Investigating the molecular mechanisms of the metabolic syndrome

This thesis aims to highlight molecular mechanisms that have been altered by prenatal undernutrition and may be involved in the metabolic syndrome. Two sepa- rate studies were conducted both using a rat model developed through manipulation of the maternal diet to provoke the key features of the metabolic syndrome in adult o spring. Microarray technology was used to detect changes in gene expression in tar- get tissues between o spring of control (normally fed, AD) and undernourished (UN) mothers to obtain a broader picture of the cellular functions and genetic pathways that may be implicated in the metabolic syndrome. The rst study compared gene expression di erences in liver, skeletal muscle, and white adipose tissue between 55 day old male o spring of AD and UN mothers. No signi cant changes were found in muscle or adipose tissue; however, the di erences in the liver suggested the UN animals had been metabolically programmed to favour fat as an energy source. To investigate whether DNA methylation might be responsible for the observed transcriptional changes, pooled liver samples from the rst study were used with the McrBC restriction enzyme assay to determine full, partial, incomplete, or no methylation between AD and UN. Two di erentially expressed genes (Zfand2a and Mapk4) showed methylation changes. The same liver samples were hybridised to a miRNA array. Two miRNAs showed a nearly 2-fold upregulation in the UN livers. Both were found to be either directly or indirectly associated with the metabolic syndrome. MiR-335 has been shown to be upregulated in the livers of obese/diabetic mice. By association with miR-27a, miR-451 might be involved in aspects of lipid metabolism in adipose tissue. A second study used microarray to analyse the liver tissues of day 170 female o - spring of the same rat model with additional insults (neonatal leptin treatment and post-weaning high-fat (HF) diet). Leptin has been shown to reverse the programming e ects of the restricted maternal diet and this study aimed to highlight mechanisms that could be involved in this reversal. The results revealed the importance of the in- teraction between treatments. Signi cant gene expression changes were only present when two or more treatments were combined. This study revealed signi cantly, dif- ferentially expressed genes involved in immune function, regulation of the circadian rhythm, and metabolism. These ndings provide a number of interesting genes and pathways for further studies and also highlight the need to conduct a thorough study in multiple tissues at di erent time-points to pinpoint the window of developmental plasticity.University of Auckland Liggins Institut

James Madison University Special Collections

This newsletter article summarizes highlights from manuscript and archival collections recently acquired by James Madison University Special Collections. Includes images and references to collections likely to be of interest to genealogical researchers of families located in the central Shenandoah Valley. Collections highlighted include the Blackley family papers, the Heatwole family papers, and the Henkel family papers. Includes information about other repositories and resources in Harrisonburg, Virginia with genealogical holdings

Initiatives to Find the Lost Einsteins through the Integration of Independent Scientific Research Projects in Early College

This exploratory study examines the effects of incorporating Independent Scientific Research Projects (ISRP) into early college biology curriculum. The authors present their findings, which are steeped in the goal of increasing minority students’ interest in STEM careers, by analyzing student engagement in classrooms with and without ISRP integration

Comparison of Primary Care Physician Reimbursement Rates in the United States

With a growing shortage of physicians, particularly primary care physicians, the issue of adequate pay in Hawai‘i is increasingly important. Anecdotal reports of low pay in Hawai‘i have rarely been substantiated. Data from FAIR Health, a company that tracks private insurance reimbursement rates, is compared across the United States (US) for the CPT code 99213. In addition, FAIR Health and Medicare rates are compared for cities with both similar and disparate cost of living to Hawai‘i. Hawai‘i is in the second lowest quintile for payment in the US for private insurances, and providers are reimbursed significantly lower than in cities with similar cost of living by both Medicare and private insurances. Methods for increasing payment to physicians in Hawai‘i are essential to recruiting the necessary workforce. Revising payment methodologies that increase pay for services in areas of unmet need, revising Medicare Geographic Price Cost Indices to better balance pay in areas of need, and making use of the 10% Medicare Bonus Program for physicians working in Health Professions Shortage Areas are first steps to creating a sustainable plan for physician payment in the future

Accredited qualifications for capacity development in disaster risk reduction and climate change adaptation

Increasingly practitioners and policy makers working across the globe are recognising the importance of bringing together disaster risk reduction and climate change adaptation. From studies across 15 Pacific island nations, a key barrier to improving national resilience to disaster risks and climate change impacts has been identified as a lack of capacity and expertise resulting from the absence of sustainable accredited and quality assured formal training programmes in the disaster risk reduction and climate change adaptation sectors. In the 2016 UNISDR Science and Technology Conference on the Implementation of the Sendai Framework for Disaster Risk Reduction 2015–2030, it was raised that most of the training material available are not reviewed either through a peer-to-peer mechanism or by the scientific community and are, thus, not following quality assurance standards. In response to these identified barriers, this paper focuses on a call for accredited formal qualifications for capacity development identified in the 2015 United Nations landmark agreements in DRR and CCA and uses the Pacific Islands Region of where this is now being implemented with the launch of the Pacific Regional Federation of Resilience Professionals, for DRR and CCA. A key issue is providing an accreditation and quality assurance mechanism that is shared across boundaries. This paper argues that by using the United Nations landmark agreements of 2015, support for a regionally accredited capacity development that ensures all countries can produce, access and effectively use scientific information for disaster risk reduction and climate change adaptation. The newly launched Pacific Regional Federation of Resilience Professionals who work in disaster risk reduction and climate change adaptation may offer a model that can be used more widely

Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming.

BACKGROUND: Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring. RESULTS: We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that "leptin reversal" is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring. CONCLUSIONS: We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This "calibration model" for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities

Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells.

Non-CG methylation is an unexplored epigenetic hallmark of pluripotent stem cells. Here we report that a reduction in non-CG methylation is associated with impaired differentiation capacity into endodermal lineages. Genome-wide analysis of 2,670 non-CG sites in a discovery cohort of 25 phenotyped human induced pluripotent stem cell (hiPSC) lines revealed unidirectional loss (Δβ=13%, P<7.4 × 10(-4)) of non-CG methylation that correctly identifies endodermal differentiation capacity in 23 out of 25 (92%) hiPSC lines. Translation into a simplified assay of only nine non-CG sites maintains predictive power in the discovery cohort (Δβ=23%, P<9.1 × 10(-6)) and correctly identifies endodermal differentiation capacity in nine out of ten pluripotent stem cell lines in an independent replication cohort consisting of hiPSCs reprogrammed from different cell types and different delivery systems, as well as human embryonic stem cell (hESC) lines. This finding infers non-CG methylation at these sites as a biomarker when assessing endodermal differentiation capacity as a readout.We thank Kerra Pearce (UCL Genomics) for array processing, and Tim Fell and Jonathan Best (CellCentric), Jason Wray (UCL) and Rosemary Drake (TAP Biosystems) for discussions. We also thank Minal Patel, Chris Kirton, Anja Kolb-Kokocinski, Willem H. Ouwehand, Richard Durbin and Fiona M. Watt on behalf of the Human Induced Pluripotent Stem Cell Initiative (HipSci) funded by grant WT098503 from the Wellcome Trust and the Medical Research Council, for sharing data and materials. This work was supported in part by a TSB/EPSRC grant (TS/H000933/1). The Vallier lab is supported by the Cambridge Hospitals National Institute for Health Research Biomedical Research Center and an ERC Starting Grant (Relieve IMDS). F.A.C.S. is funded by a PhD studentship from Fundação para a Ciência e a Tecnologia (SFRH/BD/69033/2010). The Ferguson-Smith lab is supported by grants from the MRC and Wellcome Trust, and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510). The Beck lab is supported by the Wellcome Trust (084071), a Royal Society Wolfson Research Merit Award (WM100023), and EU-FP7 projects EPIGENESYS (257082) and BLUEPRINT (282510).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1045

Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation

Background: In this phase 2 study, we evaluated the efficacy and safety of oral gepotidacin, a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor, for the treatment of uncomplicated urogenital gonorrhea. Methods: Adult participants with suspected urogenital gonorrhea were enrolled and completed baseline (day 1) and test-of-cure (days 4-8) visits. Pretreatment and posttreatment urogenital swabs were collected for Neisseria gonorrhoeae (NG) culture and susceptibility testing. Pharyngeal and rectal swab specimens were collected if there were known exposures. Participants were stratified by gender and randomized 1:1 to receive a 1500-mg or 3000-mg single oral dose of gepotidacin. Results: The microbiologically evaluable population consisted of 69 participants, with NG isolated from 69 (100%) urogenital, 2 (3%) pharyngeal, and 3 (4%) rectal specimens. Microbiological eradication of NG was achieved by 97%, 95%, and 96% of participants (lower 1-sided exact 95% confidence interval bound, 85.1%, 84.7%, and 89.1%, respectively) for the 1500-mg, 3000-mg, and combined dose groups, respectively. Microbiological cure was achieved in 66/69 (96%) urogenital infections. All 3 failures were NG isolates that demonstrated the highest observed gepotidacin minimum inhibitory concentration of 1 µg/mL and a common gene mutation. At the pharyngeal and rectal sites, 1/2 and 3/3 NG isolates, respectively, demonstrated microbiological cure. There were no treatment-limiting adverse events for either dose. Conclusions: This study demonstrated that single, oral doses of gepotidacin were ≥95% effective for bacterial eradication of NG in adult participants with uncomplicated urogenital gonorrhea