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Brown and beige adipose tissues contribute to organismal energy expenditure by generating heat. Here, Klepac et al. survey G protein-coupled receptors in brown fat and show that G_q-coupled receptors inhibit expression of thermogenic proteins in mice and in human adipocytes.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.

The bacterium Legionella pneumophila can cause severe respiratory infection, but is typically a symbiont of free-living amoeba. Here, the authors analyse the genomes of 902 clinical and environmental isolates, and identify a bacterial gene that is strongly associated with human infection and confers resistance to complement-mediated killing.

Izar and colleagues demonstrate that loss of Pip4k2c in melanoma cells promotes liver metastatic tropism driven by PI3K-AKT pathway activation in the insulin-rich liver milieu, which can be abrogated by inhibition of SGLT2 or a ketogenic diet.

The cellular organelles peroxisomes contribute to the sensitivity of cells to ferroptosis by synthesizing polyunsaturated ether phospholipids, and changes in the abundances of these lipids are associated with altered sensitivity to ferroptosis during cell-state transitions.

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.

An extinction-risk assessment of reptiles shows that at least 21.1% of species are threatened by factors such as agriculture, logging, urban development and invasive species, and that efforts to protect birds, mammals and amphibians probably also benefit many reptiles.

Whether multimorbidity accelerates brain Aβ deposition in humans remains largely unknown. Here, the authors demonstrate that higher self-reported multimorbidity burden predicts increased brain Aβ accumulation rates in the ADNI cohort.

While EGFR-targeted therapies have clinical benefit, drug-resistant brain metastases present a major obstacle. Here, the authors identify a genetic signature in brain metastatic lesions associated with osimertinib resistance and find RhoA to have an important role in the resulting phenotype.

Response rates to immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) remain low. Here the authors show that ablative treatment of tumor-draining regional lymphatics, a standard of care approach in patients, impairs the tumor response to ICI in preclinical HNSCC models.

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Detailed three-dimensional numerical models of the atmosphere, coupled as necessary to models of other parts of the climatic system, provide the most promising approach to understanding the physical basis of climate. Models of this kind can be used to investigate the impact of anthropogenic pollution on climate. At the present time, the main concern is with increasing concentrations of CO₂ which might lead to overall warming of the troposphere, but chemical and thermal pollution may also pose a threat. The possible climatic changes would take place slowly and would involve the response of the slowly reacting parts of the climatic system, particularly the oceans. The problem of how to simulate such changes of climate presents many difficulties, which are currently being studied.

Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis, a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

Some 700 approved therapies in the United States — roughly a third of all drugs on the market — target G-protein-coupled receptors (GPCRs). Now advances in high-throughput and structure-based screening are sparking a second golden age of GPCR-based drug discovery.

Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.

This study used fine-mapping to analyze genetic regions associated with bipolar disorder, identifying specific risk genes and providing new insights into the biology of the condition that may guide future research and treatment approaches.

Zinc finger protein transcription factors are developed for the selective silencing of the mutant huntingtin gene in human neurons in vitro and multiple animal models of Huntington’s disease in vivo while preserving expression of the wild-type allele.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

Many diseases are driven by the insufficient expression of critical genes, but few technologies are capable of rescuing these endogenous protein levels. Here, Cao et al. present an RNA-based technology that boosts protein production from endogenous mRNAs by upregulating their translation.

An integrated transcriptome, genome, methylome and proteome analysis of over 200 lung adenocarcinomas reveals high rates of somatic mutations, 18 statistically significantly mutated genes including RIT1 and MGA, splicing changes, and alterations in MAPK and PI(3)K pathway activity.

Alpha-synuclein fibrils can disrupt the enteric nervous system, which is mitigated by peripheral GBA1 gene transfer via systemic AAVs. Aging increases susceptibility to α-synuclein pathology progression from the gut to the brain.

Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.

A single-cell transcriptomic atlas across the lifespan of the mouse, denoted Tabula Muris Senis, provides molecular information about the hallmarks of ageing in a range of tissues and cell types.

Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.

Mangrove forests protect communities from storms and support fisheries. Here, the authors show that the association with economic growth has shifted from negatively impacting mangroves to enabling mangrove expansion, and that community forestry is promoting mangrove expansion.

There is an unmet need to improve the response to immune checkpoint blockade in patients with head and neck squamous cell carcinoma (HNSCC). Here the authors show that aberrant HER3 activation sustains the proliferation of PIK3CA wild type HNSCC cells and that HER3 inhibition increases response to PD-1 blockade in HNSCC preclinical models.

In chromosomally unstable tumour cells, rupture of micronuclei exposes genomic DNA and activates the cGAS–STING cytosolic DNA-sensing pathway, thereby promoting metastasis.

Pappalardi and colleagues identify a potent noncovalent DNMT1-selective inhibitor with improved tolerability and efficacy in preclinical AML models compared with clinically validated covalent pan-DNMT inhibitors.

A transcriptomics study demonstrates cell-type-specific responses to differentially aged blood and shows young blood to have restorative and rejuvenating effects that may be invoked through enhanced mitochondrial function.

Antibodies stimulating the T cell co-activator 4-1BB (CD137) do enhance anti-tumour T cell function, but their utility is hampered by on target, off tumor toxicity. Here authors show that anchoring anti-4-1BB to tumours via fusion with the collagen binding protein LAIR diminishes systemic dissemination of the drug, and they demonstrate a curative effect in a triple-combination-therapy that relieves regulatory T cell immunosuppression in a mouse model of cancer.

Bioluminescence imaging tends to rely on transgenic luciferase-expressing cells and animals. Here the authors report a portable bioluminescent system to non-invasively measure intra- and extracellular enzymes in vivo in non-transgenic animals which do not express luciferase.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Here, the authors profile the oral, lung, and gut microbiota of 479 patients with acute respiratory failure, revealing that reduced diversity and increased pathogen presence can predict survival outcomes, highlighting the potential for microbiota-based approaches in critical care.

Slide-tags enables multiomic sequencing of single cells and their localization within tissues.

Modular synthetic G-protein-coupled receptors with nanobody-based ligand-recognition domains can be designed and used to programme transgene expression, real-time fluorescence or endogenous G-protein activation in response to soluble or cell-surface ligands, enabling control of diverse cellular behaviours.

Last year's Dover trial resulted in intelligent design being removed from the science curriculum.

Physical realizations of qubits are often vulnerable to leakage errors, where the system ends up outside the basis used to store quantum information. A leakage removal protocol can suppress the impact of leakage on quantum error-correcting codes.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

The currently available transgenic T cell receptor (TCR) models represent high affinity antigen-TCR interactions. Authors here present an alternative approach to target an exogenous TCR into the physiological Trac locus in the germline of mice, which uncovers that the natural genomic context for TCRs can enhance the antigen sensitivity of lower affinity TCRs and enables the physiologic range of antigen-TCR interaction and a gene dosage dependent mechanism of central tolerance.