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Regulation of intestinal T-cell responses is crucial for immune homeostasis and prevention of inflammatory bowel disease (IBD). A vital cytokine in regulating intestinal T cells is transforming growth factor-β (TGFβ), which is secreted by cells as a latent complex that requires activation to function. However, how TGFβ activation is regulated in the human intestine, and how such pathways are altered in IBD is completely unknown. Here we show that a key activator of TGFβ, integrin αvβ8, is highly expressed on human intestinal dendritic cells (DCs), specifically on the CD1c+ but not the CD141+ intestinal DC subset. Expression was significantly upregulated on intestinal DC from IBD patients, indicating that inflammatory signals may upregulate expression of this key TGFβ-activating molecule. Indeed, we found that the Toll-like receptor 4 ligand lipopolysaccharide upregulates integrin αvβ8 expression and TGFβ activation by human DC. We also show that DC expression of integrin αvβ8 enhanced induction of FOXP3 in CD4+ T cells, suggesting functional importance of integrin αvβ8 expression by human DC. These results show that microbial signals enhance the TGFβ-activating ability of human DC via regulation of integrin αvβ8 expression, and that intestinal inflammation may drive this pathway in patients with IBD.

Abstract Large biobanks have dramatically advanced our understanding of genetic influences on human brain anatomy. However, most studies have combined rather than compared male and female participants. Here we screen for sex differences in the common genetic architecture of over 1000 neuroanatomical phenotypes in the UK Biobank and establish a general concordance between male and female participants in heritability estimates, genetic correlations, and variant-level effects. Notable exceptions include higher mean heritability in the female group for regional volume and surface area phenotypes; between-sex genetic correlations that are significantly below 1 in the insula and parietal cortex; and a common variant with stronger effect in male participants mapping to RBFOX1 - a gene linked to multiple neuropsychiatric disorders more common in men. This work suggests that common variant influences on human brain anatomy are largely consistent between males and females, with a few exceptions that will guide future research in growing datasets.

Thanks to methodological advances, large-scale data collections, and longitudinal designs, psychiatric neuroimaging is better equipped than ever to identify the neurobiological underpinnings of youth mental health problems. However, the complexity of such endeavors has become increasingly evident, as the field has been confronted by limited clinical relevance, inconsistent results, and small effect sizes. Some of these challenges parallel those historically encountered by psychiatric genetics. In past genetic research, robust findings were historically undermined by oversimplified biological hypotheses, mistaken assumptions about expectable effect sizes, replication problems, confounding by population structure, and shared biological patterns across disorders. Overcoming these challenges has contributed to current successes in the field. Drawing parallels across psychiatric genetics and neuroimaging, we identify key shared challenges as well as pinpoint relevant insights that could be gained in psychiatric neuroimaging from the transition that occurred from the candidate gene to (post) genome-wide “eras” of psychiatric genetics. Finally, we discuss the prominent developmental component of psychiatric neuroimaging and how that might be informed by epidemiological and omics approaches. The evolution of psychiatric genetic research offers valuable insights that may expedite the resolution of key challenges in psychiatric neuroimaging, thus potentially moving our understanding of psychiatric pathophysiology forward.

Efficient engineering of T cells to express exogenous tumor-targeting receptors such as chimeric antigen receptors (CARs) or T-cell receptors (TCRs) is a key requirement of effective adoptive cell therapy for cancer. Genome editing technologies, such as CRISPR/Cas9, can further alter the functional characteristics of therapeutic T cells through the knockout of genes of interest while knocking in synthetic receptors that can recognize cancer cells. Performing multiple rounds of gene transfer with precise genome editing, termed multiplexing, remains a key challenge, especially for non-viral delivery platforms. Here, we demonstrate the efficient production of primary human T cells incorporating the knockout of three clinically relevant genes (B2M, TRAC, and PD1) along with the non-viral transfection of a CAR targeting disialoganglioside GD2. Multiplexed knockout results in high on-target deletion for all three genes, with low off-target editing and chromosome alterations. Incorporating non-viral delivery to knock in a GD2-CAR resulted in a TRAC-B2M-PD1-deficient GD2 CAR T-cell product with a central memory cell phenotype and high cytotoxicity against GD2-expressing neuroblastoma target cells. Multiplexed gene-editing with non-viral delivery by CRISPR/Cas9 is feasible and safe, with a high potential for rapid and efficient manufacturing of highly potent allogeneic CAR T-cell products.

Abstract There is a critical need to identify new therapeutic vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). Transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 are highly overexpressed in human PDAC, and CRISPR-based homozygous deletion of Ctbp2 in a mouse PDAC cell line (CKP) dramatically decreased tumor growth, reduced metastasis, and prolonged survival in orthotopic mouse allografts. Transcriptomic profiling of tumors derived from CKP vs. Ctbp2-deleted CKP cells (CKP/KO) revealed significant downregulation of the EGFR-superfamily receptor Erbb3, the heterodimeric signaling partner for both EGFR and ErbB2. Compared with CKP cells, CKP/KO cells also demonstrated reduced Erbb2 expression and did not activate downstream Akt signaling after stimulation of Erbb3 by its ligand neuregulin-1. ErbB3 expression in human PDAC cell lines was similarly dependent on CtBP2 and depletion of ErbB3 in a human PDAC cell line severely attenuated growth, demonstrating the critical role of ErbB3 signaling in maintaining PDAC cell growth. Sensitivity to the ErbB2-targeted tyrosine kinase inhibitor lapatinib, but not the EGFR-targeted agent erlotinib, varied in proportion to the level of ErbB3 expression in mouse and human PDAC cells, suggesting that an ErBb2 inhibitor can effectively leverage CtBP2-driven transcriptional activation of physiologic ErbB2/3 expression and signaling in PDAC cells for therapeutic benefit.

Hip arthroscopy techniques continue to evolve. Historically, a post has been used as an aid to establish adequate hip joint distraction. However, this technique is associated with potentially devastating postoperative pudendal nerve injury and other urologic and gynecologic complications. In this article, we present our technique for postless hip arthroscopy.

Large rainbow trout marketed as steelhead are gaining considerable attention for production in recirculating aquaculture systems (RAS). Diploid and triploid trout with varying genetics are available from several commercial suppliers; however, the performance and processing metrics of these lines have not been compared when raised in freshwater RAS. Current data on these outcomes could support more accurate cost and profitability estimates for potential RAS projects and optimize operation for existing farms. Accordingly, the objective of this study was to quantify performance metrics, processing yield, and fillet composition of six all-female rainbow trout lines (three diploid and three triploid) exposed to an artificial winter (12:12 light: dark at 40 g (Artificial Winter Photoperiod; AWP)) or continuous, 24-h light (No Winter Photoperiod; NWP) grown in a semi-commercial scale freshwater RAS to 3.5 kg. Overall, growth was impacted by line, ploidy, and artificial winter photoperiod. Diploid and AWP trout were smaller than triploids and NWP trout at stocking and 500 g. Mean diploid and triploid weight was similar at larger sizes (>1 kg); however, triploid performance compared to diploids varied by commercial supplier. Mortality was lower in lines from commercial supplier 1 than lines from commercial supplier 2 and the United States Department of Agriculture (14.4 ± 0.8 vs 27.5 ± 2.0 and 29.8 ± 4.3%, respectively). Head-on gutted and skin-on fillet yields were related with larger fish weight. Mature prevalence in diploids may have led to differences observed between diploids and triploids in fillet lipid (10.9 ± 0.8 vs 13.3 ± 0.6%) and moisture (67.0 ± 0.6 vs 65.1 ± 0.4%). The results provide guidance for rainbow trout RAS producers to make informed decisions on optimal harvest size targets and tailor their rainbow trout line or ploidy selection to those harvest sizes.

Abstract Background The disconnect between research and clinical practice leads to research evidence that is often not useful for clinical practice. Practice-based research networks are collaborations between researchers and clinicians aimed at coproducing more useful research. Such networks are rare in the physiotherapy field. We aimed to describe (i) clinicians’ motivations behind, and enablers to, participating in a network, (ii) the process of network establishment and (iii) research priorities for a practice-based network of physiotherapists in the Hunter Region of New South Wales (NSW), Australia that supports research coproduction. Methods We describe the methods and outcomes of the three steps we used to establish the network. Step 1 involved consultation with local opinion leaders and a formative evaluation to understand clinicians’ motivations behind, and enablers to, participating in a network. Step 2 involved establishment activities to generate a founding membership group and codesign a governance model. Step 3 involved mapping clinical problems through a workshop guided by systems thinking theory with local stakeholders and prioritizing research areas. Results Through formative evaluation focus groups, we generated five key motivating themes and three key enablers for physiotherapists’ involvement in the network. Establishment activities led to a founding membership group (n = 29, 67% from private practice clinics), a network vision and mission statement, and a joint governance group (9/13 [70%] are private practice clinicians). Our problem-mapping and prioritization process led to three clinically relevant priority research areas with the potential for significant change in practice and patient outcomes. Conclusions Clinicians are motivated to break down traditional siloed research generation and collaborate with researchers to solve a wide array of issues with the delivery of care. Practice-based research networks have promise for both researchers and clinicians in the common goal of improving patient outcomes.

Background: The anterior cruciate ligament (ACL) has been extensively studied in those with alpine skiing injuries; however, less focus has been given to meniscal/chondral injuries in this population. Objectives: To perform a systematic review investigating the incidence of meniscal/chondral injuries in alpine skiers who have sustained an ACL injury. Data sources: MEDLINE, Scopus, manual journal searches. Study eligibility criteria: Studies reporting rates of meniscal and/or chondral injuries in alpine skiers with an ACL tear were included. Techniques, revisions, non-alpine skiers, and studies lacking an association between skiing and ACL diagnosis were excluded. Participants and interventions: Alpine skiers with a diagnosis of an ACL tear. Study appraisal and synthesis methods: MINORS criteria. Results: Nine hundred fifty-eight studies were identified. Screening, removal of duplicates, and assessment for inclusion/exclusion criteria resulted in 12 level III/IV studies for review. A total of 1185 skiers with ACL injuries were included (209 elite and 976 recreational). Meniscal tears were present in 47.4% of the skiers, with an increased rate seen in elite versus recreational skiers (61.2% vs 43.2%). Elite skiers were more likely to have a combined medial/lateral meniscal injury and a lateral meniscal tear repair (69.8% vs 19.2% for the latter). There were no differences in medial meniscal tear treatment. Chondral injuries presented at a rate of 11.2% and were more common in elite versus recreational skiers (20.3% vs 5.3%). Limitations: Heterogenous nature of study types included; Did not include larger databases and was limited to alpine skiing studies only; demographics were not part of the analysis. Conclusions: Approximately 47% of the alpine skiers with an ACL injury sustained a concomitant meniscal tear, with 11% having an associated chondral injury. Meniscal/chondral injuries are more common in elite skiers, and they are more likely to have their meniscus repaired. Implications of key findings: Careful consideration of the accompanying pathology is warranted in alpine skiers who present with ACL injury. Systematic review registration number: PROSPERO: CRD42022373207.

Objectives To develop a physiotherapist-led consensus statement on the definition and provision of high-value care for people with musculoskeletal conditions.Design We performed a three-stage study using Research And Development/University of California Los Angeles Appropriateness Method methodology. We reviewed evidence about current definitions through a rapid literature review and then performed a survey and interviews with network members to gather consensus. Consensus was finalised in a face-to-face meeting.Setting Australian primary care.Participants Registered physiotherapists who are members of a practice-based research network (n=31).Results The rapid review revealed two definitions, four domains of high value care and seven themes of high-quality care. Online survey responses (n=26) and interviews (n=9) generated two additional high-quality care themes, a definition of low-value care, and 21 statements on the application of high value care. Consensus was reached for three working definitions (high value, high-quality and low value care), a final model of four high value care domains (high-quality care, patient values, cost-effectiveness, reducing waste), nine high-quality care themes and 15 statements on application.Conclusion High value care for musculoskeletal conditions delivers most value for the patient, and the clinical benefits outweigh the costs to the individual or system providing the care. High-quality care is evidence based, effective and safe care that is patient-centred, consistent, accountable, timely, equitable and allows easy interaction with healthcare providers and healthcare systems.

Advanced tissue engineering approaches for direct articular cartilage replacement in vivo employ mesenchymal stem cell (MSC) sources, exploiting innate chondrogenic potential to fabricate hyaline-like constructs in vitro within three-dimensional (3D) culture conditions. Cell sheet technology represents one such advanced 3D scaffold-free cell culture platform, and previous work has shown that 3D MSC sheets are capable of in vitro hyaline-like chondrogenic differentiation. The present study aims to build upon this understanding and elucidate the effects of an established cell sheet manipulation technique, cell sheet multilayering, on fabrication of MSC-derived hyaline-like cartilage 3D layered constructs in vitro. To achieve this goal, multilayered MSC sheets are prepared and assessed for structural and biochemical transitions throughout chondrogenesis. Results support MSC multilayering as a means of increasing construct thickness and 3D cellular interactions related to in vitro chondrogenesis, including N-cadherin, connexin 43, and integrin β-1. Data indicate that increasing construct thickness from 14 μm (1-layer construct) to 25 μm (2-layer construct) increases these cellular interactions and subsequent in vitro MSC chondrogenesis. However, a clear initial thickness threshold (33 μm - 3-layer construct) is evident that decreases the rate and extent of in vitro chondrogenesis, specifically chondrogenic gene expressions (Sox9, aggrecan, type II collagen) and sulfated proteoglycan accumulation in deposited extracellular matrix (ECM). Together, these data support the utility of cell sheet multilayering as a platform for tailoring construct thickness and subsequent MSC chondrogenesis for future articular cartilage regeneration applications.

We consider how mathematical models enable predictions for conditions that are qualitatively different from the training data. We propose techniques based on information topology to find models that can apply their learning in regimes for which there is no data. The first step is to use the manifold boundary approximation method to construct simple, reduced models of target phenomena in a data-driven way. We consider the set of all such reduced models and use the topological relationships among them to reason about model selection for new, unobserved phenomena. Given minimal models for several target behaviors, we introduce the supremum principle as a criterion for selecting a new, transferable model. The supremal model, i.e., the least upper bound, is the simplest model that reduces to each of the target behaviors. We illustrate how to discover supremal models with several examples; in each case, the supremal model unifies causal mechanisms to transfer successfully to new target domains. We use these examples to motivate a general algorithm that has formal connections to theories of analogical reasoning in cognitive psychology.

Turkic languages have been shown to form words using a wide range of word-formation strategies, such as suffixation, cliticization, and auxiliaries. The present paper offers a detailed description of word formation in Uyghur, compares the patterns in Uyghur with the prior literature on Turkic, offers explicit diagnostics for suffixes and clitics, and proposes a morpho-syntactic analysis for each strategy.

Iron- and nitrogen-doped carbon materials are effective catalysts for the oxygen reduction reaction whose active sites are poorly understood. Here, the authors establish a new pyridinic iron macrocycle complex as a more effective active site model relative to legacy pyrrolic model complexes.

Uncontrolled gene editing can lead to off-target effects and chromosomal translocations. Here the authors develop CRISPRoff, light degradable sgRNAs for titratable and spatially defined gene editing.

The aim of this systematic review was to evaluate the surgical, radiological, and functional outcomes of posterior-only versus combined anterior-posterior approaches in patients with traumatic thoracolumbar burst fractures. The ideal approach (anterior-only, posterior-only, or combined anterior-posterior) for the surgical management of thoracolumbar burst fracture remains controversial, with each approach having its advantages and disadvantages. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed (registration no., CRD42018115120). The authors reviewed comparative studies evaluating posterior-only approach compared with combined anterior-posterior approaches with respect to clinical, surgical, radiographic, and functional outcome measures. Five retrospective cohort studies were included. Postoperative neurological deterioration was not reported in either group. Operative time, estimated blood loss, and postoperative length of stay were increased among patients in the combined anterior-posterior group in one study and equivalent between groups in another study. No significant difference was observed between the two approaches with regards to long-term postoperative Cobb angle (mean difference, −0.2; 95% confidence interval, −5.2 to 4.8; p =0.936). Moreover, no significant difference in functional patient outcomes was observed in the 36item Short-Form Health Survey, Visual Analog Scale, and return-to-work rates between the two groups. The available evidence does not indicate improved clinical, radiologic (including kyphotic deformity), and functional outcomes in the combined anterior-posterior and posterior-only approaches in the management of traumatic thoracolumbar burst fractures. Further studies are required to ascertain if a subset of patients will benefit from a combined anterior-posterior approach.

Background Although Beef Quality Assurance guidelines do not recommend use of darting methods to deliver drugs, cattle in the US may be raised on farms and ranches without restraint facilities, and reports from the field suggest that dart guns are being used to deliver antimicrobial drugs. Few studies report whether this route of administration results in altered drug disposition or carcass quality. Methods Forty steers were blocked by sire and then randomly assigned to treatment with saline, ceftiofur crystalline free acid, tildipirosin, or tulathromycin delivered via dart gun. To assess drug disposition, eight ceftiofur, six tulathromycin, and six tildipirosin-treated calves were selected to measure plasma concentrations of drugs up to 10 days after drug administration. Steers were then fed a balanced ration for approximately 6.5 months and slaughtered. To evaluate carcass quality, tenderness of steaks from darted-side and non-darted sides was evaluated via Warner–Bratzler shear force testing. Due to the prohibition of extralabel routes of administration for ceftiofur in the U.S., animals treated with this drug did not enter the food supply. Results Ceftiofur disposition differed from published reports with lower mean Cmax but similar mean apparent elimination half-life. Tildipirosin disposition differed from published reports with lower Cmax and shorter apparent elimination half-life. Tulathromycin was similar to previous published reports but Cmax and apparent elimination half-life was highly variable. All steaks (from darted and non-darted sides) from cattle treated with ceftiofur and saline were more tender than from cattle treated with tulathromycin or tildipirosin (P = 0.003). There was a trend toward more tenderness in steaks from the non-darted compared to the darted side. Steaks from the darted side for one treatment, tildipirosin, were less tender than the non-darted side. Conclusions Pharmacokinetic parameters of ceftiofur crystalline free acid, tildipirosin, and tulathromycin to cattle using pressure-adjustable pneumatic gas-powered dart gun were estimated in this study. Delivery of tildipirosin and tulathromycin to cattle with dart gun may also result in detectable decreases in tenderness of harvested steaks.

The scale and scope of global logistics systems make real-time visibility of individual assets in global logistics systems difficult. Aggregating global logistics data to a manageable level where interruptions and disruptions can be anticipated or resolved is high on the wish list of global logistics managers and decision makers. Asset tracking and condition visibility in global supply chains is also difficult because few standards or metrics have been assessed in a supply chain, particularly when new technology is introduced, such as unmanned aerial systems in global supply chains. In this paper, we describe the integration of an unmanned aerial system in a global logistics system, and the metrics used to assess the integrated system. We highlight the importance of supply chain process, business impact, societal and environmental sustainability metrics, in addition to economic and supply chain performance metrics, in evaluating the integrated system.

The prevalence of coral disease is steadily increasing throughout the global ocean, and there is a growing need for efficient methods for detecting and monitoring coral health. At present, coral health assessments are primarily conducted using in-situ surveys, which record visual observations of disease in the field. Recent technological advancements allow researchers to instead collect high-resolution imagery of benthic habitats, and these images can be used in conjunction with digital tools to assess the health of coral colonies at a later time. However, little is known about the relative efficacy or diagnostic accuracy of these two approaches. This study contrasts the diagnostic accuracy of in-situ and digital methodologies for detecting diseases and adverse health conditions affecting corals. Multiple 1 m2 plots are surveyed on coral reefs located on both the windward and leeward side of Hawaii Island. For each plot, an in-situ visual analysis of coral health is conducted by a diver and images are collected and rendered into a high-resolution orthomosaic for subsequent digital analysis. Both methods assess the same coral colonies, resulting in paired health diagnoses for multiple health conditions. Lacking a gold-standard diagnosis of health conditions, a latent class model is used to estimate the sensitivity (true positive rate) and specificity (true negative rate) of both methods. We find that in-situ assessments of coral health have a higher sensitivity and lower specificity in detecting health conditions when compared to digital analyses based on orthomosaics. However, the effect size is relatively modest, indicating that while the in-situ method provides a more sensitive diagnostic approach, the techniques are of comparable accuracy, and should both be considered viable methods of characterizing and monitoring coral health.

Abstract Using gauge theory, we describe how to construct generalized Kähler geometries with (2, 2) two-dimensional supersymmetry, which are analogues of familiar examples like projective spaces and Calabi-Yau manifolds. For special cases, T-dual descriptions can be found which are squashed Kähler spaces. We explore the vacuum structure of these gauge theories by studying the Coulomb branch, which usually encodes the quantum cohomology ring. Some models without Kähler dual descriptions possess unusual Coulomb branches. Specifically, there appear to be an infinite number of supersymmetric vacua.

Timely, accurate maps of invasive plant species are critical for making appropriate management decisions to eliminate emerging target populations or contain infestations. High-resolution aerial imagery is routinely used to map, monitor, and detect invasive plant populations. While conventional image interpretation involving human analysts is straightforward, it can require high demands for time and resources to produce useful intelligence. We compared the performance of human analysts with a custom Retinanet-based deep convolutional neural network (DNN) for detecting individual miconia (Miconia calvescens DC) plants, using high-resolution unmanned aerial system (UAS) imagery collected over lowland tropical forests in Hawai’i. Human analysts (n = 38) examined imagery at three linear scrolling speeds (100, 200 and 300 px/s), achieving miconia detection recalls of 74 ± 3%, 60 ± 3%, and 50 ± 3%, respectively. The DNN achieved 83 ± 3% recall and completed the image analysis in 1% of the time of the fastest scrolling speed tested. Human analysts could discriminate large miconia leaf clusters better than isolated individual leaves, while the DNN detection efficacy was independent of leaf cluster size. Optically, the contrast in the red and green color channels and all three (i.e., red, green, and blue) signal to clutter ratios (SCR) were significant factors for human detection, while only the red channel contrast, and the red and green SCRs were significant factors for the DNN. A linear cost analysis estimated the operational use of a DNN to be more cost effective than human photo interpretation when the cumulative search area exceeds a minimum area. For invasive species like miconia, which can stochastically spread propagules across thousands of ha, the DNN provides a more efficient option for detecting incipient, immature miconia across large expanses of forested canopy. Increasing operational capacity for large-scale surveillance with a DNN-based image analysis workflow can provide more rapid comprehension of invasive plant abundance and distribution in forested watersheds and may become strategically vital to containing these invasions.

Lysosomes are ubiquitous acidified organelles that degrade intracellular and extracellular material trafficked via multiple pathways. Lysosomes also sense cellular nutrient levels to regulate target of rapamycin (TOR) kinase, a signaling enzyme that drives growth and suppresses activity of the MiT/TFE family of transcription factors that control biogenesis of lysosomes. In this study, we subjected worms lacking basic helix-loop-helix transcription factor 30 (hlh-30), the Caenorhabditis elegans MiT/TFE ortholog, to starvation followed by refeeding to understand how this pathway regulates survival with variable nutrient supply. Loss of HLH-30 markedly impaired survival in starved larval worms and recovery upon refeeding bacteria. Remarkably, provision of simple nutrients in a completely defined medium (C. elegans maintenance medium [CeMM]), specifically glucose and linoleic acid, restored lysosomal acidification, TOR activation, and survival with refeeding despite the absence of HLH-30. Worms deficient in lysosomal lipase 2 (lipl-2), a lysosomal enzyme that is transcriptionally up-regulated in starvation in an HLH-30-dependent manner, also demonstrated increased mortality with starvation-refeeding that was partially rescued with glucose, suggesting a critical role for LIPL-2 in lipid metabolism under starvation. CeMM induced transcription of vacuolar proton pump subunits in hlh-30 mutant worms, and knockdown of vacuolar H+-ATPase 12 (vha-12) and its upstream regulator, nuclear hormone receptor 31 (nhr-31), abolished the rescue with CeMM. Loss of Ras-related GTP binding protein C homolog 1 RAGC-1, the ortholog for mammalian RagC/D GTPases, conferred starvation-refeeding lethality, and RAGC-1 overexpression was sufficient to rescue starved hlh-30 mutant worms, demonstrating a critical need for TOR activation with refeeding. These results show that HLH-30 activation is critical for sustaining survival during starvation-refeeding stress via regulating TOR. Glucose and linoleic acid bypass the requirement for HLH-30 in coupling lysosome nutrient sensing to survival.

Introduction: Computed tomography pulmonary angiography (CTPA) is the test of choice for diagnosis of pulmonary embolism (PE) in the emergency department (ED), but this test may be indeterminate for technical reasons such as inadequate contrast filling of the pulmonary arteries. Many hospitals have requirements for intravenous (IV) catheter size or location for CTPA studies to reduce the chances of inadequate filling, but there is a lack of clinical data to support these requirements. The objective of this study was to determine if a certain size or location of IV catheter used for contrast for CTPA is associated with an increased chance of suboptimal CTPA. Methods: This was a retrospective chart review of patients who underwent CTPA in the ED. A CTPA study was considered suboptimal if the radiology report indicated it was technically limited or inadequate to exclude a PE. The reason for the study being suboptimal, and the size and location of the IV catheter, were abstracted. We calculated the rate of inadequate contrast filling of the pulmonary vasculature and compared the rate for various IV catheter sizes and locations. In particular, we compared 20-gauge or larger IV catheters in the antecubital fossa or forearm to all other sizes and locations. Results: A total of 19.3% of the 1500 CTPA reports reviewed met our criteria as suboptimal, and 51.6% of those were due to inadequate filling. Patients with a 20-gauge IV catheter or larger placed in the antecubital fossa or forearm had inadequate filling 9.2% of the time compared to 13.2% for patients who had smaller IVs or IVs in other locations (difference: 4.0% [95% confidence interval, −1.7%–9.7%]). There were also no statistically significant differences in the rates of inadequate filling when data were further stratified by IV catheter location and size. Conclusion: We did not detect any statistically significant differences in the rate of inadequate contrast filling based on IV catheter locations or sizes. While small differences not detected in this study may exist, it seems prudent to proceed with CTPA in patients with difficult IV access who need emergent imaging even if they have a small or distally located IV.

Thrombotic thrombocytopenia purpura (TTP) is a hematological emergency that requires rapid assessment followed by prompt initiation of therapy due to high mortality associated with delayed treatment. TTP has many causes including heritable syndromes, ADAMTS13 deficiency, and drugs-related etiologies. Profound vitamin B12 deficiency can, in rare cases, mimic TTP in presentation, and since plasmapheresis can be of limited benefit, prompt diagnosis is necessary for accurate treatment with B12. Therefore, careful analysis of all clinical signs, symptoms, and labs must be assessed. We report a patient who presented with a diagnosis of TTP, and repeat assessment confirmed a diagnosis of sever vitamin B12 (B12) deficiency with pancytopenia who was appropriately treated with B12.

Articular cartilage defects represent an inciting factor for future osteoarthritis (OA) and degenerative joint disease progression. Despite multiple clinically available therapies that succeed in providing short term pain reduction and restoration of limited mobility, current treatments do not reliably regenerate native hyaline cartilage or halt cartilage degeneration at these defect sites. Novel therapeutics aimed at addressing limitations of current clinical cartilage regeneration therapies increasingly focus on allogeneic cells, specifically mesenchymal stem cells (MSCs), as potent, banked, and available cell sources that express chondrogenic lineage commitment capabilities. Innovative tissue engineering approaches employing allogeneic MSCs aim to develop three-dimensional (3D), chondrogenically differentiated constructs for direct and immediate replacement of hyaline cartilage, improve local site tissue integration, and optimize treatment outcomes. Among emerging tissue engineering technologies, advancements in cell sheet tissue engineering offer promising capabilities for achieving both in vitro hyaline-like differentiation and effective transplantation, based on controlled 3D cellular interactions and retained cellular adhesion molecules. This review focuses on 3D MSC-based tissue engineering approaches for fabricating “ready-to-use” hyaline-like cartilage constructs for future rapid in vivo regenerative cartilage therapies. We highlight current approaches and future directions regarding development of MSC-derived cartilage therapies, emphasizing cell sheet tissue engineering, with specific focus on regulating 3D cellular interactions for controlled chondrogenic differentiation and post-differentiation transplantation capabilities.

Despite the increasing trends, reports on long-term follow-up are limited on transitioning from parenteral to oral treprostinil therapy in patients with pulmonary arterial hypertension (PAH). We investigated both the effectiveness of parenteral to oral treprostinil transition and the characteristics associated with transition failure over a duration of two years. The study included 37 Group I functional class I and II patients with PAH on combination therapy. Patients were excluded if cardiac index ≤2.2 L/min/m 2 , right atrial pressure ≥11 mmHg, or 6-min walk distance ≤250 m. Patients were categorized as successful ( S Transition) or unsuccessful ( U Transition) transition based on clinical stability, or a parenteral comparator ( C Parenteral) if they remained on parenteral therapy (no transition). All patients underwent two right heart catheterizations, one at enrollment and a second post transition. Of 24 total transition patients, 46% were classified as U Transition. U Transition occurred on average 577 days post transition. Both U Transition and S Transition had similar hemodynamics at diagnosis and treprostinil dose before and after transition. Before transition, the pulmonary vascular resistance (PVR) was significantly higher in the U Transition (6.7 ± 2 WU) vs. S Transition group (3.5 ± 1.5 WU). At follow-up catheterization, the U Transition group demonstrated further increases in PVR, greater than the C Parenteral group, without recovery despite “rescue” therapy in the U Transition group. A pre-transition PVR of 4.16 WU discriminated the U Transition from the S Transition group. While a subset of PAH patients on combination therapy may be safely transitioned from parenteral to oral treprostinil, caution should be exercised in patients with elevated baseline PVR to avoid irreversible destabilization.

This paper argues that the Turkic auxiliary construction –(İ)p bol–, at least in Uyghur and Uzbek, is actually a pair of auxiliaries with distinct meanings. The first auxiliary is described as expressing “full completion” of the event, but its use is highly restricted, to events with incremental or universally quantified themes. Using targeted context-based elicitation, we find that the expression of completion is indirect. Instead, the auxiliary asserts that the event description is homomorphic, in that all of its events are both event-mapped and theme-mapped. Homomorphism requires every part of the theme to undergo a part of the event, and this derives the reported sense of completion.The second auxiliary is not attested in the literature. It applies to all kinds of events, and expresses what we call “content satisfaction,” the conventional implicature that the event as described satisfies some salient propositional content by rendering it true. For instance, it makes part of a plan come to fruition. This plan is presupposed, and the content is accessible through a content-generating function.We apply the methodologies of formal semantic fieldwork to tease these auxiliaries apart, including scope tests that apply differently to the two auxiliaries. Having distinguished them, we suggest new ways to typologically distinguish Turkic auxiliaries and auxiliaries cross-linguistically.

Background Glyburide (also known as glibenclamide) is effective in reducing the severity of tissue destruction and improving functional outcome after experimental spinal cord injury in rodents and so has promise as a therapy in humans. There are many important differences between spinal cord injury in experimental animals and in human clinical cases, making it difficult to introduce new therapies into clinical practice. Spinal cord injury is also common in pet dogs and requires new effective therapies, meaning that they can act as a translational model for the human condition while also deriving direct benefits from such research. In this study we investigated the pharmacokinetics and safety of glyburide in dogs with clinical spinal cord injury. Methods We recruited dogs that had incurred an acute thoracolumbar spinal cord injury within the previous 72 h. These had become acutely non-ambulatory on the pelvic limbs and were admitted to our veterinary hospitals to undergo anesthesia, cross sectional diagnostic imaging, and surgical decompression. Oral glyburide was given to each dog at a dose of 75 mcg/kg. In five dogs, we measured blood glucose concentrations for 10 h after a single oral dose. In six dogs, we measured serum glyburide and glucose concentrations for 24 h and estimated pharmacokinetic parameters to estimate a suitable dose for use in a subsequent clinical trial in similarly affected dogs. Results No detrimental effects of glyburide administration were detected in any participating dog. Peak serum concentrations of glyburide were attained at a mean of 13 h after dosing, and mean apparent elimination half-life was approximately 7 h. Observed mean maximum plasma concentration was 31 ng/mL. At the glyburide dose administered there was no observable association between glyburide and glucose concentrations in blood. Discussion Our data suggest that glyburide can be safely administered to dogs that are undergoing anesthesia, imaging and surgery for treatment of their acute spinal cord injury and can attain clinically-relevant serum concentrations without developing hazardous hypoglycemia. Serum glyburide concentrations achieved in this study suggest that a loading dose of 150 mcg/kg followed by repeat doses of 75 mcg/kg at 8-hourly intervals would lead to serum glyburide concentrations of 25–50 ng/mL within an acceptably short enough period after oral administration to be appropriate for a clinical trial in canine spinal cord injury.

The prevalence of obesity and eating disorders varies by sex, but the extent to which sex influences eating behaviors, especially in childhood, has received less attention. The purpose of this paper is to critically discuss the literature on sex differences in eating behavior in children and present new findings supporting the role of sex in child appetitive traits and neural responses to food cues. In children, the literature shows sex differences in food acceptance, food intake, appetitive traits, eating-related compensation, and eating speed. New analyses demonstrate that sex interacts with child weight status to differentially influence appetitive traits. Further, results from neuroimaging suggest that obesity in female children is positively related to neural reactivity to higher-energy-dense food cues in regions involved with contextual processing and object recognition, while the opposite was found in males. In addition to differences in how the brain processes information about food, other factors that may contribute to sex differences include parental feeding practices, societal emphasis on dieting, and peer influences. Future studies are needed to confirm these findings, as they may have implications for the development of effective intervention programs to improve dietary behaviors and prevent obesity.

In This Republic of Suffering Drew Faust describes Civil War hospitals as “especially dangerous places…nurses—Louisa May Alcott prominent among them—regularly fell victim to typhoid, smallpox, and even heart failure brought on by the conditions and demands of their employment” (140). In the environment Faust describes, Louisa May Alcott “would have given much to have possessed the art of sketching, for many…faces became wonderfully interesting” (33). Alcott’s desire to depict hospitalized soldiers comes to fruition in her 1863 collection of letters turned fiction, Hospital Sketches. Although Alcott’s account is presented as fiction, it contains many levels of truth, embodying the type of story central in most debates concerning truth and authority within autobiography. Alice Fahrs refers to Hospital Sketches as “a fictionalized account of Alcott’s brief experiences as a nurse in Washington” (2) while acknowledging that the story is the product of Alcott’s very real experience written to her family in a series of letters (29). Scholars classify Hospital Sketches as fiction because it is signed by Nurse Periwinkle, Alcott’s narrator and alter ego (24). Elaine Showalter explains that the letters developed into a series of sketches and then into a book: “When she turned the sketches, originally written for the Boston antislavery paper The Commonwealth, into a book, Alcott added…Tribulation Periwinkle, a doughty spinster who goes to Washington because she wants something to do, and not because she understands very well where she is going” (xxvi). Alcott’s experience remains intact but the author does not. Hospital Sketchesstands as an example of how truth and authority in autobiography become suspect, while simultaneously allowing for significance and meaning to emerge.

This paper presents an analysis of the spatial characteristics and duration of extreme wave events around the English coast. There are five geographic regions which are affected as coherent units under extreme wave conditions, incorporating a sixth micro-wave climate region (western Lyme Bay). Characteristic storm tracks are associated with each region. Storms affecting the East region (North Sea coast) seldom impact other areas of England, whilst in contrast, storms affecting the Southwest or Northwest also have some impact on the Southeast. Average storm duration varies from 5 h in the Northwest to 14 h on the East coast north of the Humber. Storm duration exceeding 12.5 h in the Southwest and East (northern half) near guarantees that storm waves will span High Water, when it is of most significance for beach management operations. Storms along the East coast can be associated with anticyclonic conditions, as well as low pressure systems.

PURPOSE:This study compared cognitive (attention, learning, and memory) and typing outcomes during slow treadmill walking or sitting. Seventy-five healthy individuals were randomly assigned to a treadmill walking group (n=37; 23 female) or sitting group (n=38; 17 female). METHODS:The treadmill walking group completed a series of tests while walking at 1.5 mph. The sitting group performed the same tests while sitting at a standard desk. Tests performed by both groups included: the Rey Auditory Verbal Learning Test and a modified version of the Paced Auditory Serial Attention Test. In addition, typing performance was evaluated. RESULTS:Participants in the treadmill walking group performed worse on the Rey Auditory Verbal Learning Test for total learning than the sitting group; the main effect was significant (F(1,73)=4.75, p=0.03, ηp2=0.06); however, short- and long-delay recall performance did not differ between groups (p>0.05). For the Paced Auditory Serial Attention Test, total number of correct responses was lower in the treadmill walking group relative to the sitting group; the main effect was significant (F(1,73)=4.97, p=0.03, ηp2=0.06). The performance of both groups followed the same learning slope (Group x Trial interactions were not significant) for the Rey Auditory Verbal Learning Test and Paced Auditory Serial Attention Test. Individuals in the treadmill walking group performed significantly worse for all measures of typing (p

Neuroprosthesis research aims to enable communication between the brain and external assistive devices while restoring lost functionality such as occurs from stroke, spinal cord injury or neurodegenerative diseases. In future closed-loop sensorimotor prostheses, one approach is to use neuromodulation as direct stimulus to the brain to compensate for a lost sensory function and help the brain to integrate relevant information for commanding external devices via, e.g. movement intention. Current neuromodulation techniques rely mainly of electrical stimulation. Here we focus specifically on the question of eliciting a biomimetically relevant sense of touch by direct stimulus of the somatosensory cortex by introducing optogenetic techniques as an alternative to electrical stimulation. We demonstrate that light activated opsins can be introduced to target neurons in the somatosensory cortex of non-human primates and be optically activated to create a reliably detected sensation which the animal learns to interpret as a tactile sensation localized within the hand. The accomplishment highlighted here shows how optical stimulation of a relatively small group of mostly excitatory somatosensory neurons in the nonhuman primate brain is sufficient for eliciting a useful sensation from data acquired by simultaneous electrophysiology and from behavioral metrics. In this first report to date on optically neuromodulated behavior in the somatosensory cortex of nonhuman primates we do not yet dissect the details of the sensation the animals exerience or contrast it to those evoked by electrical stimulation, issues of considerable future interest.

FoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4--homolog of mammalian SIRT6 and SIRT7 proteins--promotes DAF-16-dependent transcription and stress-induced DAF-16 nuclear localization. SIR-2.4 is required for resistance to multiple stressors: heat shock, oxidative insult, and proteotoxicity. By contrast, SIR-2.4 is largely dispensable for DAF-16 nuclear localization and function in response to reduced insulin/IGF-1-like signaling. Although acetylation is known to regulate localization and activity of mammalian FoxO proteins, this modification has not been previously described on DAF-16. We find that DAF-16 is hyperacetylated in sir-2.4 mutants. Conversely, DAF-16 is acetylated by the acetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalytic mutant efficiently rescues the DAF-16 localization defect in sir-2.4 null animals. Acetylation of DAF-16 by CBP-1 in vitro is inhibited by either wild-type or mutant SIR-2.4, suggesting that SIR-2.4 regulates DAF-16 acetylation indirectly, by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SIR-2.4 as a critical regulator of DAF-16 specifically in the context of stress responses. Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function.

AN245, a 6-page fact sheet by Bob Myer, Travis Maddock, and Lee McDowell, discusses aspects of a good mineral program for beef cattle. Includes references. Published by the UF Department of Animal Science, July 2010.

Revised! AN124, a 5-page fact sheet by Robert Myer and Travis Maddock, provides a list of considerations for producers who are currently using or plan to use alternative feedstuffs in their livestock operations. Includes references. Published by the UF Department of Animal Sciences, December 2009.

In all, DGS is an excellent feed for beef cattle. This feed can provide both protein and energy in many beef cattle supplement feeding and backgrounding programs. With the increasing production of ethanol for fuel, the availability of DGS will only increase in the future. University research has indicated that DGS can be safely fed up to 40% of total diet (dry basis), and the possibility of greater inclusion rates does exist. With the increase in the availability of DGS, more research is currently being conducted at several institutions that will help to more clearly define acceptable feeding levels and feeding management practices for DGS.

Antimicrobial resistance continues to be a global issue. Pathogens, such as Burkholderia pseudomallei, have evolved mechanisms to efflux certain antibiotics and manipulate the host response. New treatment strategies are therefore required, such as a layered defense approach. Here, we demonstrate, using biosafety level 2 (BSL-2) and BSL-3 in vivo murine models, that combining the antibiotic doxycycline with an immunomodulatory drug that targets the CD200 axis is superior to antibiotic treatment in combination with an isotype control. CD200-Fc treatment alone significantly reduces bacterial burden in lung tissue in both the BSL-2 and BSL-3 models. When CD200-Fc treatment is combined with doxycycline to treat the acute BSL-3 model of melioidosis, there is a 50% increase in survival compared with relevant controls. This benefit is not due to increasing the area under the concentration-time curve (AUC) of the antibiotic, suggesting the immunomodulatory nature of CD200-Fc treatment is playing an important role by potentially controlling the overactive immune response seen with many lethal bacterial infections. IMPORTANCE Traditional treatments for infectious disease have focused on the use of antimicrobial compounds (e.g. antibiotics) that target the infecting organism. However, timely diagnosis and administration of antibiotics remain crucial to ensure efficacy of these treatments especially for the highly virulent biothreat organisms. The need for early antibiotic treatment, combined with the increasing emergence of antibiotic resistant bacteria, means that new therapeutic strategies are required for organisms that cause rapid, acute infections. Here, we show that a layered defense approach, where an immunomodulatory compound is combined with an antibiotic, is better than an antibiotic combined with a relevant isotype control following infection with the biothreat agent Burkholderia pseudomallei . This approach has the potential to be truly broad spectrum and since the strategy includes manipulation of the host response it's application could be used in the treatment of a wide range of diseases., Competing Interests: The authors declare a conflict of interest. Rebecca Ashfield and Philip Huxley are shareholders in Arcutis Biotherapeutics, and Rebecca Ashfield is a consultant for Arcutis; Arcutis acquired Ducentis in 2022, including patents claiming high affinity human CD200-Fc proteins.

Innate lymphoid cells (ILCs) are capable of rapid response to a wide variety of immune challenges, including various respiratory pathogens. Despite this, their role in the immune response against the lethal intracellular bacterium Francisella tularensis is not yet known. In this study, we demonstrate that infection of the airways with F. tularensis results in a significant reduction in lung type 2 ILCs (ILC2s) in mice. Conversely, the expansion of ILC2s via treatment with the cytokine IL-33, or by adoptive transfer of ILC2s, resulted in significantly enhanced bacterial burdens in the lung, liver, and spleen, suggesting that ILC2s may favor severe infection. Indeed, specific reduction of ILC2s in a transgenic mouse model results in a reduction in lung bacterial burden. Using an in vitro culture system, we show that IFN-γ from the live vaccine strain-infected lung reduces ILC2 numbers, suggesting that this cytokine in the lung environment is mechanistically important in reducing ILC2 numbers during infection. Finally, we show Ab-mediated blockade of IL-5, of which ILC2s are a major innate source, reduces bacterial burden postinfection, suggesting that IL-5 production by ILC2s may play a role in limiting protective immunity. Thus, overall, we highlight a negative role for ILC2s in the control of infection with F. tularensis. Our work therefore highlights the role of ILC2s in determining the severity of potentially fatal airway infections and raises the possibility of interventions targeting innate immunity during infection with F. tularensis to benefit the host., (Copyright © 2023 The Authors.)

Radiotherapy (RT) is a highly effective anticancer treatment that is delivered to more than half of all patients with cancer. In addition to the well-documented direct cytotoxic effects, RT can have immunomodulatory effects on the tumour and surrounding tissues. These effects are thought to underlie the so-called abscopal responses, whereby RT generates systemic antitumour immunity outside the irradiated tumour. The full scope of these immune changes remains unclear but is likely to involve multiple components, such as immune cells, the extracellular matrix, endothelial and epithelial cells and a myriad of chemokines and cytokines, including transforming growth factor-β (TGFβ). In normal tissues exposed to RT during cancer therapy, acute immune changes may ultimately lead to chronic inflammation and RT-induced toxicity and organ dysfunction, which limits the quality of life of survivors of cancer. Here we discuss the emerging understanding of RT-induced immune effects with particular focus on the lungs and gut and the potential immune crosstalk that occurs between these tissues., (© 2021. Springer Nature Limited.)

Presence of TGFβ in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFβ is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the β8 chain of αvβ8 integrin (Itgβ8) are the main cell type in the tumors that activates TGFβ, produced by the cancer cells and stored in the tumor micro-environment. Itgβ8 ablation in Treg cells impairs TGFβ signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8 + T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgβ8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFβ and to create an immunosuppressive micro-environment., (© 2021. The Author(s).)

Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis., Competing Interests: Declaration of Competing Interest T.C. reports grants and/or personal fees from Boehringer Ingelheim, Roche, Gilead, Bayer, Intermune, AstraZeneca, BMS, Promedior, Ad Alta. C.J.B is a director and shareholder of Amplia Therapeutics, developing anti-fibrotic drugs for the treatment of IPF. P.M.H. has received funding from Pharmaxis for the study of LOX2 inhibitors, and is on the Scientific Advisory Board of Amplia Therapeutics. J.K.B has received research funding from Boehringer Ingelheim. Other authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

SapM is a secreted virulence factor from Mycobacterium tuberculosis critical for pathogen survival and persistence inside the host. Its full potential as a target for tuberculosis treatment has not yet been exploited because of the lack of potent inhibitors available. By screening over 1500 small molecules, we have identified new potent and selective inhibitors of SapM with an uncompetitive mechanism of inhibition. The best inhibitors share a trihydroxy-benzene moiety essential for activity. Importantly, the inhibitors significantly reduce mycobacterial burden in infected human macrophages at 1 µM, and they are selective with respect to other mycobacterial and human phosphatases. The best inhibitor also reduces intracellular burden of Francisella tularensis, which secretes the virulence factor AcpA, a homologue of SapM, with the same mechanism of catalysis and inhibition. Our findings demonstrate that inhibition of SapM with small molecule inhibitors is efficient in reducing intracellular mycobacterial survival in host macrophages and confirm SapM as a potential therapeutic target. These initial compounds have favourable physico-chemical properties and provide a basis for exploration towards the development of new tuberculosis treatments. The efficacy of a SapM inhibitor in reducing Francisella tularensis intracellular burden suggests the potential for developing broad-spectrum antivirulence agents to treat microbial infections.

Transforming growth factor β (TGF-β) is a multifunctional cytokine that regulates cell growth, differentiation, adhesion, migration and death dependent on cell type, developmental stage, or tissue conditions. Various cell types secrete TGF-β, but always as an inactive complex. Hence, for TGF-β to function, this latent complex must somehow be activated. Work in recent years has highlighted a critical role for members of the α v integrin family, including α v β 1 , α v β 3 , α v β 5 , α v β 6 and α v β 8 that are involved in TGF-β activation in various contexts, particularly at barrier sites such as the gut, lung and skin. The integrins facilitating this context- and location-specific regulation can be dysregulated in certain diseases, so are potential therapeutic targets in a number of disorders. In this review, we discuss the role of TGF-β at these barrier sites with a focus on how integrin-mediated TGF-β activation regulates tissue and immune homeostasis, and how this is altered in disease., (© 2019 The Authors. Immunology published by John Wiley & Sons Ltd.)

Epithelial resident memory T (eT RM ) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eT RM cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor β (TGF-β) epigenetically conditions resting naïve CD8 + T cells and prepares them for the formation of eT RM cells in a mouse model of skin vaccination. Naïve T cell conditioning occurs in lymph nodes (LNs), but not in the spleen, through major histocompatibility complex class I-dependent interactions with peripheral tissue-derived migratory dendritic cells (DCs) and depends on DC expression of TGF-β-activating α V integrins. Thus, the preimmune T cell repertoire is actively conditioned for a specialized memory differentiation fate through signals restricted to LNs., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)