Drug discovery

  • Article
    | Open Access

    Here, the authors characterize immunological and microbiome alterations in a cohort of obese asthmatics, finding that disease severity negatively correlates with fecal abundance of Akkermansia muciniphila, and show in a mouse model that administration of A. muciniphila reduces airway hyper-reactivity and airway inflammation.

    • David Michalovich
    • , Noelia Rodriguez-Perez
    • , Sylwia Smolinska
    • , Michal Pirozynski
    • , David Mayhew
    • , Sorif Uddin
    • , Stephanie Van Horn
    • , Milena Sokolowska
    • , Can Altunbulakli
    • , Andrzej Eljaszewicz
    • , Benoit Pugin
    • , Weronika Barcik
    • , Magdalena Kurnik-Lucka
    • , Ken A. Saunders
    • , Karen D. Simpson
    • , Peter Schmid-Grendelmeier
    • , Ruth Ferstl
    • , Remo Frei
    • , Noriane Sievi
    • , Malcolm Kohler
    • , Pawel Gajdanowicz
    • , Katrine B. Graversen
    • , Katrine Lindholm Bøgh
    • , Marek Jutel
    • , James R. Brown
    • , Cezmi A. Akdis
    • , Edith M. Hessel
    •  & Liam O’Mahony
  • Article
    | Open Access

    Elctrochemical water splitting is of vital significance for energy conversion and storage. Here the authors show an electrocatalyst based on amorphous ruthenium-tellurium porous nanorods which exhibit significantly improved OER performance than its crystalline counterparts

    • Juan Wang
    • , Lili Han
    • , Bolong Huang
    • , Qi Shao
    • , Huolin L. Xin
    •  & Xiaoqing Huang
  • Article
    | Open Access

    PARG catalyzes the removal of poly(ADP-ribose) (PAR) from target proteins and executes critical functions in the DNA damage response. Here the authors provide structural and biological insight with small molecule PARG inhibitors and show that PARG inhibition sensitizes cells to ionizing radiation and kills cancer cells through replication fork defects.

    • Jerry H. Houl
    • , Zu Ye
    • , Chris A. Brosey
    • , Lakshitha P. F. Balapiti-Modarage
    • , Sarita Namjoshi
    • , Albino Bacolla
    • , Daniel Laverty
    • , Brian L. Walker
    • , Yasin Pourfarjam
    • , Leslie S. Warden
    • , Naga Babu Chinnam
    • , Davide Moiani
    • , Roderick A. Stegeman
    • , Mei-Kuang Chen
    • , Mien-Chie Hung
    • , Zachary D. Nagel
    • , Tom Ellenberger
    • , In-Kwon Kim
    • , Darin E. Jones
    • , Zamal Ahmed
    •  & John A. Tainer
  • Article
    | Open Access

    Class 1 CRISPR systems are not as developed for genome editing as Class 2 systems are. Here the authors show that Cas3 can be used to generate functional knockouts and knock-ins, as well as Cas3-mediated exon-skipping in DMD cells.

    • Hiroyuki Morisaka
    • , Kazuto Yoshimi
    • , Yuya Okuzaki
    • , Peter Gee
    • , Yayoi Kunihiro
    • , Ekasit Sonpho
    • , Huaigeng Xu
    • , Noriko Sasakawa
    • , Yuki Naito
    • , Shinichiro Nakada
    • , Takashi Yamamoto
    • , Shigetoshi Sano
    • , Akitsu Hotta
    • , Junji Takeda
    •  & Tomoji Mashimo
  • Article
    | Open Access

    Trypanosoma brucei relies on uptake and conversion of purines from the host, which constitutes a potential drug target. Here, Hulpia et al. combine structural elements from known trypanocidal nucleoside analogues and develop a potent trypanocide with curative activity in animal models of acute and late stage sleeping sickness.

    • Fabian Hulpia
    • , Dorien Mabille
    • , Gustavo D. Campagnaro
    • , Gabriela Schumann
    • , Louis Maes
    • , Isabel Roditi
    • , Anders Hofer
    • , Harry P. de Koning
    • , Guy Caljon
    •  & Serge Van Calenbergh
  • Article
    | Open Access

    Siblings of those with autism spectrum disorder (ASD) have increased likelihood of ASD or related subclinical traits. Here, studying 253 ASD families, D’Abate et al. test the predictive value of genomic copy number variation involving ASD-associated loci, with confirmation in a second cohort.

    • L. D’Abate
    • , S. Walker
    • , R. K. C. Yuen
    • , K. Tammimies
    • , J. A. Buchanan
    • , R. W. Davies
    • , B. Thiruvahindrapuram
    • , J. Wei
    • , J. Brian
    • , S. E. Bryson
    • , K. Dobkins
    • , J. Howe
    • , R. Landa
    • , J. Leef
    • , D. Messinger
    • , S. Ozonoff
    • , I. M. Smith
    • , W. L. Stone
    • , Z. E. Warren
    • , G. Young
    • , L. Zwaigenbaum
    •  & S. W. Scherer
  • Article
    | Open Access

    CRISPR-Cas systems have well characterized, modular structures. Here the authors use that architecture to design a Cas12a library of 560 synthetic chimeras, with altered PAM preferences and specificities.

    • R. M. Liu
    • , L. L. Liang
    • , E. Freed
    • , H. Chang
    • , E. Oh
    • , Z. Y. Liu
    • , A. Garst
    • , C. A. Eckert
    •  & R. T. Gill
  • Article
    | Open Access

    Many cancer cells have increased glucose consumption compared to normal cells, a feature that can be exploited therapeutically. Here, the authors carry out a chemical screen and identify compounds that selectively blocks glucose metabolism in non-small-cell lung cancer cell lines.

    • Chiara Ghezzi
    • , Alicia Wong
    • , Bao Ying Chen
    • , Bernard Ribalet
    • , Robert Damoiseaux
    •  & Peter M. Clark
  • Article
    | Open Access

    Histology data exists for many cancer samples and the ability to automatically image this data may provide prognostic information. Here, the authors generated an algorithm to measure tumour infiltrating lymphocytes in melanoma histology specimens and show that the ratio of these immune cells to tumour cells has prognostic value.

    • Balazs Acs
    • , Fahad Shabbir Ahmed
    • , Swati Gupta
    • , Pok Fai Wong
    • , Robyn D. Gartrell
    • , Jaya Sarin Pradhan
    • , Emanuelle M. Rizk
    • , Bonnie Gould Rothberg
    • , Yvonne M. Saenger
    •  & David L. Rimm
  • Article
    | Open Access

    Myeloid-derived growth factor (MYDGF) is an angiogenic growth factor with therapeutic potential for ischemic tissue repair and the receptor is still unknown. Here the authors present the crystal structure of human MYDGF and identify its functional epitope through mutagenesis studies.

    • Rebecca Ebenhoch
    • , Abbas Akhdar
    • , Marc R. Reboll
    • , Mortimer Korf-Klingebiel
    • , Priyanka Gupta
    • , Julie Armstrong
    • , Yining Huang
    • , Lee Frego
    • , Irina Rybina
    • , John Miglietta
    • , Anton Pekcec
    • , Kai C. Wollert
    •  & Herbert Nar
  • Article
    | Open Access

    Several cancers harbour mutant p53 and express higher levels of p53-derived peptide-MHCs. Here, the authors report affinity matured human antibody, P1C1TM, specific for the p53125-134 peptide in complex with the HLA-A24 class I MHC molecule and show its efficacy and specificity for mutant p53 expressing tumours.

    • Lionel Low
    • , Angeline Goh
    • , Joanna Koh
    • , Samantha Lim
    •  & Cheng-I Wang
  • Article
    | Open Access

    Drug target identification is a crucial step in drug development. Here, the authors introduce a Bayesian machine learning framework that integrates multiple data types to predict the targets of small molecules, enabling identification of a new set of microtubule inhibitors and the target of the anti-cancer molecule ONC201.

    • Neel S. Madhukar
    • , Prashant K. Khade
    • , Linda Huang
    • , Kaitlyn Gayvert
    • , Giuseppe Galletti
    • , Martin Stogniew
    • , Joshua E. Allen
    • , Paraskevi Giannakakou
    •  & Olivier Elemento
  • Article
    | Open Access

    Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.

    • Julio Aguado
    • , Agustin Sola-Carvajal
    • , Valeria Cancila
    • , Gwladys Revêchon
    • , Peh Fern Ong
    • , Corey Winston Jones-Weinert
    • , Emelie Wallén Arzt
    • , Giovanna Lattanzi
    • , Oliver Dreesen
    • , Claudio Tripodo
    • , Francesca Rossiello
    • , Maria Eriksson
    •  & Fabrizio d’Adda di Fagagna
  • Article
    | Open Access

    Machine learning models can accurately predict atomistic chemical properties but do not provide access to the molecular electronic structure. Here the authors use a deep learning approach to predict the quantum mechanical wavefunction at high efficiency from which other ground-state properties can be derived.

    • K. T. Schütt
    • , M. Gastegger
    • , A. Tkatchenko
    • , K.-R. Müller
    •  & R. J. Maurer
  • Article
    | Open Access

    Metabolic reprogramming is a hallmark of pancreatic ductal adenocarcinoma (PDA). Here, the authors show that in PDA cells redox and central carbon metabolism are driven by an eIF4F dependent translation program, and combined targeting of eIF4A and glutaminase can impact PDA proliferation.

    • Karina Chan
    • , Francis Robert
    • , Christian Oertlin
    • , Dana Kapeller-Libermann
    • , Daina Avizonis
    • , Johana Gutierrez
    • , Abram Handly-Santana
    • , Mikhail Doubrovin
    • , Julia Park
    • , Christina Schoepfer
    • , Brandon Da Silva
    • , Melissa Yao
    • , Faith Gorton
    • , Junwei Shi
    • , Craig J. Thomas
    • , Lauren E. Brown
    • , John A. Porco Jr.
    • , Michael Pollak
    • , Ola Larsson
    • , Jerry Pelletier
    •  & Iok In Christine Chio
  • Article
    | Open Access

    The Aza Paternò-Büchi reaction is arguably among the most direct approaches to functionalized azetidines, which are common medicinal scaffolds. Here, the authors report a mild and selective visible light-enabled intramolecular aza Paternò-Büchi reaction yielding bicyclic azetidines in high yields and diastereoselectivity.

    • Marc R. Becker
    • , Alistair D. Richardson
    •  & Corinna S. Schindler
  • Article
    | Open Access

    While water electrolysis affords hydrogen as a carbon-neutral fuel, the oxygen evolution half-reaction limits overall performances. Here, authors examine molecular catalysts and their water oxidation mechanisms via computational methods.

    • Michael John Craig
    • , Gabriel Coulter
    • , Eoin Dolan
    • , Joaquín Soriano-López
    • , Eric Mates-Torres
    • , Wolfgang Schmitt
    •  & Max García-Melchor
  • Article
    | Open Access

    Successful anticancer immunotherapy should induce robust systemic immunity against metastases. Here, the authors engineer an inhalable nano-STING agonist, which synergizes with fractionated radiation to control lung metastases and confers long-term systemic antitumor immunity in mice.

    • Yang Liu
    • , William N. Crowe
    • , Lulu Wang
    • , Yong Lu
    • , W. Jeffrey Petty
    • , Amyn A. Habib
    •  & Dawen Zhao
  • Article
    | Open Access

    DNA-dependent protein kinase (DNA-PK) plays a major role in the DNA damage response upon double-strand break formation. Here, the authors show that the DNA-PK inhibitor AZD7648, enhances the activity of radiotherapy, chemotherapy and the PARP inhibitor olaparib in multiple mouse tumour models.

    • Jacqueline H. L. Fok
    • , Antonio Ramos-Montoya
    • , Mercedes Vazquez-Chantada
    • , Paul W. G. Wijnhoven
    • , Valeria Follia
    • , Neil James
    • , Paul M. Farrington
    • , Ankur Karmokar
    • , Sophie E. Willis
    • , Jonathan Cairns
    • , Jenni Nikkilä
    • , David Beattie
    • , Gillian M. Lamont
    • , M. Raymond V. Finlay
    • , Joanne Wilson
    • , Aaron Smith
    • , Lenka Oplustil O’Connor
    • , Stephanie Ling
    • , Stephen E. Fawell
    • , Mark J. O’Connor
    • , Simon J. Hollingsworth
    • , Emma Dean
    • , Frederick W. Goldberg
    • , Barry R. Davies
    •  & Elaine B. Cadogan
  • Article
    | Open Access

    Predicting the drug response of patients with cancer is crucial for implementing targeted therapy. Here, Su et al. make patient-derived cell lines and perform targeted sequencing and RNA-seq to identify CDKN2A/2B loss as a predictor of response to CDK4/6 inhibitors in esophageal squamous cell carcinoma.

    • Dan Su
    • , Dadong Zhang
    • , Jiaoyue Jin
    • , Lisha Ying
    • , Miao Han
    • , Kaiyan Chen
    • , Bin Li
    • , Junzhou Wu
    • , Zhenghua Xie
    • , Fanrong Zhang
    • , Yihui Lin
    • , Guoping Cheng
    • , Jing-Yu Li
    • , Minran Huang
    • , Jinchao Wang
    • , Kailai Wang
    • , Jianjun Zhang
    • , Fugen Li
    • , Lei Xiong
    • , Andrew Futreal
    •  & Weimin Mao
  • 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

    New tuberculosis therapies, targeting respiratory chain components of Mycobacterium tuberculosis, are under development. Here the authors show that, contrary to common belief, some of these components are not essential for pathogen viability and/or virulence in animal models of infection.

    • Tiago Beites
    • , Kathryn O’Brien
    • , Divya Tiwari
    • , Curtis A. Engelhart
    • , Shaun Walters
    • , Jenna Andrews
    • , Hee-Jeong Yang
    • , Michelle L. Sutphen
    • , Danielle M. Weiner
    • , Emmanuel K. Dayao
    • , Matthew Zimmerman
    • , Brendan Prideaux
    • , Prashant V. Desai
    • , Thierry Masquelin
    • , Laura E. Via
    • , Véronique Dartois
    • , Helena I. Boshoff
    • , Clifton E. Barry III
    • , Sabine Ehrt
    •  & Dirk Schnappinger
  • Article
    | Open Access

    The activation of drugs within cellular systems may provide targeted therapies for cancer. Here, the authors make a drug delivery system that is activated within the cell and exploits XIAP expression to cleave a linker region, resulting in the self-assembly of the system and drug release within cancer cells.

    • Hong-Wei An
    • , Li-Li Li
    • , Yi Wang
    • , Ziqi Wang
    • , Dayong Hou
    • , Yao-Xin Lin
    • , Sheng-Lin Qiao
    • , Man-Di Wang
    • , Chao Yang
    • , Yong Cong
    • , Yang Ma
    • , Xiao-Xiao Zhao
    • , Qian Cai
    • , Wen-Ting Chen
    • , Chu-Qi Lu
    • , Wanhai Xu
    • , Hao Wang
    •  & Yuliang Zhao
  • Article
    | Open Access

    Currently there are no therapeutics for long lasting central nervous system injuries, that can address the complex injury cascade that develops over years. Here the authors report biomaterial scaffolds that release 17β-estradiol (E2) at nanomolar concentrations over the course of 1–10 years via slow hydrolysis in vitro.

    • Anthony R. D’Amato
    • , Devan L. Puhl
    • , Samuel A. T. Ellman
    • , Bailey Balouch
    • , Ryan J. Gilbert
    •  & Edmund F. Palermo
  • Article
    | Open Access

    Recent reports suggest the spatial and temporal coupling of receptor-effector interactions, with the potential to diversify downstream responses. Here authors demonstrate the temporal coupling of cognate and non-cognate G protein interactions through priming of GPCR conformation.

    • Tejas M. Gupte
    • , Michael Ritt
    • , Matthew Dysthe
    • , Rabia U. Malik
    •  & Sivaraj Sivaramakrishnan
  • Article
    | Open Access

    While main group elements possess four valence orbitals that are accessible for bonding, quadruple bonding to main group elements is very rarely observed. Here the authors report that boron is able to form four bonding interactions with iron in the BFe(CO)3- anion complex.

    • Chaoxian Chi
    • , Jia-Qi Wang
    • , Han-Shi Hu
    • , Yang-Yang Zhang
    • , Wan-Lu Li
    • , Luyan Meng
    • , Mingbiao Luo
    • , Mingfei Zhou
    •  & Jun Li
  • Article
    | Open Access

    Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ6.

    • Richard H. Kimura
    • , Ling Wang
    • , Bin Shen
    • , Li Huo
    • , Willemieke Tummers
    • , Fabian V. Filipp
    • , Haiwei Henry Guo
    • , Thomas Haywood
    • , Lotfi Abou-Elkacem
    • , Lucia Baratto
    • , Frezghi Habte
    • , Rammohan Devulapally
    • , Timothy H. Witney
    • , Yan Cheng
    • , Suhas Tikole
    • , Subhendu Chakraborti
    • , Jay Nix
    • , Christopher A. Bonagura
    • , Negin Hatami
    • , Joshua J. Mooney
    • , Tushar Desai
    • , Scott Turner
    • , Richard S. Gaster
    • , Andrea Otte
    • , Brendan C. Visser
    • , George A. Poultsides
    • , Jeffrey Norton
    • , Walter Park
    • , Mark Stolowitz
    • , Kenneth Lau
    • , Eric Yang
    • , Arutselvan Natarajan
    • , Ohad Ilovich
    • , Shyam Srinivas
    • , Ananth Srinivasan
    • , Ramasamy Paulmurugan
    • , Juergen Willmann
    • , Frederick T. Chin
    • , Zhen Cheng
    • , Andrei Iagaru
    • , Fang Li
    •  & Sanjiv S. Gambhir
  • Article
    | Open Access

    Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a powerful tool for neuroscience, but the standard DREADD ligand, CNO, has significant drawbacks. Here the authors report two novel high-potency DREADD ligands and a novel DREADD radiotracer for imaging purposes.

    • Jordi Bonaventura
    • , Mark A. G. Eldridge
    • , Feng Hu
    • , Juan L. Gomez
    • , Marta Sanchez-Soto
    • , Ara M. Abramyan
    • , Sherry Lam
    • , Matthew A. Boehm
    • , Christina Ruiz
    • , Mitchell R. Farrell
    • , Andrea Moreno
    • , Islam Mustafa Galal Faress
    • , Niels Andersen
    • , John Y. Lin
    • , Ruin Moaddel
    • , Patrick J. Morris
    • , Lei Shi
    • , David R. Sibley
    • , Stephen V. Mahler
    • , Sadegh Nabavi
    • , Martin G. Pomper
    • , Antonello Bonci
    • , Andrew G. Horti
    • , Barry J. Richmond
    •  & Michael Michaelides
  • Article
    | Open Access

    Practical calculations of molecular inelastic collisions are computationally very demanding. Here the authors use full-dimensional quantum scattering to calculate energy transfer probabilities in inelastic collision between hydrogen fluoride molecules successfully checked by available experimental vibrational quenching rate.Practical calculations of molecular inelastic collisions are computationally very demanding. Here the authors use full-dimensional quantum scattering to calculate energy transfer probabilities in inelastic collision between hydrogen fluoride molecules successfully checked by available experimental vibrational quenching rate.

    • Dongzheng Yang
    • , Jing Huang
    • , Xixi Hu
    • , Hua Guo
    •  & Daiqian Xie
  • Article
    | Open Access

    High-throughput assays for TCR specificity are a bottleneck in understanding T cell immunity and harnessing it for medicine. Here the authors develop a functional screening method to identify T cell specificity in the natural context of peptide-MHC presentation, enabling detection of physiologically relevant T cell antigens from large libraries of peptide-coding sequences.

    • Govinda Sharma
    • , Craig M. Rive
    •  & Robert A. Holt
  • Article
    | Open Access

    Tiling-sgRNA designs allow the in situ evaluation of protein domain functions. Here the authors present ProTiler - a computational method to predict CRISPR knockout hyper-sensitive regions, revealing previously unannotated domains.

    • Wei He
    • , Liang Zhang
    • , Oscar D. Villarreal
    • , Rongjie Fu
    • , Ella Bedford
    • , Jingzhuang Dou
    • , Anish Y. Patel
    • , Mark T. Bedford
    • , Xiaobing Shi
    • , Taiping Chen
    • , Blaine Bartholomew
    •  & Han Xu
  • Article
    | Open Access

    Single-atom catalysts are widely investigated heterogeneous catalysts; however, the identification of the local environment of single atoms under experimental conditions is still challenging. Here, the authors clearly demonstrate that Rh single atoms adapt their local coordination and reactivity in response to various redox conditions.

    • Yan Tang
    • , Chithra Asokan
    • , Mingjie Xu
    • , George W. Graham
    • , Xiaoqing Pan
    • , Phillip Christopher
    • , Jun Li
    •  & Philippe Sautet
  • Article
    | Open Access

    Understanding the fusion of nanocarriers with cell membranes is important to the design of effective drug delivery methods. Here, the authors report on a study into the fusion of cubosomes with model cell membranes underflow conditions and report on the binding kinetics.

    • Brendan P. Dyett
    • , Haitao Yu
    • , Jamie Strachan
    • , Calum J. Drummond
    •  & Charlotte E. Conn
  • Article
    | Open Access

    Besides mechanical forces, the mechanosensitive channel Piezo1 is activated by the small molecule Yoda1 through an unknown mechanism. Here, using molecular dynamics simulations, calcium imaging and electrophysiology, the authors identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain.

    • Wesley M. Botello-Smith
    • , Wenjuan Jiang
    • , Han Zhang
    • , Alper D. Ozkan
    • , Yi-Chun Lin
    • , Christine N. Pham
    • , Jérôme J. Lacroix
    •  & Yun Luo
  • Article
    | Open Access

    Vectors used in gene therapy for hemoglobin disorders carry globin in a reverse-orientation to prevent the loss of key regulatory elements by RNA splicing, but this limits their efficiency. Here, the authors develop a vector carrying β-globin in a forward orientation and show that it has improved titers and transduction efficiency in humanized mice and nonhuman primates.

    • Naoya Uchida
    • , Matthew M. Hsieh
    • , Lydia Raines
    • , Juan J. Haro-Mora
    • , Selami Demirci
    • , Aylin C. Bonifacino
    • , Allen E. Krouse
    • , Mark E. Metzger
    • , Robert E. Donahue
    •  & John F. Tisdale
  • Article
    | Open Access

    In-depth characterization of adeno-associated virus (AAV)-mediated CRISPR delivery is still lacking. Here, the authors show high levels of integration into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant genes in vivo.

    • Killian S. Hanlon
    • , Benjamin P. Kleinstiver
    • , Sara P. Garcia
    • , Mikołaj P. Zaborowski
    • , Adrienn Volak
    • , Stefan E. Spirig
    • , Alissa Muller
    • , Alexander A. Sousa
    • , Shengdar Q. Tsai
    • , Niclas E. Bengtsson
    • , Camilla Lööv
    • , Martin Ingelsson
    • , Jeffrey S. Chamberlain
    • , David P. Corey
    • , Martin J. Aryee
    • , J. Keith Joung
    • , Xandra O. Breakefield
    • , Casey A. Maguire
    •  & Bence György
  • Article
    | Open Access

    Arabidopsis AGO1 binds both microRNA (miRNA) and endogenous small interfering RNA (siRNA). Here the authors show that 5′−3′ RNA degradation suppresses siRNA biogenesis from ribosomal RNA to prevent overloading of AGO1 with ribosomal siRNA and maintain miRNA-directed post translational gene silencing.

    • Chenjiang You
    • , Wenrong He
    • , Runlai Hang
    • , Cuiju Zhang
    • , Xiaofeng Cao
    • , Hongwei Guo
    • , Xuemei Chen
    • , Jie Cui
    •  & Beixin Mo
  • Article
    | Open Access

    Conserved regions of the antibody molecule impact its downstream biological effects. Here the authors show that a rigid hinge conformation increases the agonistic activity of CD40 and DR5 antibodies, distinctly from FcγR-binding, suggesting that the hinge and FcR binding regions can be separately modified to optimize therapies.

    • Xiaobo Liu
    • , Yingjie Zhao
    • , Huan Shi
    • , Yan Zhang
    • , Xueying Yin
    • , Mingdong Liu
    • , Huihui Zhang
    • , Yongning He
    • , Boxun Lu
    • , Tengchuan Jin
    •  & Fubin Li
  • Article
    | Open Access

    Control of composite nanoparticle topology can be difficult. Here the authors control the topological structure of mesoporous multipods by controlling the number of nucleation sites, and they used the resultant nanoparticles for bacterial adhesion, segregation and antibiotic delivery.

    • Tiancong Zhao
    • , Liang Chen
    • , Peiyuan Wang
    • , Benhao Li
    • , Runfeng Lin
    • , Areej Abdulkareem Al-Khalaf
    • , Wael N. Hozzein
    • , Fan Zhang
    • , Xiaomin Li
    •  & Dongyuan Zhao
  • Article
    | Open Access

    Mechanistic models provide valuable insights, but large-scale simulations are computationally expensive. Here, the authors show that it is possible to explore the dynamics of a mechanistic model over a large set of parameters by training an artificial neural network on a smaller set of simulations.

    • Shangying Wang
    • , Kai Fan
    • , Nan Luo
    • , Yangxiaolu Cao
    • , Feilun Wu
    • , Carolyn Zhang
    • , Katherine A. Heller
    •  & Lingchong You
  • Article
    | Open Access

    Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.

    • Haoxin Li
    • , Kevin Bullock
    • , Carino Gurjao
    • , David Braun
    • , Sachet A. Shukla
    • , Dominick Bossé
    • , Aly-Khan A. Lalani
    • , Shuba Gopal
    • , Chelsea Jin
    • , Christine Horak
    • , Megan Wind-Rotolo
    • , Sabina Signoretti
    • , David F. McDermott
    • , Gordon J. Freeman
    • , Eliezer M. Van Allen
    • , Stuart L. Schreiber
    • , F. Stephen Hodi
    • , William R. Sellers
    • , Levi A. Garraway
    • , Clary B. Clish
    • , Toni K. Choueiri
    •  & Marios Giannakis
  • Article
    | Open Access

    Prostate cancer progression may be enhanced by a high-fat diet. Here the authors show that a diet high in saturated fats enhance the MYC-driven transcriptional program, a feature that independently predicts prostate cancer progression and death.

    • David P. Labbé
    • , Giorgia Zadra
    • , Meng Yang
    • , Jaime M. Reyes
    • , Charles Y. Lin
    • , Stefano Cacciatore
    • , Ericka M. Ebot
    • , Amanda L. Creech
    • , Francesca Giunchi
    • , Michelangelo Fiorentino
    • , Habiba Elfandy
    • , Sudeepa Syamala
    • , Edward D. Karoly
    • , Mohammed Alshalalfa
    • , Nicholas Erho
    • , Ashley Ross
    • , Edward M. Schaeffer
    • , Ewan A. Gibb
    • , Mandeep Takhar
    • , Robert B. Den
    • , Jonathan Lehrer
    • , R. Jeffrey Karnes
    • , Stephen J. Freedland
    • , Elai Davicioni
    • , Daniel E. Spratt
    • , Leigh Ellis
    • , Jacob D. Jaffe
    • , Anthony V. DʼAmico
    • , Philip W. Kantoff
    • , James E. Bradner
    • , Lorelei A. Mucci
    • , Jorge E. Chavarro
    • , Massimo Loda
    •  & Myles Brown
  • Article
    | Open Access

    Controlled patterning of functionality within hydrogels typically involves complex chemistry. Here, the authors report on a simple competitive binding strategy using avidin and biotin analogs in an injectable biomaterial for spatiotemporally controlled presentation of biochemical stimuli to cells.

    • Tom Kamperman
    • , Michelle Koerselman
    • , Cindy Kelder
    • , Jan Hendriks
    • , João F. Crispim
    • , Xandra de Peuter
    • , Pieter J. Dijkstra
    • , Marcel Karperien
    •  & Jeroen Leijten
  • Article
    | Open Access

    Antibiotic resistance is a major global health challenge. Here, the authors report on a thermoresponsive delivery system for combined photothermal and antibiotic delivery with fluorescent tracking abilities and demonstrate application against antibiotic resistant bacteria in vitro and in vivo.

    • Guangchao Qing
    • , Xianxian Zhao
    • , Ningqiang Gong
    • , Jing Chen
    • , Xianlei Li
    • , Yaling Gan
    • , Yongchao Wang
    • , Zhen Zhang
    • , Yuxuan Zhang
    • , Weisheng Guo
    • , Yang Luo
    •  & Xing-Jie Liang
  • Article
    | Open Access

    Patient drug regime compliance is a major issue; sustained release implants could address this. Here, the authors report on a phase inverted in situ forming implant of PLGA for the sustained release of antiretroviral drugs and optimize and demonstrate the release of 6 different drugs over a period of up to a year.

    • S. Rahima Benhabbour
    • , Martina Kovarova
    • , Clinton Jones
    • , Daijha J. Copeland
    • , Roopali Shrivastava
    • , Michael D. Swanson
    • , Craig Sykes
    • , Phong T. Ho
    • , Mackenzie L. Cottrell
    • , Anush Sridharan
    • , Samantha M. Fix
    • , Orrin Thayer
    • , Julie M. Long
    • , Daria J. Hazuda
    • , Paul A. Dayton
    • , Russell J. Mumper
    • , Angela D. M. Kashuba
    •  & J. Victor Garcia
  • Article
    | Open Access

    FK506 is a potential antifungal compound that inhibits calcineurin, but it also has immunosuppressive activity. Here, Juvvadi et al. report the structure of FK506 in complex with the FK506-binding protein FKPB12 and calcineurin, and design a less immunosuppresive FK506 analog with antifungal activity in mice.

    • Praveen R. Juvvadi
    • , David Fox III
    • , Benjamin G. Bobay
    • , Michael J. Hoy
    • , Sophie M. C. Gobeil
    • , Ronald A. Venters
    • , Zanetta Chang
    • , Jackie J. Lin
    • , Anna Floyd Averette
    • , D. Christopher Cole
    • , Blake C. Barrington
    • , Joshua D. Wheaton
    • , Maria Ciofani
    • , Michael Trzoss
    • , Xiaoming Li
    • , Soo Chan Lee
    • , Ying-Lien Chen
    • , Mitchell Mutz
    • , Leonard D. Spicer
    • , Maria A. Schumacher
    • , Joseph Heitman
    •  & William J. Steinbach
  • Article
    | Open Access

    Polymerization of axin proteins is essential to suppress Wnt/β-catenin signaling. Here, the authors identify an aggregation site in the conductin/axin2 RGS domain that prevents its polymerization and show that a short peptide masking this aggregon promotes polymerization of conductin/axin2, downregulation of Wnt pathway activity and growth inhibition of colorectal cancer cells.

    • Dominic B. Bernkopf
    • , Martina Brückner
    • , Michel V. Hadjihannas
    •  & Jürgen Behrens
  • Article
    | Open Access

    The use of PET for detection of Aβ in the brain in AD has limitations; studies also indicate that retinal changes, including Aβ deposition, occur in AD. Here the authors demonstrate the potential to use in vivo retinal hyperspectral imaging as a surrogate for brain accumulation of Aβ.

    • Xavier Hadoux
    • , Flora Hui
    • , Jeremiah K. H. Lim
    • , Colin L. Masters
    • , Alice Pébay
    • , Sophie Chevalier
    • , Jason Ha
    • , Samantha Loi
    • , Christopher J. Fowler
    • , Christopher Rowe
    • , Victor L. Villemagne
    • , Edward N. Taylor
    • , Christopher Fluke
    • , Jean-Paul Soucy
    • , Frédéric Lesage
    • , Jean-Philippe Sylvestre
    • , Pedro Rosa-Neto
    • , Sulantha Mathotaarachchi
    • , Serge Gauthier
    • , Ziad S. Nasreddine
    • , Jean Daniel Arbour
    • , Marc-André Rhéaume
    • , Sylvain Beaulieu
    • , Mohamed Dirani
    • , Christine T. O. Nguyen
    • , Bang V. Bui
    • , Robert Williamson
    • , Jonathan G. Crowston
    •  & Peter van Wijngaarden
  • Article
    | Open Access

    Amino acid biosynthetic pathways are an attractive alternative to treat chronic infections such as Mycobacterium tuberculosis (Mtb). Here, the authors investigate the metabolic response to disruption of the aspartate pathway in persistent Mtb and identify essential enzymes as potential new targets for drug development.

    • Erik J. Hasenoehrl
    • , Dannah Rae Sajorda
    • , Linda Berney-Meyer
    • , Samantha Johnson
    • , JoAnn M. Tufariello
    • , Tobias Fuhrer
    • , Gregory M. Cook
    • , William R. Jacobs Jr.
    •  & Michael Berney