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Nature Medicine

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https://www.readbyqxmd.com/read/28218919/targeting-casp8-and-fadd-like-apoptosis-regulator-ameliorates-nonalcoholic-steatohepatitis-in-mice-and-nonhuman-primates
#1
Pi-Xiao Wang, Yan-Xiao Ji, Xiao-Jing Zhang, Ling-Ping Zhao, Zhen-Zhen Yan, Peng Zhang, Li-Jun Shen, Xia Yang, Jing Fang, Song Tian, Xue-Yong Zhu, Jun Gong, Xin Zhang, Qiao-Fang Wei, Yong Wang, Jing Li, Lu Wan, Qingguo Xie, Zhi-Gang She, Zhihua Wang, Zan Huang, Hongliang Li
Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1)...
February 20, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28218918/transgenic-expression-of-human-apol1-risk-variants-in-podocytes-induces-kidney-disease-in-mice
#2
Pazit Beckerman, Jing Bi-Karchin, Ae Seo Deok Park, Chengxiang Qiu, Patrick D Dummer, Irfana Soomro, Carine M Boustany-Kari, Steven S Pullen, Jeffrey H Miner, Chien-An A Hu, Tibor Rohacs, Kazunori Inoue, Shuta Ishibe, Moin A Saleem, Matthew B Palmer, Ana Maria Cuervo, Jeffrey B Kopp, Katalin Susztak
African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2)...
February 20, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28191887/the-creatine-kinase-pathway-is-a-metabolic-vulnerability-in-evi1-positive-acute-myeloid-leukemia
#3
Nina Fenouille, Christopher F Bassil, Issam Ben-Sahra, Lina Benajiba, Gabriela Alexe, Azucena Ramos, Yana Pikman, Amy S Conway, Michael R Burgess, Qing Li, Frédéric Luciano, Patrick Auberger, Ilene Galinsky, Daniel J DeAngelo, Richard M Stone, Yi Zhang, Archibald S Perkins, Kevin Shannon, Michael T Hemann, Alexandre Puissant, Kimberly Stegmaier
Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML...
February 13, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28191886/sirtuin-1-regulates-cardiac-electrical-activity-by-deacetylating-the-cardiac-sodium-channel
#4
Ajit Vikram, Christopher M Lewarchik, Jin-Young Yoon, Asma Naqvi, Santosh Kumar, Gina M Morgan, Julia S Jacobs, Qiuxia Li, Young-Rae Kim, Modar Kassan, Jing Liu, Mohanad Gabani, Ajay Kumar, Haider Mehdi, Xiaodong Zhu, Xiaoqun Guan, William Kutschke, Xiaoming Zhang, Ryan L Boudreau, Shengchuan Dai, Daniel S Matasic, Saet-Byel Jung, Kenneth B Margulies, Vikas Kumar, Markus M Bachschmid, Barry London, Kaikobad Irani
The voltage-gated cardiac Na(+) channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na(+) current (INa) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INa via lysine-deacetylation-mediated trafficking of Nav1...
February 13, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28191885/molecular-definition-of-a-metastatic-lung-cancer-state-reveals-a-targetable-cd109-janus-kinase-stat-axis
#5
Chen-Hua Chuang, Peyton G Greenside, Zoë N Rogers, Jennifer J Brady, Dian Yang, Rosanna K Ma, Deborah R Caswell, Shin-Heng Chiou, Aidan F Winters, Barbara M Grüner, Gokul Ramaswami, Andrew L Spencley, Kimberly E Kopecky, Leanne C Sayles, E Alejandro Sweet-Cordero, Jin Billy Li, Anshul Kundaje, Monte M Winslow
Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival...
February 13, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28165481/targeting-mitochondrial-dysfunction-can-restore-antiviral-activity-of-exhausted-hbv-specific-cd8-t-cells-in-chronic-hepatitis-b
#6
Paola Fisicaro, Valeria Barili, Barbara Montanini, Greta Acerbi, Manuela Ferracin, Francesca Guerrieri, Debora Salerno, Carolina Boni, Marco Massari, M Cristina Cavallo, Glenda Grossi, Tiziana Giuberti, Pietro Lampertico, Gabriele Missale, Massimo Levrero, Simone Ottonello, Carlo Ferrari
Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants...
February 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28165480/%C3%AE-lipoic-acid-treatment-prevents-cystine-urolithiasis-in-a-mouse-model-of-cystinuria
#7
Tiffany Zee, Neelanjan Bose, Jarcy Zee, Jennifer N Beck, See Yang, Jaspreet Parihar, Min Yang, Sruthi Damodar, David Hall, Monique N O'Leary, Arvind Ramanathan, Roy R Gerona, David W Killilea, Thomas Chi, Jay Tischfield, Amrik Sahota, Arnold Kahn, Marshall L Stoller, Pankaj Kapahi
Cystinuria is an incompletely dominant disorder characterized by defective urinary cystine reabsorption that results in the formation of cystine-based urinary stones. Current treatment options are limited in their effectiveness at preventing stone recurrence and are often poorly tolerated. We report that the nutritional supplement α-lipoic acid inhibits cystine stone formation in the Slc3a1(-/-) mouse model of cystinuria by increasing the solubility of urinary cystine. These findings identify a novel therapeutic strategy for the clinical treatment of cystinuria...
February 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28165479/whole-genome-single-cell-copy-number-profiling-from-formalin-fixed-paraffin-embedded-samples
#8
Luciano G Martelotto, Timour Baslan, Jude Kendall, Felipe C Geyer, Kathleen A Burke, Lee Spraggon, Salvatore Piscuoglio, Kalyani Chadalavada, Gouri Nanjangud, Charlotte K Y Ng, Pamela Moody, Sean D'Italia, Linda Rodgers, Hilary Cox, Arnaud da Cruz Paula, Asya Stepansky, Michail Schizas, Hannah Y Wen, Tari A King, Larry Norton, Britta Weigelt, James B Hicks, Jorge S Reis-Filho
A substantial proportion of tumors consist of genotypically distinct subpopulations of cancer cells. This intratumor genetic heterogeneity poses a substantial challenge for the implementation of precision medicine. Single-cell genomics constitutes a powerful approach to resolve complex mixtures of cancer cells by tracing cell lineages and discovering cryptic genetic variations that would otherwise be obscured in tumor bulk analyses. Because of the chemical alterations that result from formalin fixation, single-cell genomic approaches have largely remained limited to fresh or rapidly frozen specimens...
February 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28165478/a-distinct-innate-lymphoid-cell-population-regulates-tumor-associated-t-cells
#9
Sarah Q Crome, Linh T Nguyen, Sandra Lopez-Verges, S Y Cindy Yang, Bernard Martin, Jennifer Y Yam, Dylan J Johnson, Jessica Nie, Michael Pniak, Pei Hua Yen, Anca Milea, Ramlogan Sowamber, Sarah Rachel Katz, Marcus Q Bernardini, Blaise A Clarke, Patricia A Shaw, Philipp A Lang, Hal K Berman, Trevor J Pugh, Lewis L Lanier, Pamela S Ohashi
Antitumor T cells are subject to multiple mechanisms of negative regulation. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses led us to examine the regulatory potential of ILCs in the context of cancer. We identified a unique ILC population that inhibits tumor-infiltrating lymphocytes (TILs) from high-grade serous tumors, defined their suppressive capacity in vitro, and performed a comprehensive analysis of their phenotype. Notably, the presence of this CD56(+)CD3(-) population in TIL cultures was associated with reduced T cell numbers, and further functional studies demonstrated that this population suppressed TIL expansion and altered TIL cytokine production...
February 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28134928/blocking-microglial-pannexin-1-channels-alleviates-morphine-withdrawal-in-rodents
#10
Nicole E Burma, Robert P Bonin, Heather Leduc-Pessah, Corey Baimel, Zoe F Cairncross, Michael Mousseau, Jhenkruthi Vijaya Shankara, Patrick L Stemkowski, Dinara Baimoukhametova, Jaideep S Bains, Michael C Antle, Gerald W Zamponi, Catherine M Cahill, Stephanie L Borgland, Yves De Koninck, Tuan Trang
Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal...
January 30, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28134927/opioids-keeping-the-good-eliminating-the-bad
#11
Stephanie Puig, Howard B Gutstein
No abstract text is available yet for this article.
January 30, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28134926/dna-methylation-heterogeneity-defines-a-disease-spectrum-in-ewing-sarcoma
#12
Nathan C Sheffield, Gaelle Pierron, Johanna Klughammer, Paul Datlinger, Andreas Schönegger, Michael Schuster, Johanna Hadler, Didier Surdez, Delphine Guillemot, Eve Lapouble, Paul Freneaux, Jacqueline Champigneulle, Raymonde Bouvier, Diana Walder, Ingeborg M Ambros, Caroline Hutter, Eva Sorz, Ana T Amaral, Enrique de Álava, Katharina Schallmoser, Dirk Strunk, Beate Rinner, Bernadette Liegl-Atzwanger, Berthold Huppertz, Andreas Leithner, Gonzague de Pinieux, Philippe Terrier, Valérie Laurence, Jean Michon, Ruth Ladenstein, Wolfgang Holter, Reinhard Windhager, Uta Dirksen, Peter F Ambros, Olivier Delattre, Heinrich Kovar, Christoph Bock, Eleni M Tomazou
Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma...
January 30, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28112736/maturation-of-the-infant-microbiome-community-structure-and-function-across-multiple-body-sites-and-in-relation-to-mode-of-delivery
#13
Derrick M Chu, Jun Ma, Amanda L Prince, Kathleen M Antony, Maxim D Seferovic, Kjersti M Aagaard
Human microbial communities are characterized by their taxonomic, metagenomic and metabolic diversity, which varies by distinct body sites and influences human physiology. However, when and how microbial communities within each body niche acquire unique taxonomical and functional signatures in early life remains underexplored. We thus sought to determine the taxonomic composition and potential metabolic function of the neonatal and early infant microbiota across multiple body sites and assess the effect of the mode of delivery and its potential confounders or modifiers...
January 23, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28112735/nicotine-reverses-hypofrontality-in-animal-models-of-addiction-and-schizophrenia
#14
Fani Koukouli, Marie Rooy, Dimitrios Tziotis, Kurt A Sailor, Heidi C O'Neill, Josien Levenga, Mirko Witte, Michael Nilges, Jean-Pierre Changeux, Charles A Hoeffer, Jerry A Stitzel, Boris S Gutkin, David A DiGregorio, Uwe Maskos
The prefrontal cortex (PFC) underlies higher cognitive processes that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs. PFC spontaneous default activity is altered in neuropsychiatric disorders, including schizophrenia-a disorder that can be accompanied by heavy smoking. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia...
January 23, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28112734/jnk1-negatively-controls-antifungal-innate-immunity-by-suppressing-cd23-expression
#15
Xueqiang Zhao, Yahui Guo, Changying Jiang, Qing Chang, Shilei Zhang, Tianming Luo, Bin Zhang, Xinming Jia, Mien-Chie Hung, Chen Dong, Xin Lin
Opportunistic fungal infections are a leading cause of death among immune-compromised patients, and there is a pressing need to develop new antifungal therapeutic agents because of toxicity and resistance to the antifungal drugs currently in use. Although C-type lectin receptor- and Toll-like receptor-induced signaling pathways are key activators of host antifungal immunity, little is known about the mechanisms that negatively regulate host immune responses to a fungal infection. Here we found that JNK1 activation suppresses antifungal immunity in mice...
January 23, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28170385/exhausting-alloreactivity-of-donor-derived-car-t-cells
#16
Maksim Mamonkin, Helen E Heslop
No abstract text is available yet for this article.
February 7, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28170384/correction
#17
(no author information available yet)
No abstract text is available yet for this article.
February 7, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28170383/erratum-resting-state-connectivity-biomarkers-define-neurophysiological-subtypes-of-depression
#18
Andrew T Drysdale, Logan Grosenick, Jonathan Downar, Katharine Dunlop, Farrokh Mansouri, Yue Meng, Robert N Fetcho, Benjamin Zebley, Desmond J Oathes, Amit Etkin, Alan F Schatzberg, Keith Sudheimer, Jennifer Keller, Helen S Mayberg, Faith M Gunning, George S Alexopoulos, Michael D Fox, Alvaro Pascual-Leone, Henning U Voss, B J Casey, Marc J Dubin, Conor Liston
No abstract text is available yet for this article.
February 7, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28170382/the-double-edge-of-cancer-immunotherapy
#19
EDITORIAL
(no author information available yet)
No abstract text is available yet for this article.
February 7, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28170381/mapping-the-mind-a-new-tool-reveals-uncharted-territories-in-the-brain
#20
Madeleine Johnson
No abstract text is available yet for this article.
February 7, 2017: Nature Medicine
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