Molecular medicine

  • Article | | open

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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

    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
  • Article | | open

    Zika virus (ZIKV) is an emerging global health issue, but currently no licensed vaccine achieves lasting protective immunity. Here the authors show that a ZIKV vaccine containing the envelop protein without the transmembrane domain and the precursor membrane protein can provide effective protection in mouse models.

    • César López-Camacho
    • , Peter Abbink
    • , Rafael A. Larocca
    • , Wanwisa Dejnirattisai
    • , Michael Boyd
    • , Alex Badamchi-Zadeh
    • , Zoë R. Wallace
    • , Jennifer Doig
    • , Ricardo Sanchez Velazquez
    • , Roberto Dias Lins Neto
    • , Danilo F. Coelho
    • , Young Chan Kim
    • , Claire L. Donald
    • , Ania Owsianka
    • , Giuditta De Lorenzo
    • , Alain Kohl
    • , Sarah C. Gilbert
    • , Lucy Dorrell
    • , Juthathip Mongkolsapaya
    • , Arvind H. Patel
    • , Gavin R. Screaton
    • , Dan H. Barouch
    • , Adrian V. S. Hill
    •  & Arturo Reyes-Sandoval
  • Article | | open

    Patients with schizophrenia show varied response to antipsychotics. Here, the authors demonstrate in patients under antipsychotics treatment that a haplotype associated with lower dysbindin-1 expression correlated with better executive functions, providing further mechanistic support from mouse models.

    • Diego Scheggia
    • , Rosa Mastrogiacomo
    • , Maddalena Mereu
    • , Sara Sannino
    • , Richard E. Straub
    • , Marco Armando
    • , Francesca Managò
    • , Simone Guadagna
    • , Fabrizio Piras
    • , Fengyu Zhang
    • , Joel E. Kleinman
    • , Thomas M. Hyde
    • , Sanne S. Kaalund
    • , Maria Pontillo
    • , Genny Orso
    • , Carlo Caltagirone
    • , Emiliana Borrelli
    • , Maria A. De Luca
    • , Stefano Vicari
    • , Daniel R. Weinberger
    • , Gianfranco Spalletta
    •  & Francesco Papaleo
  • Article | | open

    T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases.

    • Samuel Y. Ng
    • , Noriaki Yoshida
    • , Amanda L. Christie
    • , Mahmoud Ghandi
    • , Neekesh V. Dharia
    • , Joshua Dempster
    • , Mark Murakami
    • , Kay Shigemori
    • , Sara N. Morrow
    • , Alexandria Van Scoyk
    • , Nicolas A. Cordero
    • , Kristen E. Stevenson
    • , Maneka Puligandla
    • , Brian Haas
    • , Christopher Lo
    • , Robin Meyers
    • , Galen Gao
    • , Andrew Cherniack
    • , Abner Louissaint Jr
    • , Valentina Nardi
    • , Aaron R. Thorner
    • , Henry Long
    • , Xintao Qiu
    • , Elizabeth A. Morgan
    • , David M. Dorfman
    • , Danilo Fiore
    • , Julie Jang
    • , Alan L. Epstein
    • , Ahmet Dogan
    • , Yanming Zhang
    • , Steven M. Horwitz
    • , Eric D. Jacobsen
    • , Solimar Santiago
    • , Jian-Guo Ren
    • , Vincent Guerlavais
    • , D. Allen Annis
    • , Manuel Aivado
    • , Mansoor N. Saleh
    • , Amitkumar Mehta
    • , Aviad Tsherniak
    • , David Root
    • , Francisca Vazquez
    • , William C. Hahn
    • , Giorgio Inghirami
    • , Jon C. Aster
    • , David M. Weinstock
    •  & Raphael Koch
  • Article | | open

    Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells. Here, the authors report the development and in vivo validation of a non-internalising ADC with the capacity to target cancer cells and release its therapeutic cargo extracellularly via a chemical trigger.

    • Raffaella Rossin
    • , Ron M. Versteegen
    • , Jeremy Wu
    • , Alisher Khasanov
    • , Hans J. Wessels
    • , Erik J. Steenbergen
    • , Wolter ten Hoeve
    • , Henk M. Janssen
    • , Arthur H. A. M. van Onzen
    • , Peter J. Hudson
    •  & Marc S. Robillard
  • Article | | open

    Many genes have oscillating gene expression pattern in circadian centers of the brain. This study shows cortical diurnal DNA methylation oscillation in a mouse model of Prader-Willi syndrome, and describes corresponding changes in gene expression and chromatin compaction.

    • Rochelle L. Coulson
    • , Dag H. Yasui
    • , Keith W. Dunaway
    • , Benjamin I. Laufer
    • , Annie Vogel Ciernia
    • , Yihui Zhu
    • , Charles E. Mordaunt
    • , Theresa S. Totah
    •  & Janine M. LaSalle
  • Article | | open

    Quorum sensing signaling molecules are known to be critical determinants in bacterial pathogenesis. Here the authors show the quorum sensing molecule cFP from Vibrio vulnificus inhibits the RIG-I mediated antiviral interferon response and enhances susceptibility to viral infection.

    • Wooseong Lee
    • , Seung-Hoon Lee
    • , Minwoo Kim
    • , Jae-Su Moon
    • , Geon-Woo Kim
    • , Hae-Gwang Jung
    • , In Hwang Kim
    • , Ji Eun Oh
    • , Hi Eun Jung
    • , Heung Kyu Lee
    • , Keun Bon Ku
    • , Dae-Gyun Ahn
    • , Seong-Jun Kim
    • , Kun-Soo Kim
    •  & Jong-Won Oh
  • Article | | open

    Surface-enhanced Raman spectroscopy (SERS) visualizes fingerprints of intermolecular vibrations of many metabolites. Here the authors report a SERS imaging technique that enables the visualization of metabolites distribution and automated extraction of tumour boundaries in frozen tissues.

    • Megumi Shiota
    • , Masayuki Naya
    • , Takehiro Yamamoto
    • , Takako Hishiki
    • , Takeharu Tani
    • , Hiroyuki Takahashi
    • , Akiko Kubo
    • , Daisuke Koike
    • , Mai Itoh
    • , Mitsuyo Ohmura
    • , Yasuaki Kabe
    • , Yuki Sugiura
    • , Nobuyoshi Hiraoka
    • , Takayuki Morikawa
    • , Keiyo Takubo
    • , Kentaro Suina
    • , Hideaki Nagashima
    • , Oltea Sampetrean
    • , Osamu Nagano
    • , Hideyuki Saya
    • , Shogo Yamazoe
    • , Hiroyuki Watanabe
    •  & Makoto Suematsu
  • Article | | open

    Antimicrobial resistance (AMR) in Shigella species is a public health concern. Here, Baker et al. show how horizontal transfer of an AMR plasmid among Shigella species contributes to epidemics in men who have sex with men in England.

    • Kate S. Baker
    • , Timothy J. Dallman
    • , Nigel Field
    • , Tristan Childs
    • , Holly Mitchell
    • , Martin Day
    • , François-Xavier Weill
    • , Sophie Lefèvre
    • , Mathieu Tourdjman
    • , Gwenda Hughes
    • , Claire Jenkins
    •  & Nicholas Thomson
  • Article | | open

    Exosomes function as intercellular information transmitters and are candidates for delivery of therapeutic agents. Here the authors present EXOtic, a synthetic biology device for in-situ production of designer exosomes and demonstrate in vivo application in models of Parkinson's disease.

    • Ryosuke Kojima
    • , Daniel Bojar
    • , Giorgio Rizzi
    • , Ghislaine Charpin-El Hamri
    • , Marie Daoud El-Baba
    • , Pratik Saxena
    • , Simon Ausländer
    • , Kelly R. Tan
    •  & Martin Fussenegger
  • Article | | open

    Aggregation is sequence-specific and nucleated by short aggregating protein segments (APR). Here authors use a multidisciplinary approach to show that in E.coli some frequently occurring APRs lead to protein aggregation and ultimately bacterial cell death, which could serve as antibacterial strategy.

    • Ladan Khodaparast
    • , Laleh Khodaparast
    • , Rodrigo Gallardo
    • , Nikolaos N. Louros
    • , Emiel Michiels
    • , Reshmi Ramakrishnan
    • , Meine Ramakers
    • , Filip Claes
    • , Lydia Young
    • , Mohammad Shahrooei
    • , Hannah Wilkinson
    • , Matyas Desager
    • , Wubishet Mengistu Tadesse
    • , K. Peter R. Nilsson
    • , Per Hammarström
    • , Abram Aertsen
    • , Sebastien Carpentier
    • , Johan Van Eldere
    • , Frederic Rousseau
    •  & Joost Schymkowitz
  • Article | | open

    Sepsis is characterized by deregulated host response to infection. Efficient therapies are still needed but a limitation for sepsis treatment is the heterogeneity in patients. Here Sweeney et al. generate prognostic models based on gene expression to improve risk stratification classification and prediction for 30-day mortality of patients.

    • Timothy E. Sweeney
    • , Thanneer M. Perumal
    • , Ricardo Henao
    • , Marshall Nichols
    • , Judith A. Howrylak
    • , Augustine M. Choi
    • , Jesús F. Bermejo-Martin
    • , Raquel Almansa
    • , Eduardo Tamayo
    • , Emma E. Davenport
    • , Katie L. Burnham
    • , Charles J. Hinds
    • , Julian C. Knight
    • , Christopher W. Woods
    • , Stephen F. Kingsmore
    • , Geoffrey S. Ginsburg
    • , Hector R. Wong
    • , Grant P. Parnell
    • , Benjamin Tang
    • , Lyle L. Moldawer
    • , Frederick E. Moore
    • , Larsson Omberg
    • , Purvesh Khatri
    • , Ephraim L. Tsalik
    • , Lara M. Mangravite
    •  & Raymond J. Langley
  • Article | | open

    Integrin-based therapeutics could block inflammatory processes but they also impair host defence, limiting their usefulness. Here the authors report an anti-Mac1 antibody that blocks its interaction with pro-inflammatory ligand CD40L but not other ligands, and show that it can protect against sepsis in mice.

    • Dennis Wolf
    • , Nathaly Anto-Michel
    • , Hermann Blankenbach
    • , Ansgar Wiedemann
    • , Konrad Buscher
    • , Jan David Hohmann
    • , Bock Lim
    • , Marina Bäuml
    • , Alex Marki
    • , Maximilian Mauler
    • , Daniel Duerschmied
    • , Zhichao Fan
    • , Holger Winkels
    • , Daniel Sidler
    • , Philipp Diehl
    • , Dirk M Zajonc
    • , Ingo Hilgendorf
    • , Peter Stachon
    • , Timoteo Marchini
    • , Florian Willecke
    • , Maximilian Schell
    • , Björn Sommer
    • , Constantin von zur Muhlen
    • , Jochen Reinöhl
    • , Teresa Gerhardt
    • , Edward F. Plow
    • , Valentin Yakubenko
    • , Peter Libby
    • , Christoph Bode
    • , Klaus Ley
    • , Karlheinz Peter
    •  & Andreas Zirlik
  • Article | | open

    The molecular chaperone Hsp90 oversees the folding of many proteins associated with cancer progression but existing small-molecule inhibitors of this pathway are not isoform-selective. Here, the authors rationally design an Hsp90 inhibitor that displays high selectivity for the Hsp90β isoform.

    • Anuj Khandelwal
    • , Caitlin N. Kent
    • , Maurie Balch
    • , Shuxia Peng
    • , Sanket J. Mishra
    • , Junpeng Deng
    • , Victor W. Day
    • , Weiya Liu
    • , Chitra Subramanian
    • , Mark Cohen
    • , Jeffery M. Holzbeierlein
    • , Robert Matts
    •  & Brian S. J. Blagg
  • Article | | open

    Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.

    • Jean-Louis Guéant
    • , Céline Chéry
    • , Abderrahim Oussalah
    • , Javad Nadaf
    • , David Coelho
    • , Thomas Josse
    • , Justine Flayac
    • , Aurélie Robert
    • , Isabelle Koscinski
    • , Isabelle Gastin
    • , Pierre Filhine-Tresarrieu
    • , Mihaela Pupavac
    • , Alison Brebner
    • , David Watkins
    • , Tomi Pastinen
    • , Alexandre Montpetit
    • , Fadi Hariri
    • , David Tregouët
    • , Benjamin A Raby
    • , Wendy K. Chung
    • , Pierre-Emmanuel Morange
    • , D. Sean Froese
    • , Matthias R. Baumgartner
    • , Jean-François Benoist
    • , Can Ficicioglu
    • , Virginie Marchand
    • , Yuri Motorin
    • , Chrystèle Bonnemains
    • , François Feillet
    • , Jacek Majewski
    •  & David S. Rosenblatt
  • Article | | open

    Identification of markers of drug response is essential for precision therapy. Here the authors introduce an algorithm that uses prior information about each gene’s importance in AML to identify the most predictive gene-drug associations from transcriptome and drug response data from 30 AML samples.

    • Su-In Lee
    • , Safiye Celik
    • , Benjamin A. Logsdon
    • , Scott M. Lundberg
    • , Timothy J. Martins
    • , Vivian G. Oehler
    • , Elihu H. Estey
    • , Chris P. Miller
    • , Sylvia Chien
    • , Jin Dai
    • , Akanksha Saxena
    • , C. Anthony Blau
    •  & Pamela S. Becker
  • Article | | open

    Intravenous illicit drug use (IDU) and hepatitis C infection (HCV) often occur among HIV-infected individuals. Here, the authors report an epigenome-wide association analysis of IDU and HCV in HIV-infected individuals, finding that their associated methylation signatures inform HIV frailty.

    • Xinyu Zhang
    • , Ying Hu
    • , Amy C Justice
    • , Boyang Li
    • , Zuoheng Wang
    • , Hongyu Zhao
    • , John H Krystal
    •  & Ke Xu
  • Article | | open

    G protein-coupled receptors are considered promising therapeutic targets. Here, the authors have identified nanobodies, or single-domain llama antibodies, that specifically enhance agonist-induced activity of a type of G protein-coupled receptor, the mGlu2 receptor.

    • Pauline Scholler
    • , Damien Nevoltris
    • , Dimitri de Bundel
    • , Simon Bossi
    • , David Moreno-Delgado
    • , Xavier Rovira
    • , Thor C. Møller
    • , Driss El Moustaine
    • , Michaël Mathieu
    • , Emilie Blanc
    • , Heather McLean
    • , Elodie Dupuis
    • , Gérard Mathis
    • , Eric Trinquet
    • , Hervé Daniel
    • , Emmanuel Valjent
    • , Daniel Baty
    • , Patrick Chames
    • , Philippe Rondard
    •  & Jean-Philippe Pin
  • Article | | open

    Crescentic rapidly progressive glomerulonephritis is a severe form of glomerula disease characterized by podocyte proliferation and migration. Here Henique et al. demonstrate that inhibition of miRNA-92a prevents kidney failure by promoting the expression of CDK inhibitor p57Kip2 that regulates podocyte cell cycle.

    • Carole Henique
    • , Guillaume Bollée
    • , Xavier Loyer
    • , Florian Grahammer
    • , Neeraj Dhaun
    • , Marine Camus
    • , Julien Vernerey
    • , Léa Guyonnet
    • , François Gaillard
    • , Hélène Lazareth
    • , Charlotte Meyer
    • , Imane Bensaada
    • , Luc Legrès
    • , Takashi Satoh
    • , Shizuo Akira
    • , Patrick Bruneval
    • , Stefanie Dimmeler
    • , Alain Tedgui
    • , Alexandre Karras
    • , Eric Thervet
    • , Dominique Nochy
    • , Tobias B. Huber
    • , Laurent Mesnard
    • , Olivia Lenoir
    •  & Pierre-Louis Tharaux
  • Article | | open

    Diabetes treatments often rely on frequent and scheduled drug administration, which reduces patient compliance and increases treatment cost. Here, the authors develop a microneedle-array patch that separately loads drug-releasing module and glucose-sensing element for on-demand, long-term diabetes therapy.

    • Wei Chen
    • , Rui Tian
    • , Can Xu
    • , Bryant C. Yung
    • , Guohao Wang
    • , Yijing Liu
    • , Qianqian Ni
    • , Fuwu Zhang
    • , Zijian Zhou
    • , Jingjing Wang
    • , Gang Niu
    • , Ying Ma
    • , Liwu Fu
    •  & Xiaoyuan Chen
  • Article | | open

    Nucleic acid nanomedicines are promising for cancer drug delivery. Here, the authors show using a mouse model the tumor immunotherapeutic efficacy of nanovaccines based on intertwining DNA-RNA nanocapsules loaded with DNA CpG, Stat3-silencing short hairpin RNA and tumor-specific peptide neoantigens.

    • Guizhi Zhu
    • , Lei Mei
    • , Harshad D. Vishwasrao
    • , Orit Jacobson
    • , Zhantong Wang
    • , Yijing Liu
    • , Bryant C. Yung
    • , Xiao Fu
    • , Albert Jin
    • , Gang Niu
    • , Qin Wang
    • , Fuwu Zhang
    • , Hari Shroff
    •  & Xiaoyuan Chen
  • Article | | open

    The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.

    • Qingbo Huang
    • , Yin Sun
    • , Xin Ma
    • , Yu Gao
    • , Xintao Li
    • , Yuanjie Niu
    • , Xu Zhang
    •  & Chawnshang Chang
  • Article | | open

    Fusion gene research traditionally focuses on fusions that result in hybrid proteins or promoter switching events. Here, the authors demonstrate enrichment of fusions in miRNA host genes in breast cancer, highlighting that disparate fusions could have convergent impact on miRNA.

    • Helena Persson
    • , Rolf Søkilde
    • , Jari Häkkinen
    • , Anna Chiara Pirona
    • , Johan Vallon-Christersson
    • , Anders Kvist
    • , Fredrik Mertens
    • , Åke Borg
    • , Felix Mitelman
    • , Mattias Höglund
    •  & Carlos Rovira
  • Article | | open

    Traditional approaches used in the pharmaceutical industry are not precise or versatile enough for customized medicine formulation and manufacture. Here the authors produce a method to form coatings, with accurate dosages, as well as a means of closely controlling dissolution kinetics.

    • Olga Shalev
    • , Shreya Raghavan
    • , J. Maxwell Mazzara
    • , Nancy Senabulya
    • , Patrick D. Sinko
    • , Elyse Fleck
    • , Christopher Rockwell
    • , Nicholas Simopoulos
    • , Christina M. Jones
    • , Anna Schwendeman
    • , Geeta Mehta
    • , Roy Clarke
    • , Gregory E. Amidon
    •  & Max Shtein
  • Article | | open

    The Singapore Genome Variation projects characterized the genetics of Singapore’s Chinese, Malay, and Indian populations. The Singapore Integrative Omics Study introduced here goes further in providing multi-omic measurements in individuals from these populations, including genetic, transcriptome, lipidome, and lifestyle data, and will facilitate the study of common diseases in Asian communities.

    • Woei-Yuh Saw
    • , Erwin Tantoso
    • , Husna Begum
    • , Lihan Zhou
    • , Ruiyang Zou
    • , Cheng He
    • , Sze Ling Chan
    • , Linda Wei-Lin Tan
    • , Lai-Ping Wong
    • , Wenting Xu
    • , Don Kyin Nwe Moong
    • , Yenly Lim
    • , Bowen Li
    • , Nisha Esakimuthu Pillai
    • , Trevor A. Peterson
    • , Tomasz Bielawny
    • , Peter J. Meikle
    • , Piyushkumar A. Mundra
    • , Wei-Yen Lim
    • , Ma Luo
    • , Kee-Seng Chia
    • , Rick Twee-Hee Ong
    • , Liam R. Brunham
    • , Chiea-Chuen Khor
    • , Heng Phon Too
    • , Richie Soong
    • , Markus R. Wenk
    • , Peter Little
    •  & Yik-Ying Teo
  • Article | | open

    Deep penetrating nevi (DPN) are unusual melanocytic neoplasms with unknown genetic drivers. Here the authors show that majority of DPN harbor activating mutations in the β-catenin and the MAP-kinase pathways; this characteristic can help in the classification and grading of these distinctive neoplasms.

    • Iwei Yeh
    • , Ursula E. Lang
    • , Emeline Durieux
    • , Meng Kian Tee
    • , Aparna Jorapur
    • , A. Hunter Shain
    • , Veronique Haddad
    • , Daniel Pissaloux
    • , Xu Chen
    • , Lorenzo Cerroni
    • , Robert L. Judson
    • , Philip E. LeBoit
    • , Timothy H. McCalmont
    • , Boris C. Bastian
    •  & Arnaud de la Fouchardière
  • Article | | open

    Megakaryocyte maturation is thought to occur as the cells migrate from a vessel-distant (endosteal) niche to the vessel within the bone. Here, the authors show that megakaryocytes represent largely sessile cells in close contact with the vasculature and homogeneously distributed in the bone marrow.

    • David Stegner
    • , Judith M. M. vanEeuwijk
    • , Oğuzhan Angay
    • , Maximilian G. Gorelashvili
    • , Daniela Semeniak
    • , Jürgen Pinnecker
    • , Patrick Schmithausen
    • , Imke Meyer
    • , Mike Friedrich
    • , Sebastian Dütting
    • , Christian Brede
    • , Andreas Beilhack
    • , Harald Schulze
    • , Bernhard Nieswandt
    •  & Katrin G. Heinze
  • Article | | open

    Humans are less sensitive to the therapeutic effects of botulinum neurotoxin B (BoNT/B) than the animal models it is tested on due to differences between the human and the mouse receptors. Here, the authors engineer BoNT/B to improve its affinity to human receptors and enhance its therapeutic efficacy.

    • Liang Tao
    • , Lisheng Peng
    • , Ronnie P.-A. Berntsson
    • , Sai Man Liu
    • , SunHyun Park
    • , Feifan Yu
    • , Christopher Boone
    • , Shilpa Palan
    • , Matthew Beard
    • , Pierre-Etienne Chabrier
    • , Pål Stenmark
    • , Johannes Krupp
    •  & Min Dong
  • Article | | open

    Sodium/proton exchangers (NHEs) are critical regulators of pH within the cell and the extracellular microenvironment. Here, the authors show that hypoxia induces mobilization of NHE6 from endosomal compartment to the plasma membrane in a PKC-dependent manner inducing hyper acidification of endosomes and drug resistance.

    • Fabrice Lucien
    • , Pierre-Paul Pelletier
    • , Roxane R. Lavoie
    • , Jean-Michel Lacroix
    • , Sébastien Roy
    • , Jean-Luc Parent
    • , Dominique Arsenault
    • , Kelly Harper
    •  & Claire M. Dubois
  • Article | | open

    A major cause of transplanted organ failure is graft arteriosclerosis. Qiu et al. show that a key protease of post-translational SUMO modification, SENP1, is crucial for graft arteriosclerosis by regulating the activity of GATA2 transcription factor in the endothelium, and promoting endothelial inflammation and alloimmunity.

    • Cong Qiu
    • , Yuewen Wang
    • , Haige Zhao
    • , Lingfeng Qin
    • , Yanna Shi
    • , Xiaolong Zhu
    • , Lin Song
    • , Xiaofei Zhou
    • , Jian Chen
    • , Hong Zhou
    • , Haifeng Zhang
    • , George Tellides
    • , Wang Min
    •  & Luyang Yu