Nod2: A Critical Regulator of Ileal Microbiota and Crohn’s Disease

The human intestinal tract harbors large bacterial community consisting of commensal, symbiotic and pathogenic strains, which are constantly interacting with the intestinal immune system. This interaction elicits a non-pathological basal level of immune responses and contributes to shaping both the intestinal immune system and bacterial community. Recent studies on human microbiota are revealing the critical role of intestinal bacterial community in the pathogenesis of both systemic and intestinal diseases including Crohn’s disease (CD). NOD2 plays a key role in the regulation of microbiota in the small intestine. NOD2 is highly expressed in ileal Paneth cells that provide critical mechanism for the regulation of ileal microbiota through the secretion of anti-bacterial compounds. Genome mapping of CD patients revealed that loss of function mutations in NOD2 are associated with ileal CD. Genome-wide association studies (GWAS) further demonstrated that NOD2 is one of the most critical genetic factor linked to ileal CD. The bacterial community in the ileum is indeed dysregulated in Nod2-deficient mice. Nod2-deficient ileal epithelia exhibit impaired ability of killing bacteria. Thus, altered interactions between ileal microbiota and mucosal immunity through NOD2 mutations play significant roles in the disease susceptibility and pathogenesis in CD patients, thereby depicting NOD2 as a critical regulator of ileal microbiota and Crohn’s disease

Crummer/Suntrust Portfolio: Analysis and Recommendations [2008]

Unfavorable economic conditions have prompted the investment team to meet a short-term goal: preserve the value of the portfolio by reducing overall risk. A top down analysis of the current portfolio resulted in recommendations to change the portfolio by eliminating funds, investing in long term government bonds, TIPS and large cap value type securities. Allocations of securities was performed by either overweighting or underweighting a particular sector, depending on its historical and expected return during a recession. Individual securities were analyzed by our sector analystsand recommendations of hold, buy or sell were made. The outcome.... a robust portfolio, that will preserve its value during the recession by reducing its overall risk by 25%

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as “NLRC5” [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers

Evaluation of variation in special educational needs provision and its impact on health and education using administrative records for England: umbrella protocol for a mixed-methods research programme

INTRODUCTION: One-third of children in England have special educational needs (SEN) provision recorded during their school career. The proportion of children with SEN provision varies between schools and demographic groups, which may reflect variation in need, inequitable provision and/or systemic factors. There is scant evidence on whether SEN provision improves health and education outcomes. METHODS: The Health Outcomes of young People in Education (HOPE) research programme uses administrative data from the Education and Child Health Insights from Linked Data-ECHILD-which contains data from all state schools, and contacts with National Health Service hospitals in England, to explore variation in SEN provision and its impact on health and education outcomes. This umbrella protocol sets out analyses across four work packages (WP). WP1 defined a range of 'health phenotypes', that is health conditions expected to need SEN provision in primary school. Next, we describe health and education outcomes (WP1) and individual, school-level and area-level factors affecting variation in SEN provision across different phenotypes (WP2). WP3 assesses the impact of SEN provision on health and education outcomes for specific health phenotypes using a range of causal inference methods to account for confounding factors and possible selection bias. In WP4 we review local policies and synthesise findings from surveys, interviews and focus groups of service users and providers to understand factors associated with variation in and experiences of identification, assessment and provision for SEN. Triangulation of findings on outcomes, variation and impact of SEN provision for different health phenotypes in ECHILD, with experiences of SEN provision will inform interpretation of findings for policy, practice and families and methods for future evaluation. ETHICS AND DISSEMINATION: Research ethics committees have approved the use of the ECHILD database and, separately, the survey, interviews and focus groups of young people, parents and service providers. These stakeholders will contribute to the design, interpretation and communication of findings

The ROS Scavenger, NAC, Regulates Hepatic Vα14iNKT Cells Signaling during Fas mAb-Dependent Fulminant Liver Failure

Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18−/− mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses

Physical activity as an aid to smoking cessation during pregnancy (LEAP) trial: study protocol for a randomized controlled trial

Background: Many women try to stop smoking in pregnancy but fail. One difficulty is that there is insufficient evidence that medications for smoking cessation are effective and safe in pregnancy and thus many women prefer to avoid these. Physical activity (PA) interventions may assist cessation; however, trials examining these interventions have been too small to detect or exclude plausible beneficial effects. The London Exercise And Pregnant smokers (LEAP) trial is investigating whether a PA intervention is effective and cost-effective when used for smoking cessation by pregnant women, and will be the largest study of its kind to date. Methods/design: The LEAP study is a pragmatic, multi-center, two-arm, randomized, controlled trial that will target pregnant women who smoke at least one cigarette a day (and at least five cigarettes a day before pregnancy), and are between 10 and 24 weeks pregnant. Eligible patients are individually randomized to either usual care (that is, behavioral support for smoking cessation) or usual care plus a intervention (entailing supervised exercise on a treadmill plus PA consultations). The primary outcome of the trial is self-reported and biochemically validated continuous abstinence from smoking between a specified quit date and the end of pregnancy. The secondary outcomes, measured at 1 and 4 weeks after the quit date, and at the end of pregnancy and 6 months after childbirth, are PA levels, depression, self-confidence, and cigarette withdrawal symptoms. Smoking status will also be self-reported at 6 months after childbirth. In addition, perinatal measures will be collected, including antenatal complications, duration of labor, mode of delivery, and birth and placental weight. Outcomes will be analyzed on an intention-to-treat basis, and logistic regression models used to compare treatment effects on the primary outcome. Discussion: This trial will assess whether a PA intervention is effective when used for smoking cessation during pregnancy

Tropical Data: Approach and Methodology as Applied to Trachoma Prevalence Surveys

PURPOSE: Population-based prevalence surveys are essential for decision-making on interventions to achieve trachoma elimination as a public health problem. This paper outlines the methodologies of Tropical Data, which supports work to undertake those surveys. METHODS: Tropical Data is a consortium of partners that supports health ministries worldwide to conduct globally standardised prevalence surveys that conform to World Health Organization recommendations. Founding principles are health ministry ownership, partnership and collaboration, and quality assurance and quality control at every step of the survey process. Support covers survey planning, survey design, training, electronic data collection and fieldwork, and data management, analysis and dissemination. Methods are adapted to meet local context and needs. Customisations, operational research and integration of other diseases into routine trachoma surveys have also been supported. RESULTS: Between 29th February 2016 and 24th April 2023, 3373 trachoma surveys across 50 countries have been supported, resulting in 10,818,502 people being examined for trachoma. CONCLUSION: This health ministry-led, standardised approach, with support from the start to the end of the survey process, has helped all trachoma elimination stakeholders to know where interventions are needed, where interventions can be stopped, and when elimination as a public health problem has been achieved. Flexibility to meet specific country contexts, adaptation to changes in global guidance and adjustments in response to user feedback have facilitated innovation in evidence-based methodologies, and supported health ministries to strive for global disease control targets

Vibrational Cueing and its Potential to Lessen the Detrimental Effects of Cognitive Tasks on Walking Stability

I have been analyzing data taken from a Parkinson’s Disease study which was conducted here at UVM in Dr. Ryan McGinnis’s wearable sensors lab. The study subjects underwent various simple tasks while accelerometry and gyroscope metrics were acquired using MC10 and APDM wearable sensors. For my research, I will be looking at one set of tasks in particular: four separate two-minute walking trials. The first trial involved the subjects walking normally for two minutes. In the second trial, the subjects were given a difficult cognitive task, such as a series of math problems. In the third trial, the subjects received a vibrational cue applied at their wrist. The final trial incorporated both the cognitive task and the vibrational cue simultaneously. I hypothesize that the cognitive task exhibited in the second trial will impair the walking stability of each subject. In order to quantify walking stability, I am using an algorithm to extract a measure of bilateral gait symmetry and cadence. These metrics will allow me to formulate a simple representation of each subject\u27s walking stability. I intend to compare the metrics obtained from the normal walking trial to the cognitive task trial. If the results show that the cognitive task impairs walking stability, I intend to look into the effects of the vibrational cue. I hypothesize that the vibrational cue will lesson the potential detrimental effects of the cognitive task on walking stability

NAC therapy ameliorates agonistic Fas mAb-induced FLF during IFN-γ deficiency.

<p>(<b>a</b>) Serum ALT levels in WT and IFN-γ^−/− mice after PBS or NAC treatment during agonistic Fas mAb-induced FLF. (<b>b</b>) H & E staining of liver sections of WT and IFN-γ^−/− mice after PBS or NAC treatment during agonistic Fas mAb-induced FLF. As shown in <b>top panel</b>, livers from Fas mAb-treated WT and IFN-γ^−/− mice displayed widespread hepatocyte damage including hemorrhagic necrosis (white arrows) and apoptosis (black arrows) that distorted normal liver architecture. In contrast, liver sections of WT and IFN-γ^−/− mice treated with NAC during Fas mAb-induced FLF (<b>bottom panel</b>) showed reduced hepatocyte damage and retained near normal architecture. (<b>c & e</b>) Western blot analysis of hepatic active caspase 3, T-bet, pSTAT-1 expression levels and nitrotyrosine formation in WT and IFN-γ^−/− mice after PBS or NAC treatment during Fas mAb-induced FLF. (<b>d</b>) TUNEL staining of liver sections from WT and IFN-γ^−/− mice treated with PBS during Fas mAb-induced FLF showed intense TUNEL staining characteristic of apoptosis whereas WT and IFN-γ^−/− mice treated with NAC mice showed minimal TUNEL staining. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038051#pone.0038051.s001" target="_blank">Figure S1</a> in <b>a</b> are presented as mean ± s.e.m with <i>n</i> = 3–6 mice/group. *<i>P</i><0.05, ^≠<i>P</i><0.05 by one-way analysis of variance followed by Newman-Kuels post hoc test. All experiments were performed twice.</p