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Nature Medicine

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https://www.readbyqxmd.com/read/27892954/a-purified-membrane-protein-from-akkermansia-muciniphila-or-the-pasteurized-bacterium-improves-metabolism-in-obese-and-diabetic-mice
#1
Hubert Plovier, Amandine Everard, Céline Druart, Clara Depommier, Matthias Van Hul, Lucie Geurts, Julien Chilloux, Noora Ottman, Thibaut Duparc, Laeticia Lichtenstein, Antonis Myridakis, Nathalie M Delzenne, Judith Klievink, Arnab Bhattacharjee, Kees C H van der Ark, Steven Aalvink, Laurent O Martinez, Marc-Emmanuel Dumas, Dominique Maiter, Audrey Loumaye, Michel P Hermans, Jean-Paul Thissen, Clara Belzer, Willem M de Vos, Patrice D Cani
Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine...
November 28, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27892953/thalamic-mir-338-3p-mediates-auditory-thalamocortical-disruption-and-its-late-onset-in-models-of-22q11-2-microdeletion
#2
Sungkun Chun, Fei Du, Joby J Westmoreland, Seung Baek Han, Yong-Dong Wang, Donnie Eddins, Ildar T Bayazitov, Prakash Devaraju, Jing Yu, Marcia M Mellado Lagarde, Kara Anderson, Stanislav S Zakharenko
Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response...
November 28, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27869805/engineered-human-pluripotent-stem-cell-derived-intestinal-tissues-with-a-functional-enteric-nervous-system
#3
Michael J Workman, Maxime M Mahe, Stephen Trisno, Holly M Poling, Carey L Watson, Nambirajan Sundaram, Ching-Fang Chang, Jacqueline Schiesser, Philippe Aubert, Edouard G Stanley, Andrew G Elefanty, Yuichiro Miyaoka, Mohammad A Mandegar, Bruce R Conklin, Michel Neunlist, Samantha A Brugmann, Michael A Helmrath, James M Wells
The enteric nervous system (ENS) of the gastrointestinal tract controls many diverse functions, including motility and epithelial permeability. Perturbations in ENS development or function are common, yet there is no human model for studying ENS-intestinal biology and disease. We used a tissue-engineering approach with embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining human-PSC-derived neural crest cells (NCCs) and developing human intestinal organoids (HIOs)...
November 21, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27869804/systemic-depletion-of-l-cyst-e-ine-with-cyst-e-inase-increases-reactive-oxygen-species-and-suppresses-tumor-growth
#4
Shira L Cramer, Achinto Saha, Jinyun Liu, Surendar Tadi, Stefano Tiziani, Wupeng Yan, Kendra Triplett, Candice Lamb, Susan E Alters, Scott Rowlinson, Yan Jessie Zhang, Michael J Keating, Peng Huang, John DiGiovanni, George Georgiou, Everett Stone
Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates...
November 21, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27869803/genome-wide-crispr-screens-reveal-a-wnt-fzd5-signaling-circuit-as-a-druggable-vulnerability-of-rnf43-mutant-pancreatic-tumors
#5
Zachary Steinhart, Zvezdan Pavlovic, Megha Chandrashekhar, Traver Hart, Xiaowei Wang, Xiaoyu Zhang, Mélanie Robitaille, Kevin R Brown, Sridevi Jaksani, René Overmeer, Sylvia F Boj, Jarrett Adams, James Pan, Hans Clevers, Sachdev Sidhu, Jason Moffat, Stéphane Angers
Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level...
November 21, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27869802/molecular-analysis-of-circulating-tumor-cells-identifies-distinct-copy-number-profiles-in-patients-with-chemosensitive-and-chemorefractory-small-cell-lung-cancer
#6
Louise Carter, Dominic G Rothwell, Barbara Mesquita, Christopher Smowton, Hui Sun Leong, Fabiola Fernandez-Gutierrez, Yaoyong Li, Deborah J Burt, Jenny Antonello, Christopher J Morrow, Cassandra L Hodgkinson, Karen Morris, Lynsey Priest, Mathew Carter, Crispin Miller, Andrew Hughes, Fiona Blackhall, Caroline Dive, Ged Brady
In most patients with small-cell lung cancer (SCLC)-a metastatic, aggressive disease-the condition is initially chemosensitive but then relapses with acquired chemoresistance. In a minority of patients, however, relapse occurs within 3 months of initial treatment; in these cases, disease is defined as chemorefractory. The molecular mechanisms that differentiate chemosensitive from chemorefractory disease are currently unknown. To identify genetic features that distinguish chemosensitive from chemorefractory disease, we examined copy-number aberrations (CNAs) in circulating tumor cells (CTCs) from pretreatment SCLC blood samples...
November 21, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27841876/cardioprotection-and-lifespan-extension-by-the-natural-polyamine-spermidine
#7
Tobias Eisenberg, Mahmoud Abdellatif, Sabrina Schroeder, Uwe Primessnig, Slaven Stekovic, Tobias Pendl, Alexandra Harger, Julia Schipke, Andreas Zimmermann, Albrecht Schmidt, Mingming Tong, Christoph Ruckenstuhl, Christopher Dammbrueck, Angelina S Gross, Viktoria Herbst, Christoph Magnes, Gert Trausinger, Sophie Narath, Andreas Meinitzer, Zehan Hu, Alexander Kirsch, Kathrin Eller, Didac Carmona-Gutierrez, Sabrina Büttner, Federico Pietrocola, Oskar Knittelfelder, Emilie Schrepfer, Patrick Rockenfeller, Corinna Simonini, Alexandros Rahn, Marion Horsch, Kristin Moreth, Johannes Beckers, Helmut Fuchs, Valerie Gailus-Durner, Frauke Neff, Dirk Janik, Birgit Rathkolb, Jan Rozman, Martin Hrabe de Angelis, Tarek Moustafa, Guenter Haemmerle, Manuel Mayr, Peter Willeit, Marion von Frieling-Salewsky, Burkert Pieske, Luca Scorrano, Thomas Pieber, Raimund Pechlaner, Johann Willeit, Stephan J Sigrist, Wolfgang A Linke, Christian Mühlfeld, Junichi Sadoshima, Joern Dengjel, Stefan Kiechl, Guido Kroemer, Simon Sedej, Frank Madeo
Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation...
November 14, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27841875/capturing-the-biology-of-disease-severity-in-a-psc-based-model-of-familial-dysautonomia
#8
Nadja Zeltner, Faranak Fattahi, Nicole C Dubois, Nathalie Saurat, Fabien Lafaille, Lei Shang, Bastian Zimmer, Jason Tchieu, Mohamed A Soliman, Gabsang Lee, Jean-Laurent Casanova, Lorenz Studer
Familial dysautonomia (FD) is a debilitating disorder that affects derivatives of the neural crest (NC). For unknown reasons, people with FD show marked differences in disease severity despite carrying an identical, homozygous point mutation in IKBKAP, encoding IκB kinase complex-associated protein. Here we present disease-related phenotypes in human pluripotent stem cells (PSCs) that capture FD severity. Cells from individuals with severe but not mild disease show impaired specification of NC derivatives, including autonomic and sensory neurons...
November 14, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27841874/hepatitis-c-virus-induced-micrornas-dampen-interferon-mediated-antiviral-signaling
#9
Abigail Jarret, Adelle P McFarland, Stacy M Horner, Alison Kell, Johannes Schwerk, MeeAe Hong, Samantha Badil, Rochelle C Joslyn, Darren P Baker, Mary Carrington, Curt H Hagedorn, Michael Gale, Ram Savan
Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients. We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes. These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence...
November 14, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27841873/dnmt3a-mutations-promote-anthracycline-resistance-in-acute-myeloid-leukemia-via-impaired-nucleosome-remodeling
#10
Olga A Guryanova, Kaitlyn Shank, Barbara Spitzer, Luisa Luciani, Richard P Koche, Francine E Garrett-Bakelman, Chezi Ganzel, Benjamin H Durham, Abhinita Mohanty, Gregor Hoermann, Sharon A Rivera, Alan G Chramiec, Elodie Pronier, Lennart Bastian, Matthew D Keller, Daniel Tovbin, Evangelia Loizou, Abby R Weinstein, Adriana Rodriguez Gonzalez, Yen K Lieu, Jacob M Rowe, Friederike Pastore, Anna Sophia McKenney, Andrei V Krivtsov, Wolfgang R Sperr, Justin R Cross, Christopher E Mason, Martin S Tallman, Maria E Arcila, Omar Abdel-Wahab, Scott A Armstrong, Stefan Kubicek, Philipp B Staber, Mithat Gönen, Elisabeth M Paietta, Ari M Melnick, Stephen D Nimer, Siddhartha Mukherjee, Ross L Levine
Although the majority of patients with acute myeloid leukemia (AML) initially respond to chemotherapy, many of them subsequently relapse, and the mechanistic basis for AML persistence following chemotherapy has not been determined. Recurrent somatic mutations in DNA methyltransferase 3A (DNMT3A), most frequently at arginine 882 (DNMT3A(R882)), have been observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. Patients with DNMT3A(R882) AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3A(R882) cells persist and drive relapse...
November 14, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27841872/iap-antagonists-induce-anti-tumor-immunity-in-multiple-myeloma
#11
Marta Chesi, Noweeda N Mirza, Victoria M Garbitt, Meaghen E Sharik, Amylou C Dueck, Yan W Asmann, Ilseyar Akhmetzyanova, Heidi E Kosiorek, Arianna Calcinotto, Daniel L Riggs, Niamh Keane, Gregory J Ahmann, Kevin M Morrison, Rafael Fonseca, Martha Q Lacy, David Dingli, Shaji K Kumar, Sikander Ailawadhi, Angela Dispenzieri, Francis Buadi, Morie A Gertz, Craig B Reeder, Yi Lin, Asher A Chanan-Khan, A Keith Stewart, David Fooksman, P Leif Bergsagel
The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway...
November 14, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27820605/molecular-level-analysis-of-the-serum-antibody-repertoire-in-young-adults-before-and-after-seasonal-influenza-vaccination
#12
Jiwon Lee, Daniel R Boutz, Veronika Chromikova, M Gordon Joyce, Christopher Vollmers, Kwanyee Leung, Andrew P Horton, Brandon J DeKosky, Chang-Han Lee, Jason J Lavinder, Ellen M Murrin, Constantine Chrysostomou, Kam Hon Hoi, Yaroslav Tsybovsky, Paul V Thomas, Aliaksandr Druz, Baoshan Zhang, Yi Zhang, Lingshu Wang, Wing-Pui Kong, Daechan Park, Lyubov I Popova, Cornelia L Dekker, Mark M Davis, Chalise E Carter, Ted M Ross, Andrew D Ellington, Patrick C Wilson, Edward M Marcotte, John R Mascola, Gregory C Ippolito, Florian Krammer, Stephen R Quake, Peter D Kwong, George Georgiou
Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine...
November 7, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27820604/influenza-immunization-elicits-antibodies-specific-for-an-egg-adapted-vaccine-strain
#13
Donald D Raymond, Shaun M Stewart, Jiwon Lee, Jack Ferdman, Goran Bajic, Khoi T Do, Michael J Ernandes, Pirada Suphaphiphat, Ethan C Settembre, Philip R Dormitzer, Giuseppe Del Giudice, Oretta Finco, Tae Hyun Kang, Gregory C Ippolito, George Georgiou, Thomas B Kepler, Barton F Haynes, M Anthony Moody, Hua-Xin Liao, Aaron G Schmidt, Stephen C Harrison
For broad protection against infection by viruses such as influenza or HIV, vaccines should elicit antibodies that bind conserved viral epitopes, such as the receptor-binding site (RBS). RBS-directed antibodies have been described for both HIV and influenza virus, and the design of immunogens to elicit them is a goal of vaccine research in both fields. Residues in the RBS of influenza virus hemagglutinin (HA) determine a preference for the avian or human receptor, α-2,3-linked sialic acid and α-2,6-linked sialic acid, respectively...
November 7, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27820603/forebrain-selective-ampa-receptor-antagonism-guided-by-tarp-%C3%AE-8-as-an-antiepileptic-mechanism
#14
Akihiko S Kato, Kevin D Burris, Kevin M Gardinier, Douglas L Gernert, Warren J Porter, Jon Reel, Chunjin Ding, Yuan Tu, Douglas A Schober, Matthew R Lee, Beverly A Heinz, Thomas E Fitch, Scott D Gleason, John T Catlow, Hong Yu, Stephen M Fitzjohn, Francesca Pasqui, He Wang, Yuewei Qian, Emanuele Sher, Ruud Zwart, Keith A Wafford, Kurt Rasmussen, Paul L Ornstein, John T R Isaac, Eric S Nisenbaum, David S Bredt, Jeffrey M Witkin
Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment...
November 7, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27798615/human-antibody-repertoire-after-vsv-ebola-vaccination-identifies-novel-targets-and-virus-neutralizing-igm-antibodies
#15
Surender Khurana, Sandra Fuentes, Elizabeth M Coyle, Supriya Ravichandran, Richard T Davey, John H Beigel
Development of an effective vaccine against Ebola virus is of high priority. However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited. Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis virus (VSV)-Ebola vaccine at 3 million, 20 million and 100 million plaque-forming units (PFU) and homologous VSV-Ebola vaccine boost in healthy adult volunteers. Whole genome-fragment phage display libraries, expressing linear and conformational epitopes of Ebola glycoprotein (GP), showed higher diversity of antibody epitopes in individuals vaccinated with 20 million PFU than in those vaccinated with 3 million or 100 million PFU...
October 31, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27798614/analysis-of-self-antigen-specificity-of-islet-infiltrating-t-cells-from-human-donors-with-type-1-diabetes
#16
Jenny Aurielle B Babon, Megan E DeNicola, David M Blodgett, Inne Crèvecoeur, Thomas S Buttrick, René Maehr, Rita Bottino, Ali Naji, John Kaddis, Wassim Elyaman, Eddie A James, Rachana Haliyur, Marcela Brissova, Lut Overbergh, Chantal Mathieu, Thomas Delong, Kathryn Haskins, Alberto Pugliese, Martha Campbell-Thompson, Clayton Mathews, Mark A Atkinson, Alvin C Powers, David M Harlan, Sally C Kent
A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets...
October 31, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27798613/genomic-diversity-in-autopsy-samples-reveals-within-host-dissemination-of-hiv-associated-mycobacterium-tuberculosis
#17
Tami D Lieberman, Douglas Wilson, Reshma Misra, Lealia L Xiong, Prashini Moodley, Ted Cohen, Roy Kishony
Mycobacterium tuberculosis remains a leading cause of death worldwide, especially among individuals infected with HIV. Whereas phylogenetic analysis has revealed M. tuberculosis spread throughout history and in local outbreaks, much less is understood about its dissemination within the body. Here we report genomic analysis of 2,693 samples collected post mortem from lung and extrapulmonary biopsies of 44 subjects in KwaZulu-Natal, South Africa, who received minimal antitubercular treatment and most of whom were HIV seropositive...
October 31, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27783068/re-evaluating-the-link-between-neuropsychiatric-disorders-and-dysregulated-adult-neurogenesis
#18
Sanghee Yun, Ryan P Reynolds, Irene Masiulis, Amelia J Eisch
People diagnosed with neuropsychiatric disorders such as depression, anxiety, addiction or schizophrenia often have dysregulated memory, mood, pattern separation and/or reward processing. These symptoms are indicative of a disrupted function of the dentate gyrus (DG) subregion of the brain, and they improve with treatment and remission. The dysfunction of the DG is accompanied by structural maladaptations, including dysregulation of adult-generated neurons. An increasing number of studies using modern inducible approaches to manipulate new neurons show that the behavioral symptoms in animal models of neuropsychiatric disorders can be produced or exacerbated by the inhibition of DG neurogenesis...
October 26, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27783067/developmental-timing-and-critical-windows-for-the-treatment-of-psychiatric-disorders
#19
Oscar Marín
There is a growing understanding that pathological genetic variation and environmental insults during sensitive periods in brain development have long-term consequences on brain function, which range from learning disabilities to complex psychiatric disorders such as schizophrenia. Furthermore, recent experiments in animal models suggest that therapeutic interventions during sensitive periods, typically before the onset of clear neurological and behavioral symptoms, might prevent or ameliorate the development of specific pathologies...
October 26, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27783066/the-search-for-imaging-biomarkers-in-psychiatric-disorders
#20
Anissa Abi-Dargham, Guillermo Horga
The field of medicine is moving toward the use of biomarkers for the optimization of individualized care. This is a particular challenge for the field of psychiatry, in which diagnosis is based on a descriptive collection of behaviors without the availability of any objective test to stratify patients. Neuroimaging techniques such as molecular imaging with positron-emission tomography (PET) or structural and functional magnetic resonance imaging (MRI) provide an opportunity to bring psychiatry from an era of subjective descriptive classification into objective and tangible brain-based measures...
October 26, 2016: Nature Medicine
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