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Protein interactions are essential for neural signaling and often perturbed in brain conditions. Here, the authors developed a CRISPR-based chemical-genetic approach to identify endogenous proximity proteomes that inform mechanism and phenotypic rescue strategies in mouse models of autism.

Acquired drug resistance is common during chemotherapy. Here, the authors describe the structural basis and molecular mechanism by which allosteric and clinically approved, ATP-competitive inhibitors of EGFR synergize to overcome resistance in lung cancer.

The soil microbiome communicates with plant roots using a chemical language. Here, using p-coumaroyl-homoserine lactone as the synthetic communication signal, the authors demonstrate programmable microbe-to-plant communication from the sender in the soil bacteria to a receiver in the plant.

It is known that exercise influences many human traits, but not which tissues and genes are most important. This study connects transcriptome data collected across 15 tissues during exercise training in rats as part of the Molecular Transducers of Physical Activity Consortium with human data to identify traits with similar tissue specific gene expression signatures to exercise.

Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.

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.

The microbes responsible for releasing the potent greenhouse gas methane from thawing permafrost remain largely unknown. Mondav and Woodcroft et al. investigate methane flux across a thaw gradient in Sweden and recover a near-complete genome of the dominant methanogen Candidatus ‘Methanoflorens stordalenmirensis’.

This Consensus Statement presents the standards for technical reporting in environmental and host-associated microbiome studies (STREAMS) guidelines.

The mechanisms regulating stem cells to give rise to human interfollicular epidermis are unclear. Here, the authors use single cell RNA sequencing to identify heterogeneity within the human neonatal interfollicular epidermis and distinct spatial positioning of at least four basal stem cell populations.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

Buruli ulcer is a necrotizing skin disease and a neglected tropical disease that is caused by Mycobacterium ulcerans infection. In this Primer, Yotsu et al. review the epidemiology, transmission and pathophysiology of the disease. They also discuss Buruli ulcer diagnosis and management, and highlight the disease burden on patients and future areas for research.

 A transcriptomic cell-type atlas of the whole adult mouse brain with ~5,300 clusters built from single-cell and spatial transcriptomic datasets with more than eight million cells reveals remarkable cell type diversity across the brain and unique cell type characteristics of different brain regions. 

Glycosylation is an attractive strategy to functionalize natural products and peptides for biomedical use, but non-enzymatic approaches usually require organic solvent and protecting groups. Now, an aqueous phenolic O-glycosylation reaction that uses glycosyl fluoride donors and a calcium salt has been developed for a wide range of substrates, including complex unprotected peptides.

This study shows how including different ancestry groups in a genome-wide association study for prostate-specific antigen levels can improve prostate cancer risk prediction, with implications for population screening.

A sequencing chemistry that separates nucleotide identification from nucleotide incorporation achieves high accuracy.

How reactive oxygen species regulate neuronal stem cell (NSC) behavior is poorly understood. Here, the authors report that Ncf1-dependent oxidation of Igfbp2 cystines represses DNA repair networks to regulate NSC self-renewal and cell fate decisions.

The response to infectious and inflammatory challenges differs among people but the reasons for this are poorly understood. Here the authors explore the impact of variables such as age, sex, and the capacity for controlling inflammation and maintaining immunocompetence, linking this capacity to favourable health outcomes and lifespan.

Lipophilic siRNA conjugates exert therapeutic activity in the mouse CNS.

Current methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) that form metastases have several limitations. Here, the authors show an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts.

Despite its great potential, immune checkpoint blockade has shown efficacy in only a restricted number of patients. In this Article, the authors present a nano-based platform for the co-delivery of chemo- and immunotherapeutics that shows efficient synergic antitumour activity in large, hard-to-treat tumour models.

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

Typical single-cell RNAseq pipelines will subcluster homogeneous cells. Here, authors present a computational algorithm for accurately identifying cell-type marker genes in single-cell data analysis with a low false discovery rate.

The controlled manipulation of the topological phases of electronic materials is a central goal of modern condensed matter research. Here, the authors demonstrate controllable switching between two distinct topological phases in a layered ferromagnet via thermal cycling.

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.

Heparan sulfates (HS) contain functionally relevant structural motifs, but determining their monosaccharide sequence remains challenging. Here, the authors develop an ion mobility mass spectrometry-based method that allows unambiguous characterization of HS sequences and structure-activity relationships.

Many RNA systems possess highly ordered 3-D structures that are essential to their function. Here the authors demonstrate that the long non-coding RNA Braveheart possesses a flexible but defined 3-D structure which is remodeled upon binding the protein CNBP.

Evidence synthesized from 252 large-herbivore exclusion studies suggests that herbivore-induced change in dominance, independent of site productivity or precipitation, best predicts herbivore effects on biodiversity in grassland and savannah sites.

H5N1 strain-specific antibodies are higher in older individuals and correlate more with birth year than with age, suggesting that younger individuals are potentially more likely to benefit from H5N1 vaccination.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

1000 Genomes imputation can increase the power of genome-wide association studies to detect genetic variants associated with human traits and diseases. Here, the authors develop a method to integrate and analyse low-coverage sequence data and SNP array data, and show that it improves imputation performance.

Deep whole-genome sequencing of 300 individuals from 142 diverse populations provides insights into key population genetic parameters, shows that all modern human ancestry outside of Africa including in Australasians is consistent with descending from a single founding population, and suggests a higher rate of accumulation of mutations in non-Africans compared to Africans since divergence.

The GEMM riboswitch is conserved in diverse bacteria and recognizes the second messenger c-di-GMP which mediates many processes, such as the transition between sedentary and motile behavior. The structure of the GEMM riboswitch with ligand now elucidates ligand recognition and specificity.

A large proportion of basal cell carcinomas develop resistance independently of the canonical mutations in genes encoding hedgehog pathway components. An unbiased analysis investigating alternative pathways of resistance uncovers the role of cytoskeletal signaling in driving noncanonical activation of hedgehog signaling through nuclear translocation of SRF and MKL1. These results advance understanding of the mechanisms underlying drug resistance and provide new actionable insights for clinical translation.

Optical observations of Dimorphos, a satellite of the asteroid 65803 Didymos, before, during and after the impact of the DART spacecraft, from a network of citizen science telescopes across the world are reported.

A weaker ocean gyre in the Pine Island Bay, suppressed by higher sea-ice concentration over the ocean near the Thwaites Eastern Ice Shelf, allows more meltwater to enter the sub-ice-shelf cavity. This increases the ocean temperature beneath the ice.

Whole-genome sequencing analyses of African populations provide insights into continental migration, gene flow and the response to human disease, highlighting the importance of including diverse populations in genomic analyses to understand human ancestry and improve health.

Interferon-ε is a tumour suppressor expressed in the epithelial cell of origin of ovarian cancer, which it restricts by direct action on tumour cells and especially by activation of anti-tumour immunity.

Spatial transcriptomics aims to pair omic data with tissue structure. Here the authors report Spatially PhotoActivatable Colour Encoded Cell Address Tags (SPACECAT) to track and isolate live cells by location; this enables spatially informed downstream assays like scRNA-seq and flow cytometry.

Image-based simulation for obtaining physical quantities is limited by the uncertainty in the underlying image segmentation. Here, the authors introduce a workflow for efficiently quantifying segmentation uncertainty and creating uncertainty distributions of the resulting physics quantities.

‘The timing and ecological dynamics of extinction in the late Pleistocene are not well understood. Here, the authors use sediment ancient DNA from permafrost cores to reconstruct the paleoecology of the central Yukon, finding a substantial turnover in ecosystem composition between 13,500-10,000 years BP and persistence of some species past their supposed extinctions.’

Inhibiting alpha-synuclein self-assembly into amyloid structures, associated with Parkinson’s disease, is a potential therapeutic intervention. Here, the authors identify the domains/sequences that are essential for alpha-synuclein aggregation and test the activity of foldamer-based antagonists to identify potential therapeutic targets.

After two doses of the BNT162b2 vaccine, virus-specific antibodies and T cells were reduced in patients with solid tumors as compared to individuals without cancer, but neutralizing antibodies increased in most patients who received a third vaccine dose.

Mirchandani and colleagues show that tissue hypoxia alters the number and phenotype of circulating monocytes and their differentiation into lung macrophages, with important implications for the resolution of inflammation in the lung.