Search

A rare variant burden analytical framework for Mendelian diseases was developed and applied to data from the 100,000 Genomes Project, identifying 69 probable new disease–gene associations.

HEV-specific antiviral treatment is still lacking. Here, the authors functionally and structurally characterize broadly neutralizing antibodies isolated from HEV convalescent individuals and show that they have protective effects in human liver-chimeric mice infected with HEV.

Using a globally distributed standardized aerial sampling of fungal spores, we show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude.

Using cryo-electron microscopy, heteromeric amyloid filaments composed of TDP-43 and ANXA11 in the brains of patients with frontotemporal lobar degeneration type C are discovered.

As healthcare professionals, scientists and educators, our intent is to empower people affected by diabetes mellitus; however, if our language is stigmatizing, our impact might be disempowerment. If we do not choose our words with care, we risk undermining the very autonomy we seek to promote.

Genome-wide association meta-analysis of AAA identifies 121 independent risk loci and highlights potential therapeutic targets such as proprotein convertase, subtilisin/kexin-type 9 (PCSK9).

Recurrent sporadic mutations are important risk factors for autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, Eichler, Xia and colleagues analyse risk genes in a large Chinese ASD cohort and find novel recurrences of potential pathogenic significance.

Analysis of transplantation of single haematopoietic stem cells in mice defines stable lineage-restricted fates in long-term self-renewing multipotent stem cells, including a class of multipotent stem cells that exclusively replenishes the megakaryocyte/platelet lineage.

The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.

USP30 has been proposed to regulate mitophagy, a relevant Parkinson’s disease mechanism. Here, the authors show that Usp30 knockout mice and USP30 inhibitors like MTX115325 demonstrate neuroprotective responses in an alpha-synuclein mouse model of Parkinson’s disease.

Planting trees in high-latitude regions can be counterproductive to climate change mitigation, according to a synthesis of the biophysical and ecological impacts of planting trees.

Erosion rates and ice cover extent of present day fjords and summit plateau landscapes beyond the last deglaciation are virtually unknown. Here, the authors constrain the long-term denudation rates and glaciation history in west Greenland based on cosmogenic nuclides.

Autologous transgenic epidermal stem cell cultures are used to reconstitute almost the entire epidermis of a patient with severe junctional epidermolysis bullosa.

A systematic review of evidence, across the key pillars of prevention, diagnosis, treatment and prognosis, outlines milestones that need to be met to enable the broad clinical implementation of precision medicine in diabetes care.

Jacobsen, Sherr et al. evaluate the utility of novel technologies in the treatment of type 1 diabetes. Their systematic review finds technologies such as continuous glucose monitoring, insulin pumps, and decision support tools improve important measures (e.g., HbA1c, time in range, quality of life) allowing precision-directed uptake of technology.

In a study of children with high genetic risk aged 2 years or older, a risk score integrating pancreatic islet autoantibodies, genetic factors and family history is highly predictive of type 1 diabetes in the subsequent 8 years.

Here the authors generate a capsid-like particle based vaccine candidate displaying the receptor-binding domain of the SARS-CoV-2 spike protein and show induction of neutralizing antibodies after intramuscular prime-boost immunization in mice.

The identification of a functionally distinct subset of haematopoietic stem cells (HSCs) that is primed for platelet-specific gene expression is described; the cells frequently have long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs, and may enable the design of therapies for enhancing platelet reconstitution.

The genetic basis of metabolic diseases is incompletely understood. Here, by high-throughput phenotyping of 2,016 knockout mouse strains, Rozman and colleagues identify candidate metabolic genes, many of which are associated with unexplored regulatory gene networks and metabolic traits in human GWAS.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

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 Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (TP53, PIK3CA and GATA3) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.

The Cancer Genome Atlas consortium reports on their genome-wide characterization of somatic alterations in colorectal cancer; in addition to revealing a remarkably consistent pattern of genomic alteration, with 24 genes being significantly mutated, the study identifies new targets for therapeutic intervention and suggests an important role for MYC-directed transcriptional activation and repression.

The randomized-controlled trial ADVICE4U demonstrates non-inferiority of an automated AI-based decision support system compared with advice from expert physicians for optimal insulin dosing in youths with type 1 diabetes.

Naylor et al. systematically review the efficacy of treatments for beta-cell monogenic diabetes. Limited evidence from the mostly non-randomized, small studies supports no treatment in glucokinase-related hyperglycemia and sulfonylureas for HNF1A-diabetes; further evidence is needed on the optimum treatments in these and other monogenic subtypes.

Type 1 diabetes mellitus is an autoimmune disease that is characterized by insulin deficiency due to pancreatic β-cell loss and results in hyperglycaemia. This Primer by Lernmark and colleagues describes this chronic disorder, which requires lifelong insulin administration and affects >500,000 children worldwide.

Ahmad, Lim, Morieri, Tam et al perform a systematic review and meta-analysis of biomarkers, genetic markers, and risk scores for prediction of cardiovascular outcomes in Type 2 diabetes. A few prognostic markers are identified that provide incremental predictive utility beyond established cardiovascular risk factors.

Murphy, Kevin, Pollin et al. perform a systematic review of the evidence on the criteria used to select individuals with diabetes for genetic testing and of the evidence for the optimal methods for variant detection in genes involved in monogenic diabetes. Based on the findings the authors make recommendations and highlight challenges for the field.

Felton et al. conduct a systematic review to determine the utility of islet autoantibodies as biomarkers of type 1 diabetes heterogeneity. They find that islet autoantibodies are most likely to be useful for patient stratification prior to clinical diagnosis.

Misra, Wagner et al. systematically review if strategies to subclassify type 2 diabetes (T2D) are associated with high quality evidence and patient outcomes. Cluster-based stratification yields T2D subtypes that associate with outcomes, suggesting subclassification could have future clinical use.

Young, McInnes, Massey et al. systematically review published studies evaluating features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies in people with type 2 diabetes. They find limited current evidence on treatment effect heterogeneity, for glycaemic, cardiovascular and renal outcomes.

Francis et al. perform a systematic review and meta-analysis to evaluate studies comparing perinatal outcomes among individuals with gestational diabetes mellitus (GDM). Their review and post hoc analysis find that maternal preconception weight and non-glucose-dependent biochemical markers could be a precision diagnostic approach to reducing variability in clinical outcomes following treatment.

Takele et al. conduct a systematic review and meta-analysis of the effects of intervention characteristics on preventing gestational diabetes. Group or healthcare facility-based physical activity interventions are found to be more effective in preventing gestational diabetes than community-based interventions.

Felton et al. conducted a systematic review to evaluate studies testing disease-modifying therapies and features linked to treatment response for type 1 diabetes prevention. While the quality of prevention and intervention trials is found to be high, precision analyses on factors associated with treatment response are of poorer quality.

Bodhini et al. systematically review the evidence on sociodemographic, clinical, behavioral, and molecular factors that modify the effect of interventions for type 2 diabetes prevention. The certainty of evidence that such factors modify the effectiveness of lifestyle and behavioral interventions is low to very low.

Lim et al. perform a systematic review and meta-analysis to identify participant characteristics associated with response to gestational diabetes prevention. Characteristics such as BMI, polycystic ovary syndrome and being in the preconception phase could determine responses to certain preventive interventions.