Molecular medicine

  • 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
  • Article
    | Open Access

    The pathways involved in exit from pluripotency in human embryonic stem cells are poorly understood. Here, the authors performed a CRISPR-based screen to identify genes that promote exit from naïve pluripotency and find a role for folliculin (FLCN) by regulating the mTOR and Wnt pathways.

    • J. Mathieu
    • , D. Detraux
    • , D. Kuppers
    • , Y. Wang
    • , C. Cavanaugh
    • , S. Sidhu
    • , S. Levy
    • , A. M. Robitaille
    • , A. Ferreccio
    • , T. Bottorff
    • , A. McAlister
    • , L. Somasundaram
    • , F. Artoni
    • , S. Battle
    • , R. D. Hawkins
    • , R. T. Moon
    • , C. B. Ware
    • , P. J. Paddison
    •  & H. Ruohola-Baker
  • Article
    | Open Access

    Adeno-associated virus is used in gene therapy in mouse models of hearing loss. Here the authors compare vectors and find AAV2.7m8 can infect cells in the inner ear with high efficiency.

    • Kevin Isgrig
    • , Devin S. McDougald
    • , Jianliang Zhu
    • , Hong Jun Wang
    • , Jean Bennett
    •  & Wade W. Chien
  • Article
    | Open Access

    Glycogen Synthase Kinase 3 (GSK3) has conserved functions across species but its role in the kidney is unclear. Here, the authors show that in the kidney podocyte cell of mice and related nephrocyte in Drosophila that GSK3 is a master regulator of function both during development and in maturity.

    • J. A. Hurcombe
    • , P. Hartley
    • , A. C. Lay
    • , L. Ni
    • , J. J. Bedford
    • , J. P. Leader
    • , S. Singh
    • , A. Murphy
    • , C. L. Scudamore
    • , E. Marquez
    • , A. F. Barrington
    • , V. Pinto
    • , M. Marchetti
    • , L.-F. Wong
    • , J. Uney
    • , M. A. Saleem
    • , P. W. Mathieson
    • , S. Patel
    • , R. J. Walker
    • , J. R. Woodgett
    • , S. E. Quaggin
    • , G. I. Welsh
    •  & R. J. M. Coward
  • Article
    | Open Access

    Small molecule modulators of RNA splicing have therapeutic potential in tumours bearing spliceosome mutations. Here, the authors identify BCL2 genes have differential sensitivities to SF3b-targeting splicing modulators and combination of SF3b-targeting splicing modulators and BCLxL inhibition induces synergistic cytotoxicity in cancer cells.

    • Daniel Aird
    • , Teng Teng
    • , Chia-Ling Huang
    • , Ermira Pazolli
    • , Deepti Banka
    • , Kahlin Cheung-Ong
    • , Cheryl Eifert
    • , Craig Furman
    • , Zhenhua Jeremy Wu
    • , Michael Seiler
    • , Silvia Buonamici
    • , Peter Fekkes
    • , Craig Karr
    • , James Palacino
    • , Eunice Park
    • , Peter G. Smith
    • , Lihua Yu
    • , Yoshiharu Mizui
    • , Markus Warmuth
    • , Agustin Chicas
    • , Laura Corson
    •  & Ping Zhu
  • Article
    | Open Access

    BAG3 is a Hsp70 co-chaperone that is highly expressed in muscles. Here the authors show that several myofibrillar myopathy causing BAG3 mutations are not impaired in Hsp70 binding, but rather impair the ADP-ATP exchange step of the Hsp70 cycle, causing the aggregation of BAG3, Hsp70 and Hsp70 clients and leading to a collapse of protein homeostasis.

    • Melanie Meister-Broekema
    • , Rebecca Freilich
    • , Chandhuru Jagadeesan
    • , Jennifer N. Rauch
    • , Rocio Bengoechea
    • , William W. Motley
    • , E. F. Elsiena Kuiper
    • , Melania Minoia
    • , Gabriel V. Furtado
    • , Maria A. W. H. van Waarde
    • , Shawn J. Bird
    • , Adriana Rebelo
    • , Stephan Zuchner
    • , Peter Pytel
    • , Steven S. Scherer
    • , Federica F. Morelli
    • , Serena Carra
    • , Conrad C. Weihl
    • , Steven Bergink
    • , Jason E. Gestwicki
    •  & Harm H. Kampinga
  • Article
    | Open Access

    The molecular pathway(s) driving antipsychotics (AP) induced hyperphagia remains unclear. A novel C. elegans system is used here to screen for FDA approved drugs that selectively suppresses this response, unraveling potential molecular mediators influencing AP induced hyperphagia in mouse models.

    • Anabel Perez-Gomez
    • , Maria Carretero
    • , Natalie Weber
    • , Veronika Peterka
    • , Alan To
    • , Viktoriya Titova
    • , Gregory Solis
    • , Olivia Osborn
    •  & Michael Petrascheck
  • Article
    | Open Access

    Molecular pathways regulating nasopharyngeal carcinoma (NPC) metastasis are unclear. Here they report higher levels of cytoplasmic leukemia inhibitory factor (cLIF) and LIF receptor (LIFR) to correlate with higher metastasis in NPC patients, and show cLIF to promote NPC metastasis and vascular dissemination via the YAP1-FAK/PXN axis.

    • Shu-Chen Liu
    • , Tien Hsu
    • , Yu-Sun Chang
    • , An-Ko Chung
    • , Shih Sheng Jiang
    • , Chun-Nan OuYang
    • , Chiou-Hwa Yuh
    • , Chuen Hsueh
    • , Ya-Ping Liu
    •  & Ngan-Ming Tsang
  • Article
    | Open Access

    Activation of PDGFRA by genomic aberrations contributes to tumor progression in several tumor types. Here, the authors perform functional characterization of 16 novel PDGFRA mutations identified from different tumor types and demonstrate that a neomorphic PDGFRA extracellular domain driver mutation is resistant to PDGFRA targeted therapies.

    • Carman K. M. Ip
    • , Patrick K. S. Ng
    • , Kang Jin Jeong
    • , S. H. Shao
    • , Zhenlin Ju
    • , P. G. Leonard
    • , Xu Hua
    • , Christopher P. Vellano
    • , Richard Woessner
    • , Nidhi Sahni
    • , Kenneth L. Scott
    •  & Gordon B. Mills
  • Article
    | Open Access

    It is challenging to design photosensitizers (PS) with high quantum yields generating singlet oxygen due to severe aggregation between the hydrophobic PSs. Here they develop organoplatinum(II) metallatocage-based PS to overcome these challenges and show excellent antitumor effect.

    • Guocan Yu
    • , Shan Yu
    • , Manik Lal Saha
    • , Jiong Zhou
    • , Timothy R. Cook
    • , Bryant C. Yung
    • , Jin Chen
    • , Zhengwei Mao
    • , Fuwu Zhang
    • , Zijian Zhou
    • , Yijing Liu
    • , Li Shao
    • , Sheng Wang
    • , Changyou Gao
    • , Feihe Huang
    • , Peter J. Stang
    •  & Xiaoyuan Chen
  • Article
    | Open Access

    RNA-seq is a powerful tool to investigate how drugs affect the transcriptome but library construction can be costly. Here the authors introduce DRUG-seq, an automated platform for high-throughput transcriptome profiling.

    • Chaoyang Ye
    • , Daniel J. Ho
    • , Marilisa Neri
    • , Chian Yang
    • , Tripti Kulkarni
    • , Ranjit Randhawa
    • , Martin Henault
    • , Nadezda Mostacci
    • , Pierre Farmer
    • , Steffen Renner
    • , Robert Ihry
    • , Leandra Mansur
    • , Caroline Gubser Keller
    • , Gregory McAllister
    • , Marc Hild
    • , Jeremy Jenkins
    •  & Ajamete Kaykas
  • Article
    | Open Access

    Measuring precise protein turnover rates in animals is technically challenging at the proteomic level. Here, Fornasiero and colleagues use isotopic labeling with mass spectrometry and mathematical modeling to accurately determine protein lifetimes in the mouse brain

    • Eugenio F. Fornasiero
    • , Sunit Mandad
    • , Hanna Wildhagen
    • , Mihai Alevra
    • , Burkhard Rammner
    • , Sarva Keihani
    • , Felipe Opazo
    • , Inga Urban
    • , Till Ischebeck
    • , M. Sadman Sakib
    • , Maryam K. Fard
    • , Koray Kirli
    • , Tonatiuh Pena Centeno
    • , Ramon O. Vidal
    • , Raza-Ur Rahman
    • , Eva Benito
    • , André Fischer
    • , Sven Dennerlein
    • , Peter Rehling
    • , Ivo Feussner
    • , Stefan Bonn
    • , Mikael Simons
    • , Henning Urlaub
    •  & Silvio O. Rizzoli
  • Article
    | Open Access

    In pancreatic neuroendocrine tumors (PanNETs) ATRX, DAXX, and MEN1 are commonly mutated (A-D-M mutant PanNETs). Here, the authors find in a cohort of PanNETS 58% are A-D-M mutant PanNETs, with a worse clinical outcome and differences in gene expression and methylation compared to A-D-M wild type cases- these gene expression differences suggest that A-D-M mutant PanNETs potentially originate from a cell type similar to alpha cells.

    • Chang S. Chan
    • , Saurabh V. Laddha
    • , Peter W. Lewis
    • , Matthew S. Koletsky
    • , Kenneth Robzyk
    • , Edaise Da Silva
    • , Paula J. Torres
    • , Brian R. Untch
    • , Janet Li
    • , Promita Bose
    • , Timothy A. Chan
    • , David S. Klimstra
    • , C. David Allis
    •  & Laura H. Tang
  • Article
    | Open Access

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency provides insufficient protection from oxidative stress, contributing to diverse human pathologies. Here, the authors identify a small molecule that increases the activity and/or stability of mutant G6PD and show that it reduces oxidative stress in zebrafish and hemolysis in isolated human erythrocytes.

    • Sunhee Hwang
    • , Karen Mruk
    • , Simin Rahighi
    • , Andrew G. Raub
    • , Che-Hong Chen
    • , Lisa E. Dorn
    • , Naoki Horikoshi
    • , Soichi Wakatsuki
    • , James K. Chen
    •  & Daria Mochly-Rosen
  • Article
    | Open Access

    Antibiotics that target the peptidoglycan precursor lipid II are promising templates for next-generation antibiotics. Here authors use solid-state NMR and monitor lipid II-binding antibiotics, such as nisin, directly in cell membranes.

    • João Medeiros-Silva
    • , Shehrazade Jekhmane
    • , Alessandra Lucini Paioni
    • , Katarzyna Gawarecka
    • , Marc Baldus
    • , Ewa Swiezewska
    • , Eefjan Breukink
    •  & Markus Weingarth
  • Article
    | Open Access

    ARID1A is highly inactivated in cancer. Here, the authors show that ARID1A has a synthetic lethal interaction with AURKA in colorectal cancer cells and that ARID1A deficiency activates the AURKA target CDC25C, whose inhibitors also cause cell death in the ARID1A-deficient cell lines.

    • Changjie Wu
    • , Junfang Lyu
    • , Eun Ju Yang
    • , Yifan Liu
    • , Baoyuan Zhang
    •  & Joong Sup Shim
  • Article
    | Open Access

    Unwanted uptake in the liver and limited accumulation in target organs is a major obstacle to targeted drug delivery. Here, the authors report on the hitchhiking of nanocarriers on red blood cells and the targeted upstream delivery to different target organs in mice, pigs and ex vivo human lungs.

    • Jacob S. Brenner
    • , Daniel C. Pan
    • , Jacob W. Myerson
    • , Oscar A. Marcos-Contreras
    • , Carlos H. Villa
    • , Priyal Patel
    • , Hugh Hekierski
    • , Shampa Chatterjee
    • , Jian-Qin Tao
    • , Hamideh Parhiz
    • , Kartik Bhamidipati
    • , Thomas G. Uhler
    • , Elizabeth D. Hood
    • , Raisa Yu. Kiseleva
    • , Vladimir S. Shuvaev
    • , Tea Shuvaeva
    • , Makan Khoshnejad
    • , Ian Johnston
    • , Jason V. Gregory
    • , Joerg Lahann
    • , Tao Wang
    • , Edward Cantu
    • , William M. Armstead
    • , Samir Mitragotri
    •  & Vladimir Muzykantov
  • Article
    | Open Access

    Resistance of gRNA to ubiquitous ribonucleases is required for CRISPR-Cas9-based therapeutics. Here, the authors explore chemical modifications at all positions of the crRNA guide and tracrRNA cofactor, and identify modified versions that are more potent and stable than their unmodified counterparts in editing human cells.

    • Aamir Mir
    • , Julia F. Alterman
    • , Matthew R. Hassler
    • , Alexandre J. Debacker
    • , Edward Hudgens
    • , Dimas Echeverria
    • , Michael H. Brodsky
    • , Anastasia Khvorova
    • , Jonathan K. Watts
    •  & Erik J. Sontheimer
  • Article
    | Open Access

    Sepsis is a life-threatening condition. Here, the authors show that intermedin alleviates organ injury and decreases mortality in septic mice by concurrently alleviating vascular leakage and inflammatory responses. Patients with high intermedin levels exhibit a low risk of shock, lower severity scores, and greatly improved survival outcomes.

    • Fei Xiao
    • , Denian Wang
    • , Lingmiao Kong
    • , Min Li
    • , Zhongxue Feng
    • , Bingxing Shuai
    • , Lijun Wang
    • , Yong’gang Wei
    • , Hongyu Li
    • , Sisi Wu
    • , Chun Tan
    • , Huan Zhao
    • , Xuejiao Hu
    • , Jin Liu
    • , Yan Kang
    • , Xuelian Liao
    • , Yan Zhou
    •  & Wei Zhang