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For Nature Aging’s fifth anniversary, we acknowledge the essential work that is done by our colleagues, without which Nature Aging’s monthly publication would not be possible. We speak with some of our internal colleagues about the process of making a journal every month. Rebecca Roberts is a production editor at Springer Nature, Mark McGranaghan is a senior sub editor, Lauren Snape is an art editor and Amanda Karmolinski is a senior editorial assistant. In this Q&A, Rebecca, Mark, Lauren and Amanda pull back the curtain and tell us about the various roles that go into putting it all together.

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

The xylosyltransferase isoenzymes XT1 and XT2 catalyze the first glycosylation step in the biosynthesis of proteoglycans. Now, bump-and-hole engineering of XT1 and XT2 enables substrate profiling and modification of proteins as designer proteoglycans to modulate cellular behavior.

Three BRAF inhibitors are used to treat melanoma and colorectal cancer. Here, the authors demonstrate that these drugs bind and activate the protein kinase GCN2, a previously unappreciated off-target effect that may modulate tumour cell responses.

Transfer RNA-derived small RNAs (tsRNAs) emerge as crucial players in biological processes but their disease relevance is unknow. Here, the authors show that tsRNA-Glu-CTC is the most abundant hepatic tsRNA that plays a key role in regulating cholesterol homeostasis and atherosclerosis development.

Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

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.

This study associates p53 loss and brain metastasis in breast cancer. Mechanistically, p53-null tumors recruit astrocytes that provide substrates for enhanced fatty acid synthesis via upregulated SCD1 expression, representing a targetable axis in the disease.

In this work, functional antibodies against the cancer-related GPCR NTS1 were generated by immunizing chickens with in silico-designed 3D peptides, offering a strategy for GPCR targeting with potential diagnostic and therapeutic applications.

Human astroviruses are a leading cause of diarrhea worldwide. Lentz et al. report the structure of the astrovirus capsid spike bound to the human neonatal Fc receptor, revealing detailed insights into how astroviruses infect human cells.

Baretić and Missoury et al. identify vertebrate proteins FAM118B and FAM118A as sirtuins similar to bacterial antiphage enzymes and show that FAM118A/B processing of NAD involves head-to-tail filament formation and a partnership between the two paralogs.

Authors demonstrate that four distinct heterodimeric complexes catalyze chondroitin sulfate chain polymerization in humans. The synthase proteins possess catalytic activity, while the polymerization factors are essential for complex formation.

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.

Computational methods are becoming an increasingly important part of biological research. Using the Rosetta framework as an example, the authors demonstrate how community-driven development of computational methods can be done in a reproducible and reliable fashion.

Palmitoylation at C64 in stimulator of interferon genes (STING) is reported and, along with engagement of C91, is involved in dynamic cross talk with C148 to alter STING oligomer states and ultimately control STING activation.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Walmsley and colleagues report that systemic hypoxia induces persistent loss of histone H3K4me3 marks and epigenetic reprogramming in neutrophil progenitors, resulting in long-term impairment of subsequent neutrophil effector functions.

Blocking peptidoglycan synthesis kills bacteria. The authors show that the E. faecium PBP5 peptidoglycan binding site is distal to the active site, which could be the focus of antibiotic strategies that hinder substrate recruitment.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

H5N1 avian influenza viruses caused an outbreak in dairy cattle. We show that the potential for avian viruses to replicate in cow cells varies across H5N1 evolution, suggesting that the risk of spillover into mammals differs between variants.

In this work, authors show that Salmonella uses its SPI-1 injectisome to infect macrophages, triggering rapid translational upregulation of transcription factors, such as EGR1 which suppresses the inflammatory response, aiding the bacteria in establishing systemic infection

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modification and identify RNF114 as an interactor. RNF114 binds tightly to this modification and further elongates it with a K11-linked ubiquitin chain.

Phosphorylation of residues in the N-terminal tail of histone H3 signals different biological outcomes. High-resolution NMR analyses now reveal a mechanistic hierarchy of H3 phosphorylation events, whereby phosphorylation of Ser10 impedes the phosphorylation of Thr6 and Thr11 by PKC and Chk1, respectively. Because both enzymes also target Ser10, this establishes an autoinhibitory feedback loop on H3 tails.

Molecular glues are monovalent compounds that can recruit a protein of interest to an E3 ligase so the protein of interest can be targeted for degradation. Here, Hughes et al. identify a molecule that selectively and potently degrades BRD9.

UBA1-mutant macrophages exposed to inflammatory stimuli undergo aberrant apoptotic and necroptotic cell death mediated by CASP8 and RIPK3–MLKL, offering insights into the mechanisms underlying VEXAS syndrome.

Myocardial infarction disrupts cardiac repair mechanisms, limiting regeneration. Here, the authors show that extracellular matrix therapies activate spatial and cell-specific pro reparative programs, revealed through spatial transcriptomics and snRNA-seq.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

Combined hormonal therapy and CDK4/6 inhibition face resistance challenges in endometrial cancer. Here, the authors present a phase 2, one-arm clinical trial, where metformin is combined with letrozole (hormonal therapy) and abemaciclib (a CDK4/6 inhibitor) reporting safety and efficacy in patients with endometrial cancer.

The autophagy protein p62 undergoes liquid-liquid phase separation but how this is regulated is unclear. Here, the authors report that the histone chaperone DAXX interacts with p62 in the cytoplasm to drive its phase separation.

Authors describe the distinct modulation by spermine on the Alzheimer’s Tau and Parkinson’s α-synuclein proteins, elucidating their protein condensation behaviors both in vitro and in vivo.

Coagulation factor IX (FIX) contributes to hemostasis through both plasma activity and binding to extravascular collagen IV. Here, the authors show that collagen binding of albumin-fused hyperactive FIX can be engineered to tailor the pharmacokinetics, distribution, and functional properties in mice for tailored short- or long-term hemophilia B therapy.

Here, authors provide a molecular view of a clustered saccharide patch on mucins as recognized by a bacterial binding module. This work provides insights into how microbes can remain attached to mucins in the mucus while grazing on their glycans.

Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.

The authors identify pathogenic variants in the SMARCA1 gene as the cause of a variable neurodevelopmental disorder. Mouse studies suggest diverse genetic mechanisms related to NURF complex composition mediate the phenotype.

How cyclins contribute to CDK1 substrate specificity during cell division is poorly understood. Here, the authors show that a phosphate-binding pocket in cyclin B1 is critical for accurate CDK1 substrate phosphorylation ensuring mitotic fidelity.

Designed novel protein nanoparticle technology integrates antibody targeting and responds to changes in environmental conditions to release protected molecular cargoes, opening new applications for precision medicine.

Chemically induced protein degradation is a powerful alternative to classical inhibition, but some proteins have deeply masked binding pockets that make the development of degrader molecules difficult. Here, the authors discover an alternate site on nuclear receptors that can be targeted by degraders.

Genetic analyses of ancestrally diverse populations show evidence of heterogeneity across ancestries and provide insights into clinical implications, highlighting the importance of including ancestrally diverse populations to maximize genetic discovery and reduce health disparities.

Therapeutic proteins are often conjugated with polymers, but separating the conjugate from unconjugated protein and free polymer is a major challenge. Here, the authors discover that proteins conjugated to charged or zwitterionic polymers maintain solubility in 100% ammonium sulfate, greatly simplifying purification.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

CRAF is one of three RAF-family kinases and is mutated in cancer and RASopathies. Jang et al. report structural and mechanistic studies of CRAF/MEK1/14-3-3 complexes that explain distinct features of CRAF regulation.

Predictive protein design and experiments are combined to develop anisotropic bifaceted protein nanomaterials using pseudosymmetric hetero-oligomeric building blocks.

This study reveals that an outer membrane protein from the predator Bdellovibrio bacteriovorus forms a pentameric assembly that traps a lipid monolayer within. This allows the discovery of two superfamilies, distributed across a wide range of bacteria, likely to adopt a similar architecture.

Developmental and epileptic encephalopathies are devastating neurological disorders. Here, the authors establish a cohort of patients with variants in the gene DENND5A and use human stem cells to discover a disease mechanism involving altered cell division.

RH5, which is part of the trimeric RCR-complex essential for invasion, is a vaccine candidate for malaria. Here, Williams et al. show that monoclonal antibodies targeting each of the three proteins in the RCR-complex can work together to more effectively block the invasion of red blood cells by Plasmodium falciparum and design a combination vaccine candidate.

Collagen proteins assemble into trimers from distinct monomers with high specificity, yet the molecular basis for this specificity remains unclear. Here the authors demonstrate the crucial role of conserved C-terminal domain cysteine residues and calcium in homotrimeric procollagen assembly.