Physiology

  • Article
    | Open Access

    The kidney is vascularized with highly specialized and zonated endothelial cells that are essential for its filtration function. Here, Barry et al. provide a single-cell RNA sequencing analysis of the kidney vasculature that highlights its transcriptional heterogeneity and uncovers pathways important for its development and function.

    • David M. Barry
    • , Elizabeth A. McMillan
    • , Balvir Kunar
    • , Raphael Lis
    • , Tuo Zhang
    • , Tyler Lu
    • , Edward Daniel
    • , Masataka Yokoyama
    • , Jesus M. Gomez-Salinero
    • , Angara Sureshbabu
    • , Ondine Cleaver
    • , Annarita Di Lorenzo
    • , Mary E. Choi
    • , Jenny Xiang
    • , David Redmond
    • , Sina Y. Rabbany
    • , Thangamani Muthukumar
    •  & Shahin Rafii
  • Article
    | Open Access

    miRNA142-3p and Tet2 are separately known to regulate Treg. Here the authors show that miRNA142-3p targets Tet2 and by this opposes Treg differentiation in autoimmune diabetes.

    • Martin G. Scherm
    • , Isabelle Serr
    • , Adam M. Zahm
    • , Jonathan Schug
    • , Saverio Bellusci
    • , Rossella Manfredini
    • , Victoria K. Salb
    • , Katharina Gerlach
    • , Benno Weigmann
    • , Anette-Gabriele Ziegler
    • , Klaus H. Kaestner
    •  & Carolin Daniel
  • Article
    | Open Access

    Graft versus host disease (GvHD) still hinders allogeneic hematopoietic stem cell transplantation. Here, the authors use metabolomics to analyze two cohorts of paired transplant recipients and donors, identifying significant differences in both host- and microbiota-derived metabolites.

    • David Michonneau
    • , Eleonora Latis
    • , Emmanuel Curis
    • , Laetitia Dubouchet
    • , Sivapriya Ramamoorthy
    • , Brian Ingram
    • , Régis Peffault de Latour
    • , Marie Robin
    • , Flore Sicre de Fontbrune
    • , Sylvie Chevret
    • , Lars Rogge
    •  & Gérard Socié
  • Article
    | Open Access

    Primary cilia have been proposed to regulate glucose metabolism and insulin secretion in beta cells, but it is not known how. Here the authors show that primary cilia play a role in adult β-cell function via a mechanism involving endosomal EphA-processing.

    • Francesco Volta
    • , M. Julia Scerbo
    • , Anett Seelig
    • , Robert Wagner
    • , Nils O’Brien
    • , Felicia Gerst
    • , Andreas Fritsche
    • , Hans-Ulrich Häring
    • , Anja Zeigerer
    • , Susanne Ullrich
    •  & Jantje M. Gerdes
  • Article
    | Open Access

    Gut microbiota alterations, including enrichment of flagellated bacteria, are associated with metabolic syndrome and chronic inflammatory diseases. Here, Tran et al. show, in mice, that elicitation of mucosal anti-flagellin antibodies protects against experimental colitis and ameliorates diet-induced obesity.

    • Hao Q. Tran
    • , Ruth E. Ley
    • , Andrew T. Gewirtz
    •  & Benoit Chassaing
  • Article
    | Open Access

    Spinal pain is a major clinical problem. Here the authors show that osteoclasts create porous area of endplates of the vertebrae and sensory innervation of porous endplates by Netrin-1 release from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice.

    • Shuangfei Ni
    • , Zemin Ling
    • , Xiao Wang
    • , Yong Cao
    • , Tianding Wu
    • , Ruoxian Deng
    • , Janet L. Crane
    • , Richard Skolask
    • , Shadpour Demehril
    • , Gehua Zhen
    • , Amit Jain
    • , Panfeng Wu
    • , Dayu Pan
    • , Bo Hu
    • , Xiao Lyu
    • , Yusheng Li
    • , Hao Chen
    • , Huabin Qi
    • , Yun Guan
    • , Xinzhong Dong
    • , Mei Wan
    • , Xuenong Zou
    • , Hongbin Lu
    • , Jianzhong Hu
    •  & Xu Cao
  • Article
    | Open Access

    Plasmodium growth is adapted to the reproductive cycle of mosquitoes, but underlying mechanisms are unclear. Here, Lampe et al. show that the blood-meal induced miR-276 balances the termination of the mosquito amino acid catabolism and egg development, providing nutrients for Plasmodium sporozoite development.

    • Lena Lampe
    • , Marius Jentzsch
    • , Sylwia Kierszniowska
    •  & Elena A. Levashina
  • Article
    | Open Access

    The adipokine leptin modulates intestinal inflammation in mice. Here the authors describe a patient with inflammatory bowel disease and lipodystrophy, providing evidence that leptin aggravates intestinal inflammation with proinflammatory effects on leukocytes that are reversible by TNFα blockade.

    • Jörn F. Ziegler
    • , Chotima Böttcher
    • , Marilena Letizia
    • , Cansu Yerinde
    • , Hao Wu
    • , Inka Freise
    • , Yasmina Rodriguez-Sillke
    • , Ani K. Stoyanova
    • , Martin E. Kreis
    • , Patrick Asbach
    • , Desiree Kunkel
    • , Josef Priller
    • , Ioannis Anagnostopoulos
    • , Anja A. Kühl
    • , Konstanze Miehle
    • , Michael Stumvoll
    • , Florian Tran
    • , Broder Fredrich
    • , Michael Forster
    • , Andre Franke
    • , Christian Bojarski
    • , Rainer Glauben
    • , Britt-Sabina Löscher
    • , Britta Siegmund
    •  & Carl Weidinger
  • Article
    | Open Access

    Glycolysis is elevated in many cancers. In this study, the authors show that lactoylglutathione, a by-product of methylglyoxal produced from increased glycolysis, is elevated in lung cancer in mouse models and humans, arguing reactive metabolite production can be a liability for cancers.

    • Alba Luengo
    • , Keene L. Abbott
    • , Shawn M. Davidson
    • , Aaron M. Hosios
    • , Brandon Faubert
    • , Sze Ham Chan
    • , Elizaveta Freinkman
    • , Lauren G. Zacharias
    • , Thomas P. Mathews
    • , Clary B. Clish
    • , Ralph J. DeBerardinis
    • , Caroline A. Lewis
    •  & Matthew G. Vander Heiden
  • Article
    | Open Access

    Understanding mechanisms of cerebral oxygen regulation is critical for healthy brain function. Here the authors show that respiration is a key modulator of cerebral oxygenation, which will be helpful in better resolving neurally-generated functional brain imaging signals, such as BOLD fMRI.

    • Qingguang Zhang
    • , Morgane Roche
    • , Kyle W. Gheres
    • , Emmanuelle Chaigneau
    • , Ravi T. Kedarasetti
    • , William D. Haselden
    • , Serge Charpak
    •  & Patrick J. Drew
  • Article
    | Open Access

    AgRP neurons in the hypothalamic arcuate nucleus (ARH) are involved in regulating hunger and energy balance. Here the authors show that knockout of the DNA methyltransferase Dnmt3a in AgRP neurons of the ARH leads to a reduction in voluntary exercise along with numerous epigenetic and gene expression changes in ARH neurons.

    • Harry MacKay
    • , C. Anthony Scott
    • , Jack D. Duryea
    • , Maria S. Baker
    • , Eleonora Laritsky
    • , Amanda E. Elson
    • , Theodore Garland Jr.
    • , Marta L. Fiorotto
    • , Rui Chen
    • , Yumei Li
    • , Cristian Coarfa
    • , Richard B. Simerly
    •  & Robert A. Waterland
  • Article
    | Open Access

    One of the underlying causes of aging is the accumulation of senescent cells, but their turnover rates and dynamics during ageing are unknown. Here the authors measure and model senescent cell production and removal and explore implications for mortality.

    • Omer Karin
    • , Amit Agrawal
    • , Ziv Porat
    • , Valery Krizhanovsky
    •  & Uri Alon
  • Article
    | Open Access

    Higher organisms regulate cellular iron concentrations through Iron Regulatory Proteins (IRPs), which regulate specific messenger RNAs. Here Huynh et al. show that IRP1 requires a Glycogen Branching Enzyme for proper function, and that IRP1 has additional regulatory roles in cell nuclei.

    • Nhan Huynh
    • , Qiuxiang Ou
    • , Pendleton Cox
    • , Roland Lill
    •  & Kirst King-Jones
  • Article
    | Open Access

    How reproducible human kidney organoids derived from different iPSC lines are, and how faithful they are to human kidney tissue remain unclear. Here, the authors use four human iPSC lines to derive kidney organoids and show how organoid composition is reproducible, comparable to human tissue and of improved quality after transplantation.

    • Ayshwarya Subramanian
    • , Eriene-Heidi Sidhom
    • , Maheswarareddy Emani
    • , Katherine Vernon
    • , Nareh Sahakian
    • , Yiming Zhou
    • , Maria Kost-Alimova
    • , Michal Slyper
    • , Julia Waldman
    • , Danielle Dionne
    • , Lan T. Nguyen
    • , Astrid Weins
    • , Jamie L. Marshall
    • , Orit Rosenblatt-Rosen
    • , Aviv Regev
    •  & Anna Greka
  • Article
    | Open Access

    Electrical stimulation of the brain can have variable effects, perhaps because of individual differences in brain structure which produce differences in the electric fields. Here, the authors show that using functional and structural brain imaging along with electric field modeling can predict the effectiveness of stimulation.

    • Florian H. Kasten
    • , Katharina Duecker
    • , Marike C. Maack
    • , Arnd Meiser
    •  & Christoph S. Herrmann
  • Article
    | Open Access

    Uterine gland development is essential for successful embryo implantation, decidua formation and placental development. Here the authors demonstrate that neonatal Wnt-dependent Lgr5 expressing stem/progenitor cells at the tips of developing glands are indispensable for uterine gland development.

    • Ryo Seishima
    • , Carly Leung
    • , Swathi Yada
    • , Katzrin Bte Ahmed Murad
    • , Liang Thing Tan
    • , Amin Hajamohideen
    • , Si Hui Tan
    • , Hideki Itoh
    • , Kazuhiro Murakami
    • , Yoshihiro Ishida
    • , Satoshi Nakamizo
    • , Yusuke Yoshikawa
    • , Esther Wong
    •  & Nick Barker
  • Article
    | Open Access

    Histone deacetylase 3 (HDAC3) is a regulator of lipid homeostasis in several tissues, however, its role in intestinal lipid metabolism was not yet known. Here the authors study intestine specific HDAC3 knock out mice and report that these animals have increased fatty acid oxidation and undergo remodeling of the intestinal epithelial cell lipidome.

    • Mercedes Dávalos-Salas
    • , Magdalene K. Montgomery
    • , Camilla M. Reehorst
    • , Rebecca Nightingale
    • , Irvin Ng
    • , Holly Anderton
    • , Sheren Al-Obaidi
    • , Analia Lesmana
    • , Cameron M. Scott
    • , Paul Ioannidis
    • , Hina Kalra
    • , Shivakumar Keerthikumar
    • , Lars Tögel
    • , Angela Rigopoulos
    • , Sylvia J. Gong
    • , David S. Williams
    • , Prusoth Yoganantharaja
    • , Kim Bell-Anderson
    • , Suresh Mathivanan
    • , Yann Gibert
    • , Scott Hiebert
    • , Andrew M. Scott
    • , Matthew J. Watt
    •  & John M. Mariadason
  • Article
    | Open Access

    The molecular mechanisms of mitochondrial dysfunction in the premature ageing Werner syndrome were elusive. Here the authors show that NAD+ depletion-induced impaired mitophagy contributes to this phenomenon, shedding light on potential therapeutics.

    • Evandro F. Fang
    • , Yujun Hou
    • , Sofie Lautrup
    • , Martin Borch Jensen
    • , Beimeng Yang
    • , Tanima SenGupta
    • , Domenica Caponio
    • , Rojyar Khezri
    • , Tyler G. Demarest
    • , Yahyah Aman
    • , David Figueroa
    • , Marya Morevati
    • , Ho-Joon Lee
    • , Hisaya Kato
    • , Henok Kassahun
    • , Jong-Hyuk Lee
    • , Deborah Filippelli
    • , Mustafa Nazir Okur
    • , Aswin Mangerich
    • , Deborah L. Croteau
    • , Yoshiro Maezawa
    • , Costas A. Lyssiotis
    • , Jun Tao
    • , Koutaro Yokote
    • , Tor Erik Rusten
    • , Mark P. Mattson
    • , Heinrich Jasper
    • , Hilde Nilsen
    •  & Vilhelm A. Bohr
  • Article
    | Open Access

    Mitochondrial calcium signaling plays an important role in neuronal bioenergetics yet its regulation by brain activity in vivo is not understood. Here, the authors show that mitochondrial and cytosolic calcium transients are dynamically coupled as a function of brain activity.

    • Yuan Lin
    • , Lin-Lin Li
    • , Wei Nie
    • , Xiaolei Liu
    • , Avital Adler
    • , Chi Xiao
    • , Fujian Lu
    • , Liping Wang
    • , Hua Han
    • , Xianhua Wang
    • , Wen-Biao Gan
    •  & Heping Cheng
  • Article
    | Open Access

    Cellular overgrowth and fibrosis in the foreign body response can compromise the function of transplanted cells. Here, the authors report on the zwitterionically modified alginates for the encapsulation of cells to reduce cellular overgrowth and demonstrate application in mice, dogs and pigs.

    • Qingsheng Liu
    • , Alan Chiu
    • , Long-Hai Wang
    • , Duo An
    • , Monica Zhong
    • , Alexandra M. Smink
    • , Bart J. de Haan
    • , Paul de Vos
    • , Kevin Keane
    • , Andreas Vegge
    • , Esther Y. Chen
    • , Wei Song
    • , Wendy F. Liu
    • , James Flanders
    • , Claude Rescan
    • , Lars Groth Grunnet
    • , Xi Wang
    •  & Minglin Ma
  • Article
    | Open Access

    Integrin-linked kinase (ILK) is an important mediator of integrin signaling. Here Park et al. show that mice with endothelial-specific deletion of Ilk develop vascular defects that resemble familial exudative vitreoretinopathy, and identify mutations in ILK in patients with exudative vitreoretinopathy suggesting a potential role in human pathogenesis.

    • Hongryeol Park
    • , Hiroyuki Yamamoto
    • , Lucas Mohn
    • , Lea Ambühl
    • , Kenichi Kanai
    • , Inga Schmidt
    • , Kee-Pyo Kim
    • , Alessia Fraccaroli
    • , Silke Feil
    • , Harald J. Junge
    • , Eloi Montanez
    • , Wolfgang Berger
    •  & Ralf H. Adams
  • Article
    | Open Access

    Pulmonary arterial hypertension (PAH) is characterised by progressive pulmonary vascular remodelling. Here, Arnold et al. develop a therapeutic antibody targeting osteoprotegerin and find it attenuates pulmonary vascular remodelling in multiple rodent models of PAH, alone or in combination with standard of care vasodilator therapy.

    • Nadine D. Arnold
    • , Josephine A. Pickworth
    • , Laura E. West
    • , Sarah Dawson
    • , Joana A. Carvalho
    • , Helen Casbolt
    • , Adam T. Braithwaite
    • , James Iremonger
    • , Lewis Renshall
    • , Volker Germaschewski
    • , Matthew McCourt
    • , Philip Bland-Ward
    • , Hager Kowash
    • , Abdul G. Hameed
    • , Alexander M. K. Rothman
    • , Maria G. Frid
    • , A. A. Roger Thompson
    • , Holly R. Evans
    • , Mark Southwood
    • , Nicholas W. Morrell
    • , David C. Crossman
    • , Moira K. B. Whyte
    • , Kurt R. Stenmark
    • , Christopher M. Newman
    • , David G. Kiely
    • , Sheila E. Francis
    •  & Allan Lawrie
  • Article
    | Open Access

    Kidney stones form in the presence of overabundance of crystal-forming substances such as Ca2+ and oxalate. Here, the authors report genome-wide association analyses for kidney stone disease, report seven previously unknown loci and find that some of these loci also associate with Ca2+ concentration and excretion.

    • Sarah A. Howles
    • , Akira Wiberg
    • , Michelle Goldsworthy
    • , Asha L. Bayliss
    • , Anna K. Gluck
    • , Michael Ng
    • , Emily Grout
    • , Chizu Tanikawa
    • , Yoichiro Kamatani
    • , Chikashi Terao
    • , Atsushi Takahashi
    • , Michiaki Kubo
    • , Koichi Matsuda
    • , Rajesh V. Thakker
    • , Benjamin W. Turney
    •  & Dominic Furniss
  • Article
    | Open Access

    Sleep duration is associated with an adverse lipid profile. Here, the authors perform genome-wide gene-by-sleep interaction analysis and find 49 previously unreported lipid loci when considering short or long total sleep time.

    • Raymond Noordam
    • , Maxime M. Bos
    • , Heming Wang
    • , Thomas W. Winkler
    • , Amy R. Bentley
    • , Tuomas O. Kilpeläinen
    • , Paul S. de Vries
    • , Yun Ju Sung
    • , Karen Schwander
    • , Brian E. Cade
    • , Alisa Manning
    • , Hugues Aschard
    • , Michael R. Brown
    • , Han Chen
    • , Nora Franceschini
    • , Solomon K. Musani
    • , Melissa Richard
    • , Dina Vojinovic
    • , Stella Aslibekyan
    • , Traci M. Bartz
    • , Lisa de las Fuentes
    • , Mary Feitosa
    • , Andrea R. Horimoto
    • , Marjan Ilkov
    • , Minjung Kho
    • , Aldi Kraja
    • , Changwei Li
    • , Elise Lim
    • , Yongmei Liu
    • , Dennis O. Mook-Kanamori
    • , Tuomo Rankinen
    • , Salman M. Tajuddin
    • , Ashley van der Spek
    • , Zhe Wang
    • , Jonathan Marten
    • , Vincent Laville
    • , Maris Alver
    • , Evangelos Evangelou
    • , Maria E. Graff
    • , Meian He
    • , Brigitte Kühnel
    • , Leo-Pekka Lyytikäinen
    • , Pedro Marques-Vidal
    • , Ilja M. Nolte
    • , Nicholette D. Palmer
    • , Rainer Rauramaa
    • , Xiao-Ou Shu
    • , Harold Snieder
    • , Stefan Weiss
    • , Wanqing Wen
    • , Lisa R. Yanek
    • , Correa Adolfo
    • , Christie Ballantyne
    • , Larry Bielak
    • , Nienke R. Biermasz
    • , Eric Boerwinkle
    • , Niki Dimou
    • , Gudny Eiriksdottir
    • , Chuan Gao
    • , Sina A. Gharib
    • , Daniel J. Gottlieb
    • , José Haba-Rubio
    • , Tamara B. Harris
    • , Sami Heikkinen
    • , Raphaël Heinzer
    • , James E. Hixson
    • , Georg Homuth
    • , M. Arfan Ikram
    • , Pirjo Komulainen
    • , Jose E. Krieger
    • , Jiwon Lee
    • , Jingmin Liu
    • , Kurt K. Lohman
    • , Annemarie I. Luik
    • , Reedik Mägi
    • , Lisa W. Martin
    • , Thomas Meitinger
    • , Andres Metspalu
    • , Yuri Milaneschi
    • , Mike A. Nalls
    • , Jeff O’Connell
    • , Annette Peters
    • , Patricia Peyser
    • , Olli T. Raitakari
    • , Alex P. Reiner
    • , Patrick C. N. Rensen
    • , Treva K. Rice
    • , Stephen S. Rich
    • , Till Roenneberg
    • , Jerome I. Rotter
    • , Pamela J. Schreiner
    • , James Shikany
    • , Stephen S. Sidney
    • , Mario Sims
    • , Colleen M. Sitlani
    • , Tamar Sofer
    • , Konstantin Strauch
    • , Morris A. Swertz
    • , Kent D. Taylor
    • , André G. Uitterlinden
    • , Cornelia M. van Duijn
    • , Henry Völzke
    • , Melanie Waldenberger
    • , Robert B. Wallance
    • , Ko Willems van Dijk
    • , Caizheng Yu
    • , Alan B. Zonderman
    • , Diane M. Becker
    • , Paul Elliott
    • , Tõnu Esko
    • , Christian Gieger
    • , Hans J. Grabe
    • , Timo A. Lakka
    • , Terho Lehtimäki
    • , Kari E. North
    • , Brenda W. J. H. Penninx
    • , Peter Vollenweider
    • , Lynne E. Wagenknecht
    • , Tangchun Wu
    • , Yong-Bing Xiang
    • , Wei Zheng
    • , Donna K. Arnett
    • , Claude Bouchard
    • , Michele K. Evans
    • , Vilmundur Gudnason
    • , Sharon Kardia
    • , Tanika N. Kelly
    • , Stephen B. Kritchevsky
    • , Ruth J. F. Loos
    • , Alexandre C. Pereira
    • , Mike Province
    • , Bruce M. Psaty
    • , Charles Rotimi
    • , Xiaofeng Zhu
    • , Najaf Amin
    • , L. Adrienne Cupples
    • , Myriam Fornage
    • , Ervin F. Fox
    • , Xiuqing Guo
    • , W. James Gauderman
    • , Kenneth Rice
    • , Charles Kooperberg
    • , Patricia B. Munroe
    • , Ching-Ti Liu
    • , Alanna C. Morrison
    • , Dabeeru C. Rao
    • , Diana van Heemst
    •  & Susan Redline
  • Article
    | Open Access

    Proper ovarian differentiation requires RUNX1. Here, the authors show that double knockout of Runx1/Foxl2 results in masculinization of fetal ovaries, and that RUNX1 and FOXL2 jointly occupy common chromatin regions to maintain pre-granulosa cell identity in the fetal ovary.

    • Barbara Nicol
    • , Sara A. Grimm
    • , Frédéric Chalmel
    • , Estelle Lecluze
    • , Maëlle Pannetier
    • , Eric Pailhoux
    • , Elodie Dupin-De-Beyssat
    • , Yann Guiguen
    • , Blanche Capel
    •  & Humphrey H.-C. Yao
  • Article
    | Open Access

    Redirection of the TCA cycle intermediate aconitate to itaconate production has anti-inflammatory effects. Here the authors show that the itaconate derivative 4-octyl-itaconate is anti-inflammatory partly as a result of inhibiting GAPDH enzymatic activity and thereby glycolysis in macrophages.

    • Shan-Ting Liao
    • , Chao Han
    • , Ding-Qiao Xu
    • , Xiao-Wei Fu
    • , Jun-Song Wang
    •  & Ling-Yi Kong
  • Article
    | Open Access

    C. elegans is a commonly used model organism in the study of ageing, and differences in genetic background can result in varying strain longevity. Here the authors demonstrate that a background mutation in fln-2 affects life-limiting pharyngeal infection and that in the mutant background the beneficial effect of sir-2.1 over-expression is suppressed.

    • Yuan Zhao
    • , Hongyuan Wang
    • , Richard J. Poole
    •  & David Gems
  • Article
    | Open Access

    During high-intensity exercise, muscles convert glucose to lactate, in a process that is energetically less efficient than respiration. Here the authors develop a computational model based on muscle proteomic data showing that bypassing mitochondrial complex I increases ATP production rates, and validate these model predictions in an exercise test on 5 subjects.

    • Avlant Nilsson
    • , Elias Björnson
    • , Mikael Flockhart
    • , Filip J. Larsen
    •  & Jens Nielsen
  • Article
    | Open Access

    Immune cells contribute to the aortic wall destruction during abdominal aortic aneurysm (AAA) development. Here, Peshkova et al. show that cytokine signaling through interleukin-27 receptor is required for Angiotensin II-induced myelopoiesis and mature myeloid cells production, thus contributing to their aortic accumulation and aneurysm progression

    • Iuliia O. Peshkova
    • , Turan Aghayev
    • , Aliia R. Fatkhullina
    • , Petr Makhov
    • , Elizaveta K. Titerina
    • , Satoru Eguchi
    • , Yin Fei Tan
    • , Andrew V. Kossenkov
    • , Marina V. Khoreva
    • , Lyudmila V. Gankovskaya
    • , Stephen M. Sykes
    •  & Ekaterina K. Koltsova
  • Article
    | Open Access

    Risk of age-related chronic disorders and decrease in resilience is associated with ageing. Here the authors analyse the human blood metabolome and identify metabolites associated with frailty.

    • Nicholas J. W. Rattray
    • , Drupad K. Trivedi
    • , Yun Xu
    • , Tarani Chandola
    • , Caroline H. Johnson
    • , Alan D. Marshall
    • , Krisztina Mekli
    • , Zahra Rattray
    • , Gindo Tampubolon
    • , Bram Vanhoutte
    • , Iain R. White
    • , Frederick C. W. Wu
    • , Neil Pendleton
    • , James Nazroo
    •  & Royston Goodacre
  • Article
    | Open Access

    The endothelium actively maintains an anticoagulant surface through expression of thrombomodulin. Here, Peghaire et al. identify an anti-thrombotic pathway that controls thrombomodulin expression selectively in regions of low shear stress, via cooperation of the transcription factors ERG and KLF2.

    • C. Peghaire
    • , N. P. Dufton
    • , M. Lang
    • , I. I. Salles-Crawley
    • , J. Ahnström
    • , V. Kalna
    • , C. Raimondi
    • , C. Pericleous
    • , L. Inuabasi
    • , R. Kiseleva
    • , V. R. Muzykantov
    • , J. C. Mason
    • , G. M. Birdsey
    •  & A. M. Randi
  • Article
    | Open Access

    Type 1 as well as type 2 diabetes are characterized by a loss of insulin-producing β-cells. Here the authors show that the FDA-approved drug neratinib has beneficial effects on β-cell survival, insulin secretion, and glycemic control in mouse models of diabetes.

    • Amin Ardestani
    • , Sijia Li
    • , Karthika Annamalai
    • , Blaz Lupse
    • , Shirin Geravandi
    • , Aleksandra Dobrowolski
    • , Shan Yu
    • , Siying Zhu
    • , Tyler D. Baguley
    • , Murali Surakattula
    • , Janina Oetjen
    • , Lena Hauberg-Lotte
    • , Raquel Herranz
    • , Sushil Awal
    • , Delsi Altenhofen
    • , Van Nguyen-Tran
    • , Sean Joseph
    • , Peter G. Schultz
    • , Arnab K. Chatterjee
    • , Nikki Rogers
    • , Matthew S. Tremblay
    • , Weijun Shen
    •  & Kathrin Maedler
  • Article
    | Open Access

    Pu-erh tea displays cholesterol-lowering properties. Here, Huang et al. show that this is mostly due to the action of a pigment in Pu-erh tea that induces changes in certain gut microbiota and bile acid levels, thus modulating the gut-liver metabolic axis.

    • Fengjie Huang
    • , Xiaojiao Zheng
    • , Xiaohui Ma
    • , Runqiu Jiang
    • , Wangyi Zhou
    • , Shuiping Zhou
    • , Yunjing Zhang
    • , Sha Lei
    • , Shouli Wang
    • , Junliang Kuang
    • , Xiaolong Han
    • , Meilin Wei
    • , Yijun You
    • , Mengci Li
    • , Yitao Li
    • , Dandan Liang
    • , Jiajian Liu
    • , Tianlu Chen
    • , Chao Yan
    • , Runmin Wei
    • , Cynthia Rajani
    • , Chengxing Shen
    • , Guoxiang Xie
    • , Zhaoxiang Bian
    • , Houkai Li
    • , Aihua Zhao
    •  & Wei Jia
  • Article
    | Open Access

    Mutations associated with SCN5A, which encodes the major cardiac sodium channel, influence impulse conduction and are associated with arrhythmia disorders. Here, the authors identify an evolutionary conserved, super enhancer-like, regulatory cluster downstream of SCN5A and show that it controls the chromatin architecture of the locus and Scn5a expression.

    • Joyce C. K. Man
    • , Rajiv A. Mohan
    • , Malou van den Boogaard
    • , Catharina R. E. Hilvering
    • , Catherine Jenkins
    • , Vincent Wakker
    • , Valerio Bianchi
    • , Wouter de Laat
    • , Phil Barnett
    • , Bastiaan J. Boukens
    •  & Vincent M. Christoffels
  • Article
    | Open Access

    Impulsive behaviour is common in various neuropsychiatric disorders. Here, the authors identify a pathway from the lateral hypothalamus to the ventral hippocampus and the role of melanin-concentrating hormone signaling in these neurons in specifically regulating impulsivity.

    • Emily E. Noble
    • , Zhuo Wang
    • , Clarissa M. Liu
    • , Elizabeth A. Davis
    • , Andrea N. Suarez
    • , Lauren M. Stein
    • , Linda Tsan
    • , Sarah J. Terrill
    • , Ted M. Hsu
    • , A-Hyun Jung
    • , Lauren M. Raycraft
    • , Joel D. Hahn
    • , Martin Darvas
    • , Alyssa M. Cortella
    • , Lindsey A. Schier
    • , Alexander W. Johnson
    • , Matthew R. Hayes
    • , Daniel P. Holschneider
    •  & Scott E. Kanoski
  • Article
    | Open Access

    Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Here, authors report crystal structures of truncated human MFN2 in different nucleotide-loading states and show that MFN2 forms sustained dimers even after GTP hydrolysis.

    • Yu-Jie Li
    • , Yu-Lu Cao
    • , Jian-Xiong Feng
    • , Yuanbo Qi
    • , Shuxia Meng
    • , Jie-Feng Yang
    • , Ya-Ting Zhong
    • , Sisi Kang
    • , Xiaoxue Chen
    • , Lan Lan
    • , Li Luo
    • , Bing Yu
    • , Shoudeng Chen
    • , David C. Chan
    • , Junjie Hu
    •  & Song Gao
  • Article
    | Open Access

    Hydralazine is a drug used in the treatment of heart failure and cancer, and it has recently been shown to promote lifespan in C. elegans. Here, the authors elucidate the mechanism of action of hydralazine, and show that it targets PKA to promote mitochondrial function via Sirtuin1/5.

    • Esmaeil Dehghan
    • , Mohammad Goodarzi
    • , Bahar Saremi
    • , Rueyling Lin
    •  & Hamid Mirzaei
  • Article
    | Open Access

    ERCC1 is involved in a number of DNA repair pathways including nucleotide excision repair. Here the authors showed that reduced transcription in Ercc1-deficient mouse livers and cells increases ATP levels, suppressing glycolysis and rerouting glucose into the pentose phosphate shunt that generates reductive stress.

    • Chiara Milanese
    • , Cíntia R. Bombardieri
    • , Sara Sepe
    • , Sander Barnhoorn
    • , César Payán-Goméz
    • , Donatella Caruso
    • , Matteo Audano
    • , Silvia Pedretti
    • , Wilbert P. Vermeij
    • , Renata M. C. Brandt
    • , Akos Gyenis
    • , Mirjam M. Wamelink
    • , Annelieke S. de Wit
    • , Roel C. Janssens
    • , René Leen
    • , André B. P. van Kuilenburg
    • , Nico Mitro
    • , Jan H. J. Hoeijmakers
    •  & Pier G. Mastroberardino
  • Article
    | Open Access

    Uterine leiomyomata (UL) or fibroids are neoplasms of the uterine smooth muscle associated with heavy menstrual bleeding and other female reproductive tract morbidity. Here, the authors identify eight previously undescribed genetic loci for UL and further look into genetic overlap with heavy menstrual bleeding and endometriosis.

    • C. S. Gallagher
    • , N. Mäkinen
    • , H. R. Harris
    • , N. Rahmioglu
    • , O. Uimari
    • , J. P. Cook
    • , N. Shigesi
    • , T. Ferreira
    • , D. R. Velez-Edwards
    • , T. L. Edwards
    • , S. Mortlock
    • , Z. Ruhioglu
    • , F. Day
    • , C. M. Becker
    • , V. Karhunen
    • , H. Martikainen
    • , M.-R. Järvelin
    • , R. M. Cantor
    • , P. M. Ridker
    • , K. L. Terry
    • , J. E. Buring
    • , S. D. Gordon
    • , S. E. Medland
    • , G. W. Montgomery
    • , D. R. Nyholt
    • , D. A. Hinds
    • , J. Y. Tung
    • , Michelle Agee
    • , Babak Alipanahi
    • , Adam Auton
    • , Robert K. Bell
    • , Katarzyna Bryc
    • , Sarah L. Elson
    • , Pierre Fontanillas
    • , Nicholas A. Furlotte
    • , Karen E. Huber
    • , Aaron Kleinman
    • , Nadia K. Litterman
    • , Matthew H. McIntyre
    • , Joanna L. Mountain
    • , Elizabeth S. Noblin
    • , Carrie A. M. Northover
    • , Steven J. Pitts
    • , J. Fah Sathirapongsasuti
    • , Olga V. Sazonova
    • , Janie F. Shelton
    • , Suyash Shringarpure
    • , Chao Tian
    • , Vladimir Vacic
    • , Catherine H. Wilson
    • , J. R. B. Perry
    • , P. A. Lind
    • , J. N. Painter
    • , N. G. Martin
    • , A. P. Morris
    • , D. I. Chasman
    • , S. A. Missmer
    • , K. T. Zondervan
    •  & C. C. Morton
  • Article
    | Open Access

    Decreased autophagy is a hallmark of ageing, but its inter-tissue regulation is poorly understood. Here, Zhou et al. identify mir-83 in C. elegans, which is transported across tissues and suppresses autophagy, contributing to age-related decline.

    • Yifei Zhou
    • , Xueqing Wang
    • , Mengjiao Song
    • , Zhidong He
    • , Guizhong Cui
    • , Guangdun Peng
    • , Christoph Dieterich
    • , Adam Antebi
    • , Naihe Jing
    •  & Yidong Shen
  • Article
    | Open Access

    It’s well known that hippocampal synaptic plasticity and memory are impaired in experimental models of metabolic diseases, however, it is unclear if maternal diet or metabolic alterations around the gestational age may multigenerationally affect learning and memory. In this study, authors demonstrate that maternal high fat diet-dependent insulin resistance affects synaptic plasticity and memory of descendants until the third generation via reduced exon specific brain-derived neurotrophic factor expression in the hippocampus of descendants

    • Salvatore Fusco
    • , Matteo Spinelli
    • , Sara Cocco
    • , Cristian Ripoli
    • , Alessia Mastrodonato
    • , Francesca Natale
    • , Marco Rinaudo
    • , Giulia Livrizzi
    •  & Claudio Grassi
  • Article
    | Open Access

    Aberrant morphology of the QRS complex in an electrocardiogram can be associated with cardiac morbidity and mortality. Here, the authors perform genome-wide association studies for ten measures of the QRS complex in 81,192 individuals and find 86 previously unreported loci that associate with at least one parameter.

    • Kristjan Norland
    • , Gardar Sveinbjornsson
    • , Rosa B. Thorolfsdottir
    • , Olafur B. Davidsson
    • , Vinicius Tragante
    • , Sridharan Rajamani
    • , Anna Helgadottir
    • , Solveig Gretarsdottir
    • , Jessica van Setten
    • , Folkert W. Asselbergs
    • , Jon Th. Sverrisson
    • , Sigurdur S. Stephensen
    • , Gylfi Oskarsson
    • , Emil L. Sigurdsson
    • , Karl Andersen
    • , Ragnar Danielsen
    • , Gudmundur Thorgeirsson
    • , Unnur Thorsteinsdottir
    • , David O. Arnar
    • , Patrick Sulem
    • , Hilma Holm
    • , Daniel F. Gudbjartsson
    •  & Kari Stefansson
  • Article
    | Open Access

    Genome-wide association studies of metabolites have revealed hundreds of genetic associations using univariate analyses. Here, the authors use a multivariate approach to perform association analyses for 158 serum metabolites, followed by fine mapping and GxE interaction tests with statin use and age.

    • Apolline Gallois
    • , Joel Mefford
    • , Arthur Ko
    • , Amaury Vaysse
    • , Hanna Julienne
    • , Mika Ala-Korpela
    • , Markku Laakso
    • , Noah Zaitlen
    • , Päivi Pajukanta
    •  & Hugues Aschard
  • Article
    | Open Access

    The majority of disease-associated genetic variants lie in non-coding regions. Here the authors generated and compiled human transcriptomic, epigenomic and chromatin conformation datasets, to identify genes associated with atrial fibrillation and functional non-coding variants.

    • Antoinette F. van Ouwerkerk
    • , Fernanda M. Bosada
    • , Karel van Duijvenboden
    • , Matthew C. Hill
    • , Lindsey E. Montefiori
    • , Koen T. Scholman
    • , Jia Liu
    • , Antoine A. F. de Vries
    • , Bastiaan J. Boukens
    • , Patrick T. Ellinor
    • , Marie José T. H. Goumans
    • , Igor R. Efimov
    • , Marcelo A. Nobrega
    • , Phil Barnett
    • , James F. Martin
    •  & Vincent M. Christoffels
  • Article
    | Open Access

    Down syndrome (DS) is caused by trisomy 21 (T21), but the underlying etiology of the related immune and neurological dysfunction is unclear. Here, the authors show that T21 activates the kynurenine pathway via increased interferon receptor copy number, which could contribute to DS pathophysiology.

    • Rani K. Powers
    • , Rachel Culp-Hill
    • , Michael P. Ludwig
    • , Keith P. Smith
    • , Katherine A. Waugh
    • , Ross Minter
    • , Kathryn D. Tuttle
    • , Hannah C. Lewis
    • , Angela L. Rachubinski
    • , Ross E. Granrath
    • , María Carmona-Iragui
    • , Rebecca B. Wilkerson
    • , Darcy E. Kahn
    • , Molishree Joshi
    • , Alberto Lleó
    • , Rafael Blesa
    • , Juan Fortea
    • , Angelo D’Alessandro
    • , James C. Costello
    • , Kelly D. Sullivan
    •  & Joaquin M. Espinosa
  • Article
    | Open Access

    Retrotransposons are silenced by an epigenetic mechanism and piRNA pathway in the mammalian germline. Here, the authors report that UHRF1 suppresses retrotransposons by interacting with PRMT5 and PIWI proteins during spermatogenesis.

    • Juan Dong
    • , Xiaoli Wang
    • , Congcong Cao
    • , Yujiao Wen
    • , Akihiko Sakashita
    • , Si Chen
    • , Jin Zhang
    • , Yue Zhang
    • , Liquan Zhou
    • , Mengcheng Luo
    • , Mingxi Liu
    • , Aihua Liao
    • , Satoshi H. Namekawa
    •  & Shuiqiao Yuan
  • Article
    | Open Access

    Large whole-exome sequencing studies have suggested that the genetic architecture of syndromic congenital heart disease (CHD) is different from sporadic forms. Here, Watkins et al. estimate the relative contribution of damaging recessive and de novo genotypes to CHD in 2391 trios and find them to be associated with different gene functions.

    • W. Scott Watkins
    • , E. Javier Hernandez
    • , Sergiusz Wesolowski
    • , Brent W. Bisgrove
    • , Ryan T. Sunderland
    • , Edwin Lin
    • , Gordon Lemmon
    • , Bradley L. Demarest
    • , Thomas A. Miller
    • , Daniel Bernstein
    • , Martina Brueckner
    • , Wendy K. Chung
    • , Bruce D. Gelb
    • , Elizabeth Goldmuntz
    • , Jane W. Newburger
    • , Christine E. Seidman
    • , Yufeng Shen
    • , H. Joseph Yost
    • , Mark Yandell
    •  & Martin Tristani-Firouzi
  • Article
    | Open Access

    Mosaic loss of chromosome Y (mLOY) is associated with age and smoking but also genetic factors play a role. Here, Terao et al. perform GWAS for mLOY in 95,380 Japanese men and identify 46 loci that overlap with hematopoietic stem cell enhancers and transcription factor binding sites critical for hematopoiesis.

    • Chikashi Terao
    • , Yukihide Momozawa
    • , Kazuyoshi Ishigaki
    • , Eiryo Kawakami
    • , Masato Akiyama
    • , Po-Ru Loh
    • , Giulio Genovese
    • , Hiroki Sugishita
    • , Tazro Ohta
    • , Makoto Hirata
    • , John R. B. Perry
    • , Koichi Matsuda
    • , Yoshinori Murakami
    • , Michiaki Kubo
    •  & Yoichiro Kamatani
  • Article
    | Open Access

    Elevated inorganic phosphate levels promote excessive parathyroid hormone secretion, which contributes to the aetiology of secondary hyperparathyroidism. Here, the authors show that phosphate directly inhibits the calcium-sensing receptor, the main regulator of parathyroid hormone secretion.

    • Patricia P. Centeno
    • , Amanda Herberger
    • , Hee-Chang Mun
    • , Chialing Tu
    • , Edward F. Nemeth
    • , Wenhan Chang
    • , Arthur D. Conigrave
    •  & Donald T. Ward