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Defective protein quality control is a key feature of neurodegeneration. Here, the authors show that mutations in Nemf/NEMF, a component of the Ribosome-associated Quality Control complex, have a neurodegenerative effect in mice and may underlie neuromuscular disease in seven unrelated families.

Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.

Cryo-electron microscopy is widely employed in structural biology and uses phase contrast imaging. Here, the authors employ electron ptychography, a quantitative phase retrieval method for high-contrast, low-dose phase imaging of cryo-state rotavirus and immature HIV-1 virus-like particles, and show that electron ptychography is more efficient for phase recovery than conventional phase contrast imaging.

Single-cell DNA sequencing data are generated from human neurons using primary template-directed amplification and analyzed using SCAN2, an improved genotyping tool. Indels are enriched in neuronal regulatory elements and may be deleterious.

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A modular architecture for managing and sharing electrophysiology, behavior, colony management and other data has been built to support individual laboratories or large consortia.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

SF3B1 mutations confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Mechanistically, this is independent of homologous recombination repair and instead relies on a defective replication stress response due to a reduction of the cyclin-dependent kinase 2 interacting protein (CINP). PARPi treatment of SF3B1 mutant (SF3B1^MUT) tumors leads to replication stress induced by increased fork origin firing and culminates in cell cycle stalling.

Mitochondrial networks are carefully positioned to facilitate energy distribution within muscle cells. Here they show that energetic demands and conserved transcription factors regulate mitochondrial network organization and contractile phenotypes independently in Drosophila.

Climate simulations suggest that the contribution of methane to climate warming and wetting due to absorption of long-wave radiation is partially counteracted by short-wave absorption.

Using genetically engineered models, Genovese and colleagues study patterns of convergent evolution in renal cancer, and pinpoint dysregulation of interferon signaling as a means of adaptation to chromosomal instability in metastatic progression.

Spatial Modeling Algorithms for Reactions and Transport (SMART) is a software package that allows users to simulate spatially resolved biochemical signaling networks within realistic geometries of cells and organelles.

Parental care involves shifts in numerous behaviours related to mating, feeding, aggression and social interaction. Here, the authors show that, in burying beetles, parenting is associated with increased levels of neuropeptides known to mediate these precursor behaviours, suggesting co-option of existing genetic pathways.

Algae hold great promise for biofuel and chemical production but their use as model systems is hampered by the absence of suitable genetic tools. Here Karas et al. present a nuclear episomal vector for diatoms that is maintained in the absence of antibiotics, and a plasmid delivery method via conjugation with E. coli.

Ontologies are powerful tools that facilitate the integration of large and disparate data sets. Here, researchers from the Kidney Precision Medicine Project provide an introduction to ontologies, including those developed by the consortium, describing how these will be used to improve the annotation of kidney-relevant data, eventually leading to new definitions of kidney disease in support of precision medicine.

A large-scale meta-analysis across eight biobank datasets identifies common genetic variants associated with mosaic loss of the X chromosome in female participants.

The neural function of cystatin B, recently implicated in EPM1, is unclear but may lead to new insights into the mechanisms of epilepsy.

In this clinical trial, the authors show that a 5-day molnupiravir treatment reduces SARS-CoV-2 viral load in at-risk outpatients by day 5 but mostly fails to clear virus, leads to lower spike antibody response by day 14 and higher virus mutation rates.

A new design for vaccines consisting of reorienting the viral glycoprotein in an ‘upside-down’ configuration broadens immune responses to diverse influenza subtypes and serves as a proof of concept for designing a universal flu vaccine.

Assessing the accuracy of evapotranspiration (ET) data is crucial for managing the water used by crops and natural vegetation. This study presents a comprehensive evaluation of the accuracy of a remotely sensed ET model ensemble from the OpenET system using in situ ET measurements collected across the contiguous United States.

Multi-modal analysis of genomically unstable ovarian tumours characterizes the contribution of anatomical sites and mutational processes to evolutionary phenotypic divergence and immune resistance mechanisms.

Evolutionary modelling shows that an initial set of inhibitory neurons serving olfactory bulbs may have been repurposed to diversify the taxonomy of interneurons found in the expanded striata and cortices in primates.

Osteocytes are the master regulatory cells within the skeleton. Here, the authors map the transcriptome of osteocytes from diverse skeletal sites, ages and between sexes and identify an osteocyte transcriptome signature associated with rare skeletal disorders and common complex skeletal diseases.

Christopher Walsh and colleagues describe a new recessive genetic disease characterized by microcephaly, early-onset intractable seizures and developmental delay (MCSZ). The authors identify mutations in PNKP that result in this severe disease and show that PNKP mutations disrupt DNA repair.

Treatment of patients with metastatic salivary gland cancer with anti-PD-1 and anti-CTLA-4 led to encouraging clinical benefit in certain histologic subtypes, with translational analyses showing pre-existing T cell clonal expansion in responding tumors.

Interactions between the immune system and adipose tissue contribute to the regulation of body weight, however, the underlying mechanisms remain incompletely understood. Here the authors dissect the role of two structurally and functionally similar immune mediators, BAFF and APRIL, in modifying diet-induced weight gain and adipocyte lipid handling.

DNA is an attractive digital data storing medium due to high information density and longevity. Here the authors use millions of sequences to investigate inherent biases in DNA synthesis and PCR amplification.

This Resource describes genetic tools for microbial eukaryotes, providing a roadmap for developing genetically tractable organisms.

A study of hospitalized patients infected with SARS-CoV-2 and who have liquid or solid cancer suggests that hematologic malignancy is an independent risk factor for mortality and that CD8⁺ T cells might limit infection in this setting irrespective of humoral immunity.

Here, the authors present cryoEMPEM, a method for high-resolution structural analysis of vaccine-elicited polyclonal antibody responses. They apply cryoEMPEM in combination with standard serology experiments to characterize the polyclonal antibody (pAb) responses elicited in rhesus macaques by HIV Env trimer immunogens and were able to determine up to 8 different polyclonal antibody structures in complex with their respective antigen from a single cryoEM dataset.

Humans can easily uncover abstract associations. Here, the authors propose that higher-order associations arise from natural errors in learning and memory. They suggest that mental errors influence the humans’ representation of the world in significant and predictable ways.

Squalene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and is a target for hypercholesteremia and cancer drug development. Here the authors present the crystal structures of the human SQLE catalytic domain alone and bound with small molecule inhibitors, which will facilitate the development of next-generation SQLE inhibitors.

Stabilizing climate change requires simultaneous mitigation of all greenhouse gas emissions (GHGs). Here the authors examine 90 mitigation scenarios pairing different levels of CO₂ and non-CO₂ GHG abatement pathways to demonstrate the contributions of different GHGs towards 1.5 °C and 2 °C goals.

The development of high performance dual-site single-atom catalysts is a promising research direction. Here, the authors report structural dynamics of dual-site nickel-iron single-atom oxygen electrocatalysts under reaction conditions, and proposes a dual-site pathway for the water oxidation reaction.

Control of macrophage activation in the lungs is essential for the prevention of tissue damage. MacDonald and colleagues show that alveolar macrophages have impaired glycolysis and are hyporesponsive during type 2 inflammation in a manner controlled by the lung environment.

Ependymoma is a type of neural tumour that arises throughout the central nervous system. Using comparative transcriptomics in mouse and human tumours, these authors home in on mutations that are specific to individual tumour subgroups. In doing so, they generate the first mouse model of ependymoma and demonstrate the power of interspecific genomic comparisons to interrogate cancer subgroups.

The next step after sequencing a genome is to figure out how the cell actually uses it as an instruction manual. A large international consortium has examined 1% of the genome for what part is transcribed, where proteins are bound, what the chromatin structure looks like, and how the sequence compares to that of other organisms.

Over the past eight years, the state of Florida has invested close to a billion dollars to attract renowned research organizations to open up shop within its borders. But even with the arrival of several heavyweights, including the Scripps Research Institute and the Max Planck Institute, some continue to question whether the investment was worthwhile. Christopher Mims reports.

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.

Analysis of SLOS patient-derived iPSCs reveals that cellular accumulation of the cholesterol precursor 7DHC, rather than cholesterol deficiency, causes dysregulation of Wnt/β-catenin signaling and aberrant neural differentiation.