Molecular medicine articles within Nature Communications

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  • Article
    | Open Access

    Motile cilia beat in a defined direction to orchestrate developmental programs, but also to execute janitorial tasks such as clearing airways. Here they show that motile cilia of the Xenopus epidermis are anchored to microridge-like membrane protrusions to maintain their directionality.

    • Takayuki Yasunaga
    • , Johannes Wiegel
    •  & Gerd Walz

  • Article
    | Open Access

    Yogurt consumption is associated with health benefits, but underlying mechanisms are unknown. Here, the authors show in a mouse model that yogurt intake prevents obesity-linked insulin resistance and hepatic steatosis through shifting the gut microbiota and enhancing production of fermentation-derived branched chain hydroxy acids.

    • Noëmie Daniel
    • , Renato Tadeu Nachbar
    •  & André Marette

  • Article
    | Open Access

    COVID-19, similarly to systemic autoimmune diseases, is characterised by the presence of autoantibodies. Authors show here that the abundance and network signature of autoantibodies targeting G protein-coupled receptors and RAS-related proteins are altered in COVID-19 patients, and the level of disruption marks clinical severity.

    • Otavio Cabral-Marques
    • , Gilad Halpert
    •  & Yehuda Shoenfeld

  • Article
    | Open Access

    While prime editing is a promising technique, some genomic sites remain difficult to edit. Here the authors present fluoPEER, fluorescent prime editing and enrichment reporter, to rank the efficiency of pegRNAs and prime editor variants.

    • I. F. Schene
    • , I. P. Joore
    •  & S. A. Fuchs

  • Article
    | Open Access

    The colon is comprised of specialized cells that interact with each other to function, however, the molecular regionalization of the colon is incompletely understood. Here, the authors use spatial transcriptomics to generate a publicly available resource defining the transcriptomic regionalization of the colon during steady state and mucosal healing.

    • Sara M. Parigi
    • , Ludvig Larsson
    •  & Eduardo J. Villablanca

  • Article
    | Open Access

    In this in vitro, in silico, and in vivo study Nguyen and colleagues show that specific and stable viral gene delivery of engineered prokaryotic voltage-gated sodium channels (BacNav) to cardiomyocytes can directly augment cardiac tissue excitability and conduction.

    • Hung X. Nguyen
    • , Tianyu Wu
    •  & Nenad Bursac

  • Article
    | Open Access

    Signalling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects in obesity. Here the authors report that a selective pharmacologic activator of IRE1/XBP1s signalling stimulates an adaptive remodelling of liver and pancreas in diet-induced obese mice and mitigates obesity-linked systemic metabolic dysfunction.

    • Aparajita Madhavan
    • , Bernard P. Kok
    •  & R. Luke Wiseman

  • Article
    | Open Access

    Gene-gating of a MYC oncogenic super-enhancer (OSE) increases its expression in colon cancer cells in a poorly understood process. Here the authors show that MYC gating requires a CTCF binding site (CTCFBS) within the OSE that directs the stepwise trafficking of the OSE to the nuclear pore to facilitate increased nuclear export of MYC mRNA, which results in a growth advantage.

    • Ilyas Chachoua
    • , Ilias Tzelepis
    •  & Anita Göndör

  • Article
    | Open Access

    The heterogeneity of cell-of-origin for papillary renal cell carcinoma (pRCC) remains unknown. Here, with single-cell ATAC-seq from normal human kidney cells and ATACseq profiles from pRCC samples, the authors show that pRCC can originate from kidney collecting duct principal cells and this subtype is associated with advanced pRCC.

    • Qi Wang
    • , Yang Zhang
    •  & Jingping Yang

  • Article
    | Open Access

    To accelerate cancer research that correlates biomarkers with clinical endpoints, methods are needed to ascertain outcomes from electronic health records at scale. Here, the authors train natural language processing to extract outcomes for participants in a precision oncology study.

    • Kenneth L. Kehl
    • , Wenxin Xu
    •  & Deborah Schrag

  • Article
    | Open Access

    Elimination of regulatory T cells via the anti-CCR4 monoclonal antibody, mogamulizumab, is expected to augment anti-tumour immune response. Authors show here that although regulatory T cell targeting is successful, clinical improvement remains minimal in patients with solid tumours due to concomitant and unintended depletion of central memory CD8+ T cells.

    • Yuka Maeda
    • , Hisashi Wada
    •  & Hiroyoshi Nishikawa

  • Article
    | Open Access

    It has been a longstanding goal to promote the propagation of functional mitochondrial DNAs at the expense of pathological molecules in cells where the two species coexist. Here, the authors show that restricting the availability of glucose and glutamine can achieve this outcome.

    • Boris Pantic
    • , Daniel Ives
    •  & Antonella Spinazzola

  • Comment
    | Open Access

    In this opinion piece, we discuss why computational tools to limit the identifiability of genomic data are a promising avenue for privacy-preservation and legal compliance. Even where these technologies do not eliminate all residual risk of individual identification, the law may still consider such data anonymised.

    • Alexander Bernier
    • , Hanshi Liu
    •  & Bartha Maria Knoppers

  • Article
    | Open Access

    Niche crosstalk with Haematopoietic cells underlies normal haematopoiesis and myeloid disorders. Here the authors report a Stabilin2-Cre driver mouse with Cre-activity restricted to bone marrow sinusoidal endothelial cells, and that Stabilin2-Cre driven overactivation of b-catenin leads to erythroid differentiation defects and anaemia.

    • Joschka Heil
    • , Victor Olsavszky
    •  & Philipp-Sebastian Koch

  • Article
    | Open Access

    Worldwide pandemics of obesity and diabetes prompt an urgent need for new approaches to their prevention and cure. Here the authors present a CRISPR-based strategy that enhances the therapeutic potential of human adipocytes when implanted in obese mice.

    • Emmanouela Tsagkaraki
    • , Sarah M. Nicoloro
    •  & Michael P. Czech

  • Article
    | Open Access

    In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel NaV1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model.

    • Philipp Bengel
    • , Nataliya Dybkova
    •  & Samuel Sossalla

  • Article
    | Open Access

    The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, the authors identify frequent focal amplifications and ecDNAs in Chinese GCA patient samples, as well as the potential associations of these alterations with prognosis and dietary habits.

    • Xue-Ke Zhao
    • , Pengwei Xing
    •  & Li-Dong Wang

  • Article
    | Open Access

    Bone marrow-derived mesenchymal stroma cells (MSCs) in myeloid neoplasia have been hypothesized to carry somatic mutations and contribute to pathogenesis. Here the authors analyse ex-vivo cultures and primary MSCs derived from patients with myelodysplastic syndromes, finding functional alterations but no evidence of clonal mutations.

    • Johann-Christoph Jann
    • , Maximilian Mossner
    •  & Daniel Nowak

  • Article
    | Open Access

    Exercise induces structural and functional adaptations in skeletal muscle that involve transcriptomic remodeling, including of miRNA expression. Here the authors examine the expression of miRNAs in human muscle following exercise training and investigate the functions of miR-19b-3p on glucose metabolism in cells and mouse muscle.

    • Julie Massart
    • , Rasmus J. O. Sjögren
    •  & Anna Krook

  • Comment
    | Open Access

    More and more clinical studies include potentially sensitive human proteomics or metabolomics datasets, but bioinformatics resources for managing the access to these data are not yet available. This commentary discusses current best practices and future perspectives for the responsible handling of clinical proteomics and metabolomics data.

    • Thomas M. Keane
    • , Claire O’Donovan
    •  & Juan Antonio Vizcaíno

  • 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

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