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An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

The mechanisms governing kidney nephrogenic capacity are incompletely understood. Here, the authors reveal that METTL3-dependent RNA transmethylation is both necessary and sufficient to promote nephron progenitor differentiation, and that targeting this pathway enhances murine nephron endowment.

Delivering immunomodulatory compounds to myeloid cells can activate innate immunity for cancer immunotherapy. Here the authors design a polymersome-based nanocarrier for delivering β-glucan to red pulp myeloid cells in the spleen and show that their strategy achieves tumour growth reduction in a melanoma model.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

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.

The authors show that reconsolidation of alcohol-related memories activates mammalian target of rapamycin complex 1 (mTORC1) in select amygdalar and cortical regions and systemic or central amygdalar inhibition of mTORC1 during reconsolidation disrupts alcohol-associated memories, leading to a long-lasting suppression of relapse, suggesting a potential therapeutic target to prevent relapse.

Sustained drug delivery is critical for patient adherence to chronic disease treatments. Here the authors apply machine learning to engineer multifunctional peptides with high melanin binding, high cell-penetration, and low cytotoxicity, enhancing the duration and efficacy of peptide-drug conjugates for sustained ocular delivery.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

In a phase 2 trial, the oral type II RAF inhibitor tovorafenib exhibited an overall response rate of 67% in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma.

Trastuzumab binding to tumor cells depends on the availability of HER2 at the cell membrane. Here the authors show that caveolin-1 (CAV1) regulates HER2 density at the cell membranes and that CAV1 gene knockdown or protein depletion via the cholesterol modulator lovastatin, increases trastuzumab binding and anti-tumor activity.

The authors found that white blood cells plug about 2% of capillaries in the brains of Alzheimer’s disease mouse models. When the adhesion of these cells was blocked, cerebral blood flow immediately increased and cognitive performance rapidly improved.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

While recurrence is frequent in ependymoma, the underlying molecular mechanisms remain to be explored. Here, the authors investigate epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses over 13 years and identify distinct patterns of DNA methylation.

Medulloblastomas lacking p53 do not express surface class I major histocompatibility complex (MHC-I) and are resistant to immune rejection. Tumor necrosis factor rescues MHC-I expression and synergizes with immune checkpoint inhibitors to promote rejection.

In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

Lower levels of ω–3 fatty acid–derived resolution mediators have been linked to insulin resistance in obese mice. André Marette and his colleagues now show that treatment of obese mice with a resolution mediator (protectin DX (PDX)) results in IL-6 release from muscle and subsequent improvement in insulin sensitivity. PDX may represent a new class of antidiabetes medication.

Gilean McVean and colleagues report the results of a large-scale clinical genome sequencing project spanning a broad spectrum of disorders. They identify factors influencing successful genetic diagnosis and highlight the challenges of interpreting findings for genetically heterogeneous disorders.

Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.

In situ tissue engineered heart valve prostheses implanted in aortic position of an ovine model up to 12 months meet several hallmarks for sustainable heart valves prostheses, but variability in tissue remodelling and valve functionality are seen.