Molecular medicine articles within Nature Communications

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  • 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

  • Article
    | Open Access

    An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, the authors sample a longitudinal wellness cohort and analyse blood molecular profiles as well as gut microbiota composition.

    • Abdellah Tebani
    • , Anders Gummesson
    •  & Linn Fagerberg

  • Article
    | Open Access

    Recently, the first orally-administered ultra-long acting insulin was shown to have clinical efficacy. Here, the authors report the molecular engineering, as well as the biological and pharmacological properties of these insulin analogues.

    • Frantisek Hubálek
    • , Hanne H. F. Refsgaard
    •  & Thomas Kjeldsen

  • Article
    | Open Access

    Targeting mitochondrial metabolism in cancer cells has shown promising therapeutic potential. Here, the authors screen FDA-approved compound library and show that the β1-blocker nebivolol inhibits oxidative phosphorylation and angiogenesis in cancer cells and can be re-purposed for cancer therapy.

    • Cristina Nuevo-Tapioles
    • , Fulvio Santacatterina
    •  & José M. Cuezva

  • Article
    | Open Access

    Adeno-associated viruses (AAVs) are vehicles for gene therapy in humans, but currently only a limited amount of AAV serotypes is available. Here, the authors identify a novel AAV, AAVv66, and demonstrate enhanced production yields, virion stability, and CNS transduction compared to the clinically approved serotype AAV2.

    • Hung-Lun Hsu
    • , Alexander Brown
    •  & Guangping Gao

  • Article
    | Open Access

    Human antigen R (HuR) is a RNA binding protein involved in the regulation of many cellular functions. Here the authors show that, hepatocyte specific deletion of HuR exacerbates high-fat diet-induced NAFLD in mice by regulating transcripts involved in lipid transport and ATP synthesis.

    • Zhuojun Zhang
    • , Chen Zong
    •  & Wengong Wang

  • Article
    | Open Access

    Production of a safe and manufacturable material to mimic anabolic bone for tissue engineering has been hard to achieve to date. Here the authors use a mesenchymal stem cell line generated from induced pluripotent stem cells to produce osteogenic cell-matrix, displaying significant healing properties in mice.

    • Eoin P. McNeill
    • , Suzanne Zeitouni
    •  & Carl A. Gregory

  • Article
    | Open Access

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

    • Thomas B. Layton
    • , Lynn Williams
    •  & Jagdeep Nanchahal

  • Article
    | Open Access

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

    • M. Fatih Abasıyanık
    • , Krysta Wolfe
    •  & Savaş Tay

  • Article
    | Open Access

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

    • Ahmet Acar
    • , Daniel Nichol
    •  & Andrea Sottoriva

  • Article
    | Open Access

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

    • Kazuki Tajima
    • , Kenji Ikeda
    •  & Shingo Kajimura

  • Article
    | Open Access

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

    • Angela Tomasovic
    • , Theresa Brand
    •  & Kristina Lorenz

  • Article
    | Open Access

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

    • Carole Trzaska
    • , Séverine Amand
    •  & Fabrice Lejeune

  • Article
    | Open Access

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

    • Charandeep Singh
    • , Vincent Tran
    •  & Jonathan E. Sears

  • Article
    | Open Access

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

    • Zbigniew Zasłona
    • , Ewelina Flis
    •  & Luke A. J. O’Neill

  • Article
    | Open Access

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

    • Valeria Barili
    • , Paola Fisicaro
    •  & Carlo Ferrari

  • Article
    | Open Access

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

    • Nicolas J. Pillon
    • , Brendan M. Gabriel
    •  & Juleen R. Zierath

  • Article
    | Open Access

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

    • Koji M. Nishiguchi
    • , Kosuke Fujita
    •  & Toru Nakazawa

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