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Autophagic activity has a protective role in Alzheimer’s disease in mice. Here the authors investigate the role of autophagy-initiating protein ULK1 and report that its overexpression stimulates autophagic flux, reduces amyloid and tau pathology and delays cognitive decline.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Recent crystal structures of the Thermoplasma acidophilum thermosome and its isolated apical domain suggest that an integral extension of the apical domain encloses the folding-active chaperonin central cavity.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Transcriptome-wide m⁶A RNA methylation profile in 162 primary prostate tumors identifies m⁶A association with prognostic clinical features and disease aggression.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Montserrat Garcia-Closas and colleagues report a meta-analysis of three genome-wide association studies for estrogen receptor (ER)-negative breast cancer, including 4,193 ER-negative breast cancer cases and 35,194 controls, with replication using the iCOGS custom genotyping array in 40 studies, including 6,514 cases and 41,455 controls. They identify four loci associated with ER-negative but not ER-positive breast cancer.

The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.

The SARS-CoV-2 spike glycoprotein is flexible, and its receptor-binding domain (RBD) fluctuates between open and closed conformations. Disulfide bonds are engineered into the spike ectodomain to lock the RBD in the closed state, leading to a construct with high thermostability.

This work challenges the view of nucleation governing halide perovskite grain morphology, showing that most additives act post-nucleation by boosting ion mobility across grain boundaries, triggering grain coarsening, similar to post-processing effects.

Antibiotics to treat carbapenem-resistant Acinetobacter baumannii infection are an urgent need. The cerastecins are potent, bactericidal and efficacious in animal models of infection, and may enable new treatment modalities targeting LOS transport.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

The transcription factors TCF1 and LEF1 promote self-renewal and regulatory functions in B-1a cells.

Leaf rust and stripe rust of wheat are two important fungal diseases of cultivated wheat and they are caused by infection of different pathogens. Here, the authors report the nucleotide-binding leucine-rich repeat (NLR) protein encoding gene Yr87/Lr85 confers resistance to both diseases.

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

Stig Bojesen, Georgia Chenevix-Trench, Alison Dunning and colleagues report common variants at the TERT-CLPTM1L locus associated with mean telomere length measured in whole blood. They also identify associations at this locus to breast or ovarian cancer susceptibility and report functional studies in breast and ovarian cancer tissue and cell lines.

SARS-CoV-2 variants of concern continue to emerge, reducing vaccine efficacy and limiting therapeutic options. Here, Chen and colleagues describe the identification and design of shark nanobodies with pansarbecovirus activity.

Pseudovirus assays and surface plasmon resonance show that the Omicron receptor-binding domain binds to human ACE2 with increased affinity relative to the ancestral virus, and that most neutralizing antibodies are considerably less potent against Omicron.

An expanded GWAS of birth weight and subsequent analysis using structural equation modeling and Mendelian randomization decomposes maternal and fetal genetic contributions and causal links between birth weight, blood pressure and glycemic traits.

A subset of renal cell carcinomas have uncertain histology and are aggressive in nature. Here, the authors examine this group of unclassified renal cancers using genomics techniques and identify further subclasses of the tumours that have differing prognoses.

Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.

In-depth analyses of protein expression studies are used to derive a new codon-influence metric that correlates with global protein levels, mRNA levels and mRNA lifetimes in vivo, indicating tight coupling between translation efficiency and mRNA stability; genes redesigned based on these analyses consistently yield high protein expression levels both in vivo and in vitro.

Xu et al. show that liver ATF3 expression is inhibited by hydrocortisone, thus promoting the development of atherosclerosis through effects on HDL cholesterol and bile acid metabolism.

Douglas Easton, Per Hall and colleagues report meta-analyses of genome-wide association studies for breast cancer, including 10,052 cases and 12,575 controls, followed by genotyping using the iCOGS array in an additional 52,675 cases and 49,436 controls from studies within the Breast Cancer Association Consortium (BCAC). They identify 41 loci newly associated with susceptibility to breast cancer.

Sarat Chandarlapaty and colleagues report the identification of mutations in the ESR1 gene affecting the ligand-binding domain of the encoded estrogen receptor in 20% of metastatic hormone-resistant breast cancers. They determine that the mutant receptor has a hormone-independent active state that likely promotes resistance to estrogen-depriving therapies.

Prostate cancer risk-associated SNPs are enriched in noncoding CREs. Here the authors perform CRISPRi screens of CREs in prostate cancer cell lines to describe a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture.

Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two central degradative mechanisms in the ER. Here the authors describe the sequence of events underlying the disposition of misfolded ER proteins by ERAD and ER-phagy.

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.

A transancestral exome-wide association study for body-fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.

A study leveraging transsynaptic tracing demonstrates rapid and extensive integration of human glioblastoma organoids into the mouse brain.

Damian Smedley and colleagues report the phenotypic characterization of the first 3,328 genes by the International Mouse Phenotyping Consortium. They develop new mouse models based on genes known to be associated with human mendelian diseases and identify potential disease-associated genes with little or no previous functional annotation.

Mark McCarthy and colleagues report a genome-wide association study of birth weight. They identified two loci, in ADCY5 and near CCNL1, that are associated with birth weight and explain 0.3% and 0.1% of the variance in birth weight, respectively.

White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

A transcriptome-wide association study identifies associations of genetically predicted gene expression with breast cancer risk. This analysis finds 48 candidate genes implicated in breast cancer susceptibility, including 14 at novel loci.

The sequence determinants governing CRISPR/Cas9 specificity are not fully understood. Here, the authors devise a high-throughput dual-target synthetic system to explore the sequence features associated with CRISPR/Cas9 off-target effect, reveal a set of sequence-dependent rules, and develop an off-target prediction model and a strategy for Cas9-based allele-specific editing.

A novel stainless-steel pin has been engineered with a pure magnesium core that promotes improved fracture healing in rats by inducing local production of a key neuropeptide for osteogenesis.

MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy.

Whole-genome bisulfite sequencing along with whole-genome and transcriptome sequencing of 100 prostate cancer metastases identifies genomic regions that are differentially methylated during disease progression and a novel epigenomic subtype.

Rectal cancer organoids retain the pathological features of matched patient tumors and recapitulate clinical responses to chemoradiation.

Association analysis identifies 65 new breast cancer risk loci, predicts target genes for known risk loci and demonstrates a strong overlap with somatic driver genes in breast tumours.

Doug Easton and colleagues report the results of a large-scale genome-wide association study of breast cancer. They discover 15 new susceptibility loci and highlight likely target genes in several of the newly associated regions.

Georgia Chenevix-Trench and colleagues report meta-analyses of genome-wide association studies identifying six loci newly associated with epithelial ovarian cancer (EOC). They also test variants at the 12 known and 6 new EOC susceptibility loci for association in BRCA1 and BRCA2 mutation carriers.