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Deep neural networks hold significant promise in capturing the complexity of biological systems. However, they suffer from a lack of interpretability. Here, authors present a generalizable method for developing, interpreting, and visualizing biologically informed neural networks for proteomics data.

cAMP export by ABCC4 is critical for localized signaling. Here, the authors revealed that PKA activation drives ABCC4 to the plasma membrane and organizes a PDZ-dependent protein network with actin cytoskeleton and scaffolds, like SCRIB, that stabilize the transporter and optimize cAMP efflux. Furthermore, the authors show that the potent ABCC4 inhibitor Ceefourin 2 disrupts this network, revealing a non-canonical mechanism of ABCC4 inhibition.

Bond et al. show that inducible PolG mutation in muscle causes mtDNA damage and muscle wasting. This is driven by the integrated stress response (ISR) and reduction in folate intermediates, linking impaired folate metabolism with ISR/disease induction.

Here the authors describe a stabilization technology that engineers crosslinks between tyrosine sidechains into a natively folded vaccine immunogen and show that immunogenicity is improved in small animal models by locking the most potently neutralizing epitopes.

A computational pipeline identifies tumor antigen post-translational modifications guiding immune responses.

This study shows that animal-based high-fat diets accelerate tumour growth and impair anti-tumour response to melanoma in obese mice, whereas plant-based high-fat diets do not.

Fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with long COVID.

Immunoglobulin light chain amyloidosis is a lethal hematologic disorder driven by clonal plasma cells producing abnormal light chains that damage healthy tissues. Fraser et al. show that BH3 mimetics, which inhibit pro-survival proteins BCL-2 or MCL-1, can effectively eliminate diseased cells.

In patient with glioblastoma, a major cause of resistance to chemotherapy and radiotherapy is the high degree to intratumoral heterogeneity and cell plasticity. Here, the authors demonstrate that chemoradiation induces the reprograming of glioblastoma cells into an invasive and vessel co-opting state, termed VC-Resist, capable of promoting resistance to therapy.

ATG5 expression in neutrophils counters type I interferon signalling and downstream activation of neutrophil swarming and NET release to limit disease severity during Mycobacterium tuberculosis infection.

A generalized precursor scoring method increases protein identification rates and overall quantitative accuracy in data independent acquisition mass spectrometry proteomics and can generalize to new data.

Here, the authors discover small molecules that inhibit glycosylation processes that occur in the Golgi apparatus of cells. The molecules reversibly inhibit formation of elaborate glycan structures without affecting secretion of glycoproteins.

US conservatives receive a steady stream of anti-environmental messaging from Republican politicians. However, clean-energy conservatives sending strong counter-messages on energy issues could mobilize moderate conservatives to break away from the dominant right-wing defence of fossil fuels.

Bacterial cell growth and division require the coordinated action of enzymes that synthesize and degrade cell wall polymers. Here, the authors identify enzymes that cleave the D-arabinan core of arabinogalactan, an unusual component of the cell wall of Mycobacterium tuberculosis and other mycobacteria.

An autophagy receptor, NDP52, is recruited to the nucleus where it can bind DNA. The authors show this promotes changes in chromatin accessibility which supports transcription initiation, providing a direct link between autophagy and transcription regulation.

Monomethylation of histone H4 lysine 20 (H4K20me1) contributes to DNA replication but the mechanism is not well understood. Here, the authors identify a conserved tandem Tudor domain of BAHCC1 as a H4K20me1-specific reader, which promotes the recruitment of MCM complex to chromatin for efficient DNA replication.

The cohesin complex maintains genome integrity by ensuring correct sister-chromatid segregation during mitosis and meiosis. Here, Chaoet al. present a pseudo-atomic model of the full-length Scc2–Scc4 cohesin loader complex and reveal key Scc2 surfaces crucial for cohesin loading.

Papa et al. show that phosphorylation by PKA of four residues in Rad, a calcium channel inhibitor, is required to mediate the β-adrenergic-induced increase in calcium current and contractile force. Additionally, Rad-phosphosite-mutant mice showed reduced basal heart rate and contractility. Conversely, expression of mutant calcium channel unable to bind wild-type or phosphosite-mutant Rad was sufficient to enhance basal calcium influx and contractility, independently of β-adrenergic stimulation.

Chemical modification of mRNA nucleobases alters hydrogen bonding during translation. Here the authors show that the N1-methylpseudouridine (m1ψ), used in therapeutics, does not change translation rate but modestly modulates its fidelity in a codon-position and tRNA dependent manner.

Discovering molecular pathways that sensitize cells to poly(ADP-ribose) polymerase (PARP)- trapping inhibitors is important for anti-cancer therapy. Here, the authors report that inactivation of the CHD6 chromatin remodelling enzyme sensitizes cells to PARP inhibitors via reduced abasic site repair, PARP-1 accumulation on chromatin, and replication stress.

Substrate-rigidity-dependent microtubule acetylation is now shown to be triggered by mechanosensing at focal adhesions, and in turn controls the mechanosensitivity of Yes-associated protein (YAP) translocation, focal adhesion distribution, actomyosin contractility and cell migration.

The BAF chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells.

Emerging SARS-CoV-2 variants of concern were detected early and multiple cases of virus spread not captured by clinical genomic surveillance were identified using high-resolution wastewater and clinical sequencing.

Here the authors demonstrate that the assembly of mitochondrial respiratory supercomplex (III₂–IV) from Toxoplasma gondii is critical for parasite fitness. They reveal the basis for cytochrome b inhibition by atovaquone and improved ELQ inhibitors.

In this study authors use morphological profiling and CRISPR/Cas9 genetic screens to investigate the mechanisms by which BiDACs induce the degradation of plasma membrane receptor tyrosine kinases (RTKs) EGFR and Her2.

Merbl and colleagues demonstrate that high expression of the proteasome regulator PSME4 is associated with immune-cold lung tumors and reduced antitumor immune responses, by functioning to modulate the protein degradome and antigen diversity.

Fully replication competent HIV-1 viruses engineered to harbour a foreign epitope tag enabled the unbiased characterization of the cellular interactomes of viral Env and Vif proteins during the natural infection of human lymphocytes.

Proteasomal degradation of cellular proteins generate defence peptides constitutively and in response to bacterial infection. Such peptides might provide a source of natural antibiotics that could lead to biotechnology applications and therapeutic interventions.

Here, Franklin et al show that the mycobacterial glycoside hydrolase LamH cleaves lipomannan and lipoarabinomannan from their lipid carrier, facilitating the export of the polysaccharide domain and signalling bacterial growth phase transition.

Glutathione has pleiotropic functions in different organs. Here the authors specifically examine deletion of a glutathione synthetic enzyme in the liver of adult mice and show that lack of glutathione affects lipid abundance through repressing NRF2.

A human binary protein interactome map that includes around 53,000 protein–protein interactions involving more than 8,000 proteins provides a reference for the study of human cellular function in health and disease.

Personalized treatment for cancer patients relies on the deep characterization of tumor cells from patient biopsies. In this study, functional multi-omics profiling of a pan-cancer cohort of malignant serous effusions (MSE) finds strong coherence between MSE and matched solid tumors, underlining the feasibility and utility of multi-modal MSE-based precision oncology.

Evidence for the abundant presentation of class II neoantigens by a human B-cell lymphoma.

VVD-133214, a clinical-stage, covalent allosteric inhibitor of the helicase WRN, was well tolerated in mice and led to robust tumour regression in multiple microsatellite-instability-high colorectal cancer cell lines and patient-derived xenograft models.

Multi-Omic approaches are a powerful way for obtaining in-depth understanding of a cell’s state. Here the authors present DISCO, combining digital microfluidics, laser cell lysis, and artificial intelligence-driven image processing to analyze single-cell genomes, transcriptomes and proteomes in a mixed population.

ATG9 is the only transmembrane protein of the core autophagy machinery known to be present at presynapses. Here, the authors show that both synaptophysin and ATG9A vesicles assemble into condensates with synapsin but remain segregated from each other.

Schizophrenia (SZ) is a severe psychiatric disorder; unfortunately, only ~1/3 of patients respond favorably to treatment. Here, the authors reveal hyperacetylation of histone H2A.Z in SZ neurons and postmortem SZ human brain tissues. They further show BRD4 is a reader of hyperacetylated H2A.Z and treatment with bromodomain inhibitor JQ1 largely rescues abnormal gene expression associated with SZ.

The mechanisms regulating mitosis and differentiation during development are thought to be distinct. Here they show that in Drosophila the mitotic kinase Polo regulates cellular morphogenesis after cell cycle exit.

Defective angiogenesis remains a high source of morbidity in multiple disorders. Here they show that β_IV-spectrin, a membrane-associated cytoskeletal protein, is essential for regulation of endothelial tip cell populations and VEGF signaling during sprouting angiogenesis.

Wiita and colleagues use cross-linking mass spectrometry and glycoprotein surface capture to identify an activated conformation of integrin β₂ present on AML cells and develop CAR T cells that target this conformation antigen in preclinical models.

Fermentation parameters of industrial processes are often not the ideal growth conditions for industrial microbes. Here, the authors reveal that young genes are more responsive to environmental stress than ancient genes using a new gene age assignment method and provide targeted genes for metabolic engineering.

Phosphorylation of CENP-A on serine 7 has been proposed to control centromere assembly and function. Here, the authors use gene targeting at both endogenous CENP-A alleles and gene replacement in human cells to demonstrate that CENP-A that cannot be phosphorylated at serine 7 maintains correct CENP-C recruitment, faithful chromosome segregation and long-term cell viability.

Genome-scale metabolic models have been widely used for quantitative exploration of the relation between genotype and phenotype. Here the authors present GECKO 2, an automated framework for continuous and version controlled update of enzyme-constrained models of metabolism, producing an interesting catalogue of high-quality models for diverse yeasts, bacteria and human metabolism, aiming to facilitate their use in basic science, metabolic engineering and synthetic biology purposes.

Cleavage products of the proteasome are profiled by mass spectrometry.

A genome-wide Tn-seq analysis of the rpoB H526Y mutant, a rifampicin-resistant Escherichia coli strain, identifies non-essential genes that modulate the fitness cost of mutations in the bacterial RNA polymerase that confer antibiotic resistance.

Lower activity of MATα1, which catalyzes the synthesis of the methyl donor S-adenosylmethionine, and mitochondrial dysfunction occur in alcohol-associated liver disease (ALD). Here the authors report that the peptidyl-prolyl cis/trans isomerase PIN1 mediates a selective depletion of MATα1 in the mitochondria, which contributes to mitochondrial dysfunction and fat accumulation, in mouse models of ALD.

The NUP98–HOXA9 oncogenic fusion protein found in leukaemia undergoes phase separation in the nucleus, which helps to promote activation of leukaemic genes and to establish aberrant chromatin looping.

The innate immune response in epithelial cells after SARS-CoV-2 infection is not fully understood. Here the authors use human air-liquid interface culture and show single cell transcription changes and delayed type I Interferon responses after SARS-CoV-2 infection compared with other respiratory viruses.