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Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

A method for de novo design of peptide macrocyles called RFpeptides has been developed. RFpeptides is an extension of RoseTTAFold2 and RFdiffusion and combines structure prediction and protein backbone generation for rapid and custom design of macrocyclic peptide binders.

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.

The choroid plexus (ChP) provides molecular cues for brain development. However, the underlying mechanisms are unclear. This study identifies an apocrine secretion mechanism in the ChP that modulates the CSF protein composition and instructs cortical development.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Climate change can affect lake water level and nearby landscape. Korosi and colleagues show recent expansion of shallow lakes in the Canadian Northwest Territories is flooding critical habitat for the wood bison, and demonstrate the trickle-down effect of climate change on ecosystem functioning.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

In a single-arm phase 2 trial evaluating intravesical delivery of the oncolytic adenovirus cretostimogene grenadenorepvec with systemic anti-PD-1 in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ, the complete response rate at 12 months was 57.1%, meeting the primary endpoint.

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.

The tumor suppressor BRCA2 protects stalled DNA replication forks from unrestrained degradation; however the mechanism whereby unprotected stalled forks are preserved and restarted has remained elusive. Here the authors show that the WRN helicase promotes stalled fork recovery and limits fork hyper-degradation in the absence of BRCA2 protection.

The structure of a social network is thought to be heritable in many animals, including humans. Here, Rooke and colleagues identify a gene, which they name “degrees of kevin bacon (dokb)”, that is expressed in the central nervous system of Drosophila melanogaster and regulates the structure of social networks.

In a voter game, information gerrymandering can sway the outcome of the vote towards one party, even when both parties have equal sizes and each player has the same influence; and this effect can be exaggerated by strategically placed zealots or automated bots.

High-throughput screening systems that better mimic the physiological complexity of diseased tissues may aid the discovery of more efficacious compounds. A co-culture system that mimics the microenvironment of leukemia stem cells (LSCs) in bone marrow enables the discovery of compounds, including lovastatin, that selectively kill LSCs.

The properties of molecular electronic devices can be tuned by tailoring the structures of the molecules from which they are built. Researchers now show that two closely related molecules — each containing a string of four aryl groups — behave very differently when strung between gold electrodes, with the non-symmetrical structure leading to diode-like behaviour.

Protein phosphorylation plays critical roles in myriad cell processes. In this work, the authors apply new mass spectrometer technology to detect and quantify tens of thousands of protein phosphorylation sites within one hour or less of analysis. This technology has potential to greatly accelerate biological discovery.

The goal of the 1000 Genomes Project is to provide in-depth information on variation in human genome sequences. In the pilot phase reported here, different strategies for genome-wide sequencing, using high-throughput sequencing platforms, were developed and compared. The resulting data set includes more than 95% of the currently accessible variants found in any individual, and can be used to inform association and functional studies.

A study of myeloid cells in gliomas, a type of brain tumour, used a factor-based computational framework to reveal four immunomodulatory gene-expression programs that are expressed across myeloid cell types, driven by microenvironmental cues and predictive of therapeutic response.

Accurate cell-type identification is vital for single-cell analysis. Here, the authors develop a computational pipeline called “LungMAP CellRef” for efficient, automated cell-type annotation of normal and disease human and mouse lung single-cell datasets.

Compound MMV006833 inhibits ring-stage development of Plasmodium falciparum. Here, the authors show that it targets lipid transfer enzyme PfSTART1 and prevents PfSTART1 from expanding the vacuole membrane encasing the parasite after red blood cell invasion, thereby blocking parasite growth.

Twisted multilayer graphene structures composed of Bernal-stacked constituents are predicted to host flat moiré bands for several layer-number combinations. Here, the authors find an array of band insulators, correlated insulators, and topological states with notable similarities across different constructions.

Monitoring of western chimpanzee populations in Guinea-Bissau and Côte d’Ivoire reveals the presence of rare and different genotypes of Mycobacterium leprae, suggesting greater circulation in wild animals than previously thought.

Cyclic peptides are of particular interest due to their pharmacological properties, but their design for binding to a target protein is challenging. Here, the authors present a computational “anchor extension” methodology for de novo design of cyclic peptides that bind to the target protein with high affinity, and validate the approach by developing cyclic peptides that inhibit histone deacetylases 2 and 6.

Designed novel protein nanoparticle technology integrates antibody targeting and responds to changes in environmental conditions to release protected molecular cargoes, opening new applications for precision medicine.

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.

A challenge in the semiconductor industry is to create integrated circuits that use new physical state variables — other than charge or voltage — to offer memory and logic functions. Memristive devices, which combine the electrical properties of a memory element and a resistor, use resistance instead, and here such 'memristors' are shown to perform logic operations as well.

Antigen-specific tolerance represents a promising strategy to treat type 1 diabetes and islet allograft rejection. Here, the authors deliver immune signals to lymph nodes to promote antigen-specific regulatory T cells and prevent disease in models of type 1 diabetes and allogenic islet transplantation.

Multi-ancestry genome-wide association meta-analysis identifies new risk loci for CAC. Functional evidence implicates candidate causal genes as regulators of smooth muscle cell-mediated calcification.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Bile salt hydrolases encoded by the gut microbiome shape the bile acid pool, including microbial conjugated bile acids, which impact Clostridioides difficile infection in the murine gut.

The authors use low-temperature transport measurements to report superconductivity in a twisted double bilayer graphene system.

Panos Deloukas, Nilesh Samani and colleagues report a large-scale association analysis using the Metabochip array in 63,746 coronary artery disease cases and 130,681 controls. They identify 15 susceptibility loci, refine previous associations and use network analysis to highlight biological pathways.

brainlife.io is a one-stop cloud platform for data management, visualization and analysis in human neuroscience. It is web-based and provides access to a variety of tools in a reproducible and reliable manner.

Clonal hematopoiesis, often caused by mutations in DNMT3A and TET2, is associated with blood cancer and coronary artery disease. Here, the authors conduct an epigenome-wide association study, finding that clonal hematopoiesis caused by DNMT3A vs. TET2 mutations has directionally opposing changes in DNA methylation profiles, with both promoting stem cell self-renewal.

The optical detection of two virulence factors of Mycobacterium tuberculosis on extracellular vesicles in blood allowed for the diagnosis of tuberculosis in paediatric cases that were missed by clinical microbiological assays.

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.

ERK reversibly regulates embryonic stem cell transcription via selective redistribution of co-factors and RNA polymerase from pluripotency to early differentiation enhancers, while leaving transcription factors bound to their enhancers, thus preserving plasticity.

Jun Yang, Clinton Stewart and colleagues report the results of a genome-wide association study of cisplatin-induced ototoxicity among children undergoing treatment for brain tumors. They identify common variants in ACYP2 strongly associated with cisplatin-induced hearing loss and ototoxicity severity.

Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.

Human respiratory bronchioles contain a unique population of secretory cells called respiratory airway secretory cells that are distinct from the cells in the larger proximal airways, and act as unidirectional progenitors for alveolar type 2 cells.

In a zebrafish model of human cutaneous and acral melanomas, CRKL amplification causes tumours to favour a fin location, indicating that tumour location is determined by both the driver oncogenes and the pre-existing positional identity gene program.

In a multicenter research program coordinated by the International Mouse Phenotyping Consortium, Spielmann et al. analyze the cardiac function and structure in ~4,000 monogenic mutant mice and identify 705 mouse genes involved in cardiac function, 75% of which have not been previously linked to cardiac heritable disease in humans. Using the UK Biobank human data, the authors validate the link between cardiovascular disease and some of the newly identified genes to illustrate the resource value and potential of their mutant mouse collection.

Bacteria assemble the surface layer (S-layer), a crystalline protein coat surrounding the curved surface, using protein self-assembly. Here authors image native and purified RsaA, the S-layer protein from C. crescentus, and show that protein crystallization alone is sufficient to assemble and maintain the S-layer in vivo.

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.

Socioeconomic status is associated with cognitive development, but the extent to which this reflects neuroanatomical differences is unclear. In 1,099 children and adolescents, family income was nonlinearly associated with brain surface area, and this association was greatest among disadvantaged children. Further, surface area mediated links between income and executive functioning.