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Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

Plasmacytoid dendritic cells produce type I interferons in response to viral sensing. Here the authors show that amines inhibit these plasmacytoid dendritic cell responses through CXCR4 engagement.

A platform using matched patient-derived lung tumouroids and healthy lung organoids enables accurate examination of patient responses to CAR T therapy and offers a faithful framework for improved CAR T design.

Therapy to allergy often targets a specific allergen without addressing cross-reactivity. Here the authors develop a consensus, cross-reactive allergen, use mRNA-lipid nanoparticle immunization to induce specific, neutralizing IgG responses, but find no therapeutic effects in mouse allergy models, hinting the need for further optimization prior to translation.

Via high-throughput imaging and tracking over 140 million single mycobacteria, the authors show that drug- and strain-specific killing predict treatment outcomes, with potential to improve drug development and personalized therapy.

This study reports a modular-cloning-based platform for high-throughput chloroplast engineering in Chlamydomonas reinhardtii that allows large-scale characterization of genetic parts and prototyping of new traits, as demonstrated for the photorespiration pathway.

Tumour-antigen-pulsed mature dendritic cells (DC) have not been as efficient for cancer therapy as hoped to be, due to their sub-optimal antigen-presentation and migration capacities. Here the authors utilise DC progenitors, constitutively expressing IL-12 and an engineered extracellular vesicle-internalizing receptor (EVIR), which give rise to mature conventional type 1 DCs with improved antigen presenting capacities, resulting in improved anti-tumour immunity in a mouse model of melanoma.

Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.

Interleukin-1β is a pro-inflammatory cytokine of medical importance. Here the authors describe the discovery of a low-molecular weight compound that antagonizes hIL-1β function in cells, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.

The Michael-type addition reaction is used for carbon-carbon bond formation; however biocatalytic methods for this reaction are rare. Here, the authors generate and exploit mutability landscapes of 4-oxalocrotonate tautomerase to direct the redesign of this promiscuous enzyme into enantio-complementary Michaelases.

Deep Visual Proteomics combines machine learning, automated image analysis and single-cell proteomics.

Compared to traditional Cas9 nucleases prime editors (PEs) are less active. Here the authors use OrthoRep, a yeast-based platform for directed protein evolution to enhance the editing efficiency of PEs: they identify mutations that have a positive effect on kinetics and use this knowledge to generate an efficient in vivo PE.

The SCOOP signalling peptide family expands to 50 members, whose activities are strictly dependent upon the receptor kinase MIK2. Two subtilase classes process PROSCOOPs, generating bioactive SCOOP peptides. A subtilase mutant phenocopies the mik2 receptor mutant.

Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants.

Melanocortin-4 receptor (MC4R) is key in controlling hunger. Here, authors discover the MC4R-specific, potent agonist nanobody pN162. The pN162-MC4R-Gs-Nb35 structure shows its distinct binding mode compared to peptide agonists.

In this paper, Mutlu et al. identifies a STING degrader, AK59, which inhibits downstream cGAS/STING activity through STING degradation employing a HECT-domain E3 ligase HERC4 and proteasomal ubiquitination pathway.

Gut microbiota contribute to the pathogenesis of ulcerative colitis (UC), but the molecular mechanisms are still unclear. Here the authors show that colonic fluid from patients with UC is enriched for bacteria extracellular vesicles (BEV) coated with host IgA, and that these IgA-coated BEV may activate CD89⁺ immune cells to aggravate inflammation and colitis in mouse models.

Light-oxygen-voltage (LOV) photoreceptors perceive blue light to elicit spatio-temporally defined cellular responses, and their signalling process has been extensively characterized. Here the authors report that the light signal is still transduced in the absence of a conserved Gln residue, thought to be key.

Truncated version of adenylyl cyclase 3 acts as a cold-induced rheostat during long-term brown adipose tissue activation.

Here, the authors show that replication protein A (RPA) tends to self-assemble into dynamic condensates, in a manner that is stimulated by ssDNA and regulated by RPA2 phosphorylation. RPA condensates are functionally important for telomere clustering and RAD52-dependent telomere maintenance.

Inhibitors of the protein kinase Wee1 are promising drugs for cancer therapy. Here, the authors show that these drugs activate the integrated stress response via GCN2, synergising with mRNA translation defects. They suggest strategies such as PROTACs or ISR inhibitors to improve WEE1 mediated toxicity.

A method combining genetic-code expansion, bioorthogonal Staudinger reduction and sortase-mediated transpeptidation enables site-specific and orthogonal modification of proteins with ubiquitin and SUMO in vitro and in living cells.

This study characterizes the interaction between the clinical candidate anle138b and Aβ₄₀ fibrils in a lipid environment. The compound reduced fibril formation by approximately 75%, providing insights relevant to Alzheimer’s drug development.

Airway epithelial repair, a key process in the recovery from lung injury, requires a metabolic shift from glycolysis to fatty acid oxidation (FAO). Pharmacological FAO promotion enhances epithelial differentiation, suggesting new therapeutic options.

This structure of human PTH1R, a key target for the treatment of osteoporosis, reveals the agonist binding mode and molecular details within conserved structural motifs critical for class B GPCR function.

The cholesterol-transfer protein GRAMD1A is identified as the target of the autophagy inhibitors autogramin-1 and autogramin-2. GRAMD1A is found to be required for autophagosome biogenesis.

The cryo-electron microscopy structure of an activated transcription elongation complex of RNA polymerase II bound to DRB sensitivity-inducing factor and the elongation factors PAF1 complex and SPT6 is reported at 3.1 Å resolution.

High-content protein arrays were used to identify cysteine dioxygenase (CDO1) as a small-molecule glue target for the von Hippel–Lindau (VHL) E3 ubiquitin ligase and induces VHL-dependent proteasomal degradation of CDO1 in cells.

Hematopoiesis influences the progression of cardiovascular disease, yet the influence of cardiovascular disease on the bone vasculature is unknown. Hoffmann, Luxán, Abplanalp et al. describe the response of the bone cell composition to myocardial infarction and provide a rationale for using anti-inflammatory therapies to prevent the deterioration of the bone vascular niche

A study of patients with COVID-19 and healthy donors found CD4⁺ T cells that react to the spike protein of SARS-CoV-2 and human endemic coronaviruses; however, the effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined.

A multigenerational single-cell tracking approach provides a framework to dissect phenotypic plasticity at the single-cell level, offering insights into cellular processes that may resemble early events during cancer development.

Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.

A light-oxygen-voltage photoreceptor was found to bind short RNA stem loops in a light-dependent manner, which can be harnessed to regulate gene expression in bacteria and mammalian cells.

Microplastics research is often based on commercial model particles. Here, the authors show that nominally identical particles may differ significantly in their properties and thus in their interactions with cells.

Targeted protein degradation (TPD) is a key modality for drug discovery. Here the authors present the discovery and analysis of reversible DCAF1-PROTACs, which show efficacy in cellular environments resistant to VHL-PROTACs or with acquired resistance to CRBN-PROTACs.

A neural stem cell culture system derived from induced pluripotent stem cells forms a network of synaptically connected and electrophysiologically active neurons that were used as a model system to identify a mechanism of TDP-43-induced neurodegeneration.

The presence of peritoneal metastasis in pancreatic cancers is associated with poor prognosis. Here the authors show that hyaluronan and proteoglycan link protein-1 (HAPLN1) promotes tumour cell plasticity and pro-tumoral immune microenvironment to facilitate peritoneal dissemination in pancreatic cancers.

This article describes a mechanism through which CD4⁺ T cells can eradicate MHC-deficient tumours that escape direct CD8⁺ T cell targeting and thereby complement the activity of CD8⁺ T cells and natural killer cells to advance cancer immunotherapies.

The number of ligand binding sites in the dopamine transporter is enigmatic due to conflicting data from structures and molecular pharmacology. Here, force spectra reveal the position and dynamics of a previously invisible transient site.

Idiopathic pulmonary fibrosis is associated with myofibroblast activation in the lungs and metabolic alterations. Here, the authors show that the antidiabetic drug metformin has antifibrotic effects in human-derived samples and mouse models, by modulating a number of metabolic pathways to induce lipogenic transdifferentiation of myofibroblasts.

Two polypeptides synthesized by common bacterial strains in human gut microbiota lower body fat and blood glucose and increase bone density, improving the metabolism of rodents.

G protein-coupled receptors are a major class of drug targets. Here, the authors develop a method whereby their biophysical and functional properties can be altered through directed evolution in mammalian cells, leading to variants exhibiting features such as high stability and expression, or increased allosteric coupling.

RNA editing by the adenosine deaminase ADAR1 controls cathepsin S expression in endothelial cells, a mechanism that is implicated in determining cathepsin S levels in patients with atherosclerotic vascular diseases.

Multiplex analyses of samples allow understanding complex processes in cancer initiation, progression and therapy response. Here, the authors present a fluorescence imaging-based visual barcode for livecell clonal-multiplexing which allows identifying signalling pathways clusters in response to different chemotherapy compounds.

Structures of GPCR neurotensin receptor 1 (NTSR1) in complex with neurotensin and Gα_i1β₁γ₁ in a lipid bilayer environment and without stabilizing antibodies reveal extensive interactions at the GPCR–G protein interface.

Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production. Here the authors characterise the new-onset IgG autoantibody response in hospitalised patients with COVID-19 which they correlate to the magnitude of the SARS-CoV2 response.

Korn and colleagues demonstrate that the site of T cell priming (gut versus skin draining lymph nodes) dictates their effector phenotypes and homing to distal sites of immunopathology.

This study reports the X-ray structure of the α_1B-adrenergic G protein-coupled receptor bound to an inverse agonist, and unveils key determinants of subtype-selective ligand binding that may help the design of aminergic drugs with fewer side-effects.