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Knee osteoarthritis has a sex-specific phenotype with post-menopausal persons experiencing the highest incidence. Here the authors investigate the underlying mechanisms in a mouse model of menopause and find that the loss of 17β-estradiol and progesterone enhanced susceptibility to senescence, extracellular matrix disassembly and cartilage degradation.

The authors characterize immune response in Omicron-infected vaccinated individuals and observe an immune enhancement. While increases in neutralizing antibodies and spike T cells are stronger in previously naïve individuals, mucosal antibodies and non-spike responses increase regardless of infection history.

B₁₂-dependent human methylmalonly-CoA mutase (MMUT) requires the chaperone MMAA. The authors report the crystal structure of MMUT-MMAA, which shows a MMAA-driven conformational change in MMUT involved n B₁₂ loading and repair and helps explain the effects of disease-causing MMAA-MMUT interface mutations.

High-resolution cryo-EM structures of S. aureus ABC transporter PmtCD in apo and ADP-bound states in multiple membrane mimetics define a large intramembrane lumen, adding insight to the export of virulence peptides during staphylococcal infections.

The optimization of organic mixed ionic-electronic conductor is critical to realize high performance organic electrochemical transistors. Here, the authors demonstrate the removal of residual palladium impurities to be the key factor to achieving a figure-of-merit of [μC*] of over 2000 V⁻¹ cm⁻¹ s⁻¹.

Cryo-electron microscopy structures of Staphylococcus aureus BlaR1 reveal dynamic signalling states regulating broad spectrum β-lactam antibiotic resistance through cleavage of the transcriptional repressor BlaI and induced expression of the β-lactamase blaZ and the β-lactam-resistant cell-wall transpeptidase mecA.

Glioblastoma is an aggressive type of cancer with poor patient prognosis. Here, the authors show that T cells armed with an FGL2-specific scFV can induce antitumour responses mediated by tissue-resident memory T cells in the brain.

Smut fungi secrete effector proteins that suppress host plant immunity. Here the authors show that the corn smut effector Erc1 has 1,3-β-glucanase activity and promotes virulence in maize leaves by attenuating β-glucan-induced defense responses.

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.

AmpG is an MFS importer of bacterial cell wall fragments. Here, authors present a cryoEM structure and supporting mutagenesis to illuminate AmpG’s essential role in bacterial fitness and derepression of broad-spectrum β-lactam antibiotic resistance.

Past experiences and future predictions both shape our decisions. Here, the authors trained participants in a foraging task in which reward rates varied systematically over time and find the dACC tracks both recent and past reward rates, leading to opposing effects on decisions about whether to stay or leave a reward environment.

Lee et al. discovered two synthetic small molecules (Maya1 and Maya2) that interact with the plant flagellin receptor FLS2 in Arabidopsis. These molecules weakly activate FLS2, eliciting an atypical immune response that helps protect plants from bacterial infection.

Two-year interim data from an ongoing phase 1/2 trial of the AAV-based gene therapy bidridistrogene xeboparvovec in six patients with limb-girdle muscular dystrophy show a safe profile and preliminary increased expression of the β-sarcoglycan protein.

Correlated light and electron microscopy (CLEM) is particularly powerful when applied in super-resolution.

Transgenerational transmission of acquired immunological traits has been demonstrated in invertebrates and plants but not mammals. Katzmarski et al. demonstrate that trained immunity that protects against heterologous infections can be transmitted to F2 offspring.

Macropinocytosis is a cellular process for the uptake of extracellular fluid. Here, the authors use lattice light sheet microscopy to examine the spatial dynamics of the plasma membrane, PI3K activity, and structural differences of various macrophage cell types during macropinocytosis.

Toll-like receptors engage TIR domain-containing adaptors to control proinflammatory gene expression in response to pathogens and tissue damage. Here the authors show that the non-TIR domain-containing transmembrane protein SCIMP is a previously unrecognized TLR adaptor expressed by macrophages.

Here the authors use UK Biobank data to identify 251 genetic loci associated with serum triglycerides to HDL-cholesterol ratio, a surrogate marker for insulin resistance. Key genes, including PLA2G12A, PLA2G6, and TNFAIP8, offer potential therapeutic targets for metabolic diseases.

Mitochondrial dysfunction is linked to various rare genetic disorders and common age-related diseases, but few compounds can stimulate mitochondrial activity. Here, the authors address this issue by developing atomic vacancy-rich molybdenum disulfide nanoparticles that can catalyze intracellular reactive oxygen species to enhance mitochondrial biogenesis and cellular respiration.

The structure of a neutralizing human monoclonal antibody isolated from an individual immunized in a Plasmodium vivax Duffy binding protein vaccine clinical trial, in complex with its target, elucidates the mechanism by which parasite invasion of immature red blood cells is inhibited.

The intact proviral DNA assay quantifies the genomically intact HIV reservoir, but assay failure due to HIV-1 polymorphism has been observed. Here, the authors report a 28% failure rate in a cohort of people with HIV-1, and note within-host HIV-1 diversity as a further challenge to IPDA accuracy.

The fork protection complex (FPC), including the proteins TIMELESS and TIPIN, stabilizes the replisome to ensure unperturbed fork progression during DNA replication. Here the authors reveal that that SDE2, a PCNA-associated protein, plays an important role in maintaining active replication and protecting stalled forks by regulating the replication fork protection complex (FPC).

Posfai, Schell, Janiszewski et al. assess candidate totipotent stem cells with in vitro and in vivo assays of increasing stringency to evaluate their developmental potential and lineage contributions.

There is growing need for ways to slow or prevent Alzheimer’s disease (AD). Here, the authors demonstrate that a low protein diet can protect against metabolic dysfunction, slow AD progression, and preserve cognitive function in a mouse model of AD.

Cocaine-generated silent synapses dictate the encoding, consolidation, retrieval-induced destabilization and reconsolidation of cocaine memories, and these syapses can be targeted to reduce drug seeking and relapse.

Profiling of single mammalian cells has revolutionized our understanding of complex biological processes. Here, the authors describe a novel mass spectrometry-based sample preparation and acquisition strategy to deeply characterize the proteome at single cell resolution.

After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice.

Targeted protein degradation uses small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation, but only a few human E3 ligases are amenable to this strategy. Here, the authors identify and characterize SP3N, a specific degrader of the prolyl isomerase FKBP12, containing an FKBP12 ligand appended with a flexible alkylamine tail that is metabolized to an active aldehyde species which recruits the SCF^FBXO22 ligase for FKBP12 degradation.

Cai et al. show that YAP forms liquid-like condensates in the nucleus that compartmentalize YAP’s DNA binding cofactors and transcription co-activators to induce transcription of YAP-specific proliferation genes.

Selective ERK5 inhibitors target ERK5 kinase activity, but they do not phenocopy the effects of ERK5 genetic depletion. Here, the authors demonstrate that the direct interaction of these inhibitors to ERK5 kinase domain induces conformational changes that promote ERK5 nuclear translocation and transcriptional activities.

Cryo-EM imaging of the needle complex of the SPI-1 type III secretion system from Salmonella enterica serovar Typhimurium at different stages of complex assembly elucidates how needle assembly initiation is regulated and how the inner membrane and outer membrane rings of the complex interact, even with apparently incompatible symmetries.

Metabolic liver disease is highly prevalent in subjects with obesity and involves inflammation, insulin resistance, and fibrosis, leading to cirrhosis. Here, the authors show the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and playing a major role in the pathogenesis of metabolic liver disease.

Small-angle X-ray scattering and crystal structures of the PA28 proteasome regulator from Plasmodium falciparum, combined with cryo-electron microscopy structures of the 20S proteasome in complex with these regulatory PA28 proteins and molecular dynamics simulations, elucidate the regulatory mechanisms of parasite proteasome degradation.

RMC-7977, a multi-selective RAS(ON) inhibitor, exhibits potent tumour-selective activity in multiple pre-clinical models of pancreatic ductal adenocarcinoma through a combination of pharmacology and oncogene dependence.

Precise profiling of dendritic RNA regulation reveals how neuronal depolarization leads to ribosome switching onto short upstream open reading frames and new coding sequences to acutely modulate local protein synthesis.

The structural connectome is the complete set of anatomical connections between brain cells. Here, the authors perform a genome-wide association study of white-matter structural connectivity in the human brain, finding 30 variants influencing the density of myelinated connections between brain regions.

Our structural understanding of class A penicillin binding proteins is incomplete due to the difficulty in their crystallization and the complexity of their substrates. Here, authors determine the structure of the 83 kDa class A PBP from Escherichia coli, PBP1b, using cryogenic electron microscopy and a styrene maleic acid anhydride membrane mimetic.

Single-cell transcriptomics and protein expression analyses of salivary glands and gingiva, along with the detection of infectious virus and virus-specific antibodies in saliva from SARS-CoV-2-infected individuals, support a potential role for the oral cavity in COVID-19 pathogenesis.

Arctic warming thaws permafrost, leading to enhanced soil mercury transport to the Arctic Ocean. Mercury isotope signatures in arctic rivers, ocean and atmosphere suggest that permafrost mercury is buried in marine sediment and not emitted to the global atmosphere

JWST observations of GRB 221009A reveal the associated supernova, confirming that the GRB resulted from the collapse of a rapidly rotating massive star. The lack of r-process emission suggests that these extreme events are not key sources of the heaviest elements.

A two-dimensional crystalline polymer of C₆₀, termed graphullerene, is synthesized by chemical vapour transport, and mechanically exfoliated to produce molecularly thin flakes with clean interfaces for potential optoelectronic applications.

Structural studies of human polysialyltransferase ST8SialII in apo form and in complex with donor sugar and sulfated glycan acceptor shed light on the substrate binding and specificity as well as the catalytic activity of this class of polysialyltransferases.

Antibodies targeting the HIV-1 fusion peptide rarely achieve more than 60% neutralization breadth. Here, the authors develop an anti-FP antibody enhancing its potency to 80% and structurally resolve the expanded FP-binding site that allows the antibody to target diverse viral variants.

A substantial proportion of patients with cardiometabolic conditions appear to have normal BMI. Conversely, not all obese individuals exhibit these disorders. Here, we show that a metabolic BMI score derived from lipidomic models, allows quantify metabolic dysregulation in obesity independently of BMI.

Deep learning-based computer vision tools are transforming animal behavioural research; however, many challenges remain. Here, Plum et al. present replicAnt, a novel tool for generating synthetic data to train computer vision models for animal behaviour studies, reducing the need for manual annotation.

The composition of lipid nanoparticles for the delivery of tumour-antigen-encoding mRNA can be optimized via a screening method to enhance antitumour activity via the modulation of the immune activity of helper T cells.