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Replication-dependent histone mRNA decay involves the RNA helicase UPF1, the histone stem-loop binding protein SLBP and the exoribonuclease 3’hExo. Here, the authors present evidence for assembly of a degradosome-like complex involving the three proteins and delineate the mechanism that drives their concerted action to achieve histone mRNA decay.

Hexokinase detachment from the outer mitochondrial membrane is shown to support aerobic glycolysis in cancer cells. Differential localization of the HK1 isoform to the outer mitochondrial membrane, compared to the HK2 isoform, explains the conditional essentiality of HK2 in cancer cells cultured in physiologic media.

SpbK protects Bacillus subtilis from phage infection by depleting NAD⁺. In this study, the authors uncover the molecular mechanisms underlying SpbK’s self association-dependent NADase activity and its activation by the SPβ phage portal protein YonE.

A genetic study of natural variation in potato tuberization onset, an important phenotype for breeding potatoes adapted to different global day lengths, has revealed a role for StCDF1, a member of the DOF family of transcription factors.

The authors report on engineering metazoan fatty acid synthase variants with tunable selectivity to obtain short- and medium-chain fatty acids, alcohols and aldehydes. Pairing these optimized enzymes with a yeast strain designed for efficient β-oxidation yields high production levels of medium-chain fatty acids.

Zygnematophycean algae are the closest algal relatives of land plants. This study compares the osmatic stress response of two of these species, finding a core set of molecular protective components and providing insights into the toolkit needed for plant terrestrialization.

Specificity in interactions with otherwise common glycan structures is likely achieved through glycan context. Here, the authors show that such glycan context is generated through tunable glycan arrangements that are translated into function by galectins.

Cancer immunotherapy benefits from antibody-lectin chimeras that block glyco-immune checkpoints.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

H3K36me3 is a marker of actively and recently transcribed genes. Here, the authors describe a 3-step mechanism of transcription-coupled H3K36me3 deposition by the mammalian methyltransferase SETD2, via the elongation factor SPT6.

Geminin regulates DNA replication by binding CDT1 and preventing MCM helicase loading. Using a reconstituted system and structural modelling, the authors find geminin inhibits via steric clash with MCM, not by blocking the CDT1–MCM interface. Combined with CDK activity, it fully halts licensing.

Ubiquitination is a versatile modification system in eukaryotic cells. Here, the authors unveil that the ubiquitin ligase HUWE1 can modify drug-like small-molecule substrates, beyond proteins. This discovery may be harnessed to develop specific tool substrates or inhibitors of HECT-type ligases.

Integrating complex multi-omics data for individual patient decision making can be challenging. Here, the authors develop Knowledge Connector as a decision support system to generate and document Molecular Tumor Board recommendations and support medical decision-making.

How do bacteria control formate flow, essential for microbial life? Researchers detected specialized molecular checkpoints that fine-tune small-molecule transport by combining cryo-electron microscopy with in silico, in vitro and in vivo approaches.

A natural circular RNA termed ciRS-7 is shown to function as a negative regulator of microRNA; ciRS-7 acts as an efficient sponge for the microRNA miR-7, and is resistant to the usual microRNA-mediated degradation pathway of exonucleolytic RNA decay.

Measles virus and canine distemper virus (CDV) are still causing health impairments in humans and animals. Here, the authors develop a synthetic antibody protecting ferrets from lethal CDV infections, providing a roadmap for antiviral drug design.

Karposi’s Sarcoma-associated herpesvirus (KSHV) infection is associated with malignancy in older infected humans. Here the authors characterise antigen presentation using a KSHV-specific CD4⁺ T cell-derived TCR in a mouse model and show that although KSHV-specific CD4⁺ T cells are difficult to detect in humans, antigen presentation is effective in vivo suggesting persistence and accumulation of these cells through antigen recognition.

Highly pathogenic avian influenza H5N1 viruses cause mass mortality in birds and have infected over 50 mammalian species, including humans. Here, the authors report the use of a propagation-defective vesicular stomatitis virus replicon vaccine in captive birds, which provides protection against lethal H5N1 challenge.

The existing ENCODE registry of candidate human and mouse cis-regulatory elements is expanded with the addition of new ENCODE data, integrating new functional data as well as new cell and tissue types.

Selective C–H amination of electronically diverse (hetero)arene substrates is reported using an electrochemical strategy. Two convergent mechanistic pathways enable the tolerance of both electron-rich and electron-deficient (hetero)arenes. When electron-deficient substrates are used the process proceeds through electrophilic N-radical dicationic intermediates, following amine oxidation, whereas electron-rich substrates undergo arene oxidation.

A proteotoxic stress response specific to exhausted T cells, governed by AKT signaling and accompanied by increased protein translation, represents a mechanistic vulnerability and a new therapeutic target to improve cancer immunotherapies.

Here, the authors present the cryoEM structure of the sodium-translocating methyltransferase (Mtr) complex from Methanosarcina mazei. Along with providing catalytic insights, they identify MtrI, an unannotated small protein, bound to the Mtr complex in a redox-dependent manner.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

Here the authors report that brown adipocyte-derived vaspin reduces heat-producing activity in brown fat by blocking adrenergic signals, helping to regulate energy expenditure and maintain metabolic balance.

The DNA-dependent protease SPRTN cleaves toxic DNA-protein crosslinks (DPCs). Here, the authors show that SPRTN is activated by DPC-ubiquitylation through an allosteric ubiquitin binding interface. This regulatory mechanism enables precise control of SPRTN activity during DNA repair.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

Covalent inhibitors that selectively target bacterial enzymes are potential antibiotic drug candidates. Here, the authors apply high-throughput screening to identify selective covalent inhibitors that target serine hydrolases in Staphylococcus aureus

The control of regulatory enzymes is essential for the modulation of biochemical cellular pathways. Here, the authors fabricate a tweezer-like DNA nanodevice to actuate the activity of an enzyme/cofactor pair, and are able to control enzyme inhibition and activation over multiple cycles.

Here, the authors show that physiological alpha-synuclein supports mitochondrial ATP homeostasis via interactions with ATP synthase and AK2, whereas its disease-linked mutants, truncated forms, and aggregates lose these interactions.

A synthetic biology system called SMART has been developed that uses conditional protein splicing for the programmable ligation of functional proteins from previously defined molecular combinations on cell surfaces.

The authors demonstrate a proof-of-principle example of an NH-π hydrogen bond on the surface of an intrinsically disordered protein through detection of weak scalar couplings by NMR, supported by Molecular Dynamics simulation and DFT calculations.

Marine sponges host bacteria that produce diverse bioactive compounds. Here, the authors conduct a large-scale metagenomic, single-bacterial and biochemical study to reveal the untapped biosynthetic potential of ‘Entotheonella’ symbionts, a talented producer taxon from microbial dark matter.

The type I interferon response is suppressed during early development, making embryos susceptible to pathogens. Here, the authors show that this suppression contributes to normal development by preventing an aberrant immune response against endogenous double stranded RNAs.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

While the emergence of immune checkpoint inhibitors has improved outcomes in patients with small cell lung cancer (SCLC), tumour that develop means of immune evasion become resistant. Here, the authors report that ERBB2 signalling induces loss of MHC Class I expression and subsequently immune evasion in preclinical models of SCLC.

In this work, authors show that colistin-resistance plasmids in Escherichia coli, via MCR-1 and a plasmid-encoded regulator, upregulate surface polysaccharide synthesis, enhancing antibiotic resistance and virulence and defining a mechanistic link between resistance and pathogenicity.

The conserved eukaryotic heterotrimeric NatC complex co-translationally acetylates the N-termini of numerous target proteins. Here, the authors provide insights into the catalytic mechanism of NatC by determining the crystal structures of Saccharomyces cerevisiae NatC in the absence and presence of cofactors and peptide substrates and reveal the molecular basis of substrate binding by further biochemical analyses.

Here the authors show that the m¹G9 post-transcriptional methylation differentially regulates the stability of the native and the MELAS variants of human mt-Leu(UAA) tRNA, contributing to mitochondrial pathology.

SARS-CoV-2 continues to evolve, necessitating updated vaccines and therapeutics. Here the authors identify three broadly binding antibodies from vaccinated or infected individuals, characterize their conserved non-overlapping RBD epitopes by structural analysis and demonstrate protective effects in a hamster model.

The loading of the replicative helicase MCM2-7 is vital for replication fork assembly. Here, the authors reconstituted human MCM2-7 loading and identified the roles of Cdc6 in complex resolution and cancer-associated mutations in Mcm3 recruitment.

Here the authors show that two conserved transcription factors are required for heat stress memory in barley by mediating proper induction of heat-response genes after recurring heat stress. Overexpressing one of them increases heat tolerance without affecting growth.

Maintenance and quality control of the mitochondrial respiratory chain complexes responsible for bulk energy production are unclear. Here, the authors show that the mitochondrial protease ClpXP is required for the rapid turnover of the core N-module of respiratory complex I, which happens independently of other modules in the complex.

FcγRI binds immune complex (IC) to contribute to various autoimmune diseases, but a specific blocking antibody has not been reported. Here the authors characterize two anti-FcγRI antibodies that block and replace IC-binding to FcγRI in the context of patient-derived samples or a mouse immune thrombocytopenia model to implicate potential clinical translation.

During infection, the Legionella effector Lem3 removes a phosphocholine moiety from the human protein Rab1. Here, the authors present the crystal structure of the stabilised Lem3:Rab1b complex, revealing the catalytic mechanism and substrate recognition of PPM phosphatases shaped Lem3.

Jungnickel, Guelle et al. use metabolomics, electrophysiology and cryo-EM approaches to show that MFSD1 is a lysosomal dipeptide uniporter, which provides an additional route to recycle lysosomal proteolysis products to lysosomal amino acid exporters.

Lymphostatin is a large protein required for Escherichia coli virulence. Here, Griessmann et al. use electron cryo-microscopy to describe the structure of lymphostatin determined at different pH values, showing three conformations, six distinct domains, and long inter-domain linkers that occlude the catalytic sites of the N-terminal glycosyltransferase and protease domains.

Polyproline motifs induce ribosome stalling during translation. Here, Ignatov et al. identify RNA-binding proteins in the pathogenic bacterium Streptococcus pyogenes, and show that one of these proteins, YebC, acts as a translation factor enhancing translation of proteins with polyproline motifs.