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The response to immunotherapy of melanoma patients is heterogeneous. Here, the authors demonstrate that a high expression of the two major components of the immunoproteasome, PSMB8 and PSMB9, modulates the production of HLA peptides and it is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients.

Through-plane conductivity in anion-exchange membranes is beneficial for their use in fuel cells as it aids movement of ions from cathode to anode. Liu and colleagues use ferrocenium polymers and an applied magnetic field to orient ion channels appropriately and achieve improvements in stability by formation of magnetically induced mixed-valence states.

Here, Delaroque et al. show that maternal intake of dietary emulsifiers alters offspring microbiota early in life, which, associated with perturbation of goblet cell function, promotes increased susceptibility to inflammatory diseases in adulthood.

Tumor-associated neutrophils exhibit heterogeneity in breast cancer. Here, the authors identify a distinct precursor population (PreNeu) in estrogen receptor-positive tumors. PreNeu suppress homologous recombination in cancer cells, promoting error-prone DNA repair and enhancing sensitivity to PARP inhibitors.

The brain is vulnerable to stress and disease, with much work focused on defining mechanisms that impact the brain’s resilience. Here the author’s reveal in Drosophila that m⁶A epitranscriptomic modification of RNA dampens the brain’s capacity to mitigate stress by regulating RNA stability and translation.

The study used Pupylation-based proximity labelling (PUP-IT) to detect protein-protein interactions (PPIs) in plants, revealing components that regulate cellulose synthesis. The work highlights PUP-IT as a powerful tool to identify plant cell PPIs.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Here the authors show that rRNA methylase DIMT-1 regulates aging by acting after mid-life in the germline, regulating specialized ribosomes that perform selective translation of mRNAs important for longevity. Thus revealing an additional layer of proteome dysfunction as an aging regulator.

R2TP is an HSP90 co-chaperone composed of an RPAP3-PIH1D1 heterodimer, which binds two essential AAA+ ATPases RUVBL1/RUVBL2. Here authors use a structural approach to study RPAP3 and find an RPAP3-like protein (SPAG1) which also forms a co-chaperone complex with PIH1D2 and RUVBL1/2 enriched in testis.

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 chromosomal kinase JIL-1 is responsible for interphase histone H3S10 phosphorylation and has been proposed to protect active chromatin from heterochromatinisation. Here, the authors show that JIL-1 is stabilized and anchored to active genes and telomeric transposons by JASPer, which binds to H3K36me3 nucleosomes via its PWWP domain.

Here, the authors unveil the evolutionary conservation of lysine-rich IDRs of snoRNPs that mediate both efficient rRNA modification during active ribosome production and nucleolar compaction when ribosome synthesis declines and snoRNPs accumulate in latent state.

A comprehensive proteomics-based interactome map of adaptor protein complexes in Arabidopsis identifies P34 as a key regulator of the stability of clathrin-associated adaptors and their related trafficking routes.

UVRAG is involved in autophagy, which loses its tumour suppressor functions when in its truncated form in cancers. Here, the authors use a mouse model that inducibly express this truncated protein and show impaired autophagy, enhanced inflammation and β-catenin stabilisation, which promotes spontaneous tumorigenesis.

Ubiquitination of misfolded proteins usually results in protein degradation. Here, the authors show that two deubiquitinases—enzymes that remove ubiquitin—are required for the proteasomal degradation of misfolded proteins in response to heat-shock in yeast.

Biogenesis of small nucleolar RNAs ribonucleoproteins (snoRNPs) requires dedicated assembly machinery. Here, the authors show that a subset of snoRNP assembly factors interacts, genetically or directly, with factors modulating chromatin architecture, suggesting a link between ribosome formation and chromatin functions.

Lu et al. created a human ocular outflow on-chip, composed of 3D Schlemm’s canal endothelium surrounded by trabecular meshwork and draining interstitial fluid, revealing ALK5/VEGFC signaling as a therapeutic target for steroid-induced glaucoma.

The order of DNA methylation and histone modifications during transcription remained unclear. Here the authors show that HMGA2 induces DNA nicks at TGFB1-responsive genes, promoting nucleosome incorporation containing γ-H2AX, which is required for repair-mediated DNA demethylation and transcription.

Aharonov et al. use in vivo genetic approaches to show that ErBB2-mediated YAP activation initiates epithelial–mesenchymal transition-like processes and dedifferentiation of cardiomyocytes to drive heart regeneration.

DNA methylation in the brain is a dynamic process, but gene-specific regulation of this process is poorly understood. Here, Day and colleagues show that extra-coding RNAs interact with DNA methyltransferases and regulate neuronal DNA methylation to control gene expression in locus-specific manner in neurons.

Experiments in mice identify the medial septum as an extrahippocampal input region that is critical for social memory formation, and show that modulation of the medial septum by serotonin regulates the stability of social memories.

Small nucleolar RNAs (snoRNAs) are known for their role in RNA modification to regulate gene expression. Here, the authors identify a snoRNA that not only guides ribosomal RNA 2’- O-methylation but also modulates the activities of RNA-binding proteins involved in fission yeast gametogenesis.

Function of nucleosomal acetyltransferase of H4 (NuA4), one major complex of HAT, remains unclear in plants. Here, the authors generate mutants targeting two components of the putative NuA4 complex in Arabidopsis (EAF1 and EPL1) and show their roles in photosynthesis genes regulation through H4K5ac and H2A.Z acetylation.

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

Insulin secretion adapts to metabolic needs, but how this happens over the short term is not clear. Here the authors show this involves upregulation of beta-cell exocytosis and requires the SUMO-protease SENP1, which responds to redox state in a zinc-dependent manner.

LATS1 is reported to regulate the transition of luminal-basal-like cell plasticity in breast cancer. Here the authors report that LATS1 limits the progression of luminal breast cancer by associating with NCOR1 nuclear corepressor to repress ERα-downregulated genes in luminal cells.

Golub and colleagues identify the phosphate exporter XPR1 as a therapeutic vulnerability in ovarian and uterine cancers, and show that phosphate efflux inhibition reduces tumor cell viability through accumulation of intracellular phosphate.

Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Nancy Y. Ip is Vice President for Research and Graduate Studies, the Morningside Professor of Life Science, and Director of the State Key Laboratory of Molecular Neuroscience at the Hong Kong University of Science and Technology, Hong Kong, China. Her career in the field of neuroscience spans over three decades.

Very little is known about biological sex differences in influenza disease outcome. In 2013, avian influenza (H7N9) infections in humans have been reported with higher frequency in men than women. Here, Bai et al. report that low testosterone levels in men correlate with poor infection outcome. They confirm the causal link between viral infection and testosterone depletion using a mouse model.

Sjögren’s syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

To correct the market failure around pediatric cell and gene therapies, the authors propose a new model to lead late-stage development and commercialize these therapies outside traditional routes.

The ubiquitin–proteasome system clears misfolded proteins to maintain cellular homeostasis. Mayor and colleagues identify the ubiquitin ligase Hul5 as a critical component of the heat-shock response and show that it selectively targets misfolded cytosolic proteins for degradation.

TDP-43 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTD-TDP). Here, the authors identify the transcriptional elongation factor Ell as a strong modifier of TDP-43-mediated neurodegeneration through the Ell transcriptional elongation complexes LEC and SEC.

High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

The use of an aryl boronic acid carbonyl warhead to target a noncatalytic lysine side chain enables the development of covalent inhibitors against the anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1).

Inborn errors of vitamin B₁₂ metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.

Induction of CD4 T follicular helper (Tfh) cells is important for antibody responses to viral infections. Here, the authors show in a rhesus macaque model of mild COVID-19 that SARS-CoV-2 infection results in transient accumulation of proliferating Tfh cells with a Th1 profile in peripheral blood and generation of germinal center Tfh cells specific for viral proteins.