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Nature Medicine

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https://www.readbyqxmd.com/read/28714991/resolution-of-inflammation-by-interleukin-9-producing-type-2-innate-lymphoid-cells
#1
Simon Rauber, Markus Luber, Stefanie Weber, Lisa Maul, Alina Soare, Thomas Wohlfahrt, Neng-Yu Lin, Katharina Dietel, Aline Bozec, Martin Herrmann, Mark H Kaplan, Benno Weigmann, Mario M Zaiss, Ursula Fearon, Douglas J Veale, Juan D Cañete, Oliver Distler, Felice Rivellese, Costantino Pitzalis, Markus F Neurath, Andrew N J McKenzie, Stefan Wirtz, Georg Schett, Jörg H W Distler, Andreas Ramming
Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss...
July 17, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28714990/an-approach-to-suppress-the-evolution-of-resistance-in-braf-v600e-mutant-cancer
#2
Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Trang Thi Mai, Neelam Chaudhary, Greg J Riely, Bob T Li, Kerry Scott, Fabiola Cechhi, Ulrika Stierner, Kalyani Chadalavada, Elisa de Stanchina, Sarit Schwartz, Todd Hembrough, Gouri Nanjangud, Michael F Berger, Jonas Nilsson, Scott W Lowe, Jorge S Reis-Filho, Neal Rosen, Piro Lito
The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF(amp)) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment...
July 17, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28714989/correction-of-a-splicing-defect-in-a-mouse-model-of-congenital-muscular-dystrophy-type-1a-using-a-homology-directed-repair-independent-mechanism
#3
Dwi U Kemaladewi, Eleonora Maino, Elzbieta Hyatt, Huayun Hou, Maylynn Ding, Kara M Place, Xinyi Zhu, Prabhpreet Bassi, Zahra Baghestani, Amit G Deshwar, Daniele Merico, Hui Y Xiong, Brendan J Frey, Michael D Wilson, Evgueni A Ivakine, Ronald D Cohn
Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice-site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle. Here we describe a strategy using nonhomologous end-joining (NHEJ) to correct a pathogenic splice-site mutation...
July 17, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28714988/snp-mediated-disruption-of-ctcf-binding-at-the-ifitm3-promoter-is-associated-with-risk-of-severe-influenza-in-humans
#4
E Kaitlynn Allen, Adrienne G Randolph, Tushar Bhangale, Pranay Dogra, Maikke Ohlson, Christine M Oshansky, Anthony E Zamora, John P Shannon, David Finkelstein, Amy Dressen, John DeVincenzo, Miguela Caniza, Ben Youngblood, Carrie M Rosenberger, Paul G Thomas
Previous studies have reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism by which risk is conferred remain controversial. We prioritized SNPs in IFITM3 on the basis of putative biological function and identified rs34481144 in the 5' UTR. We found evidence of a new association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined a role for rs34481144 as an expression quantitative trait locus (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression...
July 17, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28692064/plk1-regulates-contraction-of-postmitotic-smooth-muscle-cells-and-is-required-for-vascular-homeostasis
#5
Guillermo de Cárcer, Paulina Wachowicz, Sara Martínez-Martínez, Jorge Oller, Nerea Méndez-Barbero, Beatriz Escobar, Alejandra González-Loyola, Tohru Takaki, Aicha El Bakkali, Juan A Cámara, Luis J Jiménez-Borreguero, Xosé R Bustelo, Marta Cañamero, Francisca Mulero, María de Los Ángeles Sevilla, María Jose Montero, Juan Miguel Redondo, Marcos Malumbres
Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo...
July 10, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28692063/inflammation-dependent-cerebrospinal-fluid-hypersecretion-by-the-choroid-plexus-epithelium-in-posthemorrhagic-hydrocephalus
#6
Jason K Karimy, Jinwei Zhang, David B Kurland, Brianna Carusillo Theriault, Daniel Duran, Jesse A Stokum, Charuta Gavankar Furey, Xu Zhou, M Shahid Mansuri, Julio Montejo, Alberto Vera, Michael L DiLuna, Eric Delpire, Seth L Alper, Murat Gunel, Volodymyr Gerzanich, Ruslan Medzhitov, J Marc Simard, Kristopher T Kahle
The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept...
July 10, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28671689/reconstruction-of-the-mouse-extrahepatic-biliary-tree-using-primary-human-extrahepatic-cholangiocyte-organoids
#7
Fotios Sampaziotis, Alexander W Justin, Olivia C Tysoe, Stephen Sawiak, Edmund M Godfrey, Sara S Upponi, Richard L Gieseck, Miguel Cardoso de Brito, Natalie Lie Berntsen, María J Gómez-Vázquez, Daniel Ortmann, Loukia Yiangou, Alexander Ross, Johannes Bargehr, Alessandro Bertero, Mariëlle C F Zonneveld, Marianne T Pedersen, Matthias Pawlowski, Laura Valestrand, Pedro Madrigal, Nikitas Georgakopoulos, Negar Pirmadjid, Gregor M Skeldon, John Casey, Wenmiao Shu, Paulina M Materek, Kirsten E Snijders, Stephanie E Brown, Casey A Rimland, Ingrid Simonic, Susan E Davies, Kim B Jensen, Matthias Zilbauer, William T H Gelson, Graeme J Alexander, Sanjay Sinha, Nicholas R F Hannan, Thomas A Wynn, Tom H Karlsen, Espen Melum, Athina E Markaki, Kourosh Saeb-Parsy, Ludovic Vallier
The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties...
July 3, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28650457/fibroblast-growth-factor-19-regulates-skeletal-muscle-mass-and-ameliorates-muscle-wasting-in-mice
#8
Bérengère Benoit, Emmanuelle Meugnier, Martina Castelli, Stéphanie Chanon, Aurélie Vieille-Marchiset, Christine Durand, Nadia Bendridi, Sandra Pesenti, Pierre-Axel Monternier, Anne-Cécile Durieux, Damien Freyssenet, Jennifer Rieusset, Etienne Lefai, Hubert Vidal, Jérôme Ruzzin
The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro...
June 26, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28650456/a-tripartite-complex-of-supar-apol1-risk-variants-and-%C3%AE-v%C3%AE-3-integrin-on-podocytes-mediates-chronic-kidney-disease
#9
Salim S Hayek, Kwi Hye Koh, Morgan E Grams, Changli Wei, Yi-An Ko, Jing Li, Beata Samelko, Hyun Lee, Ranadheer R Dande, Ha Won Lee, Eunsil Hahm, Vasil Peev, Melissa Tracy, Nicholas J Tardi, Vineet Gupta, Mehmet M Altintas, Garrett Garborcauskas, Nikolina Stojanovic, Cheryl A Winkler, Michael S Lipkowitz, Adrienne Tin, Lesley A Inker, Andrew S Levey, Martin Zeier, Barry I Freedman, Jeffrey B Kopp, Karl Skorecki, Josef Coresh, Arshed A Quyyumi, Sanja Sever, Jochen Reiser
Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels...
June 26, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28697185/an-unexpected-role-for-bile-acid-synthesis-in-adaptation-to-low-temperature
#10
Folkert Kuipers, Albert K Groen
No abstract text is available yet for this article.
July 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28697184/insulin-action-and-resistance-in-obesity-and-type-2-diabetes
#11
Michael P Czech
Nutritional excess is a major forerunner of type 2 diabetes. It enhances the secretion of insulin, but attenuates insulin's metabolic actions in the liver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes, pointing to a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance...
July 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28697183/correction
#12
(no author information available yet)
No abstract text is available yet for this article.
July 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28697182/a-prescription-for-cancer-diagnostics
#13
EDITORIAL
(no author information available yet)
No abstract text is available yet for this article.
July 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28697181/battling-the-biology-of-opioid-addiction
#14
EDITORIAL
(no author information available yet)
No abstract text is available yet for this article.
July 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28697180/medicine-s-movable-feast-what-jumping-genes-can-teach-us-about-treating-disease
#15
Roxanne Khamsi
No abstract text is available yet for this article.
July 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28697179/a-mouse-model-of-renal-cell-carcinoma
#16
Laura S Schmidt, W Marston Linehan
No abstract text is available yet for this article.
July 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28697178/put-to-the-test-organoid-based-testing-becomes-a-clinical-tool
#17
Shraddha Chakradhar
No abstract text is available yet for this article.
July 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28628112/gut-microbiome-and-serum-metabolome-alterations-in-obesity-and-after-weight-loss-intervention
#18
Ruixin Liu, Jie Hong, Xiaoqiang Xu, Qiang Feng, Dongya Zhang, Yanyun Gu, Juan Shi, Shaoqian Zhao, Wen Liu, Xiaokai Wang, Huihua Xia, Zhipeng Liu, Bin Cui, Peiwen Liang, Liuqing Xi, Jiabin Jin, Xiayang Ying, Xiaolin Wang, Xinjie Zhao, Wanyu Li, Huijue Jia, Zhou Lan, Fengyu Li, Rui Wang, Yingkai Sun, Minglan Yang, Yuxin Shen, Zhuye Jie, Junhua Li, Xiaomin Chen, Huanzi Zhong, Hailiang Xie, Yifei Zhang, Weiqiong Gu, Xiaxing Deng, Baiyong Shen, Xun Xu, Huanming Yang, Guowang Xu, Yufang Bi, Shenghan Lai, Jian Wang, Lu Qi, Lise Madsen, Jiqiu Wang, Guang Ning, Karsten Kristiansen, Weiqing Wang
Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B...
July 2017: Nature Medicine
https://www.readbyqxmd.com/read/28628111/interaction-of-reactive-astrocytes-with-type-i-collagen-induces-astrocytic-scar-formation-through-the-integrin-n-cadherin-pathway-after-spinal-cord-injury
#19
Masamitsu Hara, Kazu Kobayakawa, Yasuyuki Ohkawa, Hiromi Kumamaru, Kazuya Yokota, Takeyuki Saito, Ken Kijima, Shingo Yoshizaki, Katsumi Harimaya, Yasuharu Nakashima, Seiji Okada
Central nervous system (CNS) injury transforms naive astrocytes into reactive astrocytes, which eventually become scar-forming astrocytes that can impair axonal regeneration and functional recovery. This sequential phenotypic change, known as reactive astrogliosis, has long been considered unidirectional and irreversible. However, we report here that reactive astrocytes isolated from injured spinal cord reverted in retrograde to naive astrocytes when transplanted into a naive spinal cord, whereas they formed astrocytic scars when transplanted into injured spinal cord, indicating the environment-dependent plasticity of reactive astrogliosis...
July 2017: Nature Medicine
https://www.readbyqxmd.com/read/28628110/colonic-organoids-derived-from-human-induced-pluripotent-stem-cells-for-modeling-colorectal-cancer-and-drug-testing
#20
Miguel Crespo, Eduardo Vilar, Su-Yi Tsai, Kyle Chang, Sadaf Amin, Tara Srinivasan, Tuo Zhang, Nina H Pipalia, Huanhuan Joyce Chen, Mavee Witherspoon, Miriam Gordillo, Jenny Zhaoying Xiang, Frederick R Maxfield, Steven Lipkin, Todd Evans, Shuibing Chen
With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing...
July 2017: Nature Medicine
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