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Orthogonal aminoacyl-tRNA synthetase–tRNA pairs are discovered by analyzing millions of sequences.

DNA Ligase IV (LigIV) catalyzes nick sealing of DNA double-strand break substrates during non-homologous end-joining. Here the authors present the crystal structures of two human LigIV DNA-bound catalytic states, which provide insights into its catalytic mechanism and the molecular basis of LIG4 syndrome causing disease mutations.

BAG3 is a Hsp70 co-chaperone that is highly expressed in muscles. Here the authors show that several myofibrillar myopathy causing BAG3 mutations are not impaired in Hsp70 binding, but rather impair the ADP-ATP exchange step of the Hsp70 cycle, causing the aggregation of BAG3, Hsp70 and Hsp70 clients and leading to a collapse of protein homeostasis.

Barnes et al. report a dynamic and reciprocal crosstalk between tissue tension and glycocalyx bulkiness that promotes a mesenchymal, stem-like phenotype in GBM.

N-Myc fuels neuroendocrine prostate cancer. Here, the authors describe how targeting HSP70, a major N-Myc partner, coordinates with STUB1 to facilitate the degradation of N-Myc. This process slows neuroendocrine prostate cancer growth, improves the efficacy of Aurora Kinase A inhibitors, and reduces neuroendocrine pathway activity.

PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.

The authors identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that increases with age and promotes cognitive decline. Targeting FTL1 in the brain improved cognition in old mice.

Results from a high-resolution ocean-bottom seismometer experiment at the ultraslow-spreading Gakkel Ridge show unexpected highly variable crustal thickness and a relatively large average value, which can be explained by an active mantle upwelling model.

Gene-based rare variant analyses for 601 diseases across 748,879 individuals from three biobanks identify 363 significant associations and highlight important considerations for multi-ancestry and cross-biobank sequencing studies.

Enterococci enhance the fitness and pathogenesis of Clostridioides difficile in the gut by altering the amino acid composition and providing signals that increase its virulence towards the host.

Siderophores from diet-derived or intestinal fungi can be used by Salmonella for growth in the murine gut.

The evolutionarily conserved SARS-CoV-2 spike’s S2 subunit provides the foundation for its usage as an immunogen in vaccines. Here, the authors use a simulation-driven approach to design S2-only immunogens stabilized in the closed prefusion conformation.

PELP1 is a large scaffolding protein implicated in many cellular activities, including ribosome assembly as part of the Rix1 complex, comprising PELP1, WDR18, TEX10 and other components. Here, authors present the cryo-EM structure of PELP1 in complex with its binding partner WDR18, revealing the architecture of PELP1's numerous signaling motifs.

High-resolution fMRI uncovers stronger functional connectivity between alike ocular dominance columns in human V1, varying across depth and visual subfields, providing new insights into the mesoscale functional organization of the visual system.

Venom is a complex trait with unresolved underlying toxin expression dynamics. Here, the authors compare expression across sea anemone species, revealing variation in dominant toxin diploid copy number across populations which generates distinct haplotypes.

An example of hybrid incompatibility between maize and teosinte reveals a selfish toxin–antidote system mediated by small RNAs that may have contributed to the origin of maize.

Respiratory syncytial virus (RSV) is a highly contagious illness in young children. The structure of antibody drug motavizumab in complex with a 24-residue peptide corresponding to its epitope on RSV-fusion glycoprotein suggests why it is more potent than its predecessor, palivizumab (Synagis).

Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.

Using a trait-based model that resolves key zooplankton groups, the authors reveal future shifts to food webs dominated by carnivorous and gelatinous filter-feeding zooplankton. Subsequent decreases in food nutrition are linked to declines in small pelagic fish biomass, particularly in tropical regions.

In this study, the authors characterise post-acute sequelae of SARS-CoV-2 (PASC) in two large cohorts based on electronic health records from the USA. They identify a broad range of PASC-related conditions which were only partially replicated across the two cohorts, indicating possible heterogeneity between populations.

Targeted protein degradation of cell-surface glycoproteins suppresses cancer in mice.

In order to efficiently process incoming sensory information, our brain is thought to make predictions about future events. Here, the authors show how neurons in the mouse visual cortex enhance their representation of unpredicted surprising events.

Organic cation transporters are important drug transporters that influence therapeutic outcomes. Here, the authors find that these transporters are regulated by tyrosine phosphorylation and propose that tyrosine kinase inhibitors can influence drug transporter function through post-translational mechanisms.

A high-throughput screen identified a small molecule that promoted inclusion of SMN2 exon 7, increased SMN2 protein levels and extended survival in a SMA mouse model through stabilization of the interaction between SMN2 pre-mRNA and U1 snRNP complex.

Capture Hi-C analysis reveals that DNA double-strand breaks within transcriptionally active regions of the human genome form clusters that exhibit delayed repair in the G1 phase of the cell cycle.

Anticancer treatments are tested in mice housed below thermoneutrality which represents chronic cold-stress. Here Eng et al. show that these mice have activated stress responses leading to therapeutic resistance and that inhibiting adrenergic signaling increases efficacy of anticancer therapies.

The S-layer is a two-dimensional protein array that covers the cell surface of many bacteria and archaea. Here, the authors use high-resolution X-ray crystallography and electron microscopy to provide detailed insights into S-layer organisation and assembly for the bacterial pathogen Clostridioides difficile.

Whole-ecosystem manipulations of Caribbean islands occupied by brown anoles, involving the addition of competitors (green anoles) and/or top predators (curly-tailed lizards), demonstrate that predator introductions can alter the ecological niches and destabilize the coexistence of competing prey species.

Cell-type-specific chromatin accessibility QTL during neurogenesis allow fine mapping of causal variants and more complete underlying of regulatory mechanisms underlying noncoding loci associated with gene expression and neuropsychiatric disorders.

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.

Pioneer factors are a special class of transcription factor that can associate with compacted chromatin to facilitate the binding of additional transcription factors. This Progress article discusses the importance of pioneer factors in breast cancer and prostate cancer.

An allosteric activator of Hsp70 mimics Hip and reduces neurotoxicity in a model for spinobulbar muscular atrophy by promoting ubiquitination and degradation of oligomeric polyglutamine-containing clients.

In mouse experiments and in clinical trials in humans, boosting with Omicron-specific mRNA following immunization with Wuhan-1 spike mRNA results in immune responses focused on conserved rather than variant-specific epitopes.

A systems-based approach to profile glucocorticoid (GC) receptor ligands in a broad range of assays representing different phenotypic responses linked these to transcriptional profiles and led to separation of GC therapeutic effects from side effects.

Placental dysfunction has been implicated in abnormal neurodevelopment. Vacher et al. found that loss of a neuroactive hormone from the placenta alters brain development in a regional and sex-linked manner, resulting in autism-like behaviors in male offspring.

Knowledge about the full reaction signature, such as the complete profile of products and side-products is important in accelerating discovery chemistry. Here, the authors report a methodology using high-throughput experimentation and multivariate data analysis to examine Palladium- catalyzed cross-coulpling reactions.

A correlated material SrVO₃ has been considered to be a Fermi liquid, however previous studies have been limited to disordered samples. Here the authors study transport in ultraclean films of SrVO₃, finding deviations from the Fermi liquid picture.

PTEN copy number loss is found in 25% of fusion-negative rhabdomyosarcomas (FN-RMS). Here, the authors use a Hedgehog-driven FN-RMS mouse model to show that PTEN loss drives the expression of core transcription factor PAX7 and its transcriptional axis, which determines FN-RMS tumour identity.

FAM122A is required for timely progression through the G0/G1 transition and checkpoint integrity. Here, the authors report the mechanism by which FAM122A inhibits the major B55α/PP2A Ser/Thr phosphatase using adjacent helices that dock on B55α and occlude the active site of PP2A/C.

E3 ligase subunit protein Fbxo48 interacts with phosphorylated Ampkα and mediates its proteasomal degradation. Interruption of the pAmpkα/Fbxo48 interaction by a small-molecule BC1618 promoted Ampkα activation and improved insulin sensitivity.

Here, Hiatt et al. report the knock-out of over 400 genes in primary CD4+ T cells to assess their functional role in HIV replication, finding 86 initial candidates of which 47 are validated as HIV host factors, including 23 with restrictive activity.

MYCN-amplified neuroblastoma remains an aggressive childhood cancer with its core regulatory circuits less understood. Here, the authors identify that the transcriptional corepressor Runx1t1 is indispensable for MYCN-driven neuroblastoma tumorigenesis.

A chemical screen identified BET bromodomain inhibitors as promoters of keratinocyte regenerative function and skin wound healing. Specifically, low-dose transient treatment with BET inhibitors imposes an activated, migratory state in keratinocytes.

CTLA-4 promotes glucose uptake by tumour-infiltrating regulatory T cells, making them unstable.

The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.

CLC-type channels selectively transport Cl− across biological membranes, but it is unclear how discrimination between anions is maintained. Here, authors use a combination of non-natural amino acid substitutions, electrophysiology, and molecular dynamics simulations to determine Cl⁻ specificity within this family of ion channels.

Lipophilic siRNA conjugates exert therapeutic activity in the mouse CNS.