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Analyses of snRNA genes in a French cohort of people with rare disorders, with validation through international collaboration, identify monoallelic and biallelic variants in RNU2-2 as frequent causes of neurodevelopmental disorders with epilepsy.

Riboswitches are allosteric RNA molecules that change conformation upon ligand binding to regulate downstream genes. Here, the authors use Restricted Boltzmann machines trained on natural sequences to design new riboswitch aptamer domains, and validate their functionality via chemical probing.

Broadly applicable genetically encoded probes and peptide-based compounds specifically inhibit Gα_s, the prototypical signal transducer of G-protein-coupled receptors, providing new mechanistic insights into signaling at the subcellular scale.

The authors show that Trpm5, but not Trpm4, is the main Na+ -permeant channel mediating the warmth-activated ICaN in lumbar motoneurons. Trpm5 is also critical in generating plateau potentials in bistable motoneurons that are essential for producing a postural tone in hindlimbs and amplifying the locomotor output.

Cells rely on AAA+ machines to move and remodel proteins. Here, authors show that ClpB threads proteins rapidly using ATP to bias diffusive motion, revealing a fast, stochastic Brownian-motor mechanism rather than stepwise power strokes.

While deep learning has enabled the decoding of language from intracranial brain recordings, achieving this with non-invasive recordings remains an open challenge. Here the authors introduce a deep learning pipeline to decode individual words from EEG and MEG signals

How seizure propagation occurs across cortical layers in humans is not fully understood. Here the authors use intracerebral laminar electrodes (capable of recording the six layers of the cortex) during pre-surgical evaluations, and identify a signature of the area responsible for seizures characterized by pathological activities in the granular and infragranular layers.

Sepsis induces a period of immunosuppression which can be problematic in the face of subsequent infectious challenge. Here the authors show the presence of PD-L1 expressing regulatory plasma cells that can inhibit T cells in a murine model and in patients with sepsis.

This study documents the evolution of antibiotic resistance and major growth defects in Yersinia enterocolitica in a patient over 14 years, revealing genetic changes that shed light on bacterial adaptation to infection and therapy.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.

Fluoxetine is a serotonin reuptake inhibitor antidepressant. Here, the authors demonstrate the that fluoxetine can trigger muscle regeneration in male mice by acting on muscle stem cells, vascularization, and inflammation, resulting in faster muscle healing.

Thymic epithelial tumors are associated with increased risk of immune checkpoint inhibitor (ICI)-induced myotoxicities, and the presence of anti-acetylcholine-receptor antibodies has the potential to serve as a biomarker for ICI-induced myocarditis in patients with cancer.

The immune checkpoint molecule PD-1 is expressed on a fraction of CD4⁺ T cells latently infected with HIV, but whether PD-1 plays a functional role in reservoir persistence remains unknown. Here, Fromentin et al. show that PD-1 blockade potentiates latency reversal ex vivo in CD4⁺ T cells from ART suppressed individuals.

The cause of clonal expansions in the HIV reservoir remains unclear. Here, Gantner et al. perform single-cell TCR sequencing on longitudinal samples from eight individuals on antiretroviral therapy and find that antigens inducing clonal expansions of memory cells are major contributors to the HIV reservoir.

Using biochemistry, cell biological, X-ray crystallography and cryo-EM methods, Maisonneuve et al. reveal how the scaffolding proteins CNK and HYP enhance the binding of KSR to MEK, which in turn allosterically controls RAF activation in Drosophila.

Nephrophthisis (NPH) is a common manifestation of ciliopathy diseases. Here the authors identify mutations in intraflagellar transport 54 (IFT54) in patients with NPH and discover an extra-ciliary role for IFT54 in regulating cytoplasmic microtubule dynamics, that contributes to the pathophysiology of this disease.

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development remains unknown. Here, the authors show that JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.

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).

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.

Izar and colleagues demonstrate that loss of Pip4k2c in melanoma cells promotes liver metastatic tropism driven by PI3K-AKT pathway activation in the insulin-rich liver milieu, which can be abrogated by inhibition of SGLT2 or a ketogenic diet.

The single stranded DNA binding protein RPA plays a pivotal role in DNA replication. The archaeal RPA hosts a WH domain that interacts with the DNA primase and the replicative polymerase PolD. Here the authors provide a molecular understanding of the regulatory activity of archaeal RPA.

Invariant natural killer T (NKT) cells are defined into subset based on transcription expression and cytokine production, but differences in the subset distributions of these cells are seen between inbred mouse strains. Here the authors show that CD1d mediated TCR signals along with intrinsic signals impact this strain specific difference in the composition of the NKT cell compartment.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

Some HIV-infected cells persist during antiretroviral therapies (ART) but their phenotype is less clear. Dufour et al. show that HIV-infected cells that persist in people receiving ART are phenotypically diverse and that CD4+ T cells expressing the integrin VLA-4 are highly enriched in replication-competent HIV.

Activation of anionic redox in battery materials promises great benefits for battery materials, but remains an elusive phenomenon. Here, the authors present anion-doping as a novel strategy to unlock electrochemical activity in the cobalt/nickel free cathode material, Li₂TiS_3-xSe_x.

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.

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.

The establishment of symbiotic interaction between Aeschynomene evenia and photosynthetic bradyrhizobia doesn’t involve the canonical Nod factors and infection threads. Here, the authors assemble the draft genome of A. evenia and identify a receptor-like kinase in mediating the symbiotic interaction.

Pre-leukaemic clones, together with the propensity to cause disease in mice, are characterized by appearing early in myeloid leukaemia and being found at relapse. Here, the authors identify clones in human samples and find that they are characterized by hierarchically organized genetic lesions, which can be used to track evolution of the disease.

In plant-bacteria symbiosis, frontiers between mutualism and parasitism are often crossed. Here, the authors identify a bacterial clade that includes rhizobial strains displaying both pathogenic and nodulating abilities on a single legume host.

Emergence of drug tolerant cells drives adaptive targeted therapy resistance in non-small cell lung cancer (NSCLC). Here, the authors identify a common molecular event underpinning resistance to multiple targeted therapies in a panel of mutant NSCLC models that can be targeted with farnesyltransferase inhibition.

Multimodal label-free nonlinear microscopy and advanced image analysis map single-cell metabolism and myelin dynamics in live cerebellar tissue during demyelination, supporting research in neuroinflammation and neurodegeneration.

Impact-induced acoustic and seismic wave events on Mars recorded by the InSight lander’s seismometer have been traced to fresh craters observed in spacecraft imagery.

The contractile properties of adult myofibers are shaped by their Myosin heavy chain isoform content. Here the authors show that a super enhancer controls the spatiotemporal expression of the genes at the fast myosin heavy chain locus by DNA looping and that this expression profile is recapitulated in a rainbow transgenic mouse model of the locus.

Suppressive combination antiretroviral therapy fails to eradicate HIV-1 latent reservoirs in poorly characterized cell compartments. Here, urethral macrophages, but not urethral T cells, are shown to contain integrated HIV-1 DNA and to be able to release infectious HIV-1 following reactivation with lipopolysaccharide.

Impaired adipocyte insulin signalling characterizes insulin resistance. Here the authors show that the hormone-sensitive lipase can sequester the glucose-responsive transcription factor ChREBP in the cytoplasm, which prevents transcription of its target ELOVL6, resulting in reduced insulin signalling.