Interleukin 1β and Prostaglandin E2 Affect Expression of DNA Methylating and Demethylating Enzymes in Human Gingival Fibroblasts

Periodontitis is a common chronic inflammatory condition that results in increased levels of inflammatory cytokines and inflammatory mediators. In addition to oral disease and tooth loss, it also causes low-grade systemic inflammation that contributes to development of systemic conditions including cardiovascular disease, pre-term birth, diabetes and cancer. Chronic inflammation is associated with epigenetic change, and it has been suggested that such changes can alter cell phenotypes in ways that contribute to both ongoing inflammation and development of associated pathologies. Here we show that exposure of human gingival fibroblasts to IL-1β increases expression of maintenance methyltransferase DNMT1 but decreases expression of de novo methyltransferase DNMT3a and the demethylating enzyme TET1, while exposure to PGE2 decreases expression of all three enzymes. IL-1β and PGE2 both affect global levels of DNA methylation and hydroxymethylation, as well as methylation of some specific CpG in inflammation-associated genes. The effects of IL-1β are independent of its ability to induce production of PGE2, and the effects of PGE2 on DNMT3a expression are mediated by the EP4 receptor. The finding that exposure of fibroblasts to IL-1β and PGE2 can result in altered expression of DNA methylating/demethylating enzymes and in changing patterns of DNA methylation suggests a mechanism through which inflammatory mediators might contribute to the increased risk of carcinogenesis associated with inflammation

The Cryptosporidium parvum Kinome

<p>Abstract</p> <p>Background</p> <p>Hundreds of millions of people are infected with cryptosporidiosis annually, with immunocompromised individuals suffering debilitating symptoms and children in socioeconomically challenged regions at risk of repeated infections. There is currently no effective drug available. In order to facilitate the pursuit of anti-cryptosporidiosis targets and compounds, our study spans the classification of the <it>Cryptosporidium parvum </it>kinome and the structural and biochemical characterization of representatives from the CDPK family and a MAP kinase.</p> <p>Results</p> <p>The <it>C</it>. <it>parvum </it>kinome comprises over 70 members, some of which may be promising drug targets. These <it>C. parvum </it>protein kinases include members in the AGC, Atypical, CaMK, CK1, CMGC, and TKL groups; however, almost 35% could only be classified as OPK (other protein kinases). In addition, about 25% of the kinases identified did not have any known orthologues outside of <it>Cryptosporidium spp</it>. Comparison of specific kinases with their <it>Plasmodium falciparum </it>and <it>Toxoplasma gondii </it>orthologues revealed some distinct characteristics within the <it>C. parvum </it>kinome, including potential targets and opportunities for drug design. Structural and biochemical analysis of 4 representatives of the CaMK group and a MAP kinase confirms features that may be exploited in inhibitor design. Indeed, screening <it>Cp</it>CDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC₅₀values of < 10 nM. The binding of a PP1-derivative is further described by an inhibitor-bound crystal structure of <it>Cp</it>CDPK1. In addition, structural analysis of <it>Cp</it>CDPK4 identified an unprecedented Zn-finger within the CDPK kinase domain that may have implications for its regulation.</p> <p>Conclusions</p> <p>Identification and comparison of the <it>C. parvum </it>protein kinases against other parasitic kinases shows how orthologue- and family-based research can be used to facilitate characterization of promising drug targets and the search for new drugs.</p

Development of Risk Prediction Equations for Incident Chronic Kidney Disease

IMPORTANCE ‐ Early identification of individuals at elevated risk of developing chronic kidney disease  could improve clinical care through enhanced surveillance and better management of underlying health  conditions.  OBJECTIVE – To develop assessment tools to identify individuals at increased risk of chronic kidney  disease, defined by reduced estimated glomerular filtration rate (eGFR).  DESIGN, SETTING, AND PARTICIPANTS – Individual level data analysis of 34 multinational cohorts from  the CKD Prognosis Consortium including 5,222,711 individuals from 28 countries. Data were collected  from April, 1970 through January, 2017. A two‐stage analysis was performed, with each study first  analyzed individually and summarized overall using a weighted average. Since clinical variables were  often differentially available by diabetes status, models were developed separately within participants  with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external  cohorts (N=2,253,540). EXPOSURE Demographic and clinical factors.  MAIN OUTCOMES AND MEASURES – Incident eGFR <60 ml/min/1.73 m2.  RESULTS – In 4,441,084 participants without diabetes (mean age, 54 years, 38% female), there were  660,856 incident cases of reduced eGFR during a mean follow‐up of 4.2 years. In 781,627 participants  with diabetes (mean age, 62 years, 13% female), there were 313,646 incident cases during a mean follow‐up of 3.9 years. Equations for the 5‐year risk of reduced eGFR included age, sex, ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, BMI, and albuminuria. For participants  with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction  between the two. The risk equations had a median C statistic for the 5‐year predicted probability of  0.845 (25th – 75th percentile, 0.789‐0.890) in the cohorts without diabetes and 0.801 (25th – 75th percentile, 0.750‐0.819) in the cohorts with diabetes. Calibration analysis showed that 9 out of 13 (69%) study populations had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was  similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 out of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25. CONCLUSIONS AND RELEVANCE – Equations for predicting risk of incident chronic kidney disease developed in over 5 million people from 34 multinational cohorts demonstrated high discrimination and  variable calibration in diverse populations

Type 1 diabetes: translating mechanistic observations into effective clinical outcomes

Type 1 diabetes remains an important health problem, particularly in Western countries where the incidence has been increasing in younger children(1). In 1986, Eisenbarth described Type 1 diabetes as a chronic autoimmune disease. Work over the past 3 ½ decades has identified many of the genetic, immunologic, and environmental factors that are involved in the disease and have led to hypotheses concerning its pathogenesis. Based on these findings, clinical trials have been conducted to test these hypotheses but have had mixed results. In this review, we discuss the findings that have led to current concepts of the disease mechanisms, how this understanding has prompted clinical studies, and the results of these studies. The findings from preclinical and clinical studies support the original proposed model for how type 1 diabetes develops, but have also suggested that this disease is more complex than originally thought and will require broader treatment approaches

JAFA: Java Formative Assessment – Development of a formative assessment tool to support learning of introductory computer programming

This article was first published in the Wolverhampton Intellectual Repository and E-Theses (WIRE). There is no printed version.This project contributes to the long term goal of improving the Learning and Teaching of Computer Programming. This is a core topic in The School of Computing and Information Technology (SCIT) that the majority of students must study, but historically pass rates of around 60% at first attempt have been common. This has an obvious impact on progression and retention. The work follows on from a successful project which concentrated on the assessment of Numeracy, Mathematics and Statistics (Thelwall, 1998), the resulting product of which has been used extensively in the School, but has now reached retirement only because of technical reasons. The primary focus of this stage of the project is to develop a formative assessment tool that is conceptually similar in some respects to the earlier system, but is specifically tailored to Programming and uses up to date technology to maximise effectiveness. The product will be tested with a large student cohort to ensure that it functions correctly and is fit for purpose, with the intention that a follow-on project will embed the resulting product in the curriculum. The outcomes will be twofold. Firstly, it will enable a move towards a learning style for which there is anecdotal evidence that indicates students like and overcomes issues related to the transition from their prior learning styles. Secondly, it will enable research into the behaviour of students learning to program, and will lead to enhanced provision of support for learners

Comparing The Ergogenic Effects of Mouth Guards

Many studies have looked into the ergogenic effect of wearing an oral appliance such as a mandibular orthopedic repositioning appliance or mouth guard. Little research has been done comparing the performance enhancing qualities of different types of mouth guards. In this study sixteen participants were tested on their grip strengths with a hand dynamometer under four different conditions. These conditions included mouth open, mouth closed, clenching on a generic boil and bite mouth guard, and clenching on the Under Armour ArmourBite® mouth guard. The grip strength results were analyzed and showed a significant increase in grip strength from the mouth closed condition to the Under Armour condition. The boil and bite mouth guard did not cause any significant improvement in grip strength from the mouth closed condition. The Under Armour mouth guard moves the mandible anterior and inferior to its natural position. This change in jaw posture seems to have a positive effect on grip strength results. Panoramic dental x-rays were also taken for each condition in order to analyze the interocclusal space. These x-rays showed that the Under Armour condition caused a significantly greater interocclusal space than the generic boil and bite. Future studies should continue to focus on looking into what causes these ergogenic effects, as well as what jaw and occlusion parameters optimize the ergogenic effect

Patients’ Diets and Preferences in a Pediatric Population with Inflammatory Bowel Disease

PURPOSE: To determine the dietary practices of the pediatric inflammatory bowel disease population at the Children's Hospital of the Hamilton Health Sciences Corporation and the reported effectiveness of those diets