, Sharrell B. Lee, Akanksha Verma, Franco Izzo, Geoffrey Markowitz, Hyejin Choi, Leandro Cerchietti, Linda Vahdat, Kristy A. Brown, Eleni Andreopoulou, Olivier Elemento, Jenny Chang, Giorgio Inghirami, Dingcheng Gao, Seongho Ryu, Vivek Mittal〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Epigenetic changes are increasingly being appreciated as key events in breast cancer progression. However, breast cancer subtype-specific epigenetic regulation remains poorly investigated. Here we report that EZH2 is a leading candidate of epigenetic modulators associated with the TNBC subtype and that it predicts poor overall survival in TNBC patients. We demonstrate that specific pharmacological or genetic inhibition of EZH2 catalytic activity impairs distant metastasis. We further define a specific EZH2〈sup〉high〈/sup〉 population with enhanced invasion, mammosphere formation, and metastatic potential that exhibits marked sensitivity to EZH2 inhibition. Mechanistically, EZH2 inhibition differentiates EZH2〈sup〉high〈/sup〉 basal cells to a luminal-like phenotype by derepressing GATA3 and renders them sensitive to endocrine therapy. Furthermore, dissection of human TNBC heterogeneity shows that EZH2〈sup〉high〈/sup〉 basal-like 1 and mesenchymal subtypes have exquisite sensitivity to EZH2 inhibition compared with the EZH2〈sup〉low〈/sup〉 luminal androgen receptor subtype. These preclinical findings provide a rationale for clinical development of EZH2 as a targeted therapy against TNBC metastasis.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317139-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Hayley I. Muendlein, Joseph Sarhan, Beiyun C. Liu, Wilson M. Connolly, Stephen A. Schworer, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Jodie Pietruska, Soroush Tahmasebi, Nahum Sonenberg, Alexei Degterev, Alexander Poltorak〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) are well known for their capacity to drive necroptosis via mixed-lineage kinase-like domain (MLKL). Recently, RIPK1/3 kinase activity has been shown to drive inflammation via activation of MAPK signaling. However, the regulatory mechanisms underlying this kinase-dependent cytokine production remain poorly understood. In the present study, we establish that the kinase activity of RIPK1/3 regulates cytokine translation in mouse and human macrophages. Furthermore, we show that this inflammatory response is downregulated by type I interferon (IFN) signaling, independent of type I IFN-promoted cell death. Specifically, low-level constitutive IFN signaling attenuates RIPK-driven activation of cap-dependent translation initiation pathway components AKT, mTORC1, 4E-BP and eIF4E, while promoting RIPK-dependent cell death. Altogether, these data characterize constitutive IFN signaling as a regulator of RIPK-dependent inflammation and establish cap-dependent translation as a crucial checkpoint in the regulation of cytokine production.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317309-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Wanchuan Zhang, Jing Gong, Huan Yang, Luming Wan, Yumeng Peng, Xiaolin Wang, Jin Sun, Feng Li, Yunqi Geng, Dongyu Li, Ning Liu, Gangwu Mei, Yuan Cao, Qiulin Yan, Huilong Li, Yanhong Zhang, Xiang He, Qiaozhi Zhang, Rui Zhang, Feixiang Wu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Recent reports have shown the critical role of the mitochondrial antiviral signaling (MAVS) protein in virus-induced apoptosis, but the involvement of MAVS in tumorigenesis is still poorly understood. Herein, we report that MAVS is a key regulator of p53 activation and is critical for protecting against tumorigenesis. We find that MAVS promotes p53-dependent cell death in response to DNA damage. MAVS interacts with p53 and mediates p53 mitochondrial recruitment under genotoxic stress. Mechanistically, MAVS inhibits p53 ubiquitination by blocking the formation of the p53-murine double-minute 2 (MDM2) complex, leading to the stabilization of p53. Notably, compared with their wild-type littermates, MAVS knockout mice display decreased resistance to azoxymethane (AOM) or AOM/dextran sulfate sodium salt (DSS)-induced colon cancer. MAVS expression is significantly downregulated in human colon cancer tissues. These results unveil roles for MAVS in DNA damage response and tumor suppression.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317085-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Joana Lourenço, Angela Michela De Stasi, Charlotte Deleuze, Mathilde Bigot, Antonio Pazienti, Andrea Aguirre, Michele Giugliano, Srdjan Ostojic, Alberto Bacci〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer (L) 2/3 pyramidal neurons (PNs) elicits strong feedforward inhibition (FFI) onto L5 PNs. We find that FFI involving parvalbumin (PV)-expressing cells is strongly potentiated by postsynaptic PN burst firing. FFI plasticity modifies the PN excitation-to-inhibition (E/I) ratio, strongly modulates PN gain, and alters information transfer across cortical layers. Moreover, our LTPi-inducing protocol modifies firing of L5 PNs and alters the temporal association of PN spikes to γ-oscillations both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. All of these effects are captured by unbalancing the E/I ratio in a feedforward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognition-relevant network activity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317097-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Caley J. Burrus, Spencer U. McKinstry, Namsoo Kim, M. Ilcim Ozlu, Aditya V. Santoki, Francia Y. Fang, Annie Ma, Yonca B. Karadeniz, Atesh K. Worthington, Ioannis Dragatsis, Scott Zeitlin, Henry H. Yin, Cagla Eroglu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Huntington’s disease (HD) is caused by an autosomal dominant polyglutamine expansion mutation of Huntingtin (〈em〉HTT〈/em〉). HD patients suffer from progressive motor, cognitive, and psychiatric impairments, along with significant degeneration of the striatal projection neurons (SPNs) of the striatum. HD is widely accepted to be caused by a toxic gain-of-function of mutant HTT. However, whether loss of HTT function, because of dominant-negative effects of the mutant protein, plays a role in HD and whether HTT is required for SPN health and function are not known. Here, we delete 〈em〉Htt〈/em〉 from specific subpopulations of SPNs using the Cre-Lox system and find that SPNs require HTT for motor regulation, synaptic development, cell health, and survival during aging. Our results suggest that loss of HTT function in SPNs could play a critical role in HD pathogenesis.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317267-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Bo He, Anna Johansson-Percival, Joseph Backhouse, Ji Li, Gabriel Yin Foo Lee, Juliana Hamzah, Ruth Ganss〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Due to limited current therapies, metastases are the primary cause of mortality in cancer patients. Here, we employ a fusion compound of the cytokine LIGHT and a vascular targeting peptide (LIGHT-VTP) that homes to angiogenic blood vessels in primary tumors. We show in primary mouse lung cancer that normalization of tumor vasculature by LIGHT-VTP prevents cancer cell intravasation. Further, LIGHT-VTP efficiently targets pathological blood vessels in the pre-metastatic niche, reducing vascular hyper-permeability and extracellular matrix (ECM) deposition, thus blocking metastatic lung colonization. Moreover, we demonstrate that mouse and human metastatic melanoma deposits are targetable by VTP. In overt melanoma metastases, LIGHT-VTP normalizes intra-metastatic blood vessels and increases GrzB〈sup〉+〈/sup〉 effector T cells. Successful treatment induces high endothelial venules (HEVs) and lymphocyte clusters, which sensitize refractory lung metastases to anti-PD-1 checkpoint inhibitors. These findings demonstrate an important application for LIGHT-VTP therapy in preventing metastatic development as well as exerting anti-tumor effects in established metastases.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316626-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Haruka Yamamoto, Tetsuo Kon, Yoshihiro Omori, Takahisa Furukawa〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Otx family homeoproteins Otx2 and Crx are expressed in photoreceptor precursor cells and bind to the common DNA-binding consensus sequence, but these two proteins have distinct functions in retinal development. To examine the functional substitutability of Otx2 and Crx, we generate knockin mouse lines in which 〈em〉Crx〈/em〉 is replaced by 〈em〉Otx2〈/em〉 and vice versa. We find that 〈em〉Otx2〈/em〉 and 〈em〉Crx〈/em〉 cannot be substituted in photoreceptor development. Subsequently, we investigate the function of 〈em〉Otx2〈/em〉 in photoreceptor and bipolar cell development. High 〈em〉Otx2〈/em〉 levels induce photoreceptor cell fate but not bipolar cell fate, whereas reduced 〈em〉Otx2〈/em〉 expression impairs bipolar cell maturation and survival. Furthermore, we identify 〈em〉Otx2〈/em〉 and 〈em〉Crx〈/em〉 in the lamprey genome by using synteny analysis, suggesting that the last common ancestor of vertebrates possesses both 〈em〉Otx2〈/em〉 and 〈em〉Crx〈/em〉. We find that the retinal 〈em〉Otx2〈/em〉 expression pattern is different between lampreys and mice, suggesting that neofunctionalization of 〈em〉Otx2〈/em〉 occurred in the jawed vertebrate lineage.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317292-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Ju-Gyeong Kang, Cory U. Lago, Ji-Eun Lee, Ji-Hoon Park, Matthew P. Donnelly, Matthew F. Starost, Chengyu Liu, Jaeyul Kwon, Audrey C. Noguchi, Kai Ge, Ping-yuan Wang, Paul M. Hwang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The physiological effects of the many germline mutations of 〈em〉TP53〈/em〉, encoding the tumor suppressor protein p53, are poorly understood. Here we report generating a 〈em〉p53〈/em〉 R178C knockin mouse modeling the human 〈em〉TP53〈/em〉 R181C mutation, which is notable for its prevalence and prior molecular characterization. Consistent with its weak cancer penetrance in humans, homozygous 〈em〉p53〈/em〉〈sup〉〈em〉178C/C〈/em〉〈/sup〉 mice show a modest increase in tumorigenesis but, surprisingly, are lean with decreased body fat content. They display evidence of increased lipolysis and upregulation of fatty acid metabolism in their inguinal white adipose tissue (iWAT). Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses show that the mutant p53 bound and transactivated 〈em〉Beta-3-Adrenergic Receptor〈/em〉 (〈em〉ADRB3〈/em〉), a gene that is known to promote lipolysis and is associated with obesity. This study reveals that a germline mutation of p53 can affect fat metabolism, which has been implicated in cancer development.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317395-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Gabriel Velez, Young Joo Sun, Saif Khan, Jing Yang, Jonathan Herrmann, Teja Chemudupati, Robert E. MacLaren, Lokesh Gakhar, Soichi Wakatsuki, Alexander G. Bassuk, Vinit B. Mahajan〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Increased calpain activity is linked to neuroinflammation including a heritable retinal disease caused by hyper-activating mutations in the calcium-activated calpain-5 (CAPN5) protease. Although structures for classical calpains are known, the structure of CAPN5, a non-classical calpain, remains undetermined. Here we report the 2.8 Å crystal structure of the human CAPN5 protease core (CAPN5-PC). Compared to classical calpains, CAPN5-PC requires high calcium concentrations for maximal activity. Structure-based phylogenetic analysis and multiple sequence alignment reveal that CAPN5-PC contains three elongated flexible loops compared to its classical counterparts. The presence of a disease-causing mutation (c.799G〉A, p.Gly267Ser) on the unique PC2L2 loop reveals a function in this region for regulating enzymatic activity. This mechanism could be transferred to distant calpains, using synthetic calpain hybrids, suggesting an evolutionary mechanism for fine-tuning calpain function by modifying flexible loops. Further, the open (inactive) conformation of CAPN5-PC provides structural insight into CAPN5-specific residues that can guide inhibitor design.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317425-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Alec R. Nickolls, Michelle M. Lee, David F. Espinoza, Marcin Szczot, Ruby M. Lam, Qi Wang, Jeanette Beers, Jizhong Zou, Minh Q. Nguyen, Hans J. Solinski, Aisha A. AlJanahi, Kory R. Johnson, Michael E. Ward, Alexander T. Chesler, Carsten G. Bönnemann〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Efficient and homogeneous 〈em〉in vitro〈/em〉 generation of peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. We discover that, by overexpressing 〈em〉NGN2〈/em〉 and 〈em〉BRN3A〈/em〉, human pluripotent stem cells can be transcriptionally programmed to differentiate into a surprisingly uniform culture of cold- and mechano-sensing neurons. Although such a neuronal subtype is not found in mice, we identify molecular evidence for its existence in human sensory ganglia. Combining 〈em〉NGN2〈/em〉 and 〈em〉BRN3A〈/em〉 programming with neural crest patterning, we produce two additional populations of sensory neurons, including a specialized touch receptor neuron subtype. Finally, we apply this system to model a rare inherited sensory disorder of touch and proprioception caused by inactivating mutations in 〈em〉PIEZO2〈/em〉. Together, these findings establish an approach to specify distinct sensory neuron subtypes 〈em〉in vitro〈/em〉, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471931719X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Manon Bohic, Irène Marics, Catarina Santos, Pascale Malapert, Nissim Ben-Arie, Chiara Salio, Ana Reynders, Yves Le Feuvre, Andrew J. Saurin, Aziz Moqrich〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉C-LTMRs are known to convey affective aspects of touch and to modulate injury-induced pain in humans and mice. However, a role for these neurons in temperature sensation has been suggested, but not fully demonstrated. Here, we report that deletion of C-low-threshold mechanoreceptor (C-LTMR)-expressed 〈em〉bhlha9〈/em〉 causes impaired thermotaxis behavior and exacerbated formalin-evoked pain in male, but not female, mice. Positive modulators of GABA〈sub〉A〈/sub〉 receptors failed to relieve inflammatory formalin pain and failed to decrease the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) selectively in 〈em〉bhlha9〈/em〉 knockout (KO) males. This could be explained by a drastic change in the GABA content of lamina II inner inhibitory interneurons contacting C-LTMR central terminals. Finally, C-LTMR-specific deep RNA sequencing revealed more genes differentially expressed in male than in female 〈em〉bhlha9〈/em〉 KO C-LTMRs. Our data consolidate the role of C-LTMRs in modulation of formalin pain and provide 〈em〉in vivo〈/em〉 evidence of their role in the discriminative aspects of temperature sensation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316985-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Etienne Paubelle, Florence Zylbersztejn, Thiago Trovati Maciel, Caroline Carvalho, Annalisa Mupo, Meyling Cheok, Liesbet Lieben, Pierre Sujobert, Justine Decroocq, Akihiko Yokoyama, Vahid Asnafi, Elizabeth Macintyre, Jérôme Tamburini, Valérie Bardet, Sylvie Castaigne, Claude Preudhomme, Hervé Dombret, Geert Carmeliet, Didier Bouscary, Yelena Z. Ginzburg〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Vitamin D (VD) is a known differentiating agent, but the role of VD receptor (VDR) is still incompletely described in acute myeloid leukemia (AML), whose treatment is based mostly on antimitotic chemotherapy. Here, we present an unexpected role of VDR in normal hematopoiesis and in leukemogenesis. Limited VDR expression is associated with impaired myeloid progenitor differentiation and is a new prognostic factor in AML. In mice, the lack of 〈em〉Vdr〈/em〉 results in increased numbers of hematopoietic and leukemia stem cells and quiescent hematopoietic stem cells. In addition, malignant transformation of 〈em〉Vdr〈/em〉〈sup〉−/−〈/sup〉 cells results in myeloid differentiation block and increases self-renewal. 〈em〉Vdr〈/em〉 promoter is methylated in AML as in CD34〈sup〉+〈/sup〉 cells, and demethylating agents induce VDR expression. Association of VDR agonists with hypomethylating agents promotes leukemia stem cell exhaustion and decreases tumor burden in AML mouse models. Thus, 〈em〉Vdr〈/em〉 functions as a regulator of stem cell homeostasis and leukemic propagation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317127-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): James D.P. Rhodes, Angelika Feldmann, Benjamín Hernández-Rodríguez, Noelia Díaz, Jill M. Brown, Nadezda A. Fursova, Neil P. Blackledge, Praveen Prathapan, Paula Dobrinic, Miles K. Huseyin, Aleksander Szczurek, Kai Kruse, Kim A. Nasmyth, Veronica J. Buckle, Juan M. Vaquerizas, Robert J. Klose〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉How chromosome organization is related to genome function remains poorly understood. Cohesin, loop extrusion, and CCCTC-binding factor (CTCF) have been proposed to create topologically associating domains (TADs) to regulate gene expression. Here, we examine chromosome conformation in embryonic stem cells lacking cohesin and find, as in other cell types, that cohesin is required to create TADs and regulate A/B compartmentalization. However, in the absence of cohesin, we identify a series of long-range chromosomal interactions that persist. These correspond to regions of the genome occupied by the polycomb repressive system and are dependent on PRC1. Importantly, we discover that cohesin counteracts these polycomb-dependent interactions, but not interactions between super-enhancers. This disruptive activity is independent of CTCF and insulation and appears to modulate gene repression by the polycomb system. Therefore, we discover that cohesin disrupts polycomb-dependent chromosome interactions to modulate gene expression in embryonic stem cells.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317140-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Mario Novkovic, Lucas Onder, Gennady Bocharov, Burkhard Ludewig〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Fibroblastic reticular cells (FRCs) form a road-like cellular network in lymph nodes (LNs) that provides essential chemotactic, survival, and regulatory signals for immune cells. While the topological characteristics of the FRC network have been elaborated, the network properties of the micro-tubular conduit system generated by FRCs, which drains lymph fluid through a pipeline-like system to distribute small molecules and antigens, has remained unexplored. Here, we quantify the crucial 3D morphometric parameters and determine the topological properties governing the structural organization of the intertwined networks. We find that the conduit system exhibits lesser small-worldness and lower resilience to perturbation compared to the FRC network, while the robust topological organization of both networks is maintained in a lymphotoxin-β-receptor-independent manner. Overall, the high-resolution topological analysis of the “roads-and-pipes” networks highlights essential parameters underlying the functional organization of LN micro-environments and will, hence, advance the development of multi-scale LN models.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317279-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Ine Vanderleyden, Sigrid C. Fra-Bido, Silvia Innocentin, Marisa Stebegg, Hanneke Okkenhaug, Nicola Evans-Bailey, Wim Pierson, Alice E. Denton, Michelle A. Linterman〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The germinal center (GC) response is critical for generating high-affinity humoral immunity and immunological memory, which forms the basis of successful immunization. Control of the GC response is thought to require follicular regulatory T (Tfr) cells, a subset of suppressive Foxp3〈sup〉+〈/sup〉 regulatory T cells located within GCs. Relatively little is known about the exact role of Tfr cells within the GC and how they exert their suppressive function. A unique feature of Tfr cells is their reported CXCR5-dependent localization to the GC. Here, we show that the lack of CXCR5 on Foxp3〈sup〉+〈/sup〉 regulatory T cells results in a reduced frequency, but not an absence, of GC-localized Tfr cells. This reduction in Tfr cells is not sufficient to alter the magnitude or output of the GC response. This demonstrates that additional, CXCR5-independent mechanisms facilitate Treg cell homing to the GC.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317413-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Jennifer Ann Black, Kathryn Crouch, Leandro Lemgruber, Craig Lapsley, Nicholas Dickens, Luiz R.O. Tosi, Jeremy C. Mottram, Richard McCulloch〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉〈em〉Trypanosoma brucei〈/em〉 evades mammalian immunity by using recombination to switch its surface-expressed variant surface glycoprotein (VSG), while ensuring that only one of many subtelomeric multigene VSG expression sites are transcribed at a time. DNA repair activities have been implicated in the catalysis of VSG switching by recombination, not transcriptional control. How VSG switching is signaled to guide the appropriate reaction or to integrate switching into parasite growth is unknown. Here, we show that the loss of ATR, a DNA damage-signaling protein kinase, is lethal, causing nuclear genome instability and increased VSG switching through VSG-localized damage. Furthermore, ATR loss leads to the increased transcription of silent VSG expression sites and expression of mixed VSGs on the cell surface, effects that are associated with the altered localization of RNA polymerase I and VEX1. This work shows that ATR acts in antigenic variation both through DNA damage signaling and surface antigen expression control.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317061-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Handong Ma, Jing Wang, Xueli Zhao, Tiantian Wu, Zhengjie Huang, Dafan Chen, Yingfu Liu, Gaoliang Ouyang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in 〈em〉Apc〈/em〉〈sup〉〈em〉Min/+〈/em〉〈/sup〉 mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317401-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Leo Swadling, Laura J. Pallett, Mariana O. Diniz, Josephine M. Baker, Oliver E. Amin, Kerstin A. Stegmann, Alice R. Burton, Nathalie M. Schmidt, Anna Jeffery-Smith, Nekisa Zakeri, Kornelija Suveizdyte, Farid Froghi, Giuseppe Fusai, William M. Rosenberg, Brian R. Davidson, Anna Schurich, A. Katharina Simon, Mala K. Maini〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Tissue-resident memory T cells have critical roles in long-term pathogen and tumor immune surveillance in the liver. We investigate the role of autophagy in equipping human memory T cells to acquire tissue residence and maintain functionality in the immunosuppressive liver environment. By performing 〈em〉ex vivo〈/em〉 staining of freshly isolated cells from human liver tissue, we find that an increased rate of basal autophagy is a hallmark of intrahepatic lymphocytes, particularly liver-resident CD8〈sup〉+〈/sup〉 T cells. CD8〈sup〉+〈/sup〉 T cells with increased autophagy are those best able to proliferate and mediate cytotoxicity and cytokine production. Conversely, blocking autophagy induction results in the accumulation of depolarized mitochondria, a feature of exhausted T cells. Primary hepatic stellate cells or the prototypic hepatic cytokine interleukin (IL)-15 induce autophagy in parallel with tissue-homing/retention markers. Inhibition of T cell autophagy abrogates tissue-residence programming. Thus, upregulation of autophagy adapts CD8〈sup〉+〈/sup〉 T cells to combat mitochondrial depolarization, optimize functionality, and acquire tissue residence.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317073-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Orit Harari-Steinberg, Dorit Omer, Yehudit Gnatek, Oren Pleniceanu, Sanja Goldberg, Osnat Cohen-Zontag, Sara Pri-Chen, Itamar Kanter, Nissim Ben Haim, Eli Becker, Roi Ankawa, Yaron Fuchs, Tomer Kalisky, Zohar Dotan, Benjamin Dekel〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉End-stage renal disease is a worldwide epidemic requiring renal replacement therapy. Harvesting tissue from failing kidneys and autotransplantation of tissue progenitors could theoretically delay the need for dialysis. Here we use healthy and end-stage human adult kidneys to robustly expand proliferative kidney epithelial cells and establish 3D kidney epithelial cultures termed “nephrospheres.” Formation of nephrospheres reestablishes renal identity and function in primary cultures. Transplantation into NOD/SCID mice shows that nephrospheres restore self-organogenetic properties lost in monolayer cultures, allowing long-term engraftment as tubular structures, potentially adding nephron segments and demonstrating self-organization as critical to survival. Furthermore, long-term tubular engraftment of nephrospheres is functionally beneficial in murine models of chronic kidney disease. Remarkably, nephrospheres inhibit pro-fibrotic collagen production in cultured fibroblasts via paracrine modulation, while transplanted nephrospheres induce transcriptional signatures of proliferation and release from quiescence, suggesting re-activation of endogenous repair. These data support the use of human nephrospheres for renal cell therapy.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317048-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Carmit Hillel-Karniel, Chava Rosen, Irit Milman-Krentsis, Ran Orgad, Esther Bachar-Lustig, Elias Shezen, Yair Reisner〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Induction of lung regeneration by transplantation of lung progenitor cells is a critical preclinical challenge. Recently, we demonstrated that robust lung regeneration can be achieved if the endogenous stem cell niches in the recipient’s lung are vacated by sub-lethal pre-conditioning. However, overcoming MHC barriers is an additional requirement for clinical application of this attractive approach. We demonstrate here that durable tolerance toward mis-matched lung progenitors and their derivatives can be achieved without any chronic immune suppression, by virtue of co-transplantation with hematopoietic progenitors from the same donor. Initial proof of concept of this approach was attained by transplantation of fetal lung cells comprising both hematopoietic and non-hematopoietic progenitors. Furthermore, an even higher rate of blood and epithelial lung chimerism was attained by using adult lung cells supplemented with bone marrow hematopoietic progenitors. These results lay the foundation for repair of lung injury through a procedure akin to bone marrow transplantation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317152-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Amanda H. Lewis, Jörg Grandl〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Piezo1 ion channels are activated by mechanical stimuli and mediate the sensing of blood flow. Although cryo-electron microscopy (cryo-EM) structures have revealed the overall architecture of Piezo1, the precise domains involved in activation and subsequent inactivation have remained elusive. Here, we perform a targeted chimeric screen between Piezo1 and the closely related isoform Piezo2 and use electrophysiology to characterize their inactivation kinetics during mechanical stimulation. We identify three small subdomains within the extracellular cap that individually can confer the distinct kinetics of inactivation of Piezo2 onto Piezo1. We further show by cysteine crosslinking that conformational flexibility of these subdomains is required for mechanical activation to occur and that electrostatic interactions functionally couple the cap to the extensive blades, which have been proposed to function as sensors of membrane curvature and tension. This study provides a demonstration of internal gating motions involved in mechanotransduction by Piezo1.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316973-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Jarrod S. Johnson, Nicholas De Veaux, Alexander W. Rives, Xavier Lahaye, Sasha Y. Lucas, Brieuc P. Perot, Marine Luka, Victor Garcia-Paredes, Lynn M. Amon, Aaron Watters, Ghaith Abdessalem, Alan Aderem, Nicolas Manel, Dan R. Littman, Richard Bonneau, Mickaël M. Ménager〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Transcriptional programming of the innate immune response is pivotal for host protection. However, the transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During HIV-1 infection, human dendritic cells (DCs) can detect the virus through an innate sensing pathway, leading to antiviral interferon and DC maturation. Here, we develop an iterative experimental and computational approach to map the HIV-1 innate response circuitry in monocyte-derived DCs (MDDCs). By integrating genome-wide chromatin accessibility with expression kinetics, we infer a gene regulatory network that links 542 transcription factors with 21,862 target genes. We observe that an interferon response is required, yet insufficient, to drive MDDC maturation and identify PRDM1 and RARA as essential regulators of the interferon response and MDDC maturation, respectively. Our work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting complexity and cooperativity in the regulatory circuit controlling the response to infection.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317115-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 3〈/p〉 〈p〉Author(s): Sergio D. Moreno-Velásquez, Su Hlaing Tint, Valentina del Olmo Toledo, Sanda Torsin, Sonakshi De, J. Christian Pérez〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Integrating nutrient sensing with the synthesis of complex molecules is a central feature of metabolism. Yet the regulatory mechanisms underlying such integration are often unknown. Here, we establish that the transcription regulators Rtg1/3 are key determinants of sphingolipid homeostasis in the human fungal pathogen 〈em〉Candida albicans〈/em〉. Quantitative analysis of the 〈em〉C. albicans〈/em〉 lipidome reveals Rtg1/3-dependent alterations in all complex sphingolipids and their precursors, ceramides. Mutations in the regulators render the fungus susceptible to myriocin, a sphingolipid synthesis inhibitor. Rtg1/3 exert control on the expression of several enzymes involved in the synthesis of sphingolipids’ building blocks, and the regulators are activated upon engulfment of 〈em〉C. albicans〈/em〉 cells by human neutrophils. We demonstrate that Rtg1p and Rtg3p are regulated at two levels, one in response to sphingolipids and the other by the nutrient sensor TOR. Our findings, therefore, indicate that the Rtg1/3 system integrates nutrient sensing into the synthesis of complex lipids.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316729-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Julianna Blagih, Fabio Zani, Probir Chakravarty, Marc Hennequart, Steven Pilley, Sebastijan Hobor, Andreas K. Hock, Josephine B. Walton, Jennifer P. Morton, Eva Gronroos, Susan Mason, Ming Yang, Iain McNeish, Charles Swanton, Karen Blyth, Karen H. Vousden〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Loss of p53 function contributes to the development of many cancers. While cell-autonomous consequences of p53 mutation have been studied extensively, the role of p53 in regulating the anti-tumor immune response is still poorly understood. Here, we show that loss of p53 in cancer cells modulates the tumor-immune landscape to circumvent immune destruction. Deletion of p53 promotes the recruitment and instruction of suppressive myeloid CD11b〈sup〉+〈/sup〉 cells, in part through increased expression of CXCR3/CCR2-associated chemokines and macrophage colony-stimulating factor (M-CSF), and attenuates the CD4〈sup〉+〈/sup〉 T helper 1 (Th1) and CD8〈sup〉+〈/sup〉 T cell responses 〈em〉in vivo〈/em〉. p53-null tumors also show an accumulation of suppressive regulatory T (Treg) cells. Finally, we show that two key drivers of tumorigenesis, activation of KRAS and deletion of p53, cooperate to promote immune tolerance.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471931678X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Eleni Maniati, Chiara Berlato, Ganga Gopinathan, Owen Heath, Panoraia Kotantaki, Anissa Lakhani, Jacqueline McDermott, Colin Pegrum, Robin M. Delaine-Smith, Oliver M.T. Pearce, Priyanka Hirani, Joash D. Joy, Ludmila Szabova, Ruth Perets, Owen J. Sansom, Ronny Drapkin, Peter Bailey, Frances R. Balkwill〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Although there are many prospective targets in the tumor microenvironment (TME) of high-grade serous ovarian cancer (HGSOC), pre-clinical testing is challenging, especially as there is limited information on the murine TME. Here, we characterize the TME of six orthotopic, transplantable syngeneic murine HGSOC lines established from genetic models and compare these to patient biopsies. We identify significant correlations between the transcriptome, host cell infiltrates, matrisome, vasculature, and tissue modulus of mouse and human TMEs, with several stromal and malignant targets in common. However, each model shows distinct differences and potential vulnerabilities that enabled us to test predictions about response to chemotherapy and an anti-IL-6 antibody. Using machine learning, the transcriptional profiles of the mouse tumors that differed in chemotherapy response are able to classify chemotherapy-sensitive and -refractory patient tumors. These models provide useful pre-clinical tools and may help identify subgroups of HGSOC patients who are most likely to respond to specific therapies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316845-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Jesus García-López, Kirby Wallace, Joel H. Otero, Rachelle Olsen, Yong-dong Wang, David Finkelstein, Brian L. Gudenas, Jerold E. Rehg, Paul Northcott, Andrew M. Davidoff, Kevin W. Freeman〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Loss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). 〈em〉MYCN〈/em〉 amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy 〈em〉MYCN〈/em〉 tumors, larger deletions correlate with 〈em〉MYCN〈/em〉 amplification, indicating two tumor suppressor regions in 1p36, only one of which facilitates 〈em〉MYCN〈/em〉 oncogenesis. To better define this region, we genome-edited the syntenic 1p36 locus in primary mouse neural crest cells (NCCs), a putative NBL cell of origin. In 〈em〉in vitro〈/em〉 cell transformation assays, we show that 〈em〉Chd5〈/em〉 loss confers most of the 〈em〉MYCN〈/em〉-independent tumor suppressor effects of 1p36 LOH. In contrast, 〈em〉MYCN〈/em〉-driven tumorigenesis selects for NCCs with 〈em〉Arid1a〈/em〉 deletions from a pool of NCCs with randomly sized 1p36 deletions, establishing 〈em〉Arid1a〈/em〉 as the 〈em〉MYCN〈/em〉-associated tumor suppressor. Our findings reveal that 〈em〉Arid1a〈/em〉 loss collaborates with oncogenic 〈em〉MYCN〈/em〉 and better define the tumor suppressor functions of 1p36 LOH in NBL.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471931705X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Ashley N. Opalka, Wen-qiang Huang, Jun Liu, Hualou Liang, Dong V. Wang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The hippocampus and retrosplenial cortex (RSC) play indispensable roles in memory formation, and importantly, a hippocampal oscillation known as ripple is key to consolidation of new memories. However, it remains unclear how the hippocampus and RSC communicate and the role of ripple oscillation in coordinating the activity between these two brain regions. Here, we record from the dorsal hippocampus and RSC simultaneously in freely behaving mice during sleep and reveal that the RSC displays a pre-ripple activation associated with slow and fast oscillations. Immediately after ripples, a subpopulation of RSC putative inhibitory neurons increases firing activity, while most RSC putative excitatory neurons decrease activity. Consistently, optogenetic stimulation of this hippocampus-RSC pathway activates and suppresses RSC putative inhibitory and excitatory neurons, respectively. These results suggest that the dorsal hippocampus mainly inhibits RSC activity via its direct innervation of RSC inhibitory neurons, which overshadows the RSC in supporting learning and memory functions.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471931695X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Kun Wang, Julian Hinz, Yue Zhang, Tod R. Thiele, Aristides B. Arrenberg〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Non-cortical visual areas in vertebrate brains extract relevant stimulus features, such as motion, object size, and location, to support diverse behavioral tasks. The optic tectum and pretectum, two primary visual areas in zebrafish, are involved in motion processing, and yet their differential neural representation of behaviorally relevant visual features is unclear. Here, we characterize receptive fields (RFs) of motion-sensitive neurons in the diencephalon and midbrain. We show that RFs of many pretectal neurons are large and sample the lower visual field, whereas RFs of tectal neurons are mostly small-size selective and sample the upper nasal visual field more densely. Furthermore, optomotor swimming can reliably be evoked by presenting forward motion in the lower temporal visual field alone, matching the lower visual field bias of the pretectum. Thus, tectum and pretectum extract different visual features from distinct regions of visual space, which is likely a result of their adaptations to hunting and optomotor behavior, respectively.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471931681X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Gabriella Saro, Andrei-Stefan Lia, Saurabh Thapliyal, Filipe Marques, Karl Emanuel Busch, Dominique A. Glauser〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Pain sensation and aversive behaviors entail the activation of nociceptor neurons, whose function is largely conserved across animals. The functional heterogeneity of nociceptors and ethical concerns are challenges for their study in mammalian models. Here, we investigate the function of a single type of genetically identified 〈em〉C. elegans〈/em〉 thermonociceptor named FLP. Using calcium imaging 〈em〉in vivo〈/em〉, we demonstrate that FLP encodes thermal information in a tonic and graded manner over a wide thermal range spanning from noxious cold to noxious heat (8°C–36°C). This tonic-signaling mode allows FLP to trigger sustained behavioral changes necessary for escape behavior. Furthermore, we identify specific transient receptor potential, voltage-gated calcium, and sodium “leak” channels controlling sensory gain, thermal sensitivity, and signal kinetics, respectively, and show that the ryanodine receptor is required for long-lasting activation. Our work elucidates the task distribution among specific ion channels to achieve remarkable sensory properties in a tonic thermonociceptor 〈em〉in vivo〈/em〉.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316791-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Maria Jäpel, Fabian Gerth, Takeshi Sakaba, Jelena Bacetic, Lijun Yao, Seong-Joo Koo, Tanja Maritzen, Christian Freund, Volker Haucke〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The rapid replenishment of release-ready synaptic vesicles (SVs) at a limiting number of presynaptic release sites is required to sustain high-frequency neurotransmission in CNS neurons. Failure to clear release sites from previously exocytosed material has been shown to impair vesicle replenishment and, therefore, fast neurotransmission. The identity of this material and the machinery that removes it from release sites have remained enigmatic. Here we show that the endocytic scaffold protein intersectin 1 clears release sites by direct SH3 domain-mediated association with a non-canonical proline-rich segment of synaptobrevin assembled into the SNARE complex for neuroexocytosis. Acute structure-based or sustained genetic interference with SNARE complex recognition by intersectin 1 causes a rapid stimulation frequency-dependent depression of neurotransmission due to impaired replenishment of release-ready SVs. These findings identify a key molecular mechanism that underlies exo-endocytic coupling during fast neurotransmitter release at central synapses.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316924-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 4〈/p〉 〈p〉Author(s): Shaobo Wang, Qiong Zhang, Shashi Kant Tiwari, Gianluigi Lichinchi, Edwin H. Yau, Hui Hui, Wanyu Li, Frank Furnari, Tariq M. Rana〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉We perform a CRISPR-Cas9 genome-wide screen in glioblastoma stem cells and identify integrin αvβ5 as an internalization factor for Zika virus (ZIKV). Expression of αvβ5 is correlated with ZIKV susceptibility in various cells and tropism in developing human cerebral cortex. A blocking antibody against integrin αvβ5, but not αvβ3, efficiently inhibits ZIKV infection. ZIKV binds to cells but fails to internalize when treated with integrin αvβ5-blocking antibody. αvβ5 directly binds to ZIKV virions and activates focal adhesion kinase, which is required for ZIKV infection. Finally, αvβ5 blocking antibody or two inhibitors, SB273005 and cilengitide, reduces ZIKV infection and alleviates ZIKV-induced pathology in human neural stem cells and in mouse brain. Altogether, our findings identify integrin αvβ5 as an internalization factor for ZIKV, providing a promising therapeutic target, as well as two drug candidates for prophylactic use or treatments for ZIKV infections.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719314913-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Jenny Joutsen, Alejandro Jose Da Silva, Jens Christian Luoto, Marek Andrzej Budzynski, Anna Serafia Nylund, Aurelie de Thonel, Jean-Paul Concordet, Valérie Mezger, Délara Sabéran-Djoneidi, Eva Henriksson, Lea Sistonen〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Maintenance of protein homeostasis, through inducible expression of molecular chaperones, is essential for cell survival under protein-damaging conditions. The expression and DNA-binding activity of heat shock factor 2 (HSF2), a member of the heat shock transcription factor family, increase upon exposure to prolonged proteotoxicity. Nevertheless, the specific roles of HSF2 and the global HSF2-dependent gene expression profile during sustained stress have remained unknown. Here, we found that HSF2 is critical for cell survival during prolonged proteotoxicity. Strikingly, our RNA sequencing (RNA-seq) analyses revealed that impaired viability of HSF2-deficient cells is not caused by inadequate induction of molecular chaperones but is due to marked downregulation of cadherin superfamily genes. We demonstrate that HSF2-dependent maintenance of cadherin-mediated cell-cell adhesion is required for protection against stress induced by proteasome inhibition. This study identifies HSF2 as a key regulator of cadherin superfamily genes and defines cell-cell adhesion as a determinant of proteotoxic stress resistance.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316948-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Qiang Li, Fengbiao Mao, Bo Zhou, Yuanhao Huang, Zhenhua Zou, Aaron D. denDekker, Jing Xu, Sean Hou, Jie Liu, Yali Dou, Rajesh C. Rao〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉How ubiquitous transcription factors (TFs) coordinate temporal inputs from broadly expressed epigenetic factors to control cell fate remains poorly understood. Here, we uncover a molecular relationship between p53, an abundant embryonic TF, and WDR5, an essential member of the MLL chromatin modifying complex, that regulates mouse embryonic stem cell fate. Wild-type 〈em〉Wdr5〈/em〉 or transient 〈em〉Wdr5〈/em〉 knockout promotes a distinct pattern of global chromatin accessibility and spurs neuroectodermal differentiation through an RbBP5-dependent process in which WDR5 binds to, and activates transcription of, neural genes. 〈em〉Wdr5〈/em〉 rescue after its prolonged inhibition targets WDR5 to mesoderm lineage-specifying genes, stimulating differentiation toward mesoderm fates in a p53-dependent fashion. Finally, we identify a direct interaction between WDR5 and p53 that enables their co-recruitment to, and regulation of, genes known to control cell proliferation and fate. Our results unmask p53-dependent mechanisms that temporally integrate epigenetic WDR5 inputs to drive neuroectoderm and mesoderm differentiation from pluripotent cells.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316961-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Gaëlle Cordonnier, Amit Mandoli, Nicolas Cagnard, Guillaume Hypolite, Ludovic Lhermitte, Els Verhoeyen, Vahid Asnafi, Niall Dillon, Elizabeth Macintyre, Joost H.A. Martens, Jonathan Bond〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mutations and deletions of polycomb repressive complex (PRC) components are increasingly recognized to affect tumor biology in a range of cancers. However, little is known about how genetic alterations of PRC-interacting molecules such as the core binding factor (CBF) complex influence polycomb activity. We report that the acute myeloid leukemia (AML)-associated CBFβ-SMMHC fusion oncoprotein physically interacts with the PRC1 complex and that these factors co-localize across the AML genome in an apparently PRC2-independent manner. Depletion of CBFβ-SMMHC caused substantial increases in genome-wide PRC1 binding and marked changes in the association between PRC1 and the CBF DNA-binding subunit RUNX1. PRC1 was more likely to be associated with actively transcribed genes in CBFβ-SMMHC-expressing cells. CBFβ-SMMHC depletion had heterogeneous effects on gene expression, including significant reductions in transcription of ribosomal loci occupied by PRC1. Our results provide evidence that CBFβ-SMMHC markedly and diversely affects polycomb recruitment and transcriptional regulation across the AML genome.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316766-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Jacob D. Eccles, Ronald B. Turner, Nicole A. Kirk, Lyndsey M. Muehling, Larry Borish, John W. Steinke, Spencer C. Payne, Paul W. Wright, Deborah Thacker, Sampo J. Lahtinen, Markus J. Lehtinen, Peter W. Heymann, Judith A. Woodfolk〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Human rhinoviruses cause the common cold and exacerbate chronic respiratory diseases. Although infection elicits neutralizing antibodies, these do not persist or cross-protect across multiple rhinovirus strains. To analyze rhinovirus-specific B cell responses in humans, we developed techniques using intact RV-A16 and RV-A39 for high-throughput high-dimensional single-cell analysis, with parallel assessment of antibody isotypes in an experimental infection model. Our approach identified T-bet+ B cells binding both viruses that account for ∼5% of CXCR5− memory B cells. These B cells infiltrate nasal tissue and expand in the blood after infection. Their rapid secretion of heterotypic immunoglobulin G (IgG) 〈em〉in vitro〈/em〉, but not IgA, matches the nasal antibody profile post-infection. By contrast, CXCR5+ memory B cells binding a single virus are clonally distinct, absent in nasal tissue, and secrete homotypic IgG and IgA, mirroring the systemic response. Temporal and spatial functions of dichotomous memory B cells might explain the ability to resolve infection while rendering the host susceptible to re-infection.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316778-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Madlaina Boillat, Pierre-Mehdi Hammoudi, Sunil Kumar Dogga, Stéphane Pagès, Maged Goubran, Ivan Rodriguez, Dominique Soldati-Favre〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉In rodents, the decrease of felid aversion induced by 〈em〉Toxoplasma gondii〈/em〉, a phenomenon termed fatal attraction, is interpreted as an adaptive manipulation by the neurotropic protozoan parasite. With the aim of understanding how the parasite induces such specific behavioral modifications, we performed a multiparametric analysis of 〈em〉T. gondii〈/em〉-induced changes on host behavior, physiology, and brain transcriptome as well as parasite cyst load and distribution. Using a set of complementary behavioral tests, we provide strong evidence that 〈em〉T. gondii〈/em〉 lowers general anxiety in infected mice, increases explorative behaviors, and surprisingly alters predator aversion without selectivity toward felids. Furthermore, we show a positive correlation between the severity of the behavioral alterations and the cyst load, which indirectly reflects the level of inflammation during brain colonization. Taken together, these findings refute the myth of a selective loss of cat fear in 〈em〉T. gondii〈/em〉-infected mice and point toward widespread immune-related alterations of behaviors.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316699-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Davide Pisu, Lu Huang, Jennifer K. Grenier, David G. Russell〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Dissecting the 〈em〉in vivo〈/em〉 host-pathogen interplay is crucial to understanding the molecular mechanisms governing control or progression of intracellular infections. In this work, we explore the 〈em〉in vivo〈/em〉 molecular dynamics of Mtb infection by performing dual RNA-seq on 〈em〉Mycobacterium tuberculosis〈/em〉-infected, ontogenetically distinct macrophage lineages isolated directly from murine lungs. We first define an 〈em〉in vivo〈/em〉 signature of 180 genes specifically upregulated by Mtb in mouse lung macrophages, then we uncover a divergent transcriptional response of the bacteria between alveolar macrophages that appear to sustain Mtb growth through increased access to iron and fatty acids and interstitial macrophages that restrict Mtb growth through iron sequestration and higher levels of nitric oxide. We use an enrichment protocol for bacterial transcripts, which enables us to probe Mtb physiology at the host cell level in an 〈em〉in vivo〈/em〉 environment, with broader application in understanding the infection dynamics of intracellular pathogens in general.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316833-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Sheera R. Rosenbaum, Meghan Knecht, Mehri Mollaee, Zhijiu Zhong, Dan A. Erkes, Peter A. McCue, Inna Chervoneva, Adam C. Berger, Jennifer A. Lo, David E. Fisher, Jeffrey E. Gershenwald, Michael A. Davies, Timothy J. Purwin, Andrew E. Aplin〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Immune checkpoint inhibitors have improved patient survival in melanoma, but the innate resistance of many patients necessitates the investigation of alternative immune targets. Many immune checkpoint proteins lack proper characterization, including V-domain Ig suppressor of T cell activation (VISTA). VISTA expression on immune cells can suppress T cell activity; however, few studies have investigated its expression and regulation in cancer cells. In this study, we observe that VISTA is expressed in melanoma patient samples and cell lines. Tumor cell-specific expression of VISTA promotes tumor onset 〈em〉in vivo〈/em〉, associated with increased intratumoral T regulatory cells, and enhanced PDL-1 expression on tumor-infiltrating macrophages. VISTA transcript levels are regulated by the stemness factor Forkhead box D3 (FOXD3). BRAF inhibition upregulates FOXD3 and reduces VISTA expression. Overall, this study demonstrates melanoma cell expression of VISTA and its regulation by FOXD3, contributing to the rationale for therapeutic strategies that combine targeted inhibitors with immune checkpoint blockade.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316936-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Yoshihiro Takadate, Tatsunari Kondoh, Manabu Igarashi, Junki Maruyama, Rashid Manzoor, Hirohito Ogawa, Masahiro Kajihara, Wakako Furuyama, Masahiro Sato, Hiroko Miyamoto, Reiko Yoshida, Terence E. Hill, Alexander N. Freiberg, Heinz Feldmann, Andrea Marzi, Ayato Takada〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Fruit bats are suspected to be natural hosts of filoviruses, including Ebola virus (EBOV) and Marburg virus (MARV). Interestingly, however, previous studies suggest that these viruses have different tropisms depending on the bat species. Here, we show a molecular basis underlying the host-range restriction of filoviruses. We find that bat-derived cell lines FBKT1 and ZFBK13-76E show preferential susceptibility to EBOV and MARV, respectively, whereas the other bat cell lines tested are similarly infected with both viruses. In FBKT1 and ZFBK13-76E, unique amino acid (aa) sequences are found in the Niemann-Pick C1 (NPC1) protein, one of the cellular receptors interacting with the filovirus glycoprotein (GP). These aa residues, as well as a few aa differences between EBOV and MARV GPs, are crucial for the differential susceptibility to filoviruses. Taken together, our findings indicate that the heterogeneity of bat NPC1 orthologs is an important factor controlling filovirus species-specific host tropism.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316997-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 14 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 2〈/p〉 〈p〉Author(s): Maria Paola Santini, Daniela Malide, Gabriel Hoffman, Gaurav Pandey, Valentina D’Escamard, Aya Nomura-Kitabayashi, Ilsa Rovira, Hiroshi Kataoka, Jordi Ochando, Richard P. Harvey, Toren Finkel, Jason C. Kovacic〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉PDGFRα〈sup〉+〈/sup〉 mesenchymal progenitor cells are associated with pathological fibro-adipogenic processes. Conversely, a beneficial role for these cells during homeostasis or in response to revascularization and regeneration stimuli is suggested, but remains to be defined. We studied the molecular profile and function of PDGFRα〈sup〉+〈/sup〉 cells in order to understand the mechanisms underlying their role in fibrosis versus regeneration. We show that PDGFRα〈sup〉+〈/sup〉 cells are essential for tissue revascularization and restructuring through injury-stimulated remodeling of stromal and vascular components, context-dependent clonal expansion, and ultimate removal of pro-fibrotic PDGFRα〈sup〉+〈/sup〉-derived cells. Tissue ischemia modulates the PDGFRα〈sup〉+〈/sup〉 phenotype toward cells capable of remodeling the extracellular matrix and inducing cell-cell and cell-matrix adhesion, likely favoring tissue repair. Conversely, pathological healing occurs if PDGFRα〈sup〉+〈/sup〉-derived cells persist as terminally differentiated mesenchymal cells. These studies support a context-dependent “yin-yang” biology of tissue-resident mesenchymal progenitor cells, which possess an innate ability to limit injury expansion while also promoting fibrosis in an unfavorable environment.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317024-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 7 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 1〈/p〉 〈p〉Author(s): Simon Jenni, Louis-Marie Bloyet, Ruben Diaz-Avalos, Bo Liang, Sean P.J. Whelan, Nikolaus Grigorieff, Stephen C. Harrison〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The large (L) proteins of non-segmented, negative-strand RNA viruses are multifunctional enzymes that produce capped, methylated, and polyadenylated mRNA and replicate the viral genome. A phosphoprotein (P), required for efficient RNA-dependent RNA polymerization from the viral ribonucleoprotein (RNP) template, regulates the function and conformation of the L protein. We report the structure of vesicular stomatitis virus L in complex with its P cofactor determined by electron cryomicroscopy at 3.0 Å resolution, enabling us to visualize bound segments of P. The contacts of three P segments with multiple L domains show how P induces a closed, compact, initiation-competent conformation. Binding of P to L positions its N-terminal domain adjacent to a putative RNA exit channel for efficient encapsidation of newly synthesized genomes with the nucleoprotein and orients its C-terminal domain to interact with an RNP template. The model shows that a conserved tryptophan in the priming loop can support the initiating 5′ nucleotide.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719316742-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Maria Eugenia Villar, Paul Marchal, Haydee Viola, Martin Giurfa〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Si Young Lee, Stevephen Hung, Caroline Esnault, Rakesh Pathak, Kory R. Johnson, Oluwadamilola Bankole, Akira Yamashita, Hongen Zhang, Henry L. Levin〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Maurizio Di Marzo, Humberto Herrera-Ubaldo, Elisabetta Caporali, Ondřej Novák, Miroslav Strnad, Vicente Balanzà, Ignacio Ezquer, Marta A. Mendes, Stefan de Folter, Lucia Colombo〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Oliver J. Harrison, Julia Brasch, Phinikoula S. Katsamba, Goran Ahlsen, Alex J. Noble, Hanbin Dan, Rosemary V. Sampogna, Clinton S. Potter, Bridget Carragher, Barry Honig, Lawrence Shapiro〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Evdokia Michalopoulou, Francesca R. Auciello, Vinay Bulusu, David Strachan, Andrew D. Campbell, Jacqueline Tait-Mulder, Saadia A. Karim, Jennifer P. Morton, Owen J. Sansom, Jurre J. Kamphorst〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Kim A. Ngo, Kensei Kishimoto, Jeremy Davis-Turak, Aditya Pimplaskar, Zhang Cheng, Roberto Spreafico, Emily Y. Chen, Amy Tam, Gourisankar Ghosh, Simon Mitchell, Alexander Hoffmann〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Marek Wagner, Kafi N. Ealey, Hiroe Tetsu, Tsuyoshi Kiniwa, Yasutaka Motomura, Kazuyo Moro, Shigeo Koyasu〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Xiaofei Gao, Zhaohuan Zhang, Tomoyuki Mashimo, Bo Shen, James Nyagilo, Hao Wang, Yihui Wang, Zhida Liu, Aditi Mulgaonkar, Xiao-Ling Hu, Sara G.M. Piccirillo, Ugur Eskiocak, Digant P. Davé, Song Qin, Yongjie Yang, Xiankai Sun, Yang-Xin Fu, Hui Zong, Wenzhi Sun, Robert M. Bachoo〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Laura R. Ganser, Chia-Chieh Chu, Hal P. Bogerd, Megan L. Kelly, Bryan R. Cullen, Hashim M. Al-Hashimi〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Rajiv Kumar, Patrick T. Bunn, Siddharth Sankar Singh, Susanna S. Ng, Marcela Montes de Oca, Fabian De Labastida Rivera, Shashi Bhushan Chauhan, Neetu Singh, Rebecca J. Faleiro, Chelsea L. Edwards, Teija C.M. Frame, Meru Sheel, Rebecca J. Austin, Steven W. Lane, Tobias Bald, Mark J. Smyth, Geoffrey.R. Hill, Shannon E. Best, Ashraful Haque, Dillon Corvino〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Kwok-ho Lam, Jacqueline M. Tremblay, Edwin Vazquez-Cintron, Kay Perry, Celinia Ondeck, Robert P. Webb, Patrick M. McNutt, Charles B. Shoemaker, Rongsheng Jin〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Andrew Rallis, Juan A. Navarro, Mathias Rass, Amélie Hu, Serge Birman, Stephan Schneuwly, Pascal P. Thérond〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Ben A. Duffy, ManKin Choy, Jin Hyung Lee〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Oren Peles, Uri Werner-Reiss, Hagai Bergman, Zvi Israel, Eilon Vaadia〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Yuelin Zhang, Zhao Zhang, Peikai Chen, Chui Yan Ma, Cheng Li, Tiffany Y.K. Au, Vivian Tam, Yan Peng, Ron Wu, Kenneth Man Chee Cheung, Pak C. Sham, Hung-fat Tse, Danny Chan, Victor Y. Leung, Kathryn S.E. Cheah, Qizhou Lian〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Marco Brondi, Monica Moroni, Dania Vecchia, Manuel Molano-Mazón, Stefano Panzeri, Tommaso Fellin〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Alexander J. Federation, Vivek Nandakumar, Brian C. Searle, Andrew Stergachis, Hao Wang, Lindsay K. Pino, Gennifer Merrihew, Ying S. Ting, Nicholas Howard, Tanya Kutyavin, Michael J. MacCoss, John A. Stamatoyannopoulos〈/p〉

Description: 〈p〉Publication date: 25 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 8〈/p〉 〈p〉Author(s): Yun Song, Lisbeth Dagil, Louise Fairall, Naomi Robertson, Mingxuan Wu, T.J. Ragan, Christos G. Savva, Almutasem Saleh, Nobuhiro Morone, Micha B.A. Kunze, Andrew G. Jamieson, Philip A. Cole, D. Flemming Hansen, John W.R. Schwabe〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Mu-Yan Cai, Connor E. Dunn, Wenxu Chen, Bose S. Kochupurakkal, Huy Nguyen, Lisa A. Moreau, Geoffrey I. Shapiro, Kalindi Parmar, David Kozono, Alan D. D’Andrea〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Wei Song, Jan A. Veenstra, Norbert Perrimon〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Christin Suenkel, Daniel Cavalli, Simone Massalini, Federico Calegari, Nikolaus Rajewsky〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Siddharth De, Callum Campbell, Ashok R. Venkitaraman, Alessandro Esposito〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Rocco Lucero, Valentina Zappulli, Alessandro Sammarco, Oscar D. Murillo, Pike See Cheah, Srimeenakshi Srinivasan, Eric Tai, David T. Ting, Zhiyun Wei, Matthew E. Roth, Louise C. Laurent, Anna M. Krichevsky, Xandra O. Breakefield, Aleksandar Milosavljevic〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Simone Joas, Ulrike Sauermann, Berit Roshani, Antonina Klippert, Maria Daskalaki, Kerstin Mätz-Rensing, Nicole Stolte-Leeb, Anke Heigele, Gregory K. Tharp, Prachi Mehrotra Gupta, Sydney Nelson, Steven Bosinger, Laura Parodi, Luis Giavedoni, Guido Silvestri, Daniel Sauter, Christiane Stahl-Hennig, Frank Kirchhoff〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Daniela Ivanova, Cordelia Imig, Marcial Camacho, Annika Reinhold, Debarpan Guhathakurta, Carolina Montenegro-Venegas, Michael A. Cousin, Eckart D. Gundelfinger, Christian Rosenmund, Benjamin Cooper, Anna Fejtova〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Lien Verboom, Arne Martens, Dario Priem, Esther Hoste, Mozes Sze, Hanna Vikkula, Lisette Van Hove, Sofie Voet, Jana Roels, Jonathan Maelfait, Laura Bongiovanni, Alain de Bruin, Charlotte L. Scott, Yvan Saeys, Manolis Pasparakis, Mathieu J.M. Bertrand, Geert van Loo〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Mehmet F. Keleş, Ben J. Hardcastle, Carola Städele, Qi Xiao, Mark A. Frye〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Francois Brial, Fawaz Alzaid, Kazuhiro Sonomura, Yoichiro Kamatani, Kelly Meneyrol, Aurélie Le Lay, Noémie Péan, Lyamine Hedjazi, Taka-Aki Sato, Nicolas Venteclef, Christophe Magnan, Mark Lathrop, Marc-Emmanuel Dumas, Fumihiko Matsuda, Pierre Zalloua, Dominique Gauguier〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Guifen Wu, Manfred Schmid, Leonor Rib, Patrik Polak, Nicola Meola, Albin Sandelin, Torben Heick Jensen〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Jason S. Bant, Kiah Hardcastle, Samuel A. Ocko, Lisa M. Giocomo〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Christopher E. Rudd, Kittiphat Chanthong, Alison Taylor〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Helen M. Melo, Gisele da S. Seixas da Silva, Marcella Ramos Sant’Ana, Camila Vieira Ligo Teixeira, Julia R. Clarke, Vivian S. Miya Coreixas, Bruno C. de Melo, Juliana T.S. Fortuna, Leticia Forny-Germano, José Henrique Ledo, Maíra S. Oliveira, Claudia P. Figueiredo, Raphaelle Pardossi-Piquard, Frédéric Checler, José María Delgado-García, Agnès Gruart, Licio A. Velloso, Marcio L.F. Balthazar, Dennys E. Cintra, Sergio T. Ferreira〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Cody J. Aros, Manash K. Paul, Carla J. Pantoja, Bharti Bisht, Luisa K. Meneses, Preethi Vijayaraj, Jenna M. Sandlin, Bryan France, Jonathan A. Tse, Michelle W. Chen, David W. Shia, Tammy M. Rickabaugh, Robert Damoiseaux, Brigitte N. Gomperts〈/p〉

Description: 〈p〉Publication date: 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 7〈/p〉 〈p〉Author(s): Leigh D. Plant, Dazhi Xiong, Jesus Romero, Hui Dai, Steve A.N. Goldstein〈/p〉

Description: 〈p〉Publication date: 11 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 6〈/p〉 〈p〉Author(s): Rajan Pandey, Steven Abel, Matthew Boucher, Richard J. Wall, Mohammad Zeeshan, Edward Rea, Aline Freville, Xueqing Maggie Lu, Declan Brady, Emilie Daniel, Rebecca R. Stanway, Sally Wheatley, Gayani Batugedara, Thomas Hollin, Andrew R. Bottrill, Dinesh Gupta, Anthony A. Holder, Karine G. Le Roch, Rita Tewari〈/p〉

Description: 〈p〉Publication date: 11 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 6〈/p〉 〈p〉Author(s): Patrick J. Metz, Keith A. Ching, Tao Xie, Paulina Delgado Cuenca, Sherry Niessen, John H. Tatlock, Kristen Jensen-Pergakes, Brion W. Murray〈/p〉

Description: 〈p〉Publication date: 11 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 6〈/p〉 〈p〉Author(s): Nobu Oshima, Ryo Ishida, Shun Kishimoto, Kristin Beebe, Jeffrey R. Brender, Kazutoshi Yamamoto, Daniel Urban, Ganesha Rai, Michelle S. Johnson, Gloria Benavides, Giuseppe L. Squadrito, Dan Crooks, Joseph Jackson, Abhinav Joshi, Bryan T. Mott, Jonathan H. Shrimp, Michael A. Moses, Min-Jung Lee, Akira Yuno, Tobie D. Lee〈/p〉

Description: 〈p〉Publication date: 11 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 6〈/p〉 〈p〉Author(s): Caihong Wang, Shaosen Zhang, Jie Liu, Yang Tian, Boyuan Ma, Siran Xu, Yan Fu, Yongzhang Luo〈/p〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Mi-Lang Kyun, Sun-Ok Kim, Hee Gu Lee, Jeong-Ah Hwang, Joonsung Hwang, Nak-Kyun Soung, Hyunjoo Cha-Molstad, Sangku Lee, Yong Tae Kwon, Bo Yeon Kim, Kyung Ho Lee〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Primary cilium is an antenna-like microtubule-based cellular sensing structure. Abnormal regulation of the dynamic assembly and disassembly cycle of primary cilia is closely related to ciliopathy and cancer. The Wnt signaling pathway plays a major role in embryonic development and tissue homeostasis, and defects in Wnt signaling are associated with a variety of human diseases, including cancer. In this study, we provide direct evidence of Wnt3a-induced primary ciliogenesis, which includes a continuous pathway showing that the stimulation of Wnt3a, a canonical Wnt ligand, promotes the generation of β-catenin p-S47 epitope by CK1δ, and these events lead to the reorganization of centriolar satellites resulting in primary ciliogenesis. We have also confirmed the application of our findings in MCF-7/ADR cells, a multidrug-resistant tumor cell model. Thus, our data provide a Wnt3a-induced primary ciliogenesis pathway and may provide a clue on how to overcome multidrug resistance in cancer treatment.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300280-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Ayesha Ali, Shafiq M. Syed, M. Fairuz B. Jamaluddin, Yolanda Colino-Sanguino, David Gallego-Ortega, Pradeep S. Tanwar〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The intact vaginal epithelium is essential for women’s reproductive health and provides protection against HIV and sexually transmitted infections. How this epithelium maintains itself remains poorly understood. Here, we used single-cell RNA sequencing (RNA-seq) to define the diverse cell populations in the vaginal epithelium. We show that vaginal epithelial cell proliferation is limited to the basal compartment without any obvious label-retaining cells. Furthermore, we developed vaginal organoids and show that the basal cells have increased organoid forming efficiency. Importantly, Axin2 marks a self-renewing subpopulation of basal cells that gives rise to differentiated cells over time. These cells are ovariectomy-resistant stem cells as they proliferate even in the absence of hormones. Upon hormone supplementation, these cells expand and reconstitute the entire vaginal epithelium. Wnt/β-catenin is essential for the proliferation and differentiation of vaginal stem cells. Together, these data define heterogeneity in vaginal epithelium and identify vaginal epithelial stem cells.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300036-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Takahiro Masuda, Roman Sankowski, Ori Staszewski, Marco Prinz〈/p〉 〈div〉〈p〉Microglia are resident immune cells in the central nervous system (CNS) that are capable of carrying out prominent and various functions during development and adulthood under both homeostatic and disease conditions. Although microglia are traditionally thought to be heterogeneous populations, which potentially allows them to achieve a wide range of responses to environmental changes for the maintenance of CNS homeostasis, a lack of unbiased and high-throughput methods to assess microglia heterogeneity has prevented the study of spatially and temporally distributed microglia subsets. The recent emergence of novel single-cell techniques, such as cytometry by time-of-flight mass spectrometry (CyTOF) and single-cell RNA sequencing, enabled scientists to overcome such limitations and reveal the surprising context-dependent heterogeneity of microglia. In this review, we summarize the current knowledge about the spatial, temporal, and functional diversity of microglia during development, homeostasis, and disease in mice and humans.〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Veronika Horkova, Ales Drobek, Daniel Mueller, Celine Gubser, Veronika Niederlova, Lena Wyss, Carolyn G. King, Dietmar Zehn, Ondrej Stepanek〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Overtly self-reactive T cells are removed during thymic selection. However, it has been recently established that T cell self-reactivity promotes protective immune responses. Apparently, the level of self-reactivity of mature T cells must be tightly balanced. Our mathematical model and experimental data show that the dynamic regulation of CD4- and CD8-LCK coupling establish the self-reactivity of the peripheral T cell pool. The stoichiometry of the interaction between CD8 and LCK, but not between CD4 and LCK, substantially increases upon T cell maturation. As a result, peripheral CD8〈sup〉+〈/sup〉 T cells are more self-reactive than CD4〈sup〉+〈/sup〉 T cells. The different levels of self-reactivity of mature CD8〈sup〉+〈/sup〉 and CD4〈sup〉+〈/sup〉 T cells likely reflect the unique roles of these subsets in immunity. These results indicate that the evolutionary selection pressure tuned the CD4-LCK and CD8-LCK stoichiometries, as they represent the unique parts of the proximal T cell receptor (TCR) signaling pathway, which differ between CD4〈sup〉+〈/sup〉 and CD8〈sup〉+〈/sup〉 T cells.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300176-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Lu Chen, Caitlin M. Roake, Alessandra Galati, Francesca Bavasso, Emanuela Micheli, Isabella Saggio, Stefan Schoeftner, Stefano Cacchione, Maurizio Gatti, Steven E. Artandi, Grazia D. Raffa〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5′ mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of trimethylguanosine synthase 1 (TGS1), the enzyme responsible for cap hypermethylation, increases levels of hTR and telomerase. Diminished trimethylation increases hTR association with the cap-binding complex (CBC) and with Sm chaperone proteins. Loss of TGS1 causes an increase in accumulation of mature hTR in both the nucleus and the cytoplasm compared with controls. In TGS1 mutant cells, increased hTR assembles with telomerase reverse transcriptase (TERT) protein to yield elevated active telomerase complexes and increased telomerase activity, resulting in telomere elongation in cultured human cells. Our results show that TGS1-mediated hypermethylation of the hTR cap inhibits hTR accumulation, restrains levels of assembled telomerase, and limits telomere elongation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300139-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Michael M. Dubreuil, David W. Morgens, Kanji Okumoto, Masanori Honsho, Kévin Contrepois, Brittany Lee-McMullen, Gavin McAllister Traber, Ria S. Sood, Scott J. Dixon, Michael P. Snyder, Yukio Fujiki, Michael C. Bassik〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Reactive oxygen species (ROS) play critical roles in metabolism and disease, yet a comprehensive analysis of the cellular response to oxidative stress is lacking. To systematically identify regulators of oxidative stress, we conducted genome-wide Cas9/CRISPR and shRNA screens. This revealed a detailed picture of diverse pathways that control oxidative stress response, ranging from the TCA cycle and DNA repair machineries to iron transport, trafficking, and metabolism. Paradoxically, disrupting the pentose phosphate pathway (PPP) at the level of phosphogluconate dehydrogenase (PGD) protects cells against ROS. This dramatically alters metabolites in the PPP, consistent with rewiring of upper glycolysis to promote antioxidant production. In addition, disruption of peroxisomal import unexpectedly increases resistance to oxidative stress by altering the localization of catalase. Together, these studies provide insights into the roles of peroxisomal matrix import and the PPP in redox biology and represent a rich resource for understanding the cellular response to oxidative stress.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112472030022X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Panagiota Karagianni, Panagiotis Moulos, Dominic Schmidt, Duncan T. Odom, Iannis Talianidis〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Transcription factor binding to enhancer and promoter regions critical for homeostatic adult gene activation is established during development. To understand how cell-specific gene expression patterns are generated, we study the developmental timing of association of two prominent hepatic transcription factors with gene regulatory regions. Most individual binding events display extraordinarily high temporal variations during liver development. Early and persistent binding is necessary, but not sufficient, for gene activation. Stable gene expression patterns are the result of combinatorial activity of multiple transcription factors, which mark regulatory regions long before activation and promote progressive broadening of active chromatin domains. Both temporally stable and dynamic, short-lived binding events contribute to the developmental maturation of active promoter configurations. The results reveal a developmental bookmarking function of master regulators and illuminate remarkable parallels between the principles employed for gene activation during development, during evolution, and upon mitotic exit.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300152-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Emeline Lawarée, Gytis Jankevicius, Charles Cooper, Ivan Ahel, Stephan Uphoff, Christoph M. Tang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉ADP-ribosylation of proteins is crucial for fundamental cellular processes. Despite increasing examples of DNA ADP-ribosylation, the impact of this modification on DNA metabolism and cell physiology is unknown. Here, we show that the DarTG toxin-antitoxin system from enteropathogenic 〈em〉Escherichia coli〈/em〉 (EPEC) catalyzes reversible ADP-ribosylation of single-stranded DNA (ssDNA). The DarT toxin recognizes specific sequence motifs. EPEC DarG abrogates DarT toxicity by two distinct mechanisms: removal of DNA ADP-ribose (ADPr) groups and DarT sequestration. Furthermore, we investigate how cells recognize and deal with DNA ADP-ribosylation. We demonstrate that DNA ADPr stalls replication and is perceived as DNA damage. Removal of ADPr from DNA requires the sequential activity of two DNA repair pathways, with RecF-mediated homologous recombination likely to transfer ADP-ribosylation from single- to double-stranded DNA (dsDNA) and subsequent nucleotide excision repair eliminating the lesion. Our work demonstrates that these DNA repair pathways prevent the genotoxic effects of DNA ADP-ribosylation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300231-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): S. John Liu, Stephen T. Magill, Harish N. Vasudevan, Stephanie Hilz, Javier E. Villanueva-Meyer, Sydney Lastella, Vikas Daggubati, Jordan Spatz, Abrar Choudhury, Brent A. Orr, Benjamin Demaree, Kyounghee Seo, Sean P. Ferris, Adam R. Abate, Nancy Ann Oberheim Bush, Andrew W. Bollen, Michael W. McDermott, Joseph F. Costello, David R. Raleigh〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Ependymomas exist within distinct genetic subgroups, but the molecular diversity within individual ependymomas is unknown. We perform multiplatform molecular profiling of 6 spatially distinct samples from an ependymoma with 〈em〉C11orf95-RELA〈/em〉 fusion. DNA methylation and RNA sequencing distinguish clusters of samples according to neuronal development gene expression programs that could also be delineated by differences in magnetic resonance blood perfusion. Exome sequencing and phylogenetic analysis reveal epigenomic intratumor heterogeneity and suggest that chromosomal structural alterations may precede accumulation of single-nucleotide variants during ependymoma tumorigenesis. In sum, these findings shed light on the oncogenesis and intratumor heterogeneity of ependymoma.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300279-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Katerina D. Fagan-Solis, Dennis A. Simpson, Rashmi J. Kumar, Luciano G. Martelotto, Lisle E. Mose, Naim U. Rashid, Alice Y. Ho, Simon N. Powell, Y. Hannah Wen, Joel S. Parker, Jorge S. Reis-Filho, John H.J. Petrini, Gaorav P. Gupta〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Breast tumorigenesis models engineered to express a hypomorphic Mre11 allele exhibit increased levels of oncogene-induced DNA damage, R-loop accumulation, and chromosomal instability with a characteristic copy number loss phenotype. Mre11 complex dysfunction is identified in a subset of human triple-negative breast cancers and is associated with increased sensitivity to DNA-damaging therapy and inhibitors of ataxia telangiectasia and Rad3 related (ATR) and poly (ADP-ribose) polymerase (PARP). Thus, deficiencies in the Mre11-dependent DDR drive proliferation and genome instability patterns in p53-deficient breast cancers and represent an opportunity for therapeutic exploitation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300292-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Urszula Brykczynska, Marco Geigges, Sophia J. Wiedemann, Erez Dror, Marianne Böni-Schnetzler, Christoph Hess, Marc Y. Donath, Renato Paro〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The innate immune system safeguards the organism from both pathogenic and environmental stressors. Also, physiologic levels of nutrients affect organismal and intra-cellular metabolism and challenge the immune system. In the long term, over-nutrition leads to low-grade systemic inflammation. Here, we investigate tissue-resident components of the innate immune system (macrophages) and their response to short- and long-term nutritional challenges. We analyze the transcriptomes of six tissue-resident macrophage populations upon acute feeding and identify adipose tissue macrophages and the IL-1 pathway as early sensors of metabolic changes. Furthermore, by comparing functional responses between macrophage subtypes, we propose a regulatory, anti-inflammatory role of heat shock proteins of the HSP70 family in response to long- and short-term metabolic challenges. Our data provide a resource for assessing the impact of nutrition and over-nutrition on the spectrum of macrophages across tissues with a potential for identification of systemic responses.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300140-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Marcus James Robinson, Zhoujie Ding, Catherine Pitt, Erica Janet Brodie, Isaak Quast, David Mathew Tarlinton, Dimitra Zotos〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉It is unknown whether the incremental increases in BCL6 amounts in antigen-activated B cells influence the unfolding differentiation before germinal center (GC) formation. By comparing shortly after immunization the distribution of conventional B cells to those enforced to express BCL6 at the upper quartile of normal and those lacking BCL6 altogether, we determined that B cell representation in the stages before the GC compartment was related to BCL6 amounts. This was not by increased proliferation or suppression of early plasmablast differentiation, but rather by preferential recruitment and progression through these early stages of B cell activation, culminating in preferential transition into GC. Once established, this bias was stable in GC over several weeks; other BCL6-regulated GC B cell behaviors were unaffected. We propose that setting BCL6 amounts very early in activated B cells will be central in determining clonal representation in the GC and thus memory populations.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300188-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Yetao Xu, Xiaoli Sun, Ruling Zhang, Tiefeng Cao, Shi-Ying Cai, James L. Boyer, Xuchen Zhang, Da Li, Yingqun Huang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Pathological activation of TGF-β signaling is universal in fibrosis. Aberrant TGF-β signaling in conjunction with transdifferentiation of hepatic stellate cells (HSCs) into fibrogenic myofibroblasts plays a central role in liver fibrosis. Here we report that the DNA demethylase TET3 is anomalously upregulated in fibrotic livers in both humans and mice. We demonstrate that in human HSCs, TET3 promotes profibrotic gene expression by upregulation of multiple key TGF-β pathway genes, including TGFB1. TET3 binds to target gene promoters, inducing demethylation, which in turn facilitates chromatin remodeling and transcription. We also reveal a positive feedback loop between TGF-β1 and TET3 in both HSCs and hepatocytes. Furthermore, TET3 knockdown ameliorates liver fibrosis in mice. Our results uncover a TET3/TGF-β1 positive feedback loop as a crucial determinant of liver fibrosis and suggest that inhibiting TET3 may represent a therapeutic strategy for liver fibrosis and perhaps other fibrotic diseases.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317577-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Lama AlAbdi, Debapriya Saha, Ming He, Mohd Saleem Dar, Sagar M. Utturkar, Putu Ayu Sudyanti, Stephen McCune, Brice H. Spears, James A. Breedlove, Nadia A. Lanman, Humaira Gowher〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉An aberrant increase in pluripotency gene (PpG) expression due to enhancer reactivation could induce stemness and enhance the tumorigenicity of cancer stem cells. Silencing of PpG enhancers (PpGe) during embryonic stem cell differentiation involves Lsd1-mediated H3K4me1 demethylation and DNA methylation. Here, we observed retention of H3K4me1 and DNA hypomethylation at PpGe associated with a partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post-differentiation. H3K4me1 demethylation in F9 ECCs could not be rescued by Lsd1 overexpression. Given our observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Oct4 interaction with Lsd1 affects its catalytic activity. Our data show a dose-dependent inhibition of Lsd1 activity by Oct4 and retention of H3K4me1 at PpGe in Oct4-overexpressing P19 ECCs. These data suggest that Lsd1-Oct4 interaction in cancer stem cells could establish a “primed” enhancer state that is susceptible to reactivation, leading to aberrant PpG expression.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719315220-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Carlos Mendez-Dorantes, L. Jillianne Tsai, Eva Jahanshir, Felicia Wednesday Lopezcolorado, Jeremy M. Stark〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Repeat-mediated deletions (RMDs) often involve repetitive elements (e.g., short interspersed elements) with sequence divergence that is separated by several kilobase pairs (kbps). We have examined RMDs induced by DNA double-strand breaks (DSBs) under varying conditions of repeat sequence divergence (identical versus 1% and 3% divergent) and DSB/repeat distance (16 bp–28.4 kbp). We find that the BLM helicase promotes RMDs with long DSB/repeat distances (e.g., 28.4 kbp), which is consistent with a role in extensive DSB end resection, because the resection nucleases EXO1 and DNA2 affect RMDs similarly to BLM. In contrast, BLM suppresses RMDs with sequence divergence and intermediate (e.g., 3.3 kbp) DSB/repeat distances, which supports a role in heteroduplex rejection. The role of BLM in heteroduplex rejection is not epistatic with MSH2 and is independent of the annealing factor RAD52. Accordingly, the role of BLM on RMDs is substantially affected by DSB/repeat distance and repeat sequence divergence.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124720300012-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Valeria Yartseva, Leonard D. Goldstein, Julia Rodman, Lance Kates, Mark Z. Chen, Ying-Jiun J. Chen, Oded Foreman, Christian W. Siebel, Zora Modrusan, Andrew S. Peterson, Ana Jovičić〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉How satellite cells and their progenitors balance differentiation and self-renewal to achieve sustainable tissue regeneration is not well understood. A major roadblock to understanding satellite cell fate decisions has been the difficulty of studying this process 〈em〉in vivo〈/em〉. By visualizing expression dynamics of myogenic transcription factors during early regeneration 〈em〉in vivo〈/em〉, we identify the time point at which cells undergo decisions to differentiate or self-renew. Single-cell RNA sequencing reveals heterogeneity of satellite cells, including a subpopulation enriched in 〈em〉Notch2〈/em〉 receptor expression, during both muscle homeostasis and regeneration. Furthermore, we reveal that differentiating cells express the 〈em〉Dll1〈/em〉 ligand. Using antagonistic antibodies, we demonstrate that the DLL1 and NOTCH2 signaling pair is required for satellite cell self-renewal. Thus, differentiating cells provide the self-renewing signal during regeneration, enabling proportional regeneration in response to injury while maintaining the satellite cell pool. These findings have implications for therapeutic control of muscle regeneration.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317656-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Alma Nazlie Mohebiany, Nishada Shakunty Ramphal, Khalad Karram, Giovanni Di Liberto, Tanja Novkovic, Matthias Klein, Federico Marini, Mario Kreutzfeldt, Franziska Härtner, Sonja Maria Lacher, Tobias Bopp, Thomas Mittmann, Doron Merkler, Ari Waisman〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Tumor-necrosis-factor-alpha-induced protein 3 (TNFAIP3), or A20, is a ubiquitin-modifying protein and negative regulator of canonical nuclear factor κB (NF-κB) signaling. Several single-nucleotide polymorphisms in 〈em〉TNFAIP3〈/em〉 are associated with autoimmune diseases, suggesting a role in tissue inflammation. While the role of A20 in peripheral immune cells has been well investigated, less is known about its role in the central nervous system (CNS). Here, we show that microglial A20 is crucial for maintaining brain homeostasis. Without microglial A20, CD8〈sup〉+〈/sup〉 T cells spontaneously infiltrate the CNS and acquire a viral response signature. The combination of infiltrating CD8〈sup〉+〈/sup〉 T cells and activated A20-deficient microglia leads to an increase in VGLUT1〈sup〉+〈/sup〉 terminals and frequency of spontaneous excitatory currents. Ultimately, A20-deficient microglia upregulate genes associated with the antiviral response and neurodegenerative diseases. Together, our data suggest that microglial A20 acts as a sensor for viral infection and a master regulator of CNS homeostasis.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317620-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 30, Issue 5〈/p〉 〈p〉Author(s): Annabel Qi En Ng, Amanda Yunn Ee Ng, Dan Zhang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The plasma membrane (PM) forms extensive close junctions with the cortical endoplasmic reticulum (cER) in many cell types, ranging from yeast to mammals. How cells modulate structural plasticity of ER-PM contacts to accommodate space-demanding cortical events is largely unknown. Here, we report a role for eisosome-driven PM furrows in regulating ER-PM contact plasticity in fission yeast. We demonstrate that eisosome-coated PM invaginations function to stabilize local ER-PM contacts and attenuate cER remodeling dynamics through electrostatic Scs2-Pil1 interactions. We also identify divergent roles of ER-shaping proteins in controlling cER remodeling capacity and ER-PM contact plasticity. Furthermore, we show that eisosome organization is responsive to PM tension variations during active PM remodeling, which may enable adaptive control of ER-PM contact plasticity to potentially coordinate with space-demanding PM events. We thus propose a cellular strategy of modulating membrane contact plasticity by deploying sensory elements at contact sites.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719317632-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉