Diseases

  • Article
    | Open Access

    The timely hepatitis B birth dose vaccination is recommended for all new-borns by the WHO, but coverage is inconsistent. Here, the authors model the impact of scaling-up coverage in 110 low and middle income countries and assess how it may be affected by delays for example caused by the COVID-19 pandemic.

    • Margaret J. de Villiers
    • , Shevanthi Nayagam
    •  & Timothy B. Hallett
  • Article
    | Open Access

    Caloric restriction (CR) has been shown as an effective intervention to reduce tumorigenesis, but alternative less stringent dietary interventions have also been considered. Here, the authors show that in a murine model of breast cancer CR has a larger effect on preventing tumorigenesis and metastasis compared to periodic caloric cycling.

    • Laura C. D. Pomatto-Watson
    • , Monica Bodogai
    •  & Rafael de Cabo
  • Article
    | Open Access

    Pulmonary hypertension is characterized by increased pulmonary arterial pressure, driven in part by inflammatory infiltrates. Here, the authors show that in mice, transgenic expression of mutant JAK2 leads to clonal hematopoiesis and lung accumulation of elastase- and cytokine-expressing neutrophils, and that the phenotype can be reversed by ALK1 inhibition.

    • Yusuke Kimishima
    • , Tomofumi Misaka
    •  & Yasuchika Takeishi
  • 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

    Drug target Mendelian randomization (MR) uses genetic variation in or near a gene encoding a drug target to anticipate the effect of drug action on the same target. Using drug target MR, the authors prioritized 30 targets that might elicit beneficial effects in the prevention or treatment of coronary heart disease.

    • María Gordillo-Marañón
    • , Magdalena Zwierzyna
    •  & Chris Finan
  • Article
    | Open Access

    Sofosbuvir is a common therapy in hepatitis C virus infection, which targets the NS5B polymerase. Here, Smith et al. analyze the association between whole genome HCV polymorphisms and sofosbuvir treatment failure and identify three common polymorphisms present in non-targeted NS2 and NS3 proteins associated with reduced treatment response.

    • David A. Smith
    • , Carlota Fernandez-Antunez
    •  & M. Azim Ansari
  • Article
    | Open Access

    TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.

    • Morten Tulstrup
    • , Mette Soerensen
    •  & Kirsten Grønbæk
  • Article
    | Open Access

    Azacitidine (AZA) treatment is used for patients with myelodysplasias that cannot undergo bone marrow transplantation; however, AZA treatment is only partially effective. Here the authors show synergy of AZA with compounds inhibiting the chromatin regulators CBP and p300, which is mediated by the RNA-dependent functions of AZA affecting protein translation.

    • Jeannine Diesch
    • , Marguerite-Marie Le Pannérer
    •  & Marcus Buschbeck
  • Article
    | Open Access

    Primary congenital glaucoma (PCG) is characterised by increased intraocular pressure, and variants in ANGPT1, or SVEP1 have been identified as risk alleles. Here, the authors show that deletion of these genes induces glaucoma in mice, and that activation of ANGPT1-TEK signaling ameliorates disease progression in mouse models.

    • Benjamin R. Thomson
    • , Pan Liu
    •  & Susan E. Quaggin
  • Article
    | Open Access

    Fibromuscular dysplasia is a cardiovascular disease affecting mostly women with a mostly unknown genetic basis. Here the authors have performed a genome-wide association meta-analysis of Fibromuscular dysplasia to identify genetic loci, some of which are shared with common cardiovascular disease and traits.

    • Adrien Georges
    • , Min-Lee Yang
    •  & Nabila Bouatia-Naji
  • Article
    | Open Access

    The immune response to herpes simplex virus is essential in limiting immunopathology during infection, however factors linked to neuroprotection are currently unclear. Here the authors implicate mTORC2 in the host response to viral infection and link to neuroprotection.

    • Rahul K. Suryawanshi
    • , Chandrashekhar D. Patil
    •  & Deepak Shukla
  • Article
    | Open Access

    Clonal haematopoiesis (CH) has been associated with altered inflammatory profiles and increased risk of cardiovascular and malignant diseases. Here, the authors analyze patient data from two different cohorts and show that CH is associated with severe infections and severe Covid19.

    • Kelly L. Bolton
    • , Youngil Koh
    •  & Ahmet Zehir
  • Article
    | Open Access

    ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidenephosphatidylethanolamine (N-Ret-PE) to the cytoplasmic leaflet of photoreceptor membranes. ABCA4 mutations are associated with loss of vision. Here, structures of ABCA4 with and without substrate bound provide insight into N-Ret-PE binding and suggest a lateral access mechanism.

    • Jessica Fernandes Scortecci
    • , Laurie L. Molday
    •  & Robert S. Molday
  • Article
    | Open Access

    Cilia, tiny outgrowths of cells, are essential for life. Here, the author’s describe the scaffold protein TRIP6, which promotes the assembly of ciliary proteins required for ciliogenesis, and show that its absence results in hydrocephalus.

    • Shalmali Shukla
    • , Ronny Haenold
    •  & Peter Herrlich
  • Article
    | Open Access

    Many African countries have reported relatively low numbers of COVID-19 cases but the true scale of the epidemic is unclear. Here, the authors conduct a population-based survey in a province of Cameroon and estimate 29% seroprevlance, >300 fold higher than the nationwide attack rate implied by case counts.

    • Kene Nwosu
    • , Joseph Fokam
    •  & Laura Ciaffi
  • Article
    | Open Access

    Cell encapsulation into biomaterials for transplantation is currently limited by inadequate oxygenation. Here the authors present a biomimetic scaffold featuring internal continuous air channels endowed with 10,000-fold higher O2 diffusivity than hydrogels and demonstrate correction of diabetes in immunocompetent mice using rat islets for over 6 months.

    • Long-Hai Wang
    • , Alexander Ulrich Ernst
    •  & Minglin Ma
  • Article
    | Open Access

    Lassa Fever is a rodent-borne viral haemorrhagic fever that is a public health problem in West Africa. Here, the authors develop a spatiotemporal model of the socioecological drivers of disease using surveillance data from Nigeria, and find evidence of climate sensitivity.

    • David W. Redding
    • , Rory Gibb
    •  & Chikwe Ihekweazu
  • Article
    | Open Access

    Antibodies (Abs) targeting highly conserved epitopes are important tools against emerging virus variants. Here, the authors characterize Abs that recognize a cryptic epitope in the receptor-binding domain of SARS-CoV-2 spike that is well conserved and show that these Abs can neutralize several variants of concerns.

    • Tingting Li
    • , Wenhui Xue
    •  & Ningshao Xia
  • Article
    | Open Access

    Only a subset of triple negative breast cancer patients respond to immunotherapy. Here, the authors analysed spatial immune contextures, which can be captured by a gene classifier, in relation to genomic alterations, mechanisms of T cell evasion and response to anti-PD1 treatment.

    • Dora Hammerl
    • , John W. M. Martens
    •  & Reno Debets
  • Article
    | Open Access

    Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.

    • Amand F. Schmidt
    • , Nicholas B. Hunt
    •  & Chris Finan
  • Article
    | Open Access

    Current high-throughput single-cell transcriptomic methods are incompatible with paraformaldehyde, a common cell fixation technique. Here the authors present FD-seq, a method for droplet-based RNA sequencing of paraformaldehyde-fixed, stained and sorted single cells.

    • Hoang Van Phan
    • , Michiel van Gent
    •  & Savaş Tay
  • Article
    | Open Access

    There has been limited research on the role of the mucosal immune response to SARS-CoV-2 infection. Here, the authors perform a prospective observational household study and find that mucosal antibody responses are associated with decreased viral load and faster resolution of systemic symptoms.

    • Janeri Fröberg
    • , Joshua Gillard
    •  & Dimitri A. Diavatopoulos
  • Article
    | Open Access

    The Cia21 locus on chromosome 3 has been associated with rheumatoid arthritis severity in females. Here the authors show this locus houses a non-coding polymorphic estrogen receptor binding site and how it regulates neighbouring gene expression of CD2, implicating CD2 signalling in the sexual dimorphism of a variety of T cell-dependent autoimmune diseases.

    • Gonzalo Fernandez Lahore
    • , Michael Förster
    •  & Rikard Holmdahl
  • Article
    | Open Access

    Rift Valley fever is a zoonotic haemorrhagic fever with complex transmission dynamics influenced by environmental variables and animal movements. Here, the authors develop a metapopulation model incorporating these factors and use it to identify the main drivers of transmission in the Comoros archipelago.

    • Warren S. D. Tennant
    • , Eric Cardinale
    •  & Raphaëlle Métras
  • Article
    | Open Access

    A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates

    • Tanya E. Keenan
    • , Jennifer L. Guerriero
    •  & Sara M. Tolaney
  • Article
    | Open Access

    Inherited disorders of neurotransmitter metabolism represent a group of rare neurometabolic diseases characterized by movement disorders and developmental delay. Here, the authors report a standardized evaluation of a registry of 275 patients from 42 countries, and highlight an evolving phenotypic spectrum of this disease group and factors influencing diagnostic processes.

    • Oya Kuseyri Hübschmann
    • , Gabriella Horvath
    •  & Thomas Opladen
  • Article
    | Open Access

    Here, Kodama et al. describe the discovery, isolation and characterization of a novel tick-borne orthonairovirus, designated Yezo virus (YEZV), from patients with an acute febrile illness in Japan. Serological testing of wildlife and molecular screening of ticks suggest an endemic circulation of YEZV in Japan.

    • Fumihiro Kodama
    • , Hiroki Yamaguchi
    •  & Keita Matsuno
  • Article
    | Open Access

    Here, Shaban et al. show that coronaviruses modulate ER stress and the unfolded protein response. The ER stress inducer thapsigargin exerts potent antiviral effects, partially reverses the virus-induced translational shut-down, reprograms the host proteome and suppresses autophagic flux, thereby inhibiting coronavirus replication at multiple levels.

    • Mohammed Samer Shaban
    • , Christin Müller
    •  & Michael Kracht
  • Article
    | Open Access

    Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.

    • Emilie Crouchet
    • , Simonetta Bandiera
    •  & Thomas F. Baumert
  • Article
    | Open Access

    Dual-energy X-ray absorptiometry and the Fracture Risk Assessment Tool are recommended tools for osteoporotic fracture risk evaluation, but are underutilized. Here, the authors present an opportunistic tool to identify fractures, predict bone mineral density and evaluate fracture risk using plain pelvis and lumbar spine radiographs.

    • Chen-I Hsieh
    • , Kang Zheng
    •  & Chang-Fu Kuo
  • Article
    | Open Access

    Antiretroviral therapy (ART) for the treatment of HIV-1 requires life-long daily adherence to supress viral replication, and nucleoside reverse transcriptase inhibitors that are commonly used in ART have not been converted into long-acting agents. Here, the authors report two lipophilic tenofovir (TVF) ProTide nanoformulations, NM1TFV and NM2TFV, which sustain drug levels above therapeutic concentrations for two months after a single intramuscular dose in rats.

    • Denise A. Cobb
    • , Nathan Smith
    •  & Benson Edagwa
  • Article
    | Open Access

    During herpesvirus infection, most individuals intrinsically suppress a primary infection and therewith preclude potential damage or neurodegeneration of the CNS. Here, Ames et al. show that Optineurin (OPTN), a conserved autophagy receptor, restricts HSV-1 spread, degrades viral VP16 through autophagy and is neuroprotective against HSV infection in vivo.

    • Joshua Ames
    • , Tejabhiram Yadavalli
    •  & Deepak Shukla
  • Article
    | Open Access

    Newly emerged pathogens are inherently difficult to forecast, due to many unknowns about their biology early in an epidemic. Here, the authors assess forecasts of a suite of models during the Zika epidemic in Colombia, finding that the models that performed best changed over the course of the epidemic.

    • Rachel J. Oidtman
    • , Elisa Omodei
    •  & T. Alex Perkins
  • Article
    | Open Access

    Distal-less homeobox 1 (DLX1) is reported as a prostate cancer (PCa) diagnostic biomarker, but the mechanism for its upregulation in PCa is unclear. Here the authors show that ERG, AR and FOXA1 transcriptionally regulates DLX1 expression in PCa, and the inhibition of this ERG/AR transcriptional circuitry with a BET inhibitor reduces the oncogenic effects of DLX1.

    • Sakshi Goel
    • , Vipul Bhatia
    •  & Bushra Ateeq
  • Article
    | Open Access

    Tissue circadian clocks contribute to the regulation of physiology and metabolism. Here the authors investigate the role of the intestinal circadian clock in energy homeostasis and show that the intestinal clock acts as an accelerator in dietary fat absorption.

    • Fangjun Yu
    • , Zhigang Wang
    •  & Baojian Wu
  • Article
    | Open Access

    Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci often harbor multiple functional variants.

    • Amelia C. Joslin
    • , Débora R. Sobreira
    •  & Marcelo A. Nóbrega
  • Article
    | Open Access

    Nuclear import receptors (NIRs) regulate self-association of RNA-binding proteins as phase modifiers, while C9orf72-derived arginine-rich polydipeptides lead to aberrant phase transitions. Here the authors show in molecular basis how arginine-rich poly-dipeptides impede the ability of NIRs, particularly Kapβ2.

    • Hitoki Nanaura
    • , Honoka Kawamukai
    •  & Eiichiro Mori
  • Article
    | Open Access

    The authors provide a comprehensive, single base resolution view of association between genetic variation and DNA methylation in human brain. They also show that heritability attributed to schizophrenia GWAS-associated variants reflects the epigenetic plasticity of the brain.

    • Kira A. Perzel Mandell
    • , Nicholas J. Eagles
    •  & Andrew E. Jaffe