Diseases articles within Nature Communications

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  • Article
    | Open Access

    Systematic analysis of postzygotic mosaicism (PZM) is difficult due to challenges in detecting such events. Here, Wright et al. analyse trio exome sequencing data from blood and saliva of 4,293 probands with developmental disorders from the DDD Study and estimate that >3% of causative de novo mutations result from PZM.

    • C. F. Wright
    • , E. Prigmore
    •  & M. E. Hurles

  • Article
    | Open Access

    Idiopathic pulmonary fibrosis is associated with myofibroblast activation in the lungs and metabolic alterations. Here, the authors show that the antidiabetic drug metformin has antifibrotic effects in human-derived samples and mouse models, by modulating a number of metabolic pathways to induce lipogenic transdifferentiation of myofibroblasts.

    • Vahid Kheirollahi
    • , Roxana M. Wasnick
    •  & Elie El Agha

  • Article
    | Open Access

    The adaptor protein SHN3 suppresses new bone formation by controlling osteoblast activity. Here, the authors show that ablation of SHN3 function, either genetically or by delivering an artificial miRNA via AAV9, rescues bone loss in osteoporotic mice, and show that engineering of the AAV9 capsid improves targeting to bone

    • Yeon-Suk Yang
    • , Jun Xie
    •  & Jae-Hyuck Shim

  • Article
    | Open Access

    Here, the authors show that sequential treatment with long-acting slow-effective release ART and AAV9- based delivery of CRISPR-Cas9 results in undetectable levels of virus and integrated DNA in a subset of humanized HIV-1 infected mice. This proof-of-concept study suggests that HIV-1 elimination is possible.

    • Prasanta K. Dash
    • , Rafal Kaminski
    •  & Howard E. Gendelman

  • Article
    | Open Access

    Stimuli affecting migration of filaria in host tissues are unclear. Using in situ imaging, Kilarski et al. here show that universal adaptations of nematodes allow Litomosoides sigmodontis infective larvae to mechanically break into pre-collecting lymphatics and follow the direction of flow towards the lymph node.

    • Witold W. Kilarski
    • , Coralie Martin
    •  & Melody A. Swartz

  • Article
    | Open Access

    Genetic variants in RP1 can cause hereditary retinal degeneration (HRD). Here, in a genomic screen of 331 Japanese HRD patients, the authors identify a near-polymorphic RP1 variant that causes Mendelian HRD in trans with an Alu insertion and otherwise is associated with HRD according to a complex model of inheritance.

    • Konstantinos Nikopoulos
    • , Katarina Cisarova
    •  & Carlo Rivolta

  • Article
    | Open Access

    So far identified clostridial neurotoxins target vertebrates. Here, Contreras et al. isolate the clostridial-like neurotoxin PMP1 from Paraclostridium bifermentans strains and show that it selectively targets anopheline mosquitoes by targeting mosquito syntaxin.

    • Estefania Contreras
    • , Geoffrey Masuyer
    •  & Sarjeet S. Gill

  • Article
    | Open Access

    Cryptosporidium infection can cause severe diarrhea with limited treatment options available. Here, Lunde et al. perform a drug repositioning screen with a library of benzoxaboroles and identify AN7973 as potent inhibitor of intracellular parasite development with good efficacy in murine and neonatal dairy calf disease models.

    • Christopher S. Lunde
    • , Erin E. Stebbins
    •  & Christopher D. Huston

  • Article
    | Open Access

    A number of therapeutic agents aimed at reducing pathology in Duchenne muscular dystrophy have been developed, but may have off-target effects when delivered systemically. Here, the authors express the therapeutic LIF transgene in leukocytes, and show this results in targeting to inflamed dystrophic muscle and reduced fibrosis by suppressing type 2 immunity.

    • Steven S. Welc
    • , Ivan Flores
    •  & James G. Tidball

  • Article
    | Open Access

    Increased inflammation during ageing promotes osteoporosis by activating osteoclast function and inhibiting osteoblasts. Here, the authors show that TGFβ1 release from bone matrix during ageing induces degradation of TRAF3 in mesenchymal progenitor cells, leading to reduced osteoblast differentiation and increased osteoclast formation, and suggesting that pharmacological stabilization of TRAF3 could ameliorate age-related osteoporosis.

    • Jinbo Li
    • , Akram Ayoub
    •  & Brendan F. Boyce

  • Article
    | Open Access

    Dental caries and periodontitis are among the most common medical conditions. Here, the authors report a GWAS for measures of oral health that reveals 47 risk loci for caries, find genetic correlation with 31 other complex traits and use Mendelian randomization analyses to explore potential causal relationships.

    • Dmitry Shungin
    • , Simon Haworth
    •  & Ingegerd Johansson

  • Article
    | Open Access

    Composition and function of immune populations at barrier surfaces is crucial for response to infection. Here, the authors identify a population of dendritic cells in human epidermis, abundant in anogenital epithelia and distinct from Langerhans cells by surface phenotype and by high capacity for HIV infection and transmission.

    • Kirstie M. Bertram
    • , Rachel A. Botting
    •  & Andrew N. Harman

  • Article
    | Open Access

    Here, Frisbee et al. show that hypervirulent Clostridium difficile induces IL-33 expression in the gut and IL-33 reduces mortality and morbidity via group 2 innate lymphoid cells. Furthermore, serum levels of the soluble IL-33 decoy receptor, sST2, are associated with enhanced disease severity in human C. difficile patients.

    • Alyse L. Frisbee
    • , Mahmoud M. Saleh
    •  & William A. Petri Jr.

  • Article
    | Open Access

    Systemic sepsis is a potentially life-threatening illness and immunocompromised individuals are especially vulnerable. Here, using a cohort of patients with intra-abdominal origin sepsis, the authors show an important role for the NLRP3 inflammasome in establishing a host response, and NLRP3 dysfunction is a common feature of sepsis mortality.

    • Juan José Martínez-García
    • , Helios Martínez-Banaclocha
    •  & Pablo Pelegrin

  • Article
    | Open Access

    Human cytomegalovirus (CMV) infects a wide range of host cells. Here, using a high throughput antibody screening platform, the authors identify the cell surface receptor CD46 to be required for CMV infection of epithelial cells and trophoblast-derived cells, the latter critical for congenital CMV infection.

    • Kathryn R. Stein
    • , Thomas J. Gardner
    •  & Domenico Tortorella

  • Article
    | Open Access

    Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme known to affect membrane lipid composition. Here, Mitrofanova et al. show that increased expression of SMPDL3b in diabetes impairs insulin signaling and ceramide-1-phosphate (C1P) availability in podocytes, and that C1P supplementation protects mice from diabetic kidney disease.

    • A. Mitrofanova
    • , S. K. Mallela
    •  & A. Fornoni

  • Article
    | Open Access

    Understanding genomic variation in Plasmodium falciparum parasites and inferring migration patterns can guide malaria elimination strategies. Using genome-wide data for 1722 parasites collected from 54 districts, the authors use identity-by-descent approaches to estimate regional parasite migration and spread of artemisinin drug resistance.

    • Amol C. Shetty
    • , Christopher G. Jacob
    •  & Marie A. Onyamboko

  • Article
    | Open Access

    Men and women differ in their risk of developing coronary artery disease, in part due to differences in their levels of sex hormones. Here, AlSiraj et al. show that the XX sex genotype regulates lipid metabolism and promotes atherosclerosis independently of sex hormones in mice.

    • Yasir AlSiraj
    • , Xuqi Chen
    •  & Lisa A. Cassis

  • Article
    | Open Access

    Disease transmission is particularly complex at the human-livestock-wildlife interface. Here the authors sample E. coli from wild birds near households in Nairobi and show that antimicrobial resistance gene diversity is correlated with human and lifestock density, while virulence gene diversity is correlated with avian species richness.

    • J. M. Hassell
    • , M. J. Ward
    •  & E. M. Fèvre

  • Article
    | Open Access

    Many causative genes are known for epileptic or developmental and epileptic encephalopathies (EE/DEE) yet a genetic diagnosis cannot be made for many patients. Here, the authors analyse whole exome sequencing data from a Japanese case−control cohort to identify common, rare and ultra-rare coding variants associated with EE/DEE.

    • Atsushi Takata
    • , Mitsuko Nakashima
    •  & Naomichi Matsumoto

  • Article
    | Open Access

    Failure to account for heterogeneity in TB risk can mislead model-based evaluation of proposed interventions. Here, the authors introduce a metric to estimate the distribution of risk in populations from routinely collected data and find that variation in infection acquisition is the most impactful.

    • M. Gabriela M. Gomes
    • , Juliane F. Oliveira
    •  & Christian Lienhardt

  • Article
    | Open Access

    Patients with diabetes commonly develop diabetic kidney disease (DKD). Here Gluck et al. identify a set of probes differentially methylated in renal samples from patients with DKD, and find that inclusion of these methylation probes improves current prediction models of renal function decline.

    • Caroline Gluck
    • , Chengxiang Qiu
    •  & Katalin Susztak

  • Article
    | Open Access

    GWAS have identified risk loci for osteoarthritis (OA), but the causal variants still have to be determined. Here, the authors apply a massively-parallel reporter assay to screen 1,605 candidate SNPs in 35 OA loci, which prioritizes six SNPs in four loci, one of which, rs4730222, is characterized in more detail.

    • Jason C. Klein
    • , Aidan Keith
    •  & Jay Shendure

  • Article
    | Open Access

    Fibroadipogenic precursor cells (FAPs) contribute to fibrosis and adipogenic replacement in muscular dystrophies. Here, the authors show that FAPs contribute to adipogenic loss in mouse models of limb girdle muscular dystrophy 2B via a mechanism dependent on expression of Annexin A2, and that this process can be prevented by its pharmacologic inhibition in mice.

    • Marshall W. Hogarth
    • , Aurelia Defour
    •  & Jyoti K. Jaiswal

  • Article
    | Open Access

    Wwp2 is an HECT-type E3 ubiquitin ligase abundantly expressed in articular cartilage. Here, the authors show that in mice, loss of Wwp2 leads to upregulated Runx2-Adamts5 signaling in articular cartilage and development of osteoarthritis, and that disease severity is reduced by injection of Wwp2 mRNA

    • Sho Mokuda
    • , Ryo Nakamichi
    •  & Hiroshi Asahara

  • Article
    | Open Access

    Human antigen R (HuR) is a RNA-binding protein. Here the authors investigate its role in adipose tissue and find that it protects mice from diet-induced obesity, prevents adipocyte hypertrophy, and promotes lipolysis, which may at least in part be due to HuR-dependent ATGL mRNA stability regulation demonstrated in-vitro.

    • Jingyuan Li
    • , Li Gong
    •  & Wencheng Zhang

  • Article
    | Open Access

    Diagnostic filtering is an important step to analyze the functional and clinical significance of the large number of genetic variants identified from next-generation genome sequencing data. Here, the authors develop a flexible and scalable system for diagnostic filtering of genetic variants using G2P with Ensembl VEP.

    • Anja Thormann
    • , Mihail Halachev
    •  & David R. FitzPatrick

  • Article
    | Open Access

    Stabilized, native-like trimers of the HIV envelope protein, such as SOSIP trimers, are potential antigens for an HIV vaccine. Here, the authors generate a SOSIP trimer based on the consensus sequence of group M isolates, determine its structure and exposure of common epitopes, and show immunogenicity in rabbits and non-human primates.

    • Kwinten Sliepen
    • , Byung Woo Han
    •  & Rogier W. Sanders

  • Article
    | Open Access

    Foreign aid is necessary to control tropical diseases in endemic countries. Here the authors outline the steps taken to control malaria in Africa since 2000 and present an economic model to propose that US$25−30 per capita will be needed to avoid a disease trap.

    • Eric Maskin
    • , Célestin Monga
    •  & Jean-Claude Berthélemy

  • Article
    | Open Access

    Malaria on Bioko Island has been reduced substantially but many acquire malaria while traveling. Here, the authors use survey data, geostatistical and mathematical modeling to investigate malaria prevalence and mobility patterns and find that in some parts of the island a significant fraction of prevalence is attributable to malaria acquired while traveling.

    • Carlos A. Guerra
    • , Su Yun Kang
    •  & David L. Smith

  • Article
    | Open Access

    Schistosoma mansoniinfection has been linked with an increased risk of HIV acquisition in women. Here, the authors show that standard S. mansoniinfection treatment causes a reduction of HIV entry into cervical and blood CD4+ T cells, which is sustained for up to two months and is associated with de-repression of IFN-I signaling. 

    • Sergey Yegorov
    • , Vineet Joag
    •  & Rupert Kaul

  • Article
    | Open Access

    Here, the authors determine the respiratory virome and serum cytokine profile in children diagnosed with acute respiratory tract infections (ARTI) and show that relative abundance of Propionibacterium phages as well as serum levels of TIMP-1 and PDGF-BB are increased in multiple ARTIs compared with single ARTI.

    • Yanpeng Li
    • , Xuemin Fu
    •  & Chiyu Zhang

  • Article
    | Open Access

    Complement activation contributes to vascular inflammation in the contexts of allograft rejection and connective tissue disease. Here Fang et al. identify ZFYVE21 as a novel effector of Rab5 and find it regulates pro-inflammatory NF-κB signaling in endothelial cells in response to complement activation.

    • Caodi Fang
    • , Thomas D. Manes
    •  & Dan Jane-wit

  • Article
    | Open Access

    Idiopathic pulmonary fibrosis (IPF) is a lethal disease with insufficient treatment strategies. Here the authors show that reduction of the microRNA MIRLET7D and hyperactivation of EP300 contribute to impaired epigenetic silencing by the MiCEE complex in pulmonary fibroblasts of IPF patients, and demonstrate the benefit of inhibiting EP300 for the treatment of IPF.

    • Karla Rubio
    • , Indrabahadur Singh
    •  & Guillermo Barreto

  • Article
    | Open Access

    Cells of the pulmonary vasculature show a hyperproliferative phenotype in pulmonary arterial hypertension (PAH), thus contributing to the disease pathogenesis. Here the authors show that cyclin-dependent kinases are overactivated in PAH, and that their pharmacological inhibition attenuates the disease in two independent rodent models

    • Astrid Weiss
    • , Moritz Christian Neubauer
    •  & Ralph Theo Schermuly

  • Article
    | Open Access

    Function-altering variants of immune-related genes cause rare autoimmune syndromes, whereas their contribution to common autoimmune diseases remains uncharacterized. Here the authors show that rare variants of lupus-associated genes are present in the majority of lupus patients and healthy controls, but only the variants found in lupus patients alter gene function.

    • Simon H. Jiang
    • , Vicki Athanasopoulos
    •  & Carola G. Vinuesa

  • Article
    | Open Access

    Tissue signals that prime autoreactive T cells at the onset of autoimmunity remain enigmatic. Here the authors show NK and ILC1 cells are increased in vitiligo patients, and induce melanocyte apoptosis via CXCR3B, which in turn leads to increased priming of T cell responses in cell culture.

    • Meri K. Tulic
    • , Elisa Cavazza
    •  & Thierry Passeron

  • Article
    | Open Access

    Streptococcus pneumoniae is a causative agent of meningitis and bacteremia. In a combined pathogen and host GWAS, Lees et al. find that host genetic variation is associated with both susceptibility and severity of pneumococcal meningitis, and specific bacterial genetic variation associated with susceptibility.

    • John A. Lees
    • , Bart Ferwerda
    •  & Diederik van de Beek

  • Article
    | Open Access

    Arthroplasty is the main clinical option for the treatment of osteoarticular lesions, but has limited efficacy. Here, the authors use a wound dressing with autologous mesenchymal stromal cells, functionalised for local BMP2 delivery, and show feasibility and safety in standardised preclinical tests in animal models, suggesting suitability for use in clinical trials.

    • Laetitia Keller
    • , Luc Pijnenburg
    •  & Nadia Benkirane-Jessel

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