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Gene duplication and subsequent paralogue diversification are major obstacles to genotype-to-phenotype predictability.

Inspired by the entangled structure of double-network hydrogels, the authors integrate stiff truss and compliant woven components into metamaterial architectures to realize simultaneous high stiffness and high stretchability.

This Article reports the emergence of SARS-CoV-2 escape mutations during bamlanivimab therapy in the setting of a phase II clinical trial.

PGRMC2 is a membrane-bound progesterone receptor crucial for fast-signaling responses. Here, the authors shows that PGRMC2 regulates cardiac pressure-volume relationships and mediates steroid hormone signaling to maintain calcium homeostasis, ensuring proper heart contraction and function under stress.

Snyder and colleagues show global loss of promoter–enhancer connectivity during early colorectal carcinogenesis and the dependency of gene dysregulation during this process on the baseline of promoter–enhancer interaction in normal colonic epithelium.

The application and therapeutic success of CAR-T cell approaches are limited by the development of T cell exhaustion. Here, Stewart et al discover a role for IL-4 in driving CD8⁺ CAR-T cell exhaustion and demonstrate the improvement of CAR-T cell effectivity with interruption of IL-4 signalling.

Buttar et al. explore a contactless method for screening five respiratory diseases using 6G Integrated Sensing And Communication Orthogonal Frequency Division Multiplexing (ISAC OFDM) signals from software-defined radios. Using deep learning, the approach enables accurate, real-time screening for Asthma, Chronic Obstructive Pulmonary Disease, Interstitial Lung Disease, Pneumonia and Tuberculosis.

High-throughput biocatalytic screening and metagenomics have been used to discover over 300 imine reductases (IREDs) and subsequently produce a sequence-diverse panel of IREDs suitable for optimizing the synthesis of chiral amines. Additional characterization identified biocatalysts that accommodate structurally demanding amines and ketones for enzymatic reductive aminations.

The opioid antidote naloxone used to treat opioid overdoses has a short duration of action requiring repeated doses. Here the authors develop an extended release naloxone prodrug delivery system and report the preclinical testing in rat and cynomolgus monkey models.

The coding of sensory inputs at the level of vestibular sensory organs is not well understood. In this study, the authors demonstrate that the formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid and show that Cyp26b1 cKO mice have abnormal vestibular evoked potentials and balance beam performance, but normal vestibular-ocular reflexes.

Small molecule antagonists of CCR6 are potential drugs for autoimmune disorders. Here the authors present inactive structures of CCR6 bound by different allosteric antagonists from two series simultaneously, offering multiple approaches to inhibit CCR6.

Animal husbandry and hunting has increased human exposure to pathogens. Here, the authors investigate the evolution of human host gene expression to Bacillus anthracis infection, the bacterium that causes anthrax disease. They observe recent positive selection, suggestive of human genome adaptation to anthrax disease.

There are currently a lack of genetic models to study the biology of Uterine fibroids (UFs) tumours. Here the authors precisely engineer cells with mutant MED12 Gly-44 and generate myometrial smooth muscle cells (SMCs) that recapitulate major UFs-like cellular, transcriptional, and metabolic alterations.

The ability to maintain blood stem cells (HSCs) in vitro would allow us to provide better therapies for blood diseases. Here, the authors report that polymer-organised extracellular proteins, coupled to soft environments mimicking bone marrow stiffness, allow stromal cells to maintain HSCs in vitro.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

The authors generated stem cell-derived neurons from combat veterans with and without PTSD and found PTSD-dependent gene expression changes in response to glucocorticoids. This highlights how stress response may be altered in individuals with PTSD.

Glioblastoma (GBM) is rich in tumor-associated vasculature and it remains to be understood how GBM is supported by vascular endothelial cells. Here, the authors identify that endothelial-secreted proteoglycan endocan acts as a ligand of PDGFR alpha receptor to promote GBM progression and induce therapy resistance.

This study assessed COVID-19 social science preprints’ replicability using structured groups. Both beginners and more-experienced participants used a elicitation protocol to make better-than-chance predictions about the reliability of research claims under high uncertainty.

RMC-7977, a compound that exhibits potent inhibition of the active states of mutant and wild-type KRAS, NRAS and HRAS variants has a strong anti-tumour effect on RAS-addicted tumours and is well tolerated in preclinical models.

Invertebrate and microbe communities support reef ecosystems and coral health. Here, the authors characterize these communities from degraded and healthy reefs, showing that transplanting these healthy communities improved coral health at degraded reefs.

Magnetic endoscopes have the potential to improve access, reduce patient discomfort and enhance safety. While navigation of magnetic endoscopes can be challenging for the operator, a new approach by Martin, Scaglioni and colleagues explores how to reduce this burden by offering different levels of autonomy in robotic colonoscopy.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

International challenges have become the de facto standard for comparative assessment of image analysis algorithms. Here, the authors present the results of a biomedical image segmentation challenge, showing that a method capable of performing well on multiple tasks will generalize well to a previously unseen task.

Anti-cancer immunity relies on the effector functions (e.g., IFNγ production) of T cells that reside in a hypoxic tumor microenvironment. Here, the authors show that HIF1α-controlled glycolysis is an important driver of IFNγ production in hypoxic T cells, governing anti-tumor immunity.

A secure framework that harmonizes storage and querying of clinical and genetic data using blockchain technology was developed to support combined genotype–phenotype queries, improving transparency into how and when health information is used.

Single cell RNA sequencing generates short reads from one end of a template, providing incomplete transcript coverage and limiting identification of diverse sequences such as antigen receptors. Here the authors combine long read nanopore sequencing with short read profiling of barcoded libraries to generate full-length antigen receptor sequences.

CRISPR-Cas9 genome editing is presumed to knock out gene function by generating a frameshift during NHEJ repair. Here, the authors investigate mRNA and protein expression in edited lines and find genome editing can generate internal ribosome entry sites or alternatively spliced variants.

Small GTPases of the RAS family classically function as molecular switches, adopting on and off conformations dependent on bound nucleotides. Here the authors reveal MRAS, closely related to archetypal RAS, is completely deficient in GTP exchange.

The molecular mechanisms underlying drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML) remain to be explored. Here, the use of bulk and single cell multi-omics and ex vivo drug profiling for 21 rrAML patients reveals mechanisms of resistance to the Bcl-2 inhibitor venetoclax and treatment vulnerabilities.

Cycling of the sulfur compound DMSOP by dimethylsulfoniopropionate lyase enzymes in the most abundant marine bacteria, algae and fungi is diverse and prevalent in Earth’s oceans and sediments and probably impacts climate-active gas production.

Neonatal cholestasis is a result of elevated bile acid levels, and is associated with mutations in genes regulating bile acid homeostasis. Here the authors identify mutations in the bile acid sensing farnesoid X receptor in four individuals with neonatal cholestasis from two unrelated families.

Using single-molecule biophysics methods, Le et al. discovered that etoposide, a chemotherapeutic poison of topoisomerase II (topo II), promotes topo II to compact DNA, trap DNA loops and pause DNA supercoiling relaxation, thus converting topo II into a strong roadblock to DNA processing.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

The accumulation of alpha-synuclein fibrils within neurons is the defining feature of Lewy body dementia (LBD). Here the authors report a method to produce large quantities of alpha-synuclein fibrils that reproduce the complex structure of the fibrils that accumulate in LBD brain tissue.

The gasdermin E protein is shown to act as a tumour suppressor: it is cleaved by caspase 3 and granzyme B and leads to pyroptosis of cancer cells, provoking an immune response to the tumour.

Mice lacking the anti-inflammatory cytokine IL-10 can develop colitis, which depends on inappropriate responses to commensal bacteria. Hoshiet al. now show that these responses are driven by colonic mononuclear phagocytes, providing insight to the initiating events, which may underlie inflammatory bowel disease.

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

The wildlife host range of SARS-CoV-2 is currently unknown. Here, the authors report evidence of infection in six common wild animal species (deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, Eastern red bat) out of 23 species tested in Virginia and Washington DC, USA in 2022/2023.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

Andersson et al. show that intestinal stem cells enriched for old mitochondria are metabolically distinct and have enhanced ability to regenerate the epithelial niche.

CRISPR screen identifies coactivators of the androgen receptor (AR) complex, including NSD2. NSD2 contributes to AR cistrome reprogramming during prostate cancer progression, and its degradation via a novel PROTAC reduces prostate cancer cell viability in vitro.

The deployment of lithium metal batteries is forestalled by poor control over the deposition morphology of lithium. Here, the authors discover that high electrical resistance can be leveraged for controlling lithium morphology and enabling high-performing lithium metal batteries.

Three-dimensional DNA origami constructs can be used to deliver vaccine antigens in a multi-valent form. Here the authors design a DNA origami system for SARS-CoV-2 proteins and characterize in mice the immune response and protective capacity of generated antibodies, finding that the construct itself is not immunogenic.