Molecular medicine

  • Article
    | Open Access

    New anti-fibrotics aided by a better understanding of fibrotic cell subsets and their functions are needed. Here the authors perform single-cell RNA-seq and CyTOF on nodules from patients with Dupuytren’s disease to map subsets and the state of mesenchymal cells during pathogenic fibrogenesis.

    • Thomas B. Layton
    • , Lynn Williams
    • , Fiona McCann
    • , Mingjun Zhang
    • , Marco Fritszche
    • , Huw Colin-York
    • , Marisa Cabrita
    • , Michael T. H. Ng
    • , Marc Feldmann
    • , Stephen Samson
    • , Dominic Furniss
    • , Weilin Xie
    •  & Jagdeep Nanchahal
  • Article
    | Open Access

    Ultrasensitive methods for detection of biomarkers for infectious disease are needed for diagnosing, monitoring and targeting treatment. Here the authors develop a digital assay for inflammatory markers, bacterial DNA and antibotic-resistance genes and apply it to characterise asthma patients and predict mortality from septic shock.

    • M. Fatih Abasıyanık
    • , Krysta Wolfe
    • , Hoang Van Phan
    • , Jing Lin
    • , Bharathi Laxman
    • , Steven R. White
    • , Philip A. Verhoef
    • , Gökhan M. Mutlu
    • , Bhakti Patel
    •  & Savaş Tay
  • Article
    | Open Access

    Evolutionary steering uses therapies to control tumour evolution by exploiting trade-offs. Here, using a barcoding approach applied to large cell populations, the authors explore evolutionary steering in lung cancer cells treated with EGFR inhibitors.

    • Ahmet Acar
    • , Daniel Nichol
    • , Javier Fernandez-Mateos
    • , George D. Cresswell
    • , Iros Barozzi
    • , Sung Pil Hong
    • , Nicholas Trahearn
    • , Inmaculada Spiteri
    • , Mark Stubbs
    • , Rosemary Burke
    • , Adam Stewart
    • , Giulio Caravagna
    • , Benjamin Werner
    • , Georgios Vlachogiannis
    • , Carlo C. Maley
    • , Luca Magnani
    • , Nicola Valeri
    • , Udai Banerji
    •  & Andrea Sottoriva
  • Perspective
    | Open Access

    The role microbes play in human health and the ability of synthetic biology to engineer microbial properties opens up new ways of treating disease. In this perspective, the authors describe the design and development of these living therapeutics.

    • Mark R. Charbonneau
    • , Vincent M. Isabella
    • , Ning Li
    •  & Caroline B. Kurtz
  • Article
    | Open Access

    Cardiovascular risks of cold exposure and the subsequent activation of the β3-AR pathway limit the application of beige fat thermogenesis for the treatment of obesity. Here, the authors show that optogenetics light-activated Ca2+ cycling in adipocytes triggers a fat-specific “cold-mimetic” thermogenesis response protecting mice against diet-induced obesity.

    • Kazuki Tajima
    • , Kenji Ikeda
    • , Yuji Tanabe
    • , Ella A. Thomson
    • , Takeshi Yoneshiro
    • , Yasuo Oguri
    • , Marc D. Ferro
    • , Ada S. Y. Poon
    •  & Shingo Kajimura
  • Article
    | Open Access

    Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.

    • Angela Tomasovic
    • , Theresa Brand
    • , Constanze Schanbacher
    • , Sofia Kramer
    • , Martin W. Hümmert
    • , Patricio Godoy
    • , Wolfgang Schmidt-Heck
    • , Peter Nordbeck
    • , Jonas Ludwig
    • , Susanne Homann
    • , Armin Wiegering
    • , Timur Shaykhutdinov
    • , Christoph Kratz
    • , Ruth Knüchel
    • , Hans-Konrad Müller-Hermelink
    • , Andreas Rosenwald
    • , Norbert Frey
    • , Jutta Eichler
    • , Dobromir Dobrev
    • , Ali El-Armouche
    • , Jan G. Hengstler
    • , Oliver J. Müller
    • , Karsten Hinrichs
    • , Friederike Cuello
    • , Alma Zernecke
    •  & Kristina Lorenz
  • Article
    | Open Access

    Nonsense mutations can be corrected by several molecules that activate readthrough of premature termination codon. Here, the authors report that 2,6-diaminopurine efficiently corrects UGA nonsense mutations with no significant toxicity.

    • Carole Trzaska
    • , Séverine Amand
    • , Christine Bailly
    • , Catherine Leroy
    • , Virginie Marchand
    • , Evelyne Duvernois-Berthet
    • , Jean-Michel Saliou
    • , Hana Benhabiles
    • , Elisabeth Werkmeister
    • , Thierry Chassat
    • , Romain Guilbert
    • , David Hannebique
    • , Anthony Mouray
    • , Marie-Christine Copin
    • , Pierre-Arthur Moreau
    • , Eric Adriaenssens
    • , Andreas Kulozik
    • , Eric Westhof
    • , David Tulasne
    • , Yuri Motorin
    • , Sylvie Rebuffat
    •  & Fabrice Lejeune
  • Article
    | Open Access

    Prematurely born babies need extra oxygen to survive, but this can cause damage to the eyes and lead to infant blindness. Here the authors show that this hyperoxia changes the metabolism of Müller cells in the retina such that they use up, rather than produce, glutamine and secrete excess ammonium.

    • Charandeep Singh
    • , Vincent Tran
    • , Leah McCollum
    • , Youstina Bolok
    • , Kristin Allan
    • , Alex Yuan
    • , George Hoppe
    • , Henri Brunengraber
    •  & Jonathan E. Sears
  • Article
    | Open Access

    De novo mutations significantly contribute to autism spectrum disorders (ASD). Here, the authors demonstrate that ASD-associated de novo mutations in the POGZ gene, one of a high-confidence ASD gene, lead to ASD-related impaired neuronal development and disrupted mature cortical network function.

    • Kensuke Matsumura
    • , Kaoru Seiriki
    • , Shota Okada
    • , Masashi Nagase
    • , Shinya Ayabe
    • , Ikuko Yamada
    • , Tamio Furuse
    • , Hirotoshi Shibuya
    • , Yuka Yasuda
    • , Hidenaga Yamamori
    • , Michiko Fujimoto
    • , Kazuki Nagayasu
    • , Kana Yamamoto
    • , Kohei Kitagawa
    • , Hiroki Miura
    • , Nanaka Gotoda-Nishimura
    • , Hisato Igarashi
    • , Misuzu Hayashida
    • , Masayuki Baba
    • , Momoka Kondo
    • , Shigeru Hasebe
    • , Kosei Ueshima
    • , Atsushi Kasai
    • , Yukio Ago
    • , Atsuko Hayata-Takano
    • , Norihito Shintani
    • , Tokuichi Iguchi
    • , Makoto Sato
    • , Shun Yamaguchi
    • , Masaru Tamura
    • , Shigeharu Wakana
    • , Atsushi Yoshiki
    • , Ayako M. Watabe
    • , Hideyuki Okano
    • , Kazuhiro Takuma
    • , Ryota Hashimoto
    • , Hitoshi Hashimoto
    •  & Takanobu Nakazawa
  • Article
    | Open Access

    Caspase 11 activation involves transcriptional upregulation and proteolytic cleavage. Here the authors show that prostaglandin E2 prevents caspase-11-mediated pyroptosis, blocking caspase-11 mRNA and protein upregulation in macrophages and in vivo, and that mice lacking caspase-11 are strongly protected from allergic airway inflammation.

    • Zbigniew Zasłona
    • , Ewelina Flis
    • , Mieszko M. Wilk
    • , Richard G. Carroll
    • , Eva M. Palsson-McDermott
    • , Mark M. Hughes
    • , Ciana Diskin
    • , Kathy Banahan
    • , Dylan G. Ryan
    • , Alexander Hooftman
    • , Alicja Misiak
    • , Jay Kearney
    • , Gunter Lochnit
    • , Wilhelm Bertrams
    • , Timm Greulich
    • , Bernd Schmeck
    • , Oliver J. McElvaney
    • , Kingston H. G. Mills
    • , Ed C. Lavelle
    • , Małgorzata Wygrecka
    • , Emma M. Creagh
    •  & Luke A. J. O’Neill
  • Article
    | Open Access

    Late-life cognitive dysfunction is common, but the biological substrates are largely unknown. Here, the authors examined a panel of 90 neurology-related protein biomarkers and show that plasma levels of 22 of these proteins are associated with general fluid cognitive ability in later life.

    • Sarah E. Harris
    • , Simon R. Cox
    • , Steven Bell
    • , Riccardo E. Marioni
    • , Bram P. Prins
    • , Alison Pattie
    • , Janie Corley
    • , Susana Muñoz Maniega
    • , Maria Valdés Hernández
    • , Zoe Morris
    • , Sally John
    • , Paola G. Bronson
    • , Elliot M. Tucker-Drob
    • , John M. Starr
    • , Mark E. Bastin
    • , Joanna M. Wardlaw
    • , Adam S. Butterworth
    •  & Ian J. Deary
  • Article
    | Open Access

    Here, the authors report that exhausted HCV-specific CD8+ T cells are marked by upregulation of p53 signaling already detectable in an early phase of chronic HCV infection and by a later development of a repressive chromatin state, and show that chemical targeting of these pathways improves CD8+ T cell metabolism and antiviral function.

    • Valeria Barili
    • , Paola Fisicaro
    • , Barbara Montanini
    • , Greta Acerbi
    • , Anita Filippi
    • , Giovanna Forleo
    • , Chiara Romualdi
    • , Manuela Ferracin
    • , Francesca Guerrieri
    • , Giuseppe Pedrazzi
    • , Carolina Boni
    • , Marzia Rossi
    • , Andrea Vecchi
    • , Amalia Penna
    • , Alessandra Zecca
    • , Cristina Mori
    • , Alessandra Orlandini
    • , Elisa Negri
    • , Marco Pesci
    • , Marco Massari
    • , Gabriele Missale
    • , Massimo Levrero
    • , Simone Ottonello
    •  & Carlo Ferrari
  • Article
    | Open Access

    The pathways that underlie the effects of exercise on metabolism remain incompletely described. Here, the authors perform a meta-analysis of transcriptomic data from 66 published datasets of human skeletal muscle. They identify pathways selectively activated by inactivity, aerobic or resistance exercise, and characterize NR4A3 as one of the genes responsive to inactivity.

    • Nicolas J. Pillon
    • , Brendan M. Gabriel
    • , Lucile Dollet
    • , Jonathon A. B. Smith
    • , Laura Sardón Puig
    • , Javier Botella
    • , David J. Bishop
    • , Anna Krook
    •  & Juleen R. Zierath
  • Article
    | Open Access

    Replacing mutant genes with wildtype copies using adeno-associated virus (AAV) has been explored for the treatment of inherited retinopathies, but the low cargo limit restricts its use. Here the authors describe a single AAV platform that allows local replacement of a mutated sequence with its wildtype counterpart, based on combined CRISPR-Cas9 and micro-homology-mediated end joining.

    • Koji M. Nishiguchi
    • , Kosuke Fujita
    • , Fuyuki Miya
    • , Shota Katayama
    •  & Toru Nakazawa
  • Article
    | Open Access

    Vascular senescence is closely associated with individual ageing, while its causative role remains unclear. Here Barinda et al. generate endothelial cell-specific progeroind mice, and reveal that endothelial cell senescence directly induces metabolic disorders through senescence-messaging secretomes.

    • Agian Jeffilano Barinda
    • , Koji Ikeda
    • , Dhite Bayu Nugroho
    • , Donytra Arby Wardhana
    • , Naoto Sasaki
    • , Sakiko Honda
    • , Ryota Urata
    • , Satoaki Matoba
    • , Ken-ichi Hirata
    •  & Noriaki Emoto
  • Article
    | Open Access

    Circulating cell-free mRNA holds great promise as a non-invasive diagnostic biomarker. Here the authors show that cell-free mRNA captures transcripts from the bone marrow and can be used to non-invasively monitor dynamic changes in bone marrow physiology.

    • Arkaitz Ibarra
    • , Jiali Zhuang
    • , Yue Zhao
    • , Neeraj S. Salathia
    • , Vera Huang
    • , Alexander D. Acosta
    • , Jonathan Aballi
    • , Shusuke Toden
    • , Amy P. Karns
    • , Intan Purnajo
    • , Julianna R. Parks
    • , Lucy Guo
    • , James Mason
    • , Darren Sigal
    • , Tina S. Nova
    • , Stephen R. Quake
    •  & Michael Nerenberg
  • Article
    | Open Access

    Exercise improves metabolic health and physical condition, particularly important for health in aged individuals. Here, the authors identify that Sestrins, proteins induced by exercise, are key mediators of the metabolic adaptation to exercise and increase endurance through the AKT and PGC1a axes.

    • Myungjin Kim
    • , Alyson Sujkowski
    • , Sim Namkoong
    • , Bondong Gu
    • , Tyler Cobb
    • , Boyoung Kim
    • , Allison H. Kowalsky
    • , Chun-Seok Cho
    • , Ian Semple
    • , Seung-Hyun Ro
    • , Carol Davis
    • , Susan V. Brooks
    • , Michael Karin
    • , Robert J. Wessells
    •  & Jun Hee Lee
  • Article
    | Open Access

    Post-translational O-linked β-N acetylglucosamine (O-GlcNAc) modification acts as a nutrient-sensing mechanism. Here the authors report that O-GlcNAc transferase inhibits adipose tissue lipolysis via O-GlcNAcylation of the lipid droplet protein perilipin 1 and thus promotes diet-induced obesity.

    • Yunfan Yang
    • , Minnie Fu
    • , Min-Dian Li
    • , Kaisi Zhang
    • , Bichen Zhang
    • , Simeng Wang
    • , Yuyang Liu
    • , Weiming Ni
    • , Qunxiang Ong
    • , Jia Mi
    •  & Xiaoyong Yang
  • Article
    | Open Access

    In breast cancer, the immune infiltration of the tumour associates with clinical outcome. Here, the authors infer immune context based on gene expression data and identify a new independent subtype linked to pro-tumorigenic immune infiltration.

    • Xavier Tekpli
    • , Tonje Lien
    • , Andreas Hagen Røssevold
    • , Daniel Nebdal
    • , Elin Borgen
    • , Hege Oma Ohnstad
    • , Jon Amund Kyte
    • , Johan Vallon-Christersson
    • , Marie Fongaard
    • , Eldri Undlien Due
    • , Lisa Gregusson Svartdal
    • , My Anh Tu Sveli
    • , Øystein Garred
    • , Anne-Lise Børresen-Dale
    • , Ellen Schlichting
    • , Torill Sauer
    • , Jürgen Geisler
    • , Solveig Hofvind
    • , Tone F. Bathen
    • , Olav Engebråten
    • , Gry Aarum Geitvik
    • , Anita Langerød
    • , Rolf Kåresen
    • , Gunhild Mari Mælandsmo
    • , Ole Christian Lingjærde
    • , Helle Kristine Skjerven
    • , Daehoon Park
    • , Britt Fritzman
    • , Arnoldo Frigessi
    • , Kristine Kleivi Sahlberg
    • , Therese Sørlie
    • , Hege G. Russnes
    • , Bjørn Naume
    •  & Vessela N. Kristensen
  • Article
    | Open Access

    LncRNAs at the HOX gene locus are increased in expression in NPM1 mutant acute myeloid leukemia. In this study, the authors show that one such lncRNA, HOX3B-AS3, has a role in regulating gene transcription and protein synthesis in leukemia cells.

    • Dimitrios Papaioannou
    • , Andreas Petri
    • , Oliver M. Dovey
    • , Sara Terreri
    • , Eric Wang
    • , Frances A. Collins
    • , Lauren A. Woodward
    • , Allison E. Walker
    • , Deedra Nicolet
    • , Felice Pepe
    • , Prasanthi Kumchala
    • , Marius Bill
    • , Christopher J. Walker
    • , Malith Karunasiri
    • , Krzysztof Mrózek
    • , Miranda L. Gardner
    • , Virginia Camilotto
    • , Nina Zitzer
    • , Jonathan L. Cooper
    • , Xiongwei Cai
    • , Xiaoqing Rong-Mullins
    • , Jessica Kohlschmidt
    • , Kellie J. Archer
    • , Michael A. Freitas
    • , Yi Zheng
    • , Robert J. Lee
    • , Iannis Aifantis
    • , George Vassiliou
    • , Guramrit Singh
    • , Sakari Kauppinen
    • , Clara D. Bloomfield
    • , Adrienne M. Dorrance
    •  & Ramiro Garzon
  • Article
    | Open Access

    The ERK signalling pathway is activated in many cancers, however ERK1 and ERK2 are difficult to target pharmacologically. Here, the authors identify a small molecule inhibitor that binds covalently to the D-recruitment site of ERK and induces cell death and reduces tumour growth in mice.

    • Tamer S. Kaoud
    • , William H. Johnson
    • , Nancy D. Ebelt
    • , Andrea Piserchio
    • , Diana Zamora-Olivares
    • , Sabrina X. Van Ravenstein
    • , Jacey R. Pridgen
    • , Ramakrishna Edupuganti
    • , Rachel Sammons
    • , Micael Cano
    • , Mangalika Warthaka
    • , Matthew Harger
    • , Clint D. J. Tavares
    • , Jihyun Park
    • , Mohamed F. Radwan
    • , Pengyu Ren
    • , Eric V. Anslyn
    • , Kenneth Y. Tsai
    • , Ranajeet Ghose
    •  & Kevin N. Dalby
  • 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

    Delivering biological cargo to airway epithelial cells is very challenging. Here, the authors use engineered amphiphilic peptides to shuttle proteins and CRISPR RNPs into airway cells in vivo.

    • Sateesh Krishnamurthy
    • , Christine Wohlford-Lenane
    • , Suhas Kandimalla
    • , Gilles Sartre
    • , David K. Meyerholz
    • , Vanessa Théberge
    • , Stéphanie Hallée
    • , Anne-Marie Duperré
    • , Thomas Del’Guidice
    • , Jean-Pascal Lepetit-Stoffaes
    • , Xavier Barbeau
    • , David Guay
    •  & Paul B. McCray Jr.
  • 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
  • Article
    | Open Access

    MG53 is a protein that regulates the cell membrane repair process, and it’s been suggested that it might play a role in diabetes. Here, the authors demonstrate that circulating MG53 functions as a myokine to facilitate tissue injury-repair and regeneration without impacting glucose handling.

    • Zehua Bian
    • , Qiang Wang
    • , Xinyu Zhou
    • , Tao Tan
    • , Ki Ho Park
    • , H. Fritz Kramer
    • , Alan McDougal
    • , Nicholas J. Laping
    • , Sanjay Kumar
    • , T. M. Ayodele Adesanya
    • , Matthew Sermersheim
    • , Frank Yi
    • , Xinxin Wang
    • , Junwei Wu
    • , Kristyn Gumpper
    • , Qiwei Jiang
    • , Duofen He
    • , Pei-Hui Lin
    • , Haichang Li
    • , Fangxia Guan
    • , Jingsong Zhou
    • , Mark J. Kohr
    • , Chunyu Zeng
    • , Hua Zhu
    •  & Jianjie Ma
  • Article
    | Open Access

    Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.

    • Ana S. Guerreiro Stucklin
    • , Scott Ryall
    • , Kohei Fukuoka
    • , Michal Zapotocky
    • , Alvaro Lassaletta
    • , Christopher Li
    • , Taylor Bridge
    • , Byungjin Kim
    • , Anthony Arnoldo
    • , Paul E. Kowalski
    • , Yvonne Zhong
    • , Monique Johnson
    • , Claire Li
    • , Arun K. Ramani
    • , Robert Siddaway
    • , Liana Figueiredo Nobre
    • , Pasqualino de Antonellis
    • , Christopher Dunham
    • , Sylvia Cheng
    • , Daniel R. Boué
    • , Jonathan L. Finlay
    • , Scott L. Coven
    • , Inmaculada de Prada
    • , Marta Perez-Somarriba
    • , Claudia C. Faria
    • , Michael A. Grotzer
    • , Elisabeth Rushing
    • , David Sumerauer
    • , Josef Zamecnik
    • , Lenka Krskova
    • , Miguel Garcia Ariza
    • , Ofelia Cruz
    • , Andres Morales La Madrid
    • , Palma Solano
    • , Keita Terashima
    • , Yoshiko Nakano
    • , Koichi Ichimura
    • , Motoo Nagane
    • , Hiroaki Sakamoto
    • , Maria Joao Gil-da-Costa
    • , Roberto Silva
    • , Donna L. Johnston
    • , Jean Michaud
    • , Bev Wilson
    • , Frank K. H. van Landeghem
    • , Angelica Oviedo
    • , P. Daniel McNeely
    • , Bruce Crooks
    • , Iris Fried
    • , Nataliya Zhukova
    • , Jordan R. Hansford
    • , Amulya Nageswararao
    • , Livia Garzia
    • , Mary Shago
    • , Michael Brudno
    • , Meredith S. Irwin
    • , Ute Bartels
    • , Vijay Ramaswamy
    • , Eric Bouffet
    • , Michael D. Taylor
    • , Uri Tabori
    •  & Cynthia Hawkins
  • Article
    | Open Access

    Therapeutic hypothermia is a potent tool in the treatment of neonatal hypoxic-ischemic (HI) injury, yet the underlying mechanisms remain unclear. Here, authors demonstrate how the RNA-binding motif protein RBM3, which is induced by mild cooling while global translation rate is slowed down, contributes substantially to neuroregeneration after adult HI injury, specifically in the subventricular zone and subgranular zone.

    • Xinzhou Zhu
    • , Jingyi Yan
    • , Catherine Bregere
    • , Andrea Zelmer
    • , Tessa Goerne
    • , Josef P. Kapfhammer
    • , Raphael Guzman
    •  & Sven Wellmann
  • Article
    | Open Access

    It is unclear if there is a causal link between increased neurogenesis and altered affective behaviors in major depressive disorders. Here, the authors show that selectively suppressing the excitability of newborn neurons, without altering neurogenesis, abolishes the antidepressant effects of fluoxetine.

    • Elif Tunc-Ozcan
    • , Chian-Yu Peng
    • , Yiwen Zhu
    • , Sara R. Dunlop
    • , Anis Contractor
    •  & John A. Kessler
  • Article
    | Open Access

    Conventional methods to detect AAV vector transduction can miss transient or low levels of reporter expression. Here the authors use editing-reporter mice and discover numerous sites of AAV targeting along with better prediction of the gene editing footprint.

    • Jonathan F. Lang
    • , Sushila A. Toulmin
    • , Kasey L. Brida
    • , Laurence C. Eisenlohr
    •  & Beverly L. Davidson
  • Article
    | Open Access

    The efficacy of oncolytic adenoviruses is limited by strong immune responses being induced against the oncolytic virus itself. Here, the authors generate a bispecific molecule capable of redirecting the adenovirus-specific antibodies to tumour cells and show this induces immune mediated cancer growth inhibition and enhances the therapeutic efficacy of viral oncolysis.

    • Julia Niemann
    • , Norman Woller
    • , Jennifer Brooks
    • , Bettina Fleischmann-Mundt
    • , Nikolas T. Martin
    • , Arnold Kloos
    • , Sarah Knocke
    • , Amanda M. Ernst
    • , Michael P. Manns
    • , Stefan Kubicka
    • , Thomas C. Wirth
    • , Rita Gerardy-Schahn
    •  & Florian Kühnel
  • Article
    | Open Access

    Upper tract urothelial carcinoma (UTUC) is an aggressive cancer and largely uncharacterised cancer. Here, Faltas and colleagues report its distinctive molecular and immune landscape compared to urothelial carcinoma of the bladder and explore the role of FGFR3 signaling in UTUC biology.

    • Brian D. Robinson
    • , Panagiotis J. Vlachostergios
    • , Bhavneet Bhinder
    • , Weisi Liu
    • , Kailyn Li
    • , Tyler J. Moss
    • , Rohan Bareja
    • , Kyung Park
    • , Peyman Tavassoli
    • , Joanna Cyrta
    • , Scott T. Tagawa
    • , David M. Nanus
    • , Himisha Beltran
    • , Ana M. Molina
    • , Francesca Khani
    • , Juan Miguel Mosquera
    • , Evanguelos Xylinas
    • , Shahrokh F. Shariat
    • , Douglas S. Scherr
    • , Mark A. Rubin
    • , Seth P. Lerner
    • , Surena F. Matin
    • , Olivier Elemento
    •  & Bishoy M. Faltas
  • Article
    | Open Access

    The ligand-activated transcription factor farnesoid X receptor (FXR) acts as a cellular sensor for bile acids and is of interest as a drug target. Here the authors employ X-ray crystallography and NMR to characterize the molecular determinants of FXR agonists, antagonists and a partial agonist that drive FXR activation and antagonism.

    • Daniel Merk
    • , Sridhar Sreeramulu
    • , Denis Kudlinzki
    • , Krishna Saxena
    • , Verena Linhard
    • , Santosh L. Gande
    • , Fabian Hiller
    • , Christina Lamers
    • , Ewa Nilsson
    • , Anna Aagaard
    • , Lisa Wissler
    • , Niek Dekker
    • , Krister Bamberg
    • , Manfred Schubert-Zsilavecz
    •  & Harald Schwalbe
  • Article
    | Open Access

    Histone 3 lysine 79 is mono (me1), di (me2), or tri (me3) methylated by the methyltransferase DOT1L. Here the authors reveal a group of enhancers defined by H3K79me2/3 which regulates enhancer-promoter interactions and other key enhancer features in MLL-AF4 leukemia cells.

    • Laura Godfrey
    • , Nicholas T. Crump
    • , Ross Thorne
    • , I-Jun Lau
    • , Emmanouela Repapi
    • , Dimitra Dimou
    • , Alastair L. Smith
    • , Joe R. Harman
    • , Jelena M. Telenius
    • , A. Marieke Oudelaar
    • , Damien J. Downes
    • , Paresh Vyas
    • , Jim R. Hughes
    •  & Thomas A. Milne
  • Article
    | Open Access

    Adipose tissue hypertrophy in obesity is associated with insulin resistance and other metabolic complications. Here, the authors analyze subcutaneous adipose tissue from patients with hypertrophic obesity and insulin resistance and find that adipocyte progenitor cells show features of senescence and have poor differentiation capacity.

    • Birgit Gustafson
    • , Annika Nerstedt
    •  & Ulf Smith
  • Article
    | Open Access

    The ribosomal protein RPL10 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). Here, the authors show that it promotes proliferation of T-ALL cells by upregulating the serine biosynthesis enzyme phosphoserine phosphatase which in turn modulates serine and glycine metabolism.

    • Kim R. Kampen
    • , Laura Fancello
    • , Tiziana Girardi
    • , Gianmarco Rinaldi
    • , Mélanie Planque
    • , Sergey O. Sulima
    • , Fabricio Loayza-Puch
    • , Benno Verbelen
    • , Stijn Vereecke
    • , Jelle Verbeeck
    • , Joyce Op de Beeck
    • , Jonathan Royaert
    • , Pieter Vermeersch
    • , David Cassiman
    • , Jan Cools
    • , Reuven Agami
    • , Mark Fiers
    • , Sarah-Maria Fendt
    •  & Kim De Keersmaecker
  • Article
    | Open Access

    Fibroadipogenic precursor cells (FAPs) contribute to fibrosis and adipogenic replacement in muscular dystrophies. Here, the authors show that FAPs contribute to adipogenic loss in mouse models of limb girdle muscular dystrophy 2B via a mechanism dependent on expression of Annexin A2, and that this process can be prevented by its pharmacologic inhibition in mice.

    • Marshall W. Hogarth
    • , Aurelia Defour
    • , Christopher Lazarski
    • , Eduard Gallardo
    • , Jordi Diaz Manera
    • , Terence A. Partridge
    • , Kanneboyina Nagaraju
    •  & Jyoti K. Jaiswal
  • Article
    | Open Access

    Neonatal immune responses are known to differ to those of an adult immune response. Here Dreschers and colleagues, compare macrophage populations derived from cord blood or adult peripheral blood and show a metabolic impairment of glycolysis in macrophages derived from cord blood which may impair response to infective scenarios such as sepsis.

    • Stephan Dreschers
    • , Kim Ohl
    • , Michael Lehrke
    • , Julia Möllmann
    • , Bernd Denecke
    • , Ivan Costa
    • , Thomas Vogl
    • , Dorothee Viemann
    • , Johannes Roth
    • , Thorsten Orlikowsky
    •  & Klaus Tenbrock
  • Article
    | Open Access

    Dysregulation of PPARα dependent fatty acid oxidation promotes hepatic steatosis. Here the authors show that GPS2 inhibits PPARα activity and that ablation of GPS2 ameliorates hepatic steatosis in mice.

    • Ning Liang
    • , Anastasius Damdimopoulos
    • , Saioa Goñi
    • , Zhiqiang Huang
    • , Lise-Lotte Vedin
    • , Tomas Jakobsson
    • , Marco Giudici
    • , Osman Ahmed
    • , Matteo Pedrelli
    • , Serena Barilla
    • , Fawaz Alzaid
    • , Arturo Mendoza
    • , Tarja Schröder
    • , Raoul Kuiper
    • , Paolo Parini
    • , Anthony Hollenberg
    • , Philippe Lefebvre
    • , Sven Francque
    • , Luc Van Gaal
    • , Bart Staels
    • , Nicolas Venteclef
    • , Eckardt Treuter
    •  & Rongrong Fan
  • Article
    | Open Access

    Chordomas are rare bone tumors with limited therapeutic options. Here, the authors identify molecular alterations associated with defective homologous recombination DNA repair in advanced chordomas and report prolonged response in a patient treated with a PARP inhibitor, which later acquired resistance due to a newly gained PARP1 mutation.

    • Stefan Gröschel
    • , Daniel Hübschmann
    • , Francesco Raimondi
    • , Peter Horak
    • , Gregor Warsow
    • , Martina Fröhlich
    • , Barbara Klink
    • , Laura Gieldon
    • , Barbara Hutter
    • , Kortine Kleinheinz
    • , David Bonekamp
    • , Oliver Marschal
    • , Priya Chudasama
    • , Jagoda Mika
    • , Marie Groth
    • , Sebastian Uhrig
    • , Stephen Krämer
    • , Christoph Heining
    • , Christoph E. Heilig
    • , Daniela Richter
    • , Eva Reisinger
    • , Katrin Pfütze
    • , Roland Eils
    • , Stephan Wolf
    • , Christof von Kalle
    • , Christian Brandts
    • , Claudia Scholl
    • , Wilko Weichert
    • , Stephan Richter
    • , Sebastian Bauer
    • , Roland Penzel
    • , Evelin Schröck
    • , Albrecht Stenzinger
    • , Richard F. Schlenk
    • , Benedikt Brors
    • , Robert B. Russell
    • , Hanno Glimm
    • , Matthias Schlesner
    •  & Stefan Fröhling
  • Article
    | Open Access

    Fasting is known for its beneficial effects on obesity and diabetes-related health complications. Here Zhang et al. show that fasting induces expression of arginase-2 (Arg2) in the liver, and that hepatic Arg2, by suppressing the expression of the regulator of G-protein signalling 16, recapitulates the positive effects of fasting in obesity and diabetes.

    • Yiming Zhang
    • , Cassandra B. Higgins
    • , Hannah M. Fortune
    • , Phillip Chen
    • , Alicyn I. Stothard
    • , Allyson L. Mayer
    • , Benjamin M. Swarts
    •  & Brian J. DeBosch
  • Article
    | Open Access

    Mechanical stimulation is known to affect cell proliferation, differentiation, and regeneration. Here, the authors demonstrate that stretching mouse skin recruits macrophages and polarizes them into M2 cells that facilitate hair regeneration through the release of growth factors, including HGF and IGF-1

    • Szu-Ying Chu
    • , Chih-Hung Chou
    • , Hsien-Da Huang
    • , Meng-Hua Yen
    • , Hsiao-Chin Hong
    • , Po-Han Chao
    • , Yu-Hsuan Wang
    • , Po-Yu Chen
    • , Shi-Xin Nian
    • , Yu-Ru Chen
    • , Li-Ying Liou
    • , Yu-Chen Liu
    • , Hui-Mei Chen
    • , Feng-Mao Lin
    • , Yun-Ting Chang
    • , Chih-Chiang Chen
    •  & Oscar K. Lee
  • Article
    | Open Access

    Autophagy is implicated in self-renewal of stem cells, including embryonic stem cells (ES cells). Here the authors demonstrate EPG5 is highly expressed in ES cells, and its deubiquitylation by USP8 stimulates its interaction with LC3 to promote autophagy and maintenance of stemness.

    • Haifeng Gu
    • , Xingxing Shi
    • , Chao Liu
    • , Chaoqun Wang
    • , Ning Sui
    • , Yu Zhao
    • , Jiaqi Gong
    • , Fuping Wang
    • , Hong Zhang
    • , Wei Li
    •  & Tongbiao Zhao
  • Article
    | Open Access

    Rapid and accurate detection of fusion genes is important in cancer diagnostics. Here, the authors demonstrate that targeted RNA sequencing provides fast, sensitive and quantitative gene fusion detection and overcomes the limitations of approaches currently in clinical use.

    • Erin E. Heyer
    • , Ira W. Deveson
    • , Danson Wooi
    • , Christina I. Selinger
    • , Ruth J. Lyons
    • , Vanessa M. Hayes
    • , Sandra A. O’Toole
    • , Mandy L. Ballinger
    • , Devinder Gill
    • , David M. Thomas
    • , Tim R. Mercer
    •  & James Blackburn
  • Article
    | Open Access

    Deubiquitinases have been shown to be involved in double strand break repair pathways. Here the authors reveal that USP15 deybiquitinase plays a role in homologues recombination repair by targeting BARD1 and affecting cells response to PARP inhibitors.

    • Yihan Peng
    • , Qingchao Liao
    • , Wei Tan
    • , Changmin Peng
    • , Zhaohua Hu
    • , Yali Chen
    • , Zhuqing Li
    • , Jing Li
    • , Bei Zhen
    • , Wenge Zhu
    • , Xiangpan Li
    • , Yi Yao
    • , Qibin Song
    • , Chengsheng Liu
    • , Xiangdong Qi
    • , Fuchu He
    •  & Huadong Pei
  • Article
    | Open Access

    CRISPR-Cas9 has been rapidly adopted to generate cell line models of disease. Here the authors show, while attempting to establish a congenital erythropoietic porphyria model, unexpected chromosome truncations generated by a p53-dependent mechanism.

    • Grégoire Cullot
    • , Julian Boutin
    • , Jérôme Toutain
    • , Florence Prat
    • , Perrine Pennamen
    • , Caroline Rooryck
    • , Martin Teichmann
    • , Emilie Rousseau
    • , Isabelle Lamrissi-Garcia
    • , Véronique Guyonnet-Duperat
    • , Alice Bibeyran
    • , Magalie Lalanne
    • , Valérie Prouzet-Mauléon
    • , Béatrice Turcq
    • , Cécile Ged
    • , Jean-Marc Blouin
    • , Emmanuel Richard
    • , Sandrine Dabernat
    • , François Moreau-Gaudry
    •  & Aurélie Bedel
  • Article
    | Open Access

    ATRX deficiency is linked to genomic stability in cancer cells. Here, the authors show that ATRX inactivation induces G-quadruplex formation, leading to genome-wide DNA damage, and the use of G-quadruplex stabilisers can be exploited therapeutically in ATRX deficient gliomas.

    • Yuxiang Wang
    • , Jie Yang
    • , Aaron T. Wild
    • , Wei H. Wu
    • , Rachna Shah
    • , Carla Danussi
    • , Gregory J. Riggins
    • , Kasthuri Kannan
    • , Erik P. Sulman
    • , Timothy A. Chan
    •  & Jason T. Huse
  • Article
    | Open Access

    Premature termination codon suppression therapy could be used to treat a range of genetic disorders. Here the authors present a high-throughput cell-based assay to identify anticodon engineered tRNAs with high suppression activity.

    • John D. Lueck
    • , Jae Seok Yoon
    • , Alfredo Perales-Puchalt
    • , Adam L. Mackey
    • , Daniel T. Infield
    • , Mark A. Behlke
    • , Marshall R. Pope
    • , David B. Weiner
    • , William R. Skach
    • , Paul B. McCray Jr.
    •  & Christopher A. Ahern
  • Article
    | Open Access

    Quaternary contacts mediated by an extended heavy-chain framework region 3 (FR3) have been shown to improve binding to HIV envelope and virus neutralization for a few antibodies. Here, Liu et al. engraft such an FR3 loop onto several potent broadly neutralizing antibodies, resulting in improved neutralization activity and pharmacokinetics.

    • Qingbo Liu
    • , Yen-Ting Lai
    • , Peng Zhang
    • , Mark K. Louder
    • , Amarendra Pegu
    • , Reda Rawi
    • , Mangaiarkarasi Asokan
    • , Xuejun Chen
    • , Chen-Hsiang Shen
    • , Gwo-Yu Chuang
    • , Eun Sung Yang
    • , Huiyi Miao
    • , Yuge Wang
    • , Anthony S. Fauci
    • , Peter D. Kwong
    • , John R. Mascola
    •  & Paolo Lusso
  • Article
    | Open Access

    Loss of PIK3R1 in ovarian cancer is a common event, which provides opportunities for therapeutic intervention. Here, the authors show that the STAT3 and AKT signaling pathways are activated upon PIK3R1 loss and that, in mice, inhibitors of these pathways could block tumorigenesis.

    • Xinran Li
    • , Victor C. Y. Mak
    • , Yuan Zhou
    • , Chao Wang
    • , Esther S. Y. Wong
    • , Rakesh Sharma
    • , Yiling Lu
    • , Annie N. Y. Cheung
    • , Gordon B. Mills
    •  & Lydia W. T. Cheung