W. M. Keck Foundation

To identify contextual factors that harm and protect the mental health of Black and Latinx gay and bisexual men, this study examined (a) associations between dating app use and psychological distress over time mediated by sexual racism, with (b) moderation by different sources of supportive social connections (i.e., general social support, gay community connection, and racial/ethnic community connection). Using three waves of the Healthy Young Men's Cohort Study with Black and Latinx gay and bisexual men (N = 412), multiple moderated mediation path analyses were tested. Dating app use was associated with more sexual racism, and sexual racism was positively associated with psychological distress. High, but not low, racial/ethnic community connection diminished the effects of sexual racism on psychological distress, and social support from family and friends and gay community connection did not. Furthermore, the indirect effect of dating app use on psychological symptoms through sexual racism was significant. All social support indicators modified this indirect effect, such that the indirect effects were significant only at low values of general social support and at low racial/ethnic and gay community connection. For Black and Latinx gay and bisexual men, the impact of dating app use on psychological distress may occur through elevated experiences of sexual racism. These associations may be diminished with greater access to general social support and community connection. Findings highlight the dual need for reducing racism on dating apps and for increasing access to general and community-specific forms of social connection and support. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Abstract Melt-pool morphology is a key indicator of process stability in Laser-Based Powder Bed Fusion of Metals (PBF-LB/M). Process windows defined by melt-pool morphology strongly influence part quality metrics such as density, microstructure, and mechanical properties. We propose a computationally efficient, physics-based semi-analytical predictor of melt-pool width and depth, augmented with machine-learning (ML) residual correction to improve accuracy. Rather than replacing physics, ML learns the discrepancy between experiment and the physics baseline and corrects it across multiple power–speed configurations. We evaluated three residual estimators, gradient-boosted decision trees (GBDT), random forests (RF), and a multilayer perception (MLP) and found the MLP consistently performs best. This residual-ML-corrected physics model also provides an efficient baseline to couple with accurate scanning-speed logs (including acceleration/deceleration) for more reliable layer-based qualification. The physics baseline yields mean absolute percentage error (MAPE) ≈ 20% (width) and ≈ 22% (depth), whereas the residual-corrected model improves to ≈ 4–6% (width) and ≈ 2–5% (depth), including in higher-energy regimes near the conduction–keyhole transition. The overall pipeline remains substantially faster than high-fidelity numerical methods, enabling efficient process-window optimization and qualification.

Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naïve CD4 + T cells into regulatory T cells (Tregs). Here, we demonstrate heighted capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4 + T cells and that this is linked to their unique metabolic profile and elevated expression of the NADase, CD38. Early life naïve CD4 + T cells demonstrate a metabolic preference for glycolysis, which directly facilitates their differentiation trajectory. We reveal an age-dependent gradient in CD38 levels on naïve CD4 + T cells and show that high CD38 expression contributes to both the glycolytic state and tolerogenic potential of neonatal CD4 + T cells, effects that are mediated at least in part via the NAD-dependent deacetylase SIRT1. Thus, the early life window for peripheral tolerance in humans is critically enabled by the immunometabolic state of the naïve CD4 + compartment.

It is widely believed that tissue mechanical properties, determined mainly by the extracellular matrix (ECM), are actively maintained. However, despite its broad importance to biology and medicine, tissue mechanical homeostasis is poorly understood. To explore this hypothesis, we developed mutations in the mechanosensitive protein talin1 that alter cellular sensing of ECM stiffness. Mutation of a novel mechanosensitive site between talin1 rod domain helix bundles 1 and 2 (R1 and R2) shifted cellular stiffness sensing curves, enabling cells to spread and exert tension on compliant substrates. Opening of the R1-R2 interface promotes binding of the ARP2/3 complex subunit ARPC5L, which mediates the altered stiffness sensing. Ascending aortas from mice bearing these mutations show increased compliance, less fibrillar collagen, and rupture at lower pressure. Together, these results demonstrate that cellular stiffness sensing regulates ECM mechanical properties. These data thus directly support the mechanical homeostasis hypothesis and identify a novel mechanosensitive interaction within talin that contributes to this mechanism.

Inflammaging is a theory of ageing which purports that low-level chronic inflammation leads to cellular dysfunction and premature ageing of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defence from the environment, particularly solar radiation. To better understand the impact of ageing and photoexposure on epidermal biology, we performed a system biology-based analysis of photoexposed face and arm, and photoprotected buttock sites, from women between the ages of 20s to 70s. Biopsies were analysed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1-α were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic ageing were accelerated. Genes associated with differentiation and senescence showed increasing expression in the 30s whereas genes associated with hypoxia and glycolysis increased in the 50's. Proteomics comparing 60's vs 20's confirmed elevated levels of differentiation and glycolytic-related proteins. Representative immunostaining for proteins of differentiation, senescence and oxygen sensing/hypoxia showed similar relationships. This system biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.

Protein ubiquitylation is an important posttranslational modification affecting a wide range of cellular processes. Due to the low abundance of ubiquitylated species in biological samples, considerable effort has been spent on methods to purify and detect ubiquitylated proteins. We have developed and characterized a novel tool for ubiquitin detection and purification based on OtUBD, a high-affinity ubiquitin-binding domain (UBD) derived from an Orientia tsutsugamushi deubiquitylase (DUB). We demonstrate that OtUBD can be used to purify both monoubiquitylated and polyubiquitylated substrates from yeast and human tissue culture samples and compare their performance with existing methods. Importantly, we found conditions for either selective purification of covalently ubiquitylated proteins or co-isolation of both ubiquitylated proteins and their interacting proteins. As proof of principle for these newly developed methods, we profiled the ubiquitylome and ubiquitin-associated proteome of the budding yeast Saccharomyces cerevisiae. Combining OtUBD affinity purification with quantitative proteomics, we identified potential substrates for the E3 ligases Bre1 and Pib1. OtUBD provides a versatile, efficient, and economical tool for ubiquitin research with specific advantages over certain other methods, such as in efficiently detecting monoubiquitylation or ubiquitin linkages to noncanonical sites.

ABSTRACTInflammaging is a theory of aging which purports that low-level chronic inflammation leads to cellular dysfunction and premature aging of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defense from the environment, particularly solar radiation. To better understand the impact of aging and photoexposure on epidermal biology we performed a systems biology-based analysis of photoexposed face and arm and photoprotected buttock sites from women between the ages of 20’s to 70’s. Biopsies were analyzed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss, and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1-α were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic aging was accelerated. Genes associated with differentiation and senescence show increasing expression in the 30’s whereas genes associated with hypoxia and glycolysis increase in the 50’s. Proteomics comparing 60’s vs 20’s confirmed elevated levels of differentiation and glycolytic related proteins. Representative immunostaining for proteins of differentiation, senescence, and oxygen sensing/hypoxia shows similar relationships. This systems biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.

ABSTRACTHuman gut commensal Bacteroidetes rely on multiple transport systems to acquire vitamin B12 and related cobamides for fitness in the gut. In addition to a set of conserved transport proteins, these systems also include a diverse repertoire of additional proteins with unknown function. Here, we report the function and structural characterization of one of these proteins, BtuH, which binds vitamin B12 directly via a C-terminal globular domain that has no known structural homologs. This protein is required for efficient B12 transport and competitive fitness in the gut, demonstrating that members of the heterogeneous suite of accessory proteins encoded in Bacteroides cobamide transport system loci can play key roles in vitamin acquisition.

Abstract Dendritic membrane potential was recently measured for the first time in drug-free, naturally behaving rats over several days. These showed that neuronal dendrites generate a lot of sodium spikes, up to ten times as many as the somatic spikes. These key experimental findings are reviewed here, along with a discussion of computational models, and computational consequences of such intense spike traffic in dendrites. We overview the experimental techniques that enabled these measurements as well as a variety of models, ranging from conceptual models to detailed biophysical models. The biophysical models suggest that the intense dendritic spiking activity can arise from the biophysical properties of the dendritic voltage-dependent and synaptic ion channels, and delineate some computational consequences of fast dendritic spike activity. One remarkable aspect is that in the model, with fast dendritic spikes, the efficacy of synaptic strength in terms of driving the somatic activity is much less dependent on the position of the synapse in dendrites. This property suggests that fast dendritic spikes is a way to confer to neurons the possibility to grow complex dendritic trees with little computational loss for the distal most synapses, and thus form very complex networks with high density of connections, such as typically in the human brain. Another important consequence is that dendritically localized spikes can allow simultaneous but different computations on different dendritic branches, thereby greatly increasing the computational capacity and complexity of neuronal networks.