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Synthetic receptors are a powerful approach for engineering cell-based therapies that can sense and respond to their environment. Here cytokine receptor domains have been repurposed to develop engineered T cells that can sense and respond to cues associated with cancer or immune dysfunction.

Analysis of the longest-lived mammal, the bowhead whale, reveals an improved ability to repair DNA breaks, mediated by high levels of cold-inducible RNA-binding protein.   

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.

Rhine et al. find that neuronal aging leads to widespread dysregulation of RNA biology, including mislocalization of splicing proteins like TDP-43, chronic cellular stress and reduced resiliency.

Gram-negative bacteria use a multiprotein complex, LptB₂FGC, to transport lipopolysaccharides (LPS) to the outer membrane. Here, Fiorentino et al. present cryo-EM structures of the complex from Pseudomonas aeruginosa, revealing species-specific features and providing insights into LPS transport mechanisms.

How the brain transforms reward information into actions remains poorly understood. Here, the authors found that reward expectation and sensorimotor signals are more pronounced in the output of the basal ganglia than its input or the cerebellar cortex, implying that the transformation of reward signals into motor signals is not hierarchically organized.

Berg et al. identify that primary cilia regulate early valve development in mouse embryos by participating in cushion development, where they function as mechanosensors regulating endothelial-to-mesenchymal transition through the modulation of Klf4.

Spatial transcriptomics reveals distinct microglial mechanisms driving amyloid-β clearance in both passively and actively immunized patients with Alzheimer’s disease.

Enhanced polyamine depletion in neuroblastoma models decreases translation of mRNA codons with adenosine in the third position, reprogramming the tumour proteome away from cell cycle progression and towards differentiation.

Otopetrins form proton channels in animals ranging from nematodes to humans. Here, authors identify small molecule inhibitors and characterize their binding in the intrasubunit interface region, thus highlighting the area for pharmacological targeting for channel modulation.

Modulating mitochondrial NAD⁺ levels by changing the expression of the mitochondrial NAD⁺ transporter, SLC25A51, Mukherjee et al. demonstrate that mitochondrial, rather than cytosolic or nuclear, NAD⁺ levels are a key determinant of the rate of liver regeneration.

Engineering mammalian cellular functions requires a toolkit of orthogonal and well-characterized genetic components. Here the authors develop COMET: an ensemble of transcription factors, promoters, and accompanying models for the design and construction of genetic programs.

Sick heart and vessels skew hematopoiesis toward inflammatory myeloid cells. Rhode et al. show that hypertension, atherosclerosis and myocardial infarction cause endothelial dysfunction in bone marrow (BM), which in return causes overproduction of inflammatory myeloid cells and systemic leukocytosis in mice. This process is mediated by VEGF signaling, IL-6 and versican production by the BM endothelium.

Huber et al. measure 4,780 plasma proteins in the Cardiovascular Health Study to examine the association with incident coronary heart disease. They identify 11 proteins using genomic analyses and show the complexity of MMP12 in response to atherosclerosis and development of heart disease.

The sodium-calcium exchanger (NCX1) is the primary calcium extrusion mechanism of cardiac myocytes. Here, the authors show that removal of a long questioned allosteric regulation of NCX1 by intracellular sodium alters cardiac excitation-contraction coupling.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

By constructing an evolutionary trajectory of the cyclostome-gnathostome Pou5 gene family and comparing the structural and phenotypic protein variations, the authors uncover the origin of functional characteristics for the pluripotency factor Oct4.

Human and mouse astrocytes express the protocadherin PcdhγC3, which promotes self-recognition of individual astrocytes, thereby contributing to normal astrocyte and brain development.

Cancer cells rely on NADPH to manage oxidative stress and support biosynthesis. Here, the authors show that glucose-6-phosphate dehydrogenase (G6PD) ablation suppresses KRAS-driven lung tumours with LKB1 deficiency, but not with P53 deficiency, by impairing NADPH production, suggesting a potential therapeutic strategy.

A multiomics resource characterizing human mitochondrial proteins enables identification of biological functions and supports genetic diagnosis of mitochondrial pathologies.

Subcutaneously injected biomaterial scaffolds mimicking key features of physiological T-cell activation enhance the antitumour activity of intravenously pre-administered CAR-T cells.

Understanding how cells differentiate to their final fates is a fundamental biological problem. Here, authors introduce MultiVeloVAE, a probabilistic framework that models gene expression and chromatin accessibility mechanistically, integrates multiple samples, accounts for bifurcations, and enables statistical testing over time.

The slow maturation of human neurons is regulated by epigenetic modification in nascent neurons, mediated by EZH2, EHMT1, EHMT2 and DOT1L.

Paul and colleagues report the development and characterization of an antibody–drug conjugate targeting TRBC2 for the treatment of T cell malignancies.

Analysing whole-genome sequences from 68 rattlesnakes, the authors show a role of long-term balancing selection in maintaining diversity of multiple venom gene families and find reduced selective interference of venom genes with neighbouring loci.

Using different genetic mice models, Sung et al. show that VEGF-C/VEGFR3 signaling is required for sinusoidal vascular growth in the fetal liver and bone marrow. CDH5 (VE-cadherin) negatively regulates VEGF-C/VEGFR3 signaling and sinusoidal and lymphatic growth. Loss of CDH5 enables growth of sinusoidal and lymphatic vessels in the absence of VEGFR3 signaling through VEGF-C/VEGFR2 signaling.

A forward genetic screen in Caenorhabditis elegans reveals that decreased levels of the ferredoxin FDX2 suppress the loss of frataxin in worms and in mice by relief of FDX2 inhibition of frataxin-stimulated NFS1 activity.

The authors show that, unlike the consolidation and refinement of excitatory connections observed during sensory map formation, a dramatic broadening of patterned activation domains, connectivity, and tuning occurs in interneurons in the olfactory bulb. This developmental expansion is sensitive to activity manipulations and may reveal general principles of interneuron network development.

Myelofibrosis causes a pathological remodelling of the bone marrow, which becomes stiffer and more elastic, thus promoting the proliferation of proinflammatory monocytes and their differentiation into dendritic cells.

Here the authors describe a simple reverse genetics method that relies on overlapping cDNA fragments for generation of positive-strand viruses including SARS-CoV-2 and characterize them in vitro and in vivo.

Human iPSC-CMs are invaluable for cardiac disease modeling and regeneration. Here, authors developed an optimized suspension culture protocol to efficiently and reproducibly differentiate hiPSCs into cardiomyocytes and cardiac organoids.

The role of Ifi27l2a, an interferon-induced gene, remains poorly understood in diseased brains. Here, authors show age and stroke-dependent upregulation of Ifi27l2a in microglia, and that reduction of Ifi27l2a leads to reduced brain injury and functional deficits after ischemic stroke.

Sleep involves dynamic changes in brain activity that unfold over time, reflected in the brain’s aperiodic EEG patterns. Incorporating the spectral ‘knee’—a bend in the EEG power spectrum—reveals stage-specific shifts in neural processing timescales, providing valuable insights into sleep dynamics.

Structural and single-molecule analyses show the CTPase, KorB, is a sliding DNA clamp that interacts with a clamp-locking protein KorA to inhibit gene expression over distances of more than 1 kb in the multi-drug resistance RK2 plasmid.

Using single-molecule visualization and manipulation, Chang et al. show that the eukaryotic Smc5/6 complex preferentially binds to and stabilizes ssDNA-dsDNA junctions, which could serve as the molecular basis for its diverse roles in genome maintenance.

Examination of the sulfur and copper contents of global cratonic peridotites combined with new high-pressure experiments shows that the migration of carbonated melts towards cratonic margins explains the co-location of magmatic metal deposits with carbonatites.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Amyloid-like proteins are central to age-related diseases, such as Alzheimer’s and Parkinson’s. Here, the authors show that transcription errors can produce mutant proteins with enhanced amyloid- and prion-like properties in human cells.

Pancreatic ductal adenocarcinoma is characterized by a highly immunosuppressive tumour microenvironment. Here, the authors show that specialized subsets of tumour-infiltrating dendritic cells induce distinct CD4⁺ T cell programs and specifically identify a CD103^–CD11b⁺ subset which induces tumor-promoting FoxP3^– Type-1 regulatory T cells.

Using single-molecule techniques, the authors find that the methyl-CpG-binding protein MeCP2, whose mutations cause Rett syndrome, exhibits distinctive behaviors when bound to nucleosomes versus free DNA, thus directing its multifaceted functions on chromatin.

Neurons derived from stem cells are rapidly matured with a GENtoniK cocktail.

Partitioning of FtsN and the septal peptidoglycan synthesis complex between an active synthesis track and an inactive denuded glycan track coordinates opposing peptidoglycan synthesis and degradation activities in E. coli.

Toxoplasma gondii can persist in neurons in the central nervous system, presumably because neurons have limited cell-intrinsic immune responses. However, here, Chandrasekaran et al. show that IFN-gamma stimulated primary murine neurons can clear T. gondii and that IFN-gamma stimulated murine and human neurons show decreased infection rates.

The Arabidopsis CC1 protein maintains microtubule array stability and cellulose synthesis during salt stress. Here the authors show that CC1 engages microtubules via an intrinsically disordered N-terminus that suggests it controls microtubule dynamics in a similar way to the mammalian Tau protein.

Repetitive head impacts from contact sports are associated with brain inflammation, vascular damage and neuron loss that are independent of hyperphosphorylated tau pathology.

Antigen-specific tolerance represents a promising strategy to treat type 1 diabetes and islet allograft rejection. Here, the authors deliver immune signals to lymph nodes to promote antigen-specific regulatory T cells and prevent disease in models of type 1 diabetes and allogenic islet transplantation.

The core circadian transcription factor BMAL1 regulates circadian-dependent myocardial injury.

The response to infectious and inflammatory challenges differs among people but the reasons for this are poorly understood. Here the authors explore the impact of variables such as age, sex, and the capacity for controlling inflammation and maintaining immunocompetence, linking this capacity to favourable health outcomes and lifespan.

Excitatory spiny stellate neurons in the somatosensory cortex are shaped by innervating thalamic inputs and unique expression of genes. Here, the authors show that these neurons play a crucial role in processing distinct whisker signals and forming specialized circuits for sensory perception.