Health sciences articles within Nature Communications

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  • Article
    | Open Access

    A subset of chemically-modified siRNAs conjugated to trivalent GalNAc may fail during nonclinical development due to rat hepatotoxicity. Here, the authors show that hepatotoxicity may be accounted for by microRNA-like off-target effects of siRNA and can be mitigated by a thermally destabilizing modification in the siRNA seed region.

    • Maja M. Janas
    • , Mark K. Schlegel
    •  & Vasant Jadhav

  • Article
    | Open Access

    Gut microbial dysbiosis in infancy is associated with childhood atopy and the development of asthma. Here, the authors show that gut microbiota perturbation is evident in the very earliest stages of postnatal life, continues throughout infancy, and can be partially rescued by Lactobacillus supplementation in high-risk for asthma infants.

    • Juliana Durack
    • , Nikole E. Kimes
    •  & Susan V. Lynch

  • Article
    | Open Access

    During early postnatal development in mammals, cardiomyocytes exit the cell cycle, losing their regenerative capacity. Here the authors show that, following myocardial infarction, loss of microRNA-128 promotes cardiomyocyte proliferation and cardiac regeneration in adult mice partly via enhancing the expression of the chromatin modifier SUZ12.

    • Wei Huang
    • , Yuliang Feng
    •  & Yigang Wang

  • Article
    | Open Access

    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
    •  & Raymond J. Langley

  • Article
    | Open Access

    T-cell prolymphocytic leukemia (T-PLL) is a rare malignancy with a poor prognosis. Here, the authors investigate the genomic landscape, gene expression profiles and functional mechanisms in 111 patients, highlighting TCL1 overexpression and ATM aberrations as core lesions which co-operate to impair DNA damage processing.

    • A. Schrader
    • , G. Crispatzu
    •  & M. Herling

  • Article
    | Open Access

    Asthenozoospermia is a major cause of male infertility, and multiple morphological abnormalities of the flagella (MMAF) is a particularly severe form. Here, using whole-exome sequencing of 78 MMAF patients, the authors identify mutations in two WDR proteins, CFAP43 and CFAP44, and confirm that these proteins are required for flagellogenesis in mouse and Trypanosoma brucei.

    • Charles Coutton
    • , Alexandra S. Vargas
    •  & Pierre F. Ray

  • Article
    | Open Access

    Malignant pleural effusion (MPE) is a life-threatening cancer-related disorder. Here, the authors show that KRAS-mutant tumor cells require IKKα, activated via host-provided IL-1β, to promote MPE development and that co-inhibition of both KRAS and IKKα ameliorates the development of MPE in mouse models.

    • Antonia Marazioti
    • , Ioannis Lilis
    •  & Georgios T. Stathopoulos

  • Article
    | Open Access

    Biomarkers of the tipping point before metastasis in hepatocellular carcinoma (HCC) could help stratify patient treatment. Here, the authors study dynamic network biomarkers to identify CALM3 as a potential suppressor of metastasis, the level of which can predict overall survival and relapse-free survival in postoperative HCC.

    • Biwei Yang
    • , Meiyi Li
    •  & Jinglin Xia

  • Article
    | Open Access

    Microrchidia CW-type zinc finger protein 2 (MORC2) is an effector of epigenetic silencing by the human silencing hub (HUSH). Here the authors present the crystal structures of MORC2 and disease-causing MORC2 mutants and give mechanistic insights into how MORC2 mediates HUSH-dependent silencing.

    • Christopher H. Douse
    • , Stuart Bloor
    •  & Yorgo Modis

  • Article
    | Open Access

    Mechanisms of acquired resistance to RET tyrosine kinase inhibitors in lung cancers are largely unknown. Here, the authors report in a lung adenocarcinoma patient harboring a CCDC6-RET mutation in the RET kinase (S904F) that results in resistance to the kinase inhibitor vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase.

    • Takashi Nakaoku
    • , Takashi Kohno
    •  & Koichi Goto

  • Article
    | Open Access

    FGF21 exerts beneficial metabolic effects on multiple tissues. Here the authors show that the Fgf21 gene is demethylated during the postnatal suckling period, creating an epigenetic memory that determines the responsiveness of the Fgf21 gene to inducers such as PPARα activators or fasting in adulthood.

    • Xunmei Yuan
    • , Kazutaka Tsujimoto
    •  & Yoshihiro Ogawa

  • Article
    | Open Access

    TNF is a major therapeutic target for rheumatoid arthritis (RA) and synovial fibroblasts are central to the pathogenesis of RA. Here the authors dissect TNF-induced death and activation signalling in RA synovial fibroblasts and TNF-driven arthritis and indicate that a successful therapeutic strategy might be to target both IKK2 and RIPK3 at the same time.

    • Marietta Armaka
    • , Caroline Ospelt
    •  & George Kollias

  • Article
    | Open Access

    The mechanism of tumor progression robustly promoted by co-existing BRAF V600E and TERT promoter mutations is not known. Here, the authors show a mechanism of mutant TERT activation by BRAF V600E and MAPK pathways in which FOS, as a transcription factor of the GABPB promoter, functionally links the two oncogenes.

    • Rengyun Liu
    • , Tao Zhang
    •  & Mingzhao Xing

  • Article
    | Open Access

    Naturally acquired antibodies may inhibit Plasmodium survival in mosquitoes, alter malaria transmission dynamics, and form the basis for transmission-blocking vaccines. Here, using sera from malaria-exposed individuals, Stone et al. reveal novel antibody correlates of transmission-reducing activity.

    • Will J. R. Stone
    • , Joseph J. Campo
    •  & Matthijs M. Jore

  • Article
    | Open Access

    Heterotopic ossification (HO) is a painful disease of unknown etiology characterized by extraskeletal bone formation after injury. Here the authors show that TGF-β is increased in HO lesions, where it promotes the early stages of HO pathology, and demonstrate that TGF-β inhibition ameliorates HO in mice.

    • Xiao Wang
    • , Fengfeng Li
    •  & Xu Cao

  • Article
    | Open Access

    Glucagon secretion is promoted during hypoglycemia and inhibited by increased glucose levels. Here, Basco et al. show that glucokinase suppresses glucose-regulated glucagon secretion by modulating the intracellular ATP/ADP ratio and the closure of KATP channels in α-cells.

    • Davide Basco
    • , Quan Zhang
    •  & Bernard Thorens

  • Article
    | Open Access

    Methyl metabolites in the one-carbon cycle, such as phosphatidylcholines and S-adenosylmethionine, play a role in hepatic triglyceride regulation. Here Kim et al. show that AhR and SHP are both involved in the expression of several key enzymes of one-carbon metabolism, with the former regulating them early after feeding and the latter inhibiting AhR at later stages.

    • Young-Chae Kim
    • , Sunmi Seok
    •  & Jongsook Kim Kemper

  • Article
    | Open Access

    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
    •  & Andreas Zirlik

  • Article
    | Open Access

    Factor H binding protein (fHbp) is a meningococcal virulence factor and a component of vaccines against serogroup B Neisseria meningitidis. Here, the authors characterize the vaccine-elicited human antibody Fab 1A12 and present both the free and the fHbp-bound Fab 1A12 crystal structures.

    • Jacinto López-Sagaseta
    • , Peter T. Beernink
    •  & Matthew J. Bottomley

  • Article
    | Open Access

    Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.

    • John B. Lees-Shepard
    • , Masakazu Yamamoto
    •  & David J. Goldhamer

  • Article
    | Open Access

    Adult beta cells, which are highly specialised insulin-secreting cells, rarely replicate. Puri et al. demonstrate that beta cell proliferative capacity is inversely correlated with their functionality and differentiation state, by inducing proliferation of adult cells with ectopic overexpression of the cell cycle regulator c-Myc.

    • Sapna Puri
    • , Nilotpal Roy
    •  & Matthias Hebrok

  • Article
    | Open Access

    Though transcranial electric stimulation has been used to influence brain activity, it is debated whether neuronal spiking activity is directly affected by commonly-used protocols. Here, the authors quantify the voltage gradients necessary to instantaneously affect neuronal spiking and show that they are higher than commonly-used protocols.

    • Mihály Vöröslakos
    • , Yuichi Takeuchi
    •  & Antal Berényi

  • Article
    | Open Access

    XLP-2 syndrome is caused by XIAP mutation. Here the authors show that mouse and human XIAP-deficient regulatory T cells have defective suppressive function as a result of conversion to proinflammatory cytokine producing cells, an effect that can be prevented by blocking the IL-6 receptor.

    • Wan-Chen Hsieh
    • , Tzu-Sheng Hsu
    •  & Ming-Zong Lai

  • Article
    | Open Access

    It is not clear if it is the embryonic origin or anatomical location of cardiomyocytes that restrict their contribution to zebrafish heart regeneration. Here, the authors show a plasticity of embryonic precursors following tbx5a fate mapping and that trabecular cardiomyocytes help to rebuild the cortical myocardium.

    • Héctor Sánchez-Iranzo
    • , María Galardi-Castilla
    •  & Nadia Mercader

  • Article
    | Open Access

    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
    •  & Brian S. J. Blagg

  • Article
    | Open Access

    Ageing is associated with a pronounced shift in mortality from cancer to degenerative diseases. Here, the authors show that in concordance with this shift, conserved transcriptional alterations during ageing across four vertebrates align with degenerative diseases but are opposite to those in cancer.

    • Peer Aramillo Irizar
    • , Sascha Schäuble
    •  & Christoph Kaleta

  • Article
    | Open Access

    Epigenetic clocks based on DNA methylation levels are estimators of chronological age. Here, the authors perform a GWAS of epigenetic aging rates in blood and find SNP variants in the TERT locus associated with increased intrinsic epigenetic age are also associated with longer telomeres.

    • Ake T. Lu
    • , Luting Xue
    •  & Steve Horvath

  • Article
    | Open Access

    Satellite cells can differentiate both into myocytes and brown adipocytes. Here, the authors show that the histone demethylase Lsd1 prevents adipogenic differentiation of satellite cells by repressing expression of Glis1, and that its ablation changes satellite cell fate towards brown adipocytes and delays muscle regeneration in mice.

    • Milica Tosic
    • , Anita Allen
    •  & Roland Schüle

  • Article
    | Open Access

    Heart development requires compaction of the ventricular wall into a dense myocardium at mid-gestation. Here, Rhee and colleagues show that the chromatin remodeller Ino80 is critical for the formation of the coronary vasculature, and show that coronary vessels are needed for successful cardiac compaction during embryonic development.

    • Siyeon Rhee
    • , Jae I. Chung
    •  & Kristy Red-Horse

  • Article
    | Open Access

    AMPK activation inhibits cardiac hypertrophy. Here the authors show that this occurs independently of previously proposed mechanisms and that AMPK controls the phosphorylation of the aminotransferase GFAT, thereby preventing cardiac hypertrophy through the reduction of protein O-GlcNAcylation.

    • Roselle Gélinas
    • , Florence Mailleux
    •  & Luc Bertrand

  • Article
    | Open Access

    About a quarter of pre-menopausal women will suffer from heavy menstrual bleeding in their lives. Here, Maybin and colleagues show hypoxia and subsequent activation of HIF-1α during menses are required for normal endometrial repair, and identify pharmacological stabilisation of HIF-1α as a potential therapeutic strategy for this debilitating condition.

    • Jacqueline A. Maybin
    • , Alison A. Murray
    •  & Hilary O. D. Critchley

  • Article
    | Open Access

    Long-acting antimalarials could provide improved prophylaxis and treatment options in the field. Here, Bakshi et al. develop a long-acting injectable atovaquone nanomedicine that prevents malaria infection prophylactically for up to 4 weeks in mice with no evidence for generation of resistant parasites.

    • Rahul P. Bakshi
    • , Lee M. Tatham
    •  & Theresa A. Shapiro

  • Article
    | Open Access

    Genome-wide association studies have uncovered several loci associated with diabetes risk. Here, the authors reanalyse public type 2 diabetes GWAS data to fine map 50 known loci and identify seven new ones, including one near ATGR2 on the X-chromosome that doubles the risk of diabetes in men.

    • Sílvia Bonàs-Guarch
    • , Marta Guindo-Martínez
    •  & David Torrents

  • Article
    | Open Access

    Communication between osteoblasts and osteoclasts is essential for bone homeostasis, but the mode of interaction is unclear. The authors use intravital two-photon microscopy in mice to show that these cells directly interact, regulating activity of osteoclasts, and that the interaction is modulated by parathyroid hormone administration.

    • Masayuki Furuya
    • , Junichi Kikuta
    •  & Masaru Ishii

  • Article
    | Open Access

    The activity of protein tyrosine phosphatase PTP1B, a major metabolic regulator, depends on its oxidation state. Here the authors identify and characterize a small molecule that targets the oxidized, inactive form of PTP1B, suggesting a new therapeutic approach to diabetes and obesity.

    • Navasona Krishnan
    • , Christopher A. Bonham
    •  & Nicholas K. Tonks

  • Article
    | Open Access

    Bloom syndrome is characterized by high levels of sister chromatid exchanges (SCEs). Here, the authors use single-cell DNA template strand-sequencing to map SCEs in patient cells, and propose that the BLM helicase protects the genome against unwanted recombination at sites of G-quadruplex structures.

    • Niek van Wietmarschen
    • , Sarra Merzouk
    •  & Peter M. Lansdorp

  • Article
    | Open Access

    Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.

    • Xia Jiang
    • , Paul F. O’Reilly
    •  & Douglas P. Kiel

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