Agelessness is possible under the disposable soma theory but system complexity makes it unlikely.

Although demographic studies have failed to find evidence of aging in certain animal species, classic evolutionary theories of aging struggle to explain how evolution could favor agelessness in such cases. Here, we develop mathematical models of the disposable soma theory to identify conditions in which agelessness would be evolutionarily favored. For any given type of damage that could accumulate and cause age-accelerating mortality risk, we find that evolution could select for its complete removal if the mortality risk it poses is severe enough and its repair does not pose too large of a penalty to reproduction.

Inducing novel endosymbioses by implanting bacteria in fungi.

Endosymbioses have profoundly impacted the evolution of life and continue to shape the ecology of a wide range of species. They give rise to new combinations of biochemical capabilities that promote innovation and diversification. Despite the many examples of known endosymbioses across the tree of life, their de novo emergence is rare and challenging to uncover in retrospect.

Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application.

Inflammasome activation results in the cleavage of gasdermin D (GSDMD) by pro-inflammatory caspases. The N-terminal domains (GSDMD) oligomerize and assemble pores penetrating the target membrane. As methods to study pore formation in living cells are insufficient, the order of conformational changes, oligomerization, and membrane insertion remained unclear.

Optimized expansion microscopy reveals species-specific spindle microtubule organization in egg extracts.

The spindle is a key structure in cell division as it orchestrates the accurate segregation of genetic material. While its assembly and function are well-studied, the mechanisms regulating spindle architecture remain elusive. In this study, we investigate the differences in spindle organization between and , leveraging expansion microscopy (ExM) to overcome the limitations of conventional imaging techniques.

Genetically encoded fluorescent reporter for polyamines.

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway.

A translational framework to DELIVER nanomedicines to the clinic.

Nanomedicines have created a paradigm shift in healthcare. Yet fundamental barriers still exist that prevent or delay the clinical translation of nanomedicines. Critical hurdles inhibiting clinical success include poor understanding of nanomedicines' physicochemical properties, limited exposure in the cell or tissue of interest, poor reproducibility of preclinical outcomes in clinical trials, and biocompatibility concerns.

The genome sequence of (Chiroptera, Emballonuridae, Rhynchonycteris).

We present a reference genome assembly from an individual male (Chordata; Mammalia; Chiroptera; Emballonuridae). The genome sequence is 2.46 Gb in span.

Mitochondrial dysfunction and increased reactive oxygen species production in MECP2 mutant astrocytes and their impact on neurons.

Studies on MECP2 function and its implications in Rett Syndrome (RTT) have traditionally centered on neurons. Here, using human embryonic stem cell (hESC) lines, we modeled MECP2 loss-of-function to explore its effects on astrocyte (AST) development and dysfunction in the brain. Ultrastructural analysis of RTT hESC-derived cerebral organoids revealed significantly smaller mitochondria compared to controls (CTRs), particularly pronounced in glia versus neurons.

The structural basis for RNA slicing by human Argonaute2.

Argonaute (AGO) proteins associate with guide RNAs to form complexes that slice transcripts that pair to the guide. This slicing drives post-transcriptional gene-silencing pathways that are essential for many eukaryotes and the basis for new clinical therapies. Despite this importance, structural information on eukaryotic AGOs in a fully paired, slicing-competent conformation-hypothesized to be intrinsically unstable-has been lacking.

Robustness and reliability of single-cell regulatory multi-omics with deep mitochondrial mutation profiling.

The detection of mitochondrial DNA (mtDNA) mutations in single cells holds considerable potential to define clonal relationships coupled with information on cell state in humans. Previous methods focused on higher heteroplasmy mutations that are limited in number and can be influenced by functional selection, introducing biases for lineage tracing. Although more challenging to detect, intermediate to low heteroplasmy mtDNA mutations are valuable due to their high diversity, abundance, and lower propensity to selection.

Diffusion barriers imposed by tissue topology shape Hedgehog morphogen gradients.

Animals use a small number of morphogens to pattern tissues, but it is unclear how evolution modulates morphogen signaling range to match tissues of varying sizes. Here, we used single-molecule imaging in reconstituted morphogen gradients and in tissue explants to determine that Hedgehog diffused extracellularly as a monomer, and rapidly transitioned between membrane-confined and -unconfined states. Unexpectedly, the vertebrate-specific protein SCUBE1 expanded Hedgehog gradients by accelerating the transition rates between states without affecting the relative abundance of molecules in each state.

On the role of antibody affinity and avidity in the IgE-mediated allergic response.

Type I hypersensitivity, also known as classical allergy, is mediated via allergen-specific IgE antibodies bound to type I FcR (FcεRI) on the surface of mast cells and basophils upon cross-linking by allergens. This IgE-mediated cellular activation may be blocked by allergen-specific IgG through multiple mechanisms, including direct neutralization of the allergen or engagement of the inhibitory receptor FcγRIIb which blocks IgE signal transduction. In addition, co-engagement of FcεRI and FcγRIIb by IgE-IgG-allergen immune complexes causes down regulation of receptor-bound IgE, resulting in desensitization of the cells.

Physically informed deep neural networks for metabolite-corrected plasma input function estimation in dynamic PET imaging.

Introduction: We propose a novel approach for the non-invasive quantification of dynamic PET imaging data, focusing on the arterial input function (AIF) without the need for invasive arterial cannulation.

Methods: Our method utilizes a combination of three-dimensional depth-wise separable convolutional layers and a physically informed deep neural network to incorporatea priori knowledge about the AIF's functional form and shape, enabling precise predictions of the concentrations of [C]PBR28 in whole blood and the free tracer in metabolite-corrected plasma.

Results: We found a robust linear correlation between our model's predicted AIF curves and those obtained through traditional, invasive measurements.

Rapid phagosome isolation enables unbiased multiomic analysis of human microglial phagosomes.

Microglia are the resident macrophages of the central nervous system (CNS). Their phagocytic activity is central during brain development and homeostasis-and in a plethora of brain pathologies. However, little is known about the composition, dynamics, and function of human microglial phagosomes under homeostatic and pathological conditions.

Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids.

Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MeCP2 mutations - a missense mutation (R306C) and a truncating mutation (V247X) - using calcium imaging with three-photon microscopy.

Sotos Syndrome: Deep Neuroimaging Phenotyping Reveals a High Prevalence of Malformations of Cortical Development.

Background And Purpose: Sotos syndrome is a rare autosomal dominant condition caused by pathogenic mutations in the gene that presents with craniofacial dysmorphism, overgrowth, seizures, and neurodevelopmental delay. Macrocephaly, ventriculomegaly, and corpus callosal dysmorphism are typical neuroimaging features that have been described in the medical literature. The purpose of this study was to expand on the neuroimaging phenotype by detailed analysis of a large cohort of patients with genetically proved Sotos syndrome.

SPARK regulates AGC kinases central to the asexual cycle.

Apicomplexan parasites balance proliferation, persistence, and spread in their metazoan hosts. AGC kinases, such as PKG, PKA, and the PDK1 ortholog SPARK, integrate environmental signals to toggle parasites between replicative and motile life stages. Recent studies have cataloged pathways downstream of apicomplexan PKG and PKA; however, less is known about the global integration of AGC kinase signaling cascades.

Cognitive and psychiatric symptom trajectories 2-3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK.

Background: COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning.

Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ≥18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK.

Sequence programmable nucleic acid coacervates.

Nature uses bottom-up self-assembly to build structures with remarkable complexity and functionality. Understanding how molecular-scale interactions translate to macroscopic properties remains a major challenge and requires systems that effectively bridge these two scales. Here, we generate DNA and RNA liquids with exquisite programmability in their material properties.

Multi-species genome-wide CRISPR screens identify conserved suppressors of cold-induced cell death.

Cells must adapt to environmental changes to maintain homeostasis. One of the most striking environmental adaptations is entry into hibernation during which core body temperature can decrease from 37°C to as low at 4°C. How mammalian cells, which evolved to optimally function within a narrow range of temperatures, adapt to this profound decrease in temperature remains poorly understood.