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Fatty liver disease exacerbates atherosclerosis, but the underlying mechanisms remain unclear. Here, the authors show that D-dopachrome tautomerase (D-DT/MIF-2) acts as an atypical chemokine, promoting both atherosclerosis and hepatic lipid accumulation.

Increased river incision and landscape erosion can be attributed to late Cenozoic cooling/changes in hydroclimate, according to cosmogenic isotope and luminescence ages of a sequence of bedrock terraces in the Yukon River basin.

Better approaches are crucial to improve identification of people with active tuberculosis (TB), accelerate treatment and curtail disease transmission. A randomized trial suggests that a mobile clinic using DNA-based diagnosis is one such tool to reduce time to treatment of individuals with TB.

Single-cell profiling studies of the human gastrointestinal tract are increasing, offering an excellent opportunity to generate the first Human Gut Cell Atlas. This Roadmap presents a structured direction towards this goal and provides a detailed overview of the major challenges.

Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3.

Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

Large peatlands exist at high latitudes because flooded conditions and cold temperatures slow decomposition, so the presence of (sub)tropical peat is enigmatic. Here the authors show that low-latitude peat is preserved due to lower carbohydrate and greater aromatic content resulting in chemical recalcitrance.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Mammalian gene silencing is associated with both histone and DNA methylation. The PRMT5 arginine histone methyltransferase is now found to affect DNA methylation at the γ-globin locus in mice. This is mediated by an effect on recruitment of the DNA methyltransferase DNMT3A, but through interaction with the product of PRMT5 activity. This suggests that DNMT3A reads the histone methylation, coupling it to nearby DNA methylation.

Unravelling the molecular basis of hypertension remains a major challenge. Here, the authors identify the transcription factor GATA5 as a novel regulator of blood pressure and potential genetic determinant of human hypertension and describe a unique mouse model for research of salt-sensitive hypertension.

A new method to trace the lineage of slow cycling label-retaining cells (LRCs) in vivo identifies a population of LRCs that have features of committed Paneth cells but still express stem-cell markers such as Lgr5; the slow cycling cells differentiate into Paneth cells without cell division, but after injury can also repopulate the stem-cell niche and contribute to the regeneration of all intestinal lineages.

S1PR3 is a G protein coupled receptor, that has a role in inflammation. Here the authors show that in the CNS, S1PR3 may contribute to resilience to stressful experiences; resilient rodents show elevated S1pr3, and knockdown results in greater susceptibility to stress.

A paleogenome from an approximately 100,000-year-old polar bear shows massive prehistoric, and largely unidirectional, gene flow from polar bears into brown bears at a time of climate change-induced overlap in the ranges of the two species. This admixture event cannot be detected using genomic data from living polar bears.

The Trans-ABySS pipeline is an integrated approach for transcript assembly and analysis to identify new mRNA isoforms and structures.

Whole-exome sequencing of 250 parent–offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder.

Activation of mucosal-associated invariant T (MAIT) cells is shown to require key genes encoding an early intermediate in bacterial riboflavin synthesis, 5-amino-6-d-ribitylaminouracil; this reacts non-enzymatically with metabolites to form short-lived antigens that are captured and stabilized by MR1 for presentation to MAIT cells.

To address the question of whether a recurrent tumour is genetically similar to the tumour at diagnosis, the evolution of medulloblastoma has been studied in both an in vivo mouse model of clinical tumour therapy as well as in humans with recurrent disease; targeted tumour therapies are usually based on targets present in the tumour at diagnosis but the results from this study indicate that post-treatment recurring tumours (compared with the tumour at diagnosis) have undergone substantial clonal divergence of the initial dominant tumour clone.

Comprehensive analyses of 178 lung squamous cell carcinomas by The Cancer Genome Atlas project show that the tumour type is characterized by complex genomic alterations, with statistically recurrent mutations in 11 genes, including TP53 in nearly all samples; a potential therapeutic target is identified in most of the samples studied.

The hormone prolactin is a known modulator of mammalian lactation and hair growth. Here, the authors describe two dominant mutations in bovine prolactin and its receptor, demonstrating antagonistic effects on these traits and highlighting a role for this pathway in sweat gland function and thermoregulation.

T-cell receptors expressed on mucosal-associated invariant T cells function in a similar manner to innate immune receptors by recognizing small molecules such as microbial metabolites. Here, the authors report structures of this receptor in complex with vitamin B metabolites presented by the MHC-like protein MR1.

The contribution of astrocytic Ca²⁺ signaling to the modulation of sensory transmission in different brain states remains largely unknown. Here, the authors show two types of Ca²⁺ signals in the mouse barrel cortex with distinct function in sensory transmission during sleep and arousal states.

The CONSORT-AI extension was developed to provide specific guidance for randomised controlled trials involving Artificial Intelligence (AI) interventions. Here, the authors show that since publication of CONSORT-AI, several AI-specific considerations remain systematically underreported.

V-___domain immunoglobulin suppressor of T cell activation (VISTA) selectively engages P-selectin glycoprotein ligand-1 (PSGL-1) and suppresses T cells at acidic pH similar to those in tumour microenvironments, thereby mediating resistance to anti-tumour immune responses.

The validation and analysis of X-ray crystallographic data is essential for reproducibility and the development of crystallographic methods. Here, the authors describe a repository for crystallographic datasets and demonstrate some of the ways it could serve the crystallographic community.

Pumas are experiencing increased isolation as human persecution and habitat loss fragment the populations of this once widespread species. Here, the authors estimate the genomic consequences of this isolation by analyzing the genomes of ten pumas from across North and South America.

This study reports a global analysis of binding sites for over 200 RNA-binding proteins (RBPs) from 24 species; conserved RNA-binding motifs are identified, and their analysis allows prediction of interaction sites based on the sequence of the RNA-binding ___domain alone.

The structure of the major histocompatibility complex (MHC)-class-I-like molecule MR1 in complex with a vitamin B9 derivative is determined; metabolites of vitamin B2 are shown to activate MR1-restricted mucosal-associated invariant T cells, implicating them in microbial immunosurveillance.

The mode by which NK cell receptors are bound to their ligands has been unclear. Rossjohn and colleagues show that the cytomegalovirus immunoevasin m157 binds the NK cell receptor Ly49 by its stalk region and not via the expected membrane-distal lectin ___domain.

FLOWERING LOCUS T is an important mobile signal that regulates plant development and flowering. In this study, Lee et al. demonstrate that multiple FLOWERING LOCUS Tgenes are involved in onion flowering and bulb formation.

Mucosal associated invariant T (MAIT) cells have been implicated in antibacterial responses. Here the authors show MAIT cells confer IFN-γ-mediated protection from lethal infection in a mouse model of Legionella infection, which can be enhanced by synthetic MR1 ligands.

Mucosal-associated invariant T cells recognize vitamin-B-derived ligands presented via the major-histocompatibility-complex-like molecule MR1. Rossjohn and colleagues demonstrate that these cells recognize a wide variety of ligands, some derived from common drugs, in an agonist or antagonist manner.

Alternative expression analysis by sequencing (ALEXA-seq) aligns RNA-seq reads from different cell types to a database of alternative expression sequence features and quantifies isoforms that are differentially expressed between samples.

Acne vulgarisis a common, inflammatory skin disorder. Here the authors carry out a genome-wide association study and identify three genetic variants that associate with an increased risk of developing acne, which together suggest a mechanistic role for the TGFβ cell signalling pathway in acne development and progression.

Marco Marra and colleagues identify somatic mutations in EZH2 in diffuse large B-cell lymphomas and follicular lymphomas. EZH2 is a histone methyltransferase that participates in trimethylation of H3 Lys27 (H3K27) as part of the PRC2 complex. The mutations alter a single tyrosine residue in the SET ___domain of EZH2 and reduce the ability of PRC2 to trimethylate H3K27 in vitro.

Marra and colleagues describe POG570, a pan-cancer, whole-genome, transcriptome and clinical dataset stressing the molecular interactions in advanced and post-therapy cancer patients.

Using unique barcodes for tumour cells, the authors explore the dynamics of human glioblastoma subpopulations, and suggest that clonal heterogeneity emerges through stochastic fate decisions of a neutral proliferative hierarchy.

Tarpey et al. carry out a large-scale systematic sequencing of the majority of X-chromosome coding exons from 208 families with multiple individuals with mental retardation and a pattern of transmission compatible with X linkage in order to identify XLMR-causative mutations. They find several mutations that appear to be causative in loci already known to be involved in XLMR, as well as new data about those loci, and make inferences about the role of the different classes of variants in these diseases.

Acne vulgaris is a chronic inflammation of the skin, the genetic basis of which is incompletely understood. Here, Petridis et al. perform GWAS and meta-analysis for acne in 26,722 individuals and identify 12 novel risk loci that implicate structure and maintenance of the skin in severe acne risk.

tRNA function and gene expression profiles are dynamically regulated by post-transcriptional tRNA modifications. Here, Orellana et al. discuss the canonical role of tRNAs in mRNA translation, focusing on alterations in tRNA abundance or function implicated in human diseases.

John Maris, Matthew Meyerson, Marco Marra and colleagues report results of a large-scale sequencing study of neuroblastoma. They observe a low median exonic mutation frequency and strikingly few recurrently mutated genes in these tumors, highlighting challenges for developing targeted therapeutic strategies based on frequently mutated oncogenic drivers.

Michael Taylor, Marco Marra and colleagues analyze spatial tumor heterogeneity in 9 medulloblastomas, 16 high-grade gliomas and 10 renal cell carcinomas, using a combination of transcriptomic and genomic profiling of multiregional biopsies. They find that medulloblastomas have spatially homogeneous transcriptomes, whereas somatic mutations that affect genes suitable for targeted therapeutics are spatially heterogeneous.