Bilirubin acts as an endogenous regulator of inflammation by disrupting adhesion molecule-mediated leukocyte migration

There is a growing body of evidence that bilirubin, which is generated during the physiological breakdown of heme, exerts potent anti-inflammatory effects.  Previous work by our group suggests that bilirubin is able to suppress inflammatory responses by preventing the migration of leukocytes into target tissues through disruption of vascular cell adhesion molecule-1 (VCAM-1)-dependent cell signaling. As VCAM-1 is an important mediator of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. As anticipated, bilirubin-treated animals manifested significantly less colonic injury and reduced infiltration of inflammatory cells into colon tissues. We further observed that bilirubin administration was associated with a reduced number of eosinophils and monocytes in the small intestine, with a corresponding increase in peripheral blood eosinophilia, regardless of whether mice received DSS. These findings suggest that bilirubin impairs the normal migration of eosinophils into intestinal tissues, as supported by in vitro experiments showing that bilirubin blocks the VCAM-1-dependent movement of Jurkat cells across human endothelial cell monolayers. Taken together, our findings support that bilirubin ameliorates DSS-induced colitis and disrupts the physiological trafficking of leukocytes to the intestine by preventing transmigration across the vascular endothelium, potentially through the inhibition VCAM-1-mediated signaling. Our findings raise the possibility that bilirubin functions as an endogenous regulator of inflammatory responses

Athlete Perceptions of Flavored, Menthol-enhanced Energy Gels Ingested Prior to Running in the Heat

Thermal perception during exercise is known to influence endurance performance and the onset of fatigue. L-menthol, an organic compound derived from peppermint, evokes a cooling sensation through its action on TRPM8 channels which also respond to cold stimuli. Recent work identified that the internal application of menthol-enhanced fluids can be ergogenic during exercise in the heat. Hence, the addition of menthol to energy gels may be practical and beneficial for athletes. PURPOSE: To determine athlete acceptability and preferences for flavored energy gels with different menthol concentrations. METHODS: With a randomized, crossover, and double-blind placebo-controlled design, 27 endurance athletes (34.8±6.7 y, BMI: 21.7±1.6 kg·m-2, 9 female) ingested an energy gel with a menthol additive at relative concentrations: low (0.1%), medium-low (0.3%), medium-high (0.5%), high (0.7%), or a non-menthol, flavor-matched placebo (CON), on separate days before outdoor running sessions. Athletes rated the gels for cooling sensation, irritation (tingling/burning), flavor, and overall experience on 100-point sensory and hedonic labeled magnitude scales. The duration of any cooling sensation was also reported. Repeated measures ANOVAs with a Bonferroni adjustment for pairwise comparisons were used to determine differences. RESULTS: All menthol gels successfully delivered a greater cooling sensation compared to CON (7.4±8.1 AU) with a significantly greater response for 0.7% (59.9±20.5 AU) and 0.5% (57.7±21.8 AU), compared to all others, which were both rated “moderate-strong” for intensity. Irritation intensity was higher for all menthol gels compared to CON (3.4±7.2 AU), and for 0.7% compared to 0.1% (31.1±31.0 vs 16.3±21.0 AU, p=0.041), with none reported higher than a “mild-moderate” intensity. The menthol gels delivered a significantly longer cooling duration (range: 12.3-19.6 min) compared to CON (2.2±4.8 min) with no significant difference between menthol gels. Ratings of overall experience and flavor were not different between gels (p\u3e.05). CONCLUSION: A flavored energy gel with the addition of menthol at 0.1-0.7% provides a cooling sensation for athletes when ingested before exercise. The 0.5% concentration is recommended to maximize the cooling sensation of the gel whilst minimizing irritation

STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation

The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity. To investigate whether these mutations are the cause or consequence of CD

STAT3 gain-of-function syndrome

STAT3 gain-of-function (GOF) syndrome is a multi-organ primary immune regulatory disorder characterized by early onset autoimmunity. Patients present early in life, most commonly with lymphoproliferation, autoimmune cytopenias, and growth delay. However, disease is often progressive and can encompass a wide range of clinical manifestations such as: enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, and rarely neurologic disease, vasculopathy, and malignancy. Treatment of the autoimmune and immune dysregulatory features of STAT3-GOF patients relies heavily on immunosuppression and is often challenging and fraught with complications including severe infections. Defects in the T cell compartment leading to effector T cell accumulation and decreased T regulatory cells may contribute to autoimmunity. While T cell exhaustion and apoptosis defects likely contribute to the lymphoproliferative phenotype, no conclusive correlations are yet established. Here we review the known mechanistic and clinical characteristics of this heterogenous PIRD

Onboarding Employees Through Shared Values

How employees are on-boarded and welcomed into their new positions sets the tone for the culture of a place, the people, and the values of a new institution and can have a significant impact on employees sense of belonging. At Ohio University, the Division of Student Affairs employs approximately 400 staff and annually welcomes around 40-50 new employees a year, 25 of which are College Student Personnel (CSP) graduate students. New employees are welcomed with an ethic of care through a five day onboarding process rooted in Bolman and Deal’s human resource frame. This process includes departmental specific welcomes and trainings, along with division-wide team building, sexual misconduct training, social justice training, and suicide prevention training. This session outlined the correlation with Bolman and Deal’s human resource frame and NASPA/ ACPA competencies as well as lessons learned from implementing such a process, specifically include how these trainings intersect with the learning and development of new professionals

Athlete perceptions of flavored, menthol-enhanced energy gels ingested prior to endurance exercise in the heat

Background L-menthol evokes a cooling sensation by activating cold sensing cation channels. Menthol-enhanced fluids can be ergogenic during exercise in the heat by improving thermal perception; hence, the addition of menthol to energy gels may benefit athletes. Previously, unflavored menthol gels were deemed acceptable at 0.1% concentration, but no research has been undertaken on menthol gels with additional flavoring. Therefore, we determined athlete perceptions of flavored energy gels with different menthol concentrations. Methods With a randomized, crossover, double-blind, placebo-controlled design, 27 athletes (34.8 ± 6.7 y, 9 females) ingested an energy gel with either 0.1%, 0.3%, 0.5%, or 0.7% menthol concentration, or a non-menthol, flavor-matched placebo (CON), on separate occasions before outdoor exercise. Gels were rated for cooling sensation, irritation, flavor, and overall experience on 100-point sensory and hedonic labeled magnitude scales. The duration of any cooling sensation was also reported. Results All menthol gels delivered a greater cooling sensation compared to CON (7.4 ± 8.1 AU) with a significantly greater response for 0.7% (59.9 ± 20.5 AU) and 0.5% (57.7 ± 21.8 AU), compared to all others. Irritation was higher for all menthol gels compared to CON (3.4 ± 7.2 AU) and for 0.7% compared to 0.1% (31.1 ± 31.0 vs. 16.3 ± 21.0 AU, p = 0.041), with none rated above a ‘mild-moderate’ intensity. The menthol gels delivered a significantly longer cooling sensation duration (12.3-19.6 min) versus CON (2.2 ± 4.8 min) with no difference between menthol gels. Conclusion A flavored menthol energy gel at 0.1–0.7% concentration provides a cooling sensation for athletes when ingested before exercise. The 0.5% concentration is recommended to maximize the cooling sensation whilst minimizing irritation

A menthol-enhanced “cooling” energy gel does not influence laboratory time trial performance in trained runners

l-menthol (menthol) is an organic compound derived from peppermint which imparts a refreshing mint flavor and aroma to oral hygiene products, chewing gum, and topical analgesics. Menthol has been identified as a non-thermal sensory cooling strategy for athletes when ingested or mouth-rinsed during exercise in hot environments. Therefore, sports nutrition products delivering a controlled concentration of menthol could be beneficial for athletes exercising in the heat. We sought to test the performance and perceptual outcomes of a novel menthol energy gel during treadmill running in the heat (33 °C, 49% RH). Fourteen trained runners (mean ± SD; age: 31 ± 6 years, VO2max: 56.5 ± 10.1 mL·kg−1·min−1, BMI: 23.2 ± 2.4 kg/m2; six female) participated in a randomized, crossover, double-blind, and placebo-controlled study. A menthol-enhanced energy gel (0.5% concentration; MEN) or flavor-matched placebo (PLA) was ingested 5 min before and again at 20 and 40 min of a 40 min treadmill exercise preload at 60% VO2max, followed by a 20 min self-paced time trial. The total distance, vertical distance, perceptual measures (thermal comfort, thermal sensation, rating of perceived exertion, and affect), and cognitive performance via computerized neurocognitive assessment were measured. No difference between 20 min self-paced time trial total distance (MEN: 4.22 ± 0.54 km, PLA: 4.22 ± 0.55 km, p = 0.867), vertical distance (MEN: 49.2 ± 24.6 m, PLA: 44.4 ± 11.4 m, p = 0.516), or any perceptual measures was observed (all p > 0.05). Cognitive performance was not different between the trials (all p > 0.05). These results suggest that a menthol energy gel is not superior to a non-menthol gel in terms of performance or perception during treadmill running in the heat. More research is needed to confirm whether these findings translate to ecologically valid settings, including outdoor exercise in ambient heat and during competition

Translating Scientific Advances in the AOP Framework to Decision Making for Nanomaterials

Much of the current innovation in advanced materials is occurring at the nanoscale, specifically in manufactured nanomaterials (MNs). MNs display unique attributes and behaviors, and may be biologically and physically unique, making them valuable across a wide range of applications. However, as the number, diversity and complexity of MNs coming to market continue to grow, assessing their health and environmental risks with traditional animal testing approaches is too time- and cost-intensive to be practical, and is undesirable for ethical reasons. New approaches are needed that meet current requirements for regulatory risk assessment while reducing reliance on animal testing and enabling safer-by-design product development strategies to be implemented. The adverse outcome pathway (AOP) framework presents a sound model for the advancement of MN decision making. Yet, there are currently gaps in technical and policy aspects of AOPs that hinder the adoption and use for MN risk assessment and regulatory decision making. This review outlines the current status and next steps for the development and use of the AOP framework in decision making regarding the safety of MNs. Opportunities and challenges are identified concerning the advancement and adoption of AOPs as part of an integrated approach to testing and assessing (IATA) MNs, as are specific actions proposed to advance the development, use and acceptance of the AOP framework and associated testing strategies for MN risk assessment and decision making. The intention of this review is to reflect the views of a diversity of stakeholders including experts, researchers, policymakers, regulators, risk assessors and industry representatives on the current status, needs and requirements to facilitate the future use of AOPs in MN risk assessment. It incorporates the views and feedback of experts that participated in two workshops hosted as part of an Organization for Economic Cooperation and Development (OECD) Working Party on Manufactured Nanomaterials (WPMN) project titled, “Advancing AOP Development for Nanomaterial Risk Assessment and Categorization”, as well as input from several EU-funded nanosafety research consortia

Genetic interaction network of the Saccharomyces cerevisiae type 1 phosphatase Glc7

<p>Abstract</p> <p>Background</p> <p>Protein kinases and phosphatases regulate protein phosphorylation, a critical means of modulating protein function, stability and localization. The identification of functional networks for protein phosphatases has been slow due to their redundant nature and the lack of large-scale analyses. We hypothesized that a genome-scale analysis of genetic interactions using the Synthetic Genetic Array could reveal protein phosphatase functional networks. We apply this approach to the conserved type 1 protein phosphatase Glc7, which regulates numerous cellular processes in budding yeast.</p> <p>Results</p> <p>We created a novel <it>glc7 </it>catalytic mutant (<it>glc7-E101Q</it>). Phenotypic analysis indicates that this novel allele exhibits slow growth and defects in glucose metabolism but normal cell cycle progression and chromosome segregation. This suggests that <it>glc7-E101Q </it>is a hypomorphic <it>glc7 </it>mutant. Synthetic Genetic Array analysis of <it>glc7-E101Q </it>revealed a broad network of 245 synthetic sick/lethal interactions reflecting that many processes are required when Glc7 function is compromised such as histone modification, chromosome segregation and cytokinesis, nutrient sensing and DNA damage. In addition, mitochondrial activity and inheritance and lipid metabolism were identified as new processes involved in buffering Glc7 function. An interaction network among 95 genes genetically interacting with <it>GLC7 </it>was constructed by integration of genetic and physical interaction data. The obtained network has a modular architecture, and the interconnection among the modules reflects the cooperation of the processes buffering Glc7 function.</p> <p>Conclusion</p> <p>We found 245 genes required for the normal growth of the <it>glc7-E101Q </it>mutant. Functional grouping of these genes and analysis of their physical and genetic interaction patterns bring new information on Glc7-regulated processes.</p

Translating Developmental Origins:Improving the Health of Women and Their Children Using a Sustainable Approach to Behaviour Change

Theories of the developmental origins of health and disease imply that optimising the growth and development of babies is an essential route to improving the health of populations. A key factor in the growth of babies is the nutritional status of their mothers. Since women from more disadvantaged backgrounds have poorer quality diets and the worst pregnancy outcomes, they need to be a particular focus. The behavioural sciences have made a substantial contribution to the development of interventions to support dietary changes in disadvantaged women. Translation of such interventions into routine practice is an ideal that is rarely achieved, however. This paper illustrates how re-orientating health and social care services towards an empowerment approach to behaviour change might underpin a new developmental focus to improving long-term health, using learning from a community-based intervention to improve the diets and lifestyles of disadvantaged women. The Southampton Initiative for Health aimed to improve the diets and lifestyles of women of child-bearing age through training health and social care practitioners in skills to support behaviour change. Analysis illustrates the necessary steps in mounting such an intervention: building trust; matching agendas and changing culture. The Southampton Initiative for Health demonstrates that developing sustainable; workable interventions and effective community partnerships; requires commitment beginning long before intervention delivery but is key to the translation of developmental origins research into improvements in human health