Acute B-Cell Inhibition by Soluble Antigen Arrays Is Valency-Dependent and Predicts Immunomodulation in Splenocytes

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biomacromolecules, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biomac.9b00328.Antigen valency plays a fundamental role in directing the nature of an immune response to be stimulatory or tolerogenic. Soluble Antigen Arrays (SAgAs) are an antigen-specific immunotherapy that combats autoimmunity through the multivalent display of autoantigen. While mechanistic studies have shown SAgAs to induce T and B-cell anergy, the effect of SAgA valency has never been experimentally tested. Here, SAgAs of discrete antigen valencies were synthesized by click chemistry and evaluated for acute B-cell signaling inhibition as well as downstream immunomodulatory effects in splenocytes. Initial studies using the Raji B-cell line demonstrated SAgA valency dictated the extent of calcium flux. Lower valency constructs elicited the largest reductions in B-cell activation. In splenocytes from mice with experimental autoimmune encephalomyelitis, the same valency-dependent effects were evident in the downregulation of the costimulatory marker CD86. The reduction of calcium flux observed in Raji B-cells correlated strongly with downregulation in splenocyte CD86 expression after 72 hours. Here, a thorough analysis of SAgA antigenic valency illustrates that low, but not monovalent, presentation of autoantigen was ideal for eliciting the most potent immunomodulatory effects.Madison and Lila Self Graduate Fellowship at the University of KansasNIH T32 GM00854

Experience Within the Emergency Department and Improved Productivity for First-Year Residents in Emergency Medicine and Other Specialties

Introduction: Resident productivity is an important educational and operational measure in emergency medicine (EM). The ability to continue effectively seeing new patients throughout a shift is fundamental to an emergency physician’s development, and residents are integral to the workforce of many academic emergency departments (ED). Our previous work has demonstrated that residents make gains in productivity over the course of intern year; however, it is unclear whether this is from experience as a physician in general on all rotations, or specific to experience in the ED. Methods: This was a retrospective cohort study, conducted in an urban academic hospital ED, with a three-year EM training program in which first-year residents see new patients ad libitum. We evaluated resident shifts for the total number of new patients seen. We constructed a generalized estimating equation to predict productivity, defined as the number of new patients seen per shift, as a function of the week of the academic year, the number of weeks spent in the ED, and their interaction. Off-service residents’ productivity in the ED was analyzed in a secondary analysis. Results: We evaluated 7,779 EM intern shifts from 7/1/2010 to 7/1/2016. Interns started at 7.16 (95% confidence interval [CI] [6.87 – 7.45]) patients per nine-hour shift, with an increase of 0.20 (95% CI [0.17 – 0.24]) patients per shift for each week in the ED, over 22 weeks, leading to 11.5 (95% CI [10.6 – 12.7]) patients per shift at the end of their training in the ED. The effects of the week of the academic year and its interaction with weeks in the ED were not significant. We evaluated 2,328 off-service intern shifts, in which off-service residents saw 5.43 (95% CI [5.02 – 5.84]) patients per nine-hour shift initially, with 0.46 additional patients per week in the ED (95% CI [0.25 – 0.68]). The weeks of the academic year were not significant. Conclusion: Intern productivity in EM correlates with time spent training in the ED, and not with experience on other rotations. Accordingly, an EM intern’s productivity should be evaluated relative to their aggregate time in the ED, rather than the time in the academic year

Effect of Compression Garments in the Speed Performance among Track and Field and Swimming student-athletes in a Catholic University of the Philippines

Background and Purpose: Speed is critical for sports such as swimming and track and field. One of the sports industry's solutions is compression garments to enhance athletic performance. This study aims to determine the effect of short and long compression garments on the speed performance of track and field and swimming athletes of the University of Santo Tomas. Methodology: The researchers used quantitative and experimental methods. This study focused on the athletes of the track and field and swimming teams of the University of Santo Tomas. The researchers conducted the study at the open field and swimming pool within the vicinity of the University; 14 athletes from track and field and 16 from the swimming team were invited to participate in the 60M Sprint Test and Critical Swim Speed Test. Results: The study shows a slight difference in the speed performance of track and field athletes when using short compression garments (7.54m/s) and long compression garments (7.44m/s). While swimming, the speed performance when using a long compression garment (1.450m/s) is higher than the short compression garment (1.512m/s). Both swimming (0.887) and track and field (0.559) show no significant difference in using the compression garment. Conclusion and Recommendations: Based on the study, there is a minimal difference in using long compression garments against short compression garments. Therefore, the researchers recommend using long compression garments since this garment slightly increases participants' speed which is vital in any sport measuring speed to win a race. The researchers recommend further study by increasing the number of participants, only endurance athletes participants, and including the materials used in making the garments. This further helps the claim that long and short compression garments affect speed performance regardless of sports or events

Succinylated Octopamine Ascarosides and a New Pathway of Biogenic Amine Metabolism in Caenorhabditis elegans

The ascarosides, small-molecule signals derived from combinatorial assembly of primary metabolism-derived building blocks, play a central role in Caenorhabditis elegans biology and regulate many aspects of development and behavior in this model organism as well as in other nematodes. Using HPLCMS/ MS-based targeted metabolomics, we identified novel ascarosides incorporating a side chain derived from succinylation of the neurotransmitter octopamine. These compounds, named osas#2, osas#9, and osas#10, are produced predominantly by L1 larvae, where they serve as part of a dispersal signal, whereas these ascarosides are largely absent from the metabolomes of other life stages. Investigating the biogenesis of these octopamine- derived ascarosides, we found that succinylation represents a previously unrecognized pathway of biogenic amine metabolism. At physiological concentrations, the neurotransmitters serotonin, dopamine, and octopamine are converted to a large extent into the corresponding succinates, in addition to the previously described acetates. Chemically, bimodal deactivation of biogenic amines via acetylation and succinylation parallels posttranslational modification of proteins via acetylation and succinylation of L-lysine. Our results reveal a small-molecule connection between neurotransmitter signaling and interorganismal regulation of behavior and suggest that ascaroside biosynthesis is based in part on co-option of degradative biochemical pathways

GALC Deletions Increase the Risk of Primary Open-Angle Glaucoma: The Role of Mendelian Variants in Complex Disease

DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI −1.1–12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6–16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG

Comparison of diet consumption, body composition and lipoprotein lipid values of Kuwaiti fencing players with international norms

<p>Abstract</p> <p>Background</p> <p>No published data is currently available that describes the dietary patterns or physiological profiles of athletes participating on the Kuwaiti national fencing team and its potential impact on health and physical performance. The purpose of this investigation was to: 1) collect baseline data on nutrient intake 2) collect, analyze and report baseline for body composition, plasma lipid and lipoprotein concentrations during the competitive season, 3) compare the results with the international norms, 4) and provide necessary health and nutritional information in order to enhance the athletes' performance and skills.</p> <p>Methods</p> <p>Fifteen national-class fencers 21.5 ± 2.6 years of age participated in this study. Food intake was measured using a 3-day food record. Body composition was estimated using both the BOD POD and Body Mass Index (BMI). Total blood lipid profiles and maximum oxygen consumption was measured for each of the subjects during the competitive season.</p> <p>Results</p> <p>The results of the present study showed significant differences in dietary consumption in comparison with the recommended dietary allowances (RDA). The blood lipids profile and body composition (BMI and % body fat) were in normal range in comparison with international norms However, the average VO_{2 max}value was less than the value of the other fencers.</p> <p>Conclusion</p> <p>Due to the results of the research study, a dietary regimen can be designed that would better enhance athletic performance and minimize any health risks associated with nutrition. Percent body fat and BMI will also be categorized for all players. In addition, the plasma blood tests will help to determine if any of the players have an excessive level of lipids or any blood abnormalities. The outcomes of present study will have a direct impact on the players health and therefore their skills and athletic performance.</p

Lung transcriptional unresponsiveness and loss of early influenza virus control in infected neonates is prevented by intranasal Lactobacillus rhamnosus GG

Respiratory viral infections contribute substantially to global infant losses and disproportionately affect preterm neonates. Using our previously established neonatal murine model of influenza infection, we demonstrate that three-day old mice are exceptionally sensitive to influenza virus infection and exhibit high mortality and viral load. Intranasal pre- and post-treatment of neonatal mice with Lactobacillus rhamnosus GG (LGG), an immune modulator in respiratory viral infection of adult mice and human preterm neonates, considerably improves neonatal mice survival after influenza virus infection. We determine that both live and heat-killed intranasal LGG are equally efficacious in protection of neonates. Early in influenza infection, neonatal transcriptional responses in the lung are delayed compared to adults. These responses increase by 24 hours post-infection, demonstrating a delay in the kinetics of the neonatal anti-viral response. LGG pretreatment improves immune gene transcriptional responses during early infection and specifically upregulates type I IFN pathways. This is critical for protection, as neonatal mice intranasally pre-treated with IFNβ before influenza virus infection are also protected. Using transgenic mice, we demonstrate that the protective effect of LGG is mediated through a MyD88-dependent mechanism, specifically via TLR4. LGG can improve both early control of virus and transcriptional responsiveness and could serve as a simple and safe intervention to protect neonates