Diseases

  • Article
    | Open Access

    Environmental and genetic risk factors affect the distal airway epithelium in idiopatic pulmonary fibrosis (IPF) but the role of the epithelium in IPF remains unclear. Here the authors show that pathologic activation of the ERBB-YAP axis induces dynamic and structural dysfunction in the distal airway epithelium eliciting a pro-fibrotic phenotype in mesenchymal cells.

    • Ian T. Stancil
    • , Jacob E. Michalski
    •  & David A. Schwartz
  • Article
    | Open Access

    Repeating fever is a hallmark of malaria. Here, a large-scale forward genetic screen in malaria-causing Plasmodium falciparum identifies genes associated with parasite tolerance to host fever, including apicoplast targeted isoprenoid biosynthesis—sharing features with artemisinin resistance.

    • Min Zhang
    • , Chengqi Wang
    •  & John H. Adams
  • Article
    | Open Access

    While polygenic risk scores have been shown to be correlated with disease risk, there is little agreement on how the score should be calculated. Here the authors investigate risk scores for Alzheimer’s disease, finding that the most effective approach includes an APOE score and a polygenic score excluding APOE.

    • Ganna Leonenko
    • , Emily Baker
    •  & Valentina Escott-Price
  • Article
    | Open Access

    The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.

    • Cecile Geuijen
    • , Paul Tacken
    •  & Mark Throsby
  • Article
    | Open Access

    3-hydroxy-L-kynurenamine (3-HKA) is a metabolite deriving from a lateral pathway of tryptophan catabolism. Here the authors identify 3-HKA as a biogenic amine and show it has anti-inflammatory properties that can protect mice against psoriasis and nephrotoxic nephritis.

    • Cristina C. Clement
    • , Angelo D’Alessandro
    •  & Laura Santambrogio
  • Article
    | Open Access

    Uncontrolled activation of fibroblasts contributes to tissue fibrosis and organ dysfunction. Here the authors demonstrate that the epigenetic control of autophagy is disturbed by a TGFβ-dependent downregulation of MYST1 in systemic sclerosis patients. Restoration of the epigenetic control of autophagy reduces fibroblast activation and ameliorates fibrotic tissue remodeling.

    • Ariella Zehender
    • , Yi-Nan Li
    •  & Jörg H. W. Distler
  • Article
    | Open Access

    Different types of mesenchymal progenitors participate in ectopic bone formation. Here, the authors show Col2+ lineage cells adopt a lymphatic endothelium cell fate, which regulates local inflammatory microenvironment after trauma, thus influencing heterotopic ossification (HO) development via a FGFR3-BMPR1a pathway.

    • Dali Zhang
    • , Junlan Huang
    •  & Yangli Xie
  • Article
    | Open Access

    Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.

    • Kira J. Stanzick
    • , Yong Li
    •  & Thomas W. Winkler
  • Article
    | Open Access

    A SNP distant from the human insulin (INS) gene near the KRTAP5-6 gene confers increased susceptibility to type 2 diabetes when present on the paternal allele while decreased susceptibility when on the maternal allele. Here the authors show that long-range contacts between the INS locus and the KRTAP5-6 gene locus distinguish paternal and maternal alleles.

    • Xing Jian
    •  & Gary Felsenfeld
  • Article
    | Open Access

    Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients.

    • Linh T. Bui
    • , Nichelle I. Winters
    •  & Laure Emmanuelle Zaragosi
  • Article
    | Open Access

    Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.

    • Toshiko Yamazawa
    • , Takuya Kobayashi
    •  & Takashi Murayama
  • Article
    | Open Access

    RIFINs are Plasmodium surface antigens that suppress the immune response by binding inhibitory receptors such as LAIR1. Here, Xu et al. characterize the interaction between RIFIN-variable 2 domain and a LAIR1 domain and identify LAIR1-binding RIFINs in several Plasmodium species.

    • Kai Xu
    • , Yiran Wang
    •  & Peter D. Kwong
  • Article
    | Open Access

    The genomic characterisation of nasopharyngeal carcinoma (NPC) remains crucial. Here, the authors perform whole-genome sequencing for 70 NPCs with EBV gene expression, report the somatic alterations and EBV-mediated effects converging on NF-κB activation and immune escape and identify targetable homozygous MTAP deletions.

    • Jeff P. Bruce
    • , Ka-Fai To
    •  & Kwok-Wai Lo
  • Article
    | Open Access

    Plasmodium vivax generally accounts for a low proportion of malaria cases in Africa, but population-level data on the distribution of infections is limited. Here, the authors use data from the Democratic Republic of the Congo and show that the prevalence is low (~3%) and diffusely spread.

    • Nicholas F. Brazeau
    • , Cedar L. Mitchell
    •  & Jonathan J. Juliano
  • Article
    | Open Access

    Many domestic animals, among them dogs, have been infected with SARS-CoV-2 during the COVID-19 pandemic. Here, the authors present the crystal structure of the SARS-CoV-2 spike protein receptor binding domain (RBD) bound to its receptor, dog angiotensin-converting enzyme 2 (dACE2), and show that the RBD N501Y mutation increases the infectivity and host range of SARS-CoV-2, which highlights the need to monitor emerging SARS-CoV-2 mutations in domestic animals.

    • Zengyuan Zhang
    • , Yanfang Zhang
    •  & Yeping Sun
  • Article
    | Open Access

    Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.

    • Yoshiaki Ito
    • , Tokio Matsuzaki
    •  & Hiroshi Asahara
  • Article
    | Open Access

    Chromosomal translocations involving the AF10 gene, especially with CALM, are associated with aggressive leukemias. Here the authors show that the PZP domain of AF10, a histone reader, is always excluded/impaired in AF10 fusions, whereas incorporation of this domain downregulates Hoxa genes and blocks leukemogenesis.

    • Brianna J. Klein
    • , Anagha Deshpande
    •  & Tatiana G. Kutateladze
  • Article
    | Open Access

    T cells are instrumental to protective immune responses against SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic. Here the authors show that, in convalescent COVID-19 patients, memory T cell responses are detectable up to 317 days post-symptom onset, in which the presence of stem cell-like memory T cells further hints long-lasting immunity.

    • Jae Hyung Jung
    • , Min-Seok Rha
    •  & Eui-Cheol Shin
  • Article
    | Open Access

    Iron is essential during pregnancy for embryo and placental development and maternal health. However, in this study using mouse models, the authors demonstrate that excess maternal iron causes adverse embryo outcomes in pregnancies with underlying systemic inflammation.

    • Allison L. Fisher
    • , Veena Sangkhae
    •  & Elizabeta Nemeth
  • Article
    | Open Access

    Current HIV cure-focused clinical trials rely on analytic treatment interruption (ATI) to evaluate post-treatment control (PTC). Here, combining untargetted metabolomics and glycomics in two HIV clinical cohorts, in vitro assays, and machine learning, the authors identify and validate metabolic and glycomic biomarkers linked to inflammatory pathways and HIV latency reactivation associated with PTC, suggesting non-invasive biomarkers as an alternative to predict HIV remission.

    • Leila B. Giron
    • , Clovis S. Palmer
    •  & Mohamed Abdel-Mohsen
  • Article
    | Open Access

    Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.

    • Min-A Jhun
    • , Michael Mendelson
    •  & Themistocles L. Assimes
  • Article
    | Open Access

    Release of freshwater into the oceans as a result of ice sheet melting could impact the distribution of climate-sensitive diseases. Here, the authors show that a rapid ice sheet melting in Greenland could cause an emergence of malaria in Southern Africa whilst transmission risks in West Africa may decline.

    • Alizée Chemison
    • , Gilles Ramstein
    •  & Cyril Caminade
  • Article
    | Open Access

    Human Treg cells are central to immune tolerance, yet their heterogeneity and differentiation remain incompletely understood. Here the authors perform single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease revealing Treg complexity in health and disease.

    • Yuechen Luo
    • , Changlu Xu
    •  & Xiaoming Feng
  • Article
    | Open Access

    Resistance of Neisseria gonorrhoeae to extended spectrum cephalosporins is an increasing concern. Here, the authors conduct whole genome sequencing of isolates from the United States and find that most resistant isolates were associated with a persistent circulating lineage.

    • Jesse C. Thomas IV
    • , Sandeep J. Joseph
    •  & Zach Perry
  • Article
    | Open Access

    Applying complexome profiling, Evers et al. unravel the composition of mitochondrial oxidative phosphorylation complexes in P. falciparum asexual and sexual blood stages. Abundance of these complexes differs between both stages, supporting the hypothesis that a mitochondrial metabolic switch is central to gametocyte development and functioning.

    • Felix Evers
    • , Alfredo Cabrera-Orefice
    •  & Taco W. A. Kooij
  • Article
    | Open Access

    Selection of COVID-19 mitigation measures requires balancing health outcomes with economic impacts. Here, the authors derive a system to set triggers for increasing mitigation measures to preserve healthcare capacity, and describe how it has been used to support public health decision making in Austin, Texas.

    • Haoxiang Yang
    • , Özge Sürer
    •  & Lauren Ancel Meyers
  • Article
    | Open Access

    Pernicious anemia shows co-incidence with autoimmune disorders, yet the genetic basis for this condition is understudied. Here, the authors perform a genome-wide association study meta-analysis on pernicious anemia, identifying five susceptibility loci that map to genes with known roles in autoimmune disease.

    • Triin Laisk
    • , Maarja Lepamets
    •  & Reedik Mägi
  • Article
    | Open Access

    Estimating the effectiveness of COVID-19 control measures requires large prospective data including symptoms and personal risk factors. Here, the authors used data from smartphone-based application and found that individual face mask use was associated with a 64% reduced risk of COVID-19 symptoms.

    • Sohee Kwon
    • , Amit D. Joshi
    •  & Andrew T. Chan
  • Article
    | Open Access

    Keratitis is the main cause of corneal blindness worldwide, but most vision loss caused by keratitis can be avoidable via early detection and treatment, which are challenging in resource-limited settings. Here, the authors develop a deep learning system for the automated classification of keratitis and other cornea abnormalities.

    • Zhongwen Li
    • , Jiewei Jiang
    •  & Wei Chen
  • Article
    | Open Access

    Rapid, accurate and specific point-of-care diagnostics can help manage and contain fast-spreading infections. Here, the authors present a nanopore-based system that uses artificial intelligence to discriminate between four coronaviruses in saliva, with little need for sample pre-processing.

    • Masateru Taniguchi
    • , Shohei Minami
    •  & Kazunori Tomono
  • Article
    | Open Access

    Base editing is one approach used to correct mutations causing cause Duchenne muscular dystrophy (DMD), but limitations are in the requirement for a specific PAM motif and the large size beyond the packaging capacity of adeno-associated virus (AAV). Here, the authors modify the NG-targeting adenine base editor to recognize a broader PAM, devise an intein split strategy to package the otherwise oversized adenine base editor into AAV, and show it efficiently restores dystrophin expression in muscle and heart when systemically injected in a mouse model of DMD

    • Li Xu
    • , Chen Zhang
    •  & Renzhi Han
  • Article
    | Open Access

    To provide in depth characterization of HIV reservoir cells, the authors here develop a single-cell approach to simultaneously sequence TCR, integration sites and proviral genomes, called STIP-Seq, and show that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5’-end of the genome.

    • Basiel Cole
    • , Laurens Lambrechts
    •  & Linos Vandekerckhove
  • Article
    | Open Access

    A central problem in the COVID-19 pandemic is that there is not enough testing to prevent infectious spread of SARS-CoV-2, causing surges and lockdowns with human and economic toll. Here, the authors evaluate an alternative strategy based on the monitoring of olfactory dysfunction with a mathematical model.

    • Daniel B. Larremore
    • , Derek Toomre
    •  & Roy Parker
  • Article
    | Open Access

    SARS-CoV-2 3CL protease (3CLpro) is essential for coronavirus replication and of great interest as an antiviral drug target. Here, the authors show that the naturally occurring flavonoid myricetin is a non-peptidomimetic and covalent inhibitor of 3CLpro, and they solve crystal structures of 3CLpro with myricetin and derivatives, which reveal that the pyrogallol group covalently modifies the catalytic cysteine.

    • Haixia Su
    • , Sheng Yao
    •  & Yechun Xu
  • Article
    | Open Access

    Yellow fever virus (YFV) is an arbovirus affecting humans and non-human primates (NHPs) with seasonal transmission. Here Hamlet et al. model the monthly occurrence of YF in humans and NHPs across Brazil and show that seasonality of agriculture is an important predictor of seasonal YF transmission.

    • Arran Hamlet
    • , Daniel Garkauskas Ramos
    •  & Neil M. Ferguson
  • Article
    | Open Access

    Disentangling the impacts of non-pharmaceutical interventions on COVID-19 transmission is challenging as they have been used in different combinations across time and space. This study shows that, early in the epidemic, school/daycare closures and stopping nursing home visits were associated with the biggest reduction in transmission in the United States.

    • Bingyi Yang
    • , Angkana T. Huang
    •  & Derek A. T. Cummings
  • Article
    | Open Access

    Population-based surveys are the gold standard for estimating seroprevalence but are expensive and often only capture a small geographic area or window of time. This study describes a new platform, SCALE-IT, for serosurveillance based on algorithmic sampling of electronic health records, and uses it to estimate the seroprevalence of SARS-CoV-2 in San Francisco.

    • Isobel Routledge
    • , Adrienne Epstein
    •  & Isabel Rodriguez-Barraquer