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Background: The role of neutrophils in mediating neurovascular vulnerability has been increasingly implicated in various acute inflammatory models of neuroimmune crosstalk between the periphery and the brain. Whether neurovascular vulnerability is similarly modulated in the context of frequent, but not acute, inflammatory activation in the periphery is the aim of our study. Such a model of frequent inflammatory irritation is pertinent to understanding the neurologic risk of constant exposure to aerosolized environmental hazards leading to progressive pulmonary disease.

Methods: To model repeated pulmonary inflammation, we applied a three-dose regimen of intranasal (i.n.) lipopolysaccharide (LPS) in C57BL/6J mice and studied the impact on the inflammatory environment of the brain, with a specific focus on neutrophil dynamics at the neurovascular unit (NVU). Tissue and circulatory inflammatory profiles were screened via bronchoalveolar lavage (BAL) protein content and cellularity, transcript analysis of brain tissue, and flow cytometry of peripheral blood. Intravital two-photon microscopy (2PM) of the brain vasculature identified neutrophil dynamics at the NVU. Immunofluorescence validated neutrophil dynamics and identified neuroinflammatory hallmarks and peripheral immune factor interactions at the NVU. In vivo findings were corroborated and replicated in murine and human microphysiological systems (MPS) modeling the blood-brain barrier as a proxy demonstration of the translational relevance of our findings.

Results: 2PM of tdTomato-Ly6G+ neutrophils demonstrated increased levels of circulating neutrophils and corresponding engagement with the brain vasculature after the three-dose repeated i.n. exposure regimen. Neutrophilia at the NVU was corroborated with increased transcript levels of Ly6G and other pro-inflammatory markers. This coordination between endothelial physiology and neutrophil phenotypes was recapitulated in murine and human MPS models. System-wide neutrophilia in the lung and circulation was found to be cotemporaneous to neutrophilia at the NVU based on the cellularity of BAL and peripheral blood samples collected at the same endpoints. Immunohistochemical analysis of brain tissue implicates temporal coordination between vascular surface adhesion molecules with changes in neutrophil dynamics from adhesion, crawling, stalling, and transmigration. Extravasation of neutrophils was complemented by sustained paravascular deposition of fibrinogen and microgliosis up to 72 hours after the final i.n. dosing. Microglia-associated effector functions for synaptic pruning and regulation of neutrophil activity demonstrated distinct temporal profiles.

Conclusions: Our results identify systemic levels of neutrophilia accompanied by ingress and extravascular accumulation in brain parenchyma that correlated with sustained microglial activation. This neut

Changes in gene regulation were a major driver of the divergence of archaic hominins (AHs)-Neanderthals and Denisovans-and modern humans (MHs). The three-dimensional (3D) folding of the genome is critical for regulating gene expression; however, its role in recent human evolution has not been explored because the degradation of ancient samples does not permit experimental determination of AH 3D genome folding. To fill this gap, we apply novel deep learning methods for inferring 3D genome organization from DNA sequence to Neanderthal, Denisovan, and diverse MH genomes. Using the resulting 3D contact maps across the genome, we identify 167 distinct regions with diverged 3D genome organization between AHs and MHs. We show that these 3D-diverged loci are enriched for genes related to the function and morphology of the eye, supra-orbital ridges, hair, lungs, immune response, and cognition. Despite these specific diverged loci, the 3D genome of AHs and MHs is more similar than expected based on sequence divergence, suggesting that the pressure to maintain 3D genome organization constrained hominin sequence evolution. We also find that 3D genome organization constrained the landscape of AH ancestry in MHs today: regions more tolerant of 3D variation are enriched for introgression in modern Eurasians. Finally, we identify loci where modern Eurasians have inherited novel 3D genome folding patterns from AH ancestors and validate folding differences in a high-frequency locus using Hi-C, revealing a putative molecular mechanism for phenotypes associated with archaic introgression. In summary, our application of deep learning to predict archaic 3D genome organization illustrates the potential of inferring molecular phenotypes from ancient DNA to reveal previously unobservable biological differences.

Cell-cell communication dynamically changes across time while involving diverse cell populations and ligand types such as proteins and metabolites. While single-cell transcriptomics enables its inference, existing tools typically analyze ligand types separately and overlook their coordinated activity. Here, we present Tensor-cell2cell v2, a computational tool that can jointly analyze protein- and metabolite-mediated communication over time using coupled tensor component analysis, while preserving each modality of inferred communication scores independently, as well as their data structures and distributions. Applied to brain organoid development, Tensor-cell2cell v2 uncovers dynamic, coordinated communication programs involving key proteins and metabolites across relevant cell types across specific time points.

Occam's razor is the principle that, all else being equal, simpler explanations should be preferred over more complex ones. This principle is thought to guide human decision-making, but the nature of this guidance is not known. Here we used preregistered behavioral experiments to show that people tend to prefer the simpler of two alternative explanations for uncertain data. These preferences match predictions of formal theories of model selection that penalize excessive flexibility. These penalties emerge when considering not just the best explanation but the integral over all possible, relevant explanations. We further show that these simplicity preferences persist in humans, but not in certain artificial neural networks, even when they are maladaptive. Our results imply that principled notions of statistical model selection, including integrating over possible, latent causes to avoid overfitting to noisy observations, may play a central role in human decision-making.

Rab-dependent membrane trafficking is critical for changing the structure and function of dendritic spines during synaptic plasticity. Here, we developed highly sensitive sensors to monitor Rab protein activity in single dendritic spines undergoing structural long-term potentiation (sLTP) in rodent organotypic hippocampal slices. During sLTP, Rab10 was persistently inactivated (>30 min) in the stimulated spines, whereas Rab4 was transiently activated over ~5 min. Inhibiting or deleting Rab10 enhanced sLTP, electrophysiological LTP and AMPA receptor (AMPAR) trafficking during sLTP. In contrast, disrupting Rab4 impaired sLTP only in the first few minutes, and decreased AMPAR trafficking during sLTP. Thus, our results suggest that Rab10 and Rab4 oppositely regulate AMPAR trafficking during sLTP, and inactivation of Rab10 signaling facilitates the induction of LTP and associated spine structural plasticity.

We report a population of multipotent cells isolated from term human placentas that exhibit clonal expansion and migratory capacity, along with a gene expression profile that indicates immune privilege. Previously known largely for its role in early placentation, the developmental regulator CDX2 marks cells capable of differentiating into cardiomyocytes and vascular lineages. Building on our prior findings that murine Cdx2 cells improved cardiac function in mice after myocardial infarction (MI), we isolated CDX2⁺ cells from placentas of 180 healthy pregnancies. These human CDX2 cells spontaneously generate cardiac and vascular lineages in vitro, in vivo, and express transcriptomic signatures associated with cardiogenesis, vasculogenesis, immune modulation, and chemotaxis. When administered to NOD/SCID mice after MI, the cells restore cardiac function. Additionally, CDX2 cells can be clonally propagated while retaining cardiovascular differentiation potential. Our findings support the therapeutic potential of placental CDX2 cells as an ethically accessible and regenerative strategy for cardiovascular disease.

Characterization of the structural integrity of cortex in adults who have undergone resection for epilepsy treatment has, in some cases, revealed persistent or even accelerated cortical atrophy but, in others, the converse is evident, and atrophy decelerates or even reverses. Whether this variability applies to a pediatric population, for whom postoperative plasticity may be greater than in adulthood, remains to be determined. Furthermore, understanding the morphometrics of this patient population is important, as cognitive gains have been associated with the anatomical status of preserved cortex post-resection. Here, we used high-resolution structural T1 magnetic resonance imaging data to compare the (1) gross anatomy, (2) cortical thickness, volume, and surface area for 34 cortical regions, and (3) volume for nine subcortical regions of 32 pediatric post-surgical cases and 51 healthy controls. Patients with either a preserved right hemisphere (RH) or left hemisphere (LH) had lower total white matter volume and select subcortical structures' volumes, relative to controls; lateral ventricle size of both preserved RH and LH patients was also significantly larger than that of controls. However, relative to controls, only patients with a preserved RH had significantly lower total gray matter volume and lower thickness, volume, and surface area in multiple cortical regions, primarily in frontal and temporal cortex. The differences in preserved RH cortex of LH resection patients may relate to transfer of language function from the resected LH. Our findings lay the foundation for future studies probing associations of the morphometric differences in pediatric epilepsy surgery patients with neuropsychological outcomes.

Understanding how populations evolve requires accounting for both intrinsic fitness, defined by genotype and environment, and ecological interactions that emerge in mixed communities. While evolutionary experiments typically assess fitness in isolation, such monoculture measures may misrepresent dynamics in realistic, interacting populations. Here, we present a game-theoretic framework that explicitly separates intrinsic and ecological contributions to fitness, allowing us to map how ecological interactions can mask, mirror, maintain, or mimic selection driven by genetic differences. We derive analytical conditions for these regimes using deterministic replicator dynamics and validate them in stochastic Wright-Fisher models with mutation and drift. Applying our model to published microbial and cancer co-culture data, we show that real systems span both intrinsic-dominant and ecology-dominant regimes, with ecological effects sometimes reversing or neutralizing intrinsic fitness advantages. These results expose a critical blind spot in experimental design and interpretation, emphasizing the need to account for ecological interactions when inferring evolutionary dynamics and designing therapeutic strategies.

The main olfactory epithelium initiates the process of odor encoding. Recent studies have demonstrated intergenerationally inherited changes in the olfactory system in response to fear conditioning, resulting in increases in olfactory sensory neuron frequencies and altered responses to odors. We investigated changes in the cellular composition of the olfactory epithelium in response to an aversive stimulus. Here, we achieve volumetric cellular resolution to demonstrate that olfactory fear conditioning increases the number of odor-encoding neurons in mice that experience odor-shock conditioning (F0), as well as their unconditioned offspring (F1). We demonstrate that the increase in F0 is due, in part, to the biasing of the stem cell layer of the main olfactory epithelium. Detailed analysis of F1 behavior revealed subtle odor-specific differences between the offspring of unconditioned and conditioned parents, despite the absence of an active aversion to the conditioned odor. Thus, we reveal intergenerational regulation of olfactory epithelium composition in response to olfactory fear conditioning, providing insight into the heritability of acquired phenotypes.

One-sentence summary: Olfactory fear conditioning induces heritable changes to the mouse olfactory system and biases neurogenesis and behavior in both parent and offspring.

DNA origami information storage is a promising alternative to silicon-based data storage, offering a secure molecular cryptography technique that conceals information within arbitrarily folded DNA origami nanostructures. Routing, sliding, and interlacing staple strands lead to the creation of a large 700-bit key size. The realization of practical DNA data storage requires high information density, robust security, and accurate and rapid information retrieval. To meet these requirements, advanced readout techniques and large encryption key sizes are essential. In this study, we report an enhanced DNA origami cryptography protocol to encrypt information in 2D and 3D DNA origami structures, increasing the number of possible scaffold routings and increasing the encryption key size. We employed all-DNA-based steganography with fast readout through high-speed 2D and 3D DNA-PAINT super-resolution imaging, which enables higher information density. By combining 2D and 3D DNA-PAINT data with unsupervised clustering, we achieved an accuracy of up to 89% and high ratios of correct-to-wrong readout, despite the significant flexibility in the 3D DNA origami structure shown by oxDNA simulation. Furthermore, we propose design criteria that ensure complete information retrieval for the DNA origami cryptography protocol. Our findings demonstrate that DNA-based cryptography is a highly secure and versatile solution for transmitting and storing information, making it an attractive choice for the post-silicon era.