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Barrier tissues are populated by functionally plastic CD4 + resident memory T (T RM ) cells. Whether the barrier epithelium regulates CD4 + T RM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC) low MHC high epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4 + T RM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4 + T RM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4 + T RM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4 + T RM cell function and identify epithelial-CD4 + T RM cell immune interactions as core elements of barrier immunity. The maintenance of T resident memory (T RM ) cells within pulmonary tissues is incompletely understood. Here the authors show that antigen presentation by lung epithelial cells maintains function and phenotype of pulmonary T RM cells within specific locational niches.

Sepsis is a leading cause of hospitalization and death in the United States, and rural patients are at particularly high risk. Telehealth has been proposed as one strategy to narrow rural-urban disparities. The objective of this study was to understand why rural emergency department (ED) staff use provider-to-provider telehealth (tele-ED) and how tele-ED care changes the care for rural patients with sepsis. We conducted a qualitative interview study between February 15, 2022, and May 22, 2023, with participants from upper Midwest rural EDs and tele-ED hub physicians in a single tele-ED network that delivers provider-to-provider consultation for sepsis patients. One interviewer conducted individual telephone interviews, then we used standard qualitative methods based on modified grounded theory to identify themes and domains. We interviewed 27 participants, and from the interviews we identified nine themes within three domains. Participants largely felt tele-ED for sepsis was valuable in their practice. We identified that telehealth was consulted to facilitate interhospital transfer, provide surge capacity for small teams, to adhere with provider scope-of-practice policies, for inexperienced providers, and for patients with increased severity of illness or complex comorbidities. Barriers to tele-ED use and impact included increased sepsis care standardization, provider reluctance, and sepsis diagnostic uncertainty. Additionally, we identified that real-time education and training were important secondary benefits identified from tele-ED use. Tele-ED care was used by rural providers for sepsis treatment, but many barriers existed that may have limited potential benefits to its use.

Throughout his entire career, from his debut in the 1860s up to his final works post 1900, the Opera formed the focal point of Degas's output. It was his own 'front room'. He explored the theatre's various spaces - auditorium and stage, boxes, foyers and dance studios - and followed those who frequented them: dancers, singers, orchestral musicians, audience members and black-attired patrons lurking in the wings. This closed world presented a microcosm of infinite possibilities, allowing all manner of experimentations: multiple points of view, contrasts of lighting, the study of motion and the precision of movement. This book considers the Opera as a whole, examining not only Degas' passionate relationship with the House and his musical tastes, but also the limitless resources of this marvellous 'toolbox'. The work of a truly great artist offers us a unique portrait of the Paris Opera in the 19th century.

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain. RNA-sequencing analysis of cells in the human cortex enabled identification of diverse cell types, revealing well-conserved architecture and homologous cell types as well as extensive differences when compared with datasets covering the analogous region of the mouse brain.

Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A + CD8 T cells in the anti-tumor response and the regulation of NKG2A expression on human tumor-infiltrating T cells are still poorly understood. Here, by performing CITE-seq on T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced on CD8 T cells differentiating into cytotoxic, CD39 + CD103 + double positive (DP) cells, a phenotype associated with tumor-reactive T cells. This developmental trajectory leads to TCR repertoire overlap between the NKG2A – and NKG2A + DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of NKG2A on CD8 T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8 T cells exposed to a TGF-β-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation. Effective strategies to enhance T cell anti-tumor cytotoxicity are pivotal to improve treatment outcomes. By analyzing tumor samples from patients with head and neck or colon cancers, here the authors show that IL-12 can induce the expression of the inhibitory receptor NKG2A on tumor-reactive CD8 cytotoxic lymphocytes.

Syngnathid fishes (pipefishes, seahorses and seadragons) are characterized by a unique mode of paternal care in which embryos develop on or in the male's body, often within a structure known as a brood pouch. Evidence suggests that this pouch plays a role in mediating postcopulatory sexual selection and that males have some control over the events occurring within the pouch during the pregnancy. These observations lead to the prediction that males should invest differently in broods depending on the availability of food. Here, we use the Gulf pipefish to test this prediction by monitoring growth rate and offspring survivorship during the pregnancies of males under low- or high-food conditions. Our results show that pregnant males grow less rapidly on average than non-pregnant males, and pregnant males under low-food conditions grow less than pregnant males under high-food conditions. Offspring survivorship, on the other hand, does not differ between food treatments, suggesting that male Gulf pipefish sacrifice investment in somatic growth, and thus indirectly sacrifice future reproduction, in favor of current reproduction. However, a positive relationship between number of failed eggs and male growth rate in our low-food treatments suggests that undeveloped eggs reduce the pregnancy's overall cost to the male compared to broods containing only viable offspring.

Background Over 5000 community anti-drug coalitions operating in the USA serve as a cornerstone of federal drug prevention. These coalitions, however, have demonstrated effectiveness in preventing substance use only when they use technical assistance (TA) and implement evidence-based programs (EBPs). The absence of TA and EBP implementation by coalitions is a key research-to-practice gap. The Coalition Check-Up TA system is designed to fill this gap by supporting community coalition implementation of EBPs. Existing TA models for evidence-based coalition approaches are resource intensive and coalition model specific. The Coalition Check-Up is a lower cost strategy that works with a variety of types of coalitions to support sustainable implementation of EBPs. This study protocol describes a hybrid type 3 effectiveness-implementation trial applying Wandersman’s Interactive Systems Framework to test the effects of the Coalition Check-Up on coalition EBP implementation capacity and outcomes. The Interactive Systems Framework outlines how the prevention support system—especially TA—bolsters EBP dissemination and implementation. Methods Using a cluster randomized controlled design, this trial will test the overall effectiveness of the Coalition Check-Up, including how it contributes to EBP implementation and prevention of youth substance use. The first aim is to estimate the impact of the Coalition Check-Up on coalitions’ capacity to do their work. We will recruit 68 anti-drug coalitions for random assignment to the Coalition Check-Up or “TA as usual” condition. We will evaluate whether the Coalition Check-Up improves coalition capacity using measures of coalition member responses about team processes, coalition network composition, and collaborative structure. Our second aim is to estimate the impact of the Coalition Check-Up on implementation of EBPs, and our third aim is to estimate the impact of the Coalition Check-Up on youth substance use. Discussion This project will clarify how the Coalition Check-Up, a scalable approach to TA due to its low cost, affects coalition capacity to support EBP implementation. Analyses also provide insight into causal pathways from the prevention support system to the prevention delivery system outlined by the Interactive Systems Framework. Results will build the evidence-base for how to support community coalitions’ sustainable implementation of evidence-based prevention programs and policies. Trial registration Clinicaltrials.gov registration number NCT04592120 . Registered on October 19, 2020.

Background Once antibiotic-resistant bacteria become established within the gut microbiota, they can cause infections in the host and be transmitted to other people and the environment. Currently, there are no effective modalities for decreasing or preventing colonization by antibiotic-resistant bacteria. Intestinal microbiota restoration can prevent Clostridioides difficile infection (CDI) recurrences. Another potential application of microbiota restoration is suppression of non- C. difficile multidrug-resistant bacteria and overall decrease in the abundance of antibiotic resistance genes (the resistome) within the gut microbiota. This study characterizes the effects of RBX2660, a microbiota-based investigational therapeutic, on the composition and abundance of the gut microbiota and resistome, as well as multidrug-resistant organism carriage, after delivery to patients suffering from recurrent CDI. Methods An open-label, multi-center clinical trial in 11 centers in the USA for the safety and efficacy of RBX2660 on recurrent CDI was conducted. Fecal specimens from 29 of these subjects with recurrent CDI who received either one ( N  = 16) or two doses of RBX2660 ( N  = 13) were analyzed secondarily. Stool samples were collected prior to and at intervals up to 6 months post-therapy and analyzed in three ways: (1) 16S rRNA gene sequencing for microbiota taxonomic composition, (2) whole metagenome shotgun sequencing for functional pathways and antibiotic resistome content, and (3) selective and differential bacterial culturing followed by isolate genome sequencing to longitudinally track multidrug-resistant organisms. Results Successful prevention of CDI recurrence with RBX2660 correlated with taxonomic convergence of patient microbiota to the donor microbiota as measured by weighted UniFrac distance. RBX2660 dramatically reduced the abundance of antibiotic-resistant Enterobacteriaceae in the 2 months after administration. Fecal antibiotic resistance gene carriage decreased in direct relationship to the degree to which donor microbiota engrafted. Conclusions Microbiota-based therapeutics reduce resistance gene abundance and resistant organisms in the recipient gut microbiome. This approach could potentially reduce the risk of infections caused by resistant organisms within the patient and the transfer of resistance genes or pathogens to others. Trial registration ClinicalTrials.gov, NCT01925417 ; registered on August 19, 2013.