Molecular medicine

  • Article
    | Open Access

    A randomized phase 2 study recently showed that the addition of ATR inhibitor berzosertib to gemcitabine improved PFS compared to gemcitabine alone in patients with ovarian cancer. In this preplanned exploratory study, the authors demonstrate that a genomic biomarker of replication-stress is associated with outcome to gemcitabine alone and may predict which patients benefit from addition of the ATR inhibitor berzosertib.

    • Panagiotis A. Konstantinopoulos
    • , Alexandre André B. A. da Costa
    •  & Geoffrey I. Shapiro
  • Article
    | Open Access

    Here the authors describe high depth mitochondrial DNA (mtDNA) sequence analysis of 146 human induced pluripotent stem cell (hiPSC) lines as well as single cell RNA-seq (scRNAseq) of hiPSCs undergoing differentiation from 125 donors; reporting mtDNA diversity and some variants favoured after reprogramming.

    • Wei Wei
    • , Daniel J. Gaffney
    •  & Patrick F. Chinnery
  • Article
    | Open Access

    Here, the authors perform transcriptional profiling on tracheal aspirates of adults requiring mechanical ventilation for SARS-CoV2-induced acute respiratory distress syndrome (ARDS) and identify a dysregulated host response predicted to predicted to be potentially modulated by dexamethasone.

    • Aartik Sarma
    • , Stephanie A. Christenson
    •  & Charles R. Langelier
  • Article
    | Open Access

    The SARS-CoV-2 NSP13 helicase is essential for viral replication and of interest as a drug target. Here, the authors present the crystal structures of NSP13 in the apo form and bound to either phosphate or the non-hydrolysable ATP analog AMP-PNP and discuss the helicase mechanism. They also perform a crystallographic fragment screening and identify 65 bound fragments, which could help in the design of new antiviral agents.

    • Joseph A. Newman
    • , Alice Douangamath
    •  & Opher Gileadi
  • Article
    | Open Access

    Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer.

    • Alexander Bolaender
    • , Danuta Zatorska
    •  & Gabriela Chiosis
  • Article
    | Open Access

    Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.

    • Mengfei Liu
    • , Sheng Cao
    •  & Vijay H. Shah
  • Article
    | Open Access

    Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.

    • Andrew J. King
    • , Duantida Songdej
    •  & Christian Babbs
  • Article
    | Open Access

    Lysosomal storage diseases like mucopolysaccharidosis type I (MPS I) cause pathology before birth and result in early morbidity and mortality. Here, the authors show that in utero base editing mediates multi-organ phenotypic and survival benefits in a mouse model recapitulating a common human MPSI mutation.

    • Sourav K. Bose
    • , Brandon M. White
    •  & William H. Peranteau
  • Article
    | Open Access

    Nucleoside analogs (NNA), such as acyclovir (ACV) and ganciclovir (GCV), are widely used as anti-virals to treat herpes virus infection. Here, Nishii et al. show that diphosphatase NUDT15 hydrolyzes ACV and GCV, therewith reducing NNA activity in vitro and link NUDT15 variation to inter-patient variability in ACV and GCV therapeutic effects.

    • Rina Nishii
    • , Takanori Mizuno
    •  & Jun J. Yang
  • Article
    | Open Access

    In human cells, P5B‐ATPases execute export of spermine from lysosomes to the cytosol, but the mechanisms of spermine recognition, uptake and transport remain elusive. Here the authors present cryo‐EM structures of a yeast homolog of human ATP13A2‐5, Ypk9, which depict three separate transport cycle intermediates, including spermine‐bound conformations

    • Ping Li
    • , Kaituo Wang
    •  & Pontus Gourdon
  • Article
    | Open Access

    The class Frizzled of G protein-coupled receptors (GPCRs) consist of ten Frizzled (FZD1-10) subtypes and Smoothened (SMO). Here the Schulte laboratory demonstrates that FZDs differ substantially from SMO in receptor activation-associated conformational changes, while SMO manifests a preference for a straight TM6, the TM6 of FZDs is kinked upon activation.

    • Ainoleena Turku
    • , Hannes Schihada
    •  & Gunnar Schulte
  • Article
    | Open Access

    Age-related macular degeneration (AMD) has been connected to deficits in autophagy. Here, the authors demonstrate, in mice and dry-AMD patient samples, that calcium and integrin binding protein 2 (CIB2) regulates Rheb-mTORC1 signaling axis, and subsequently autophagy.

    • Saumil Sethna
    • , Patrick A. Scott
    •  & Zubair M. Ahmed
  • Article
    | Open Access

    The human voltage-gated proton channel (hHv1) maintains intracellular pH and membrane potential in sperm and neutrophils. Here, the authors show that albumin activates hHv1, by binding to the channel voltage sensor domains to enhance open probability and increases proton current, and that activation is required to trigger sperm to allow oocyte fertilization and to sustain production and release of immune inflammatory mediators during the neutrophil respiratory burst.

    • Ruiming Zhao
    • , Hui Dai
    •  & Steve A. N. Goldstein
  • Article
    | Open Access

    Wip1 is a negative regulator of the tumor suppressor p53 and is overexpressed in several human cancers. Here the authors show that inactivation of Wip1 in neutrophils promotes p53-dependent expression of co-stimulatory ligands and anti-tumor immune responses, reducing tumor growth in preclinical cancer models.

    • Burhan Uyanik
    • , Anastasia R. Goloudina
    •  & Oleg N. Demidov
  • Article
    | Open Access

    Sjögren’s syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

    • Perrine Soret
    • , Christelle Le Dantec
    •  & Jacques-Olivier Pers
  • Article
    | Open Access

    Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

    • Julia K. Goodrich
    • , Moriel Singer-Berk
    •  & Miriam S. Udler
  • Article
    | Open Access

    Lysosomal storage disorders, characterized by altered metabolism of heparan sulfate, cause autistic symptoms followed by dementia in children. Here, the authors show that embryonic dopaminergic neurodevelopmental defects due to altered function of heparan sulfate cause autistic behaviours in mice.

    • Maria De Risi
    • , Michele Tufano
    •  & Elvira De Leonibus
  • Article
    | Open Access

    The identification of HLA peptides by mass spectrometry is non-trivial. Here, the authors extended and used the wealth of data from the ProteomeTools project to improve the prediction of non-tryptic peptides using deep learning, and show their approach enables a variety of immunological discoveries.

    • Mathias Wilhelm
    • , Daniel P. Zolg
    •  & Bernhard Kuster
  • Article
    | Open Access

    Age at onset of X-linked dystonia-parkinsonism is 50% explained by the length of a repeat in an SVA insert. The authors perform a GWAS for genetic modifiers and discover three more loci, accounting for another 13% of variability in age at onset with the protective alleles delaying onset by seven years.

    • Björn-Hergen Laabs
    • , Christine Klein
    •  & Ana Westenberger
  • Article
    | Open Access

    Data-rich networks can be difficult to interpret beyond a certain size. Here, the authors introduce a platform that uses virtual reality to allow the visual exploration of large networks, while interfacing with data repositories and other analytical methods to improve the interpretation of big data.

    • Sebastian Pirch
    • , Felix Müller
    •  & Jörg Menche
  • Article
    | Open Access

    The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.

    • Swayam Prakash Srivastava
    • , Han Zhou
    •  & Julie Goodwin
  • Article
    | Open Access

    The essential SARS-CoV-2 3CL protease is of interest as a drug target. Here, the authors identify three 3CL inhibitors and characterize them both in vitro and with a cell-based assay, and they also present the inhibitor-bound 3CL crystal structures, which may allow for the design of improved compounds.

    • Sho Iketani
    • , Farhad Forouhar
    •  & David D. Ho
  • Article
    | Open Access

    Pulmonary arterial hypertension is a progressive fatal disease characterized by pathological pulmonary artery remodeling. Here the authors show that the dysregulation of the activin A-bone morphogenetic protein receptor type 2 link in the endothelium is involved in the progression of pulmonary hypertension.

    • Gusty R. T. Ryanto
    • , Koji Ikeda
    •  & Noriaki Emoto
  • Article
    | Open Access

    POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.

    • Monika Oláhová
    • , Bradley Peter
    •  & Robert W. Taylor
  • Article
    | Open Access

    The physiological role of GDF15 remains poorly defined. Here, the authors show that circulating GDF15 increases in response to prolonged exercise, but that this exercise-induced GDF15, unlike pharmacological GDF15, does not affect post-exercise food intake or exercise motivation.

    • Anders B. Klein
    • , Trine S. Nicolaisen
    •  & Christoffer Clemmensen
  • Article
    | Open Access

    Understanding patient-specific pathobiological pathways is a critical step for advancing precision medicine. Here the authors show that individualized protein-protein interaction networks provide key insight on patient-level pathobiology and clinically relevant pathophenotypic characteristics in a complex disease.

    • Bradley A. Maron
    • , Rui-Sheng Wang
    •  & Joseph Loscalzo
  • Article
    | Open Access

    Progression from asymptomatic smoldering multiple myeloma (SMM) to symptomatic Multiple Myeloma occurs at different rates in different patients. Here, the authors report fewer NRAS and FAM46C mutations and adverse translocations in SMM compared to MM, while KRAS mutations are associated with a shorter time to progression.

    • Eileen M. Boyle
    • , Shayu Deshpande
    •  & Brian A. Walker
  • Article
    | Open Access

    High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.

    • Anil Kumar
    • , Kumaran Sundaram
    •  & Huang-Ge Zhang
  • Article
    | Open Access

    α1-Antitrypsin (AAT) is a 52 kDa serum glycoprotein, the misfolding and polymerisation of which is associated with COPD and liver disease. Here the authors demonstrate the use of high-resolution multidimensional solution-state NMR spectroscopy to characterise the structure and dynamics in solution of Z AAT purified directly from clinical patients.

    • Alistair M. Jagger
    • , Christopher A. Waudby
    •  & David A. Lomas
  • Article
    | Open Access

    Here the authors combine next generation sequencing on plasma from participants of the ADVANCE clinical trial with virological and follow-up data to investigate the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second-generation integrase inhibitors and find an association between NNRTI resistance prior to treatment and long-term treatment.

    • Mark J. Siedner
    • , Michelle A. Moorhouse
    •  & Ravindra K. Gupta
  • Article
    | Open Access

    ETNK1 mutations are recurrent in leukemia but how they contribute to oncogenesis is still unclear. Here, the authors show that ETNK1 mutations increase mitochondrial activity, ROS and H2AX levels and that these effects can be rescued upon phosphoethanolamine supplementation.

    • Diletta Fontana
    • , Mario Mauri
    •  & Rocco Piazza
  • Article
    | Open Access

    Understanding the molecular events controlling melanoma progression are necessary to find improved therapeutics. Here, the authors report oncogenic SOX2-GLI1 transcriptional complex to drive melanoma invasion through the induction of the sialyltransferase ST3GAL1, and report ST3GAL1-AXL axis as driver of melanoma metastasis.

    • Silvia Pietrobono
    • , Giulia Anichini
    •  & Barbara Stecca
  • Article
    | Open Access

    Here, the authors provide upper airway gene expression data from patients with COVID-19 and other viral and non-viral acute respiratory illnesses. They find attenuated activation of innate immune and pro-inflammatory pathways in COVID-19 as compared to other viral infections, which may contribute to its propensity for pre-symptomatic transmission.

    • Eran Mick
    • , Jack Kamm
    •  & Charles Langelier
  • Article
    | Open Access

    The human skin is a highly complex organ comprising multiple tissue layers and diverse cell types. Here, the authors present a spatially-resolved quantitative proteomic atlas of the healthy human skin, characterizing the protein profiles of four skin layers and nine cell types.

    • Beatrice Dyring-Andersen
    • , Marianne Bengtson Løvendorf
    •  & Matthias Mann
  • Article
    | Open Access

    Here, the authors isolate several nanobodies from a synthetic library that bind the receptor-binding domain (RBD) of SARS-CoV-2 spike protein (S) and neutralize S pseudotyped viruses. Cryo-EM structure of Spike with one nanobody and further biophysical analysis shows competition with ACE2 binding.

    • Tânia F. Custódio
    • , Hrishikesh Das
    •  & Christian Löw
  • Perspective
    | Open Access

    The Human Proteome Project (HPP) was launched in 2010 to enhance accurate annotation of the genome-encoded proteome. Ten years later, the HPP releases its first blueprint of the human proteome, annotating 90% of all known proteins at high-stringency and discussing the implications of proteomics for precision medicine.

    • Subash Adhikari
    • , Edouard C. Nice
    •  & Mark S. Baker
  • Article
    | Open Access

    The bacterial pathogen Helicobacter pylori is known for its ability to induce DNA double-strand breaks in the genome of its target cells. Here, we show that H. pylori-induced DNA damage and replication stress occurs in S-phase cells as a result of R-loop-mediated transcription/replication conflicts that are triggered by activation of the ALPK1/TIFA/NF-κB signaling axis.

    • Michael Bauer
    • , Zuzana Nascakova
    •  & Anne Müller
  • Article
    | Open Access

    HIF-1α is known to repress regulatory T (Treg) cell function, but less is known about the effect of HIF-2α on these cells. Here, the authors use three different mouse models of inflammatory diseases to show that HIF-2α limits HIF-1α expression and is critical for Treg cell function.

    • Tzu-Sheng Hsu
    • , Yen-Lin Lin
    •  & Ming-Zong Lai
  • Article
    | Open Access

    There are currently only a few biomarkers to predict the response of muscle invasive bladder cancer to therapy. Here, the authors analyse 300 tumors using exome and RNA sequencing and find that tumors with a high degree of genomic instability and a non-basal/squamous gene expression subtype are most likely to respond to treatment.

    • Ann Taber
    • , Emil Christensen
    •  & Lars Dyrskjøt
  • Article
    | Open Access

    Diabetic foot ulcers (DFU) represent a complex disease with limited treatment options. Here, the authors compare human RNASeq patient data from DFU, oral mucosa and skin acute wounds, identifying FOXM1 as a mediator of macrophage and neutrophil recruitment, which contributes to disease pathogenesis and is dysregulated in patients.

    • Andrew P. Sawaya
    • , Rivka C. Stone
    •  & Marjana Tomic-Canic