Maternal Diabetes and Obesity Influence the Fetal Epigenome in a Largely Hispanic Population

BACKGROUND: Obesity and diabetes mellitus are directly implicated in many adverse health consequences in adults as well as in the offspring of obese and diabetic mothers. Hispanic Americans are particularly at risk for obesity, diabetes, and end-stage renal disease. Maternal obesity and/or diabetes through prenatal programming may alter the fetal epigenome increasing the risk of metabolic disease in their offspring. The aims of this study were to determine if maternal obesity or diabetes mellitus during pregnancy results in a change in infant methylation of CpG islands adjacent to targeted genes specific for obesity or diabetes disease pathways in a largely Hispanic population. METHODS: Methylation levels in the cord blood of 69 newborns were determined using the Illumina Infinium MethylationEPIC BeadChip. Over 850,000 different probe sites were analyzed to determine whether maternal obesity and/or diabetes mellitus directly attributed to differential methylation; epigenome-wide and regional analyses were performed for significant CpG sites. RESULTS: Following quality control, agranular leukocyte samples from 69 newborns (23 normal term (NT), 14 diabetes (DM), 23 obese (OB), 9 DM/OB) were analyzed for over 850,000 different probe sites. Contrasts between the NT, DM, OB, and DM/OB were considered. After correction for multiple testing, 15 CpGs showed differential methylation from the NT, associated with 10 differentially methylated genes between the diabetic and non-diabetic subgroups, CCDC110, KALRN, PAG1, GNRH1, SLC2A9, CSRP2BP, HIVEP1, RALGDS, DHX37, and SCNN1D. The effects of diabetes were partly mediated by the altered methylation of HOOK2, LCE3C, and TMEM63B. The effects of obesity were partly mediated by the differential methylation of LTF and DUSP22. CONCLUSIONS: The presented data highlights the associated altered methylation patterns potentially mediated by maternal diabetes and/or obesity. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the effects on newborn body composition and future health risk factors for metabolic disease. Additional future consideration should be targeted to the role of Hispanic inheritance. Potential future targeting of transgenerational propagation and developmental programming may reduce population obesity and diabetes risk

Photon-Photon and Electron-Photon Colliders with Energies Below a TeV

We investigate the potential for detecting and studying Higgs bosons in $\gamma\gamma$ and $e\gamma$ collisions at future linear colliders with energies below a TeV. Our study incorporates realistic $\gamma\gamma$ spectra based on available laser technology, and NLC and CLIC acceleration techniques. Results include detector simulations. We study the cases of: a) a SM-like Higgs boson based on a devoted low energy machine with $\sqrt{s_{ee}}\le 200$ GeV; b) the heavy MSSM Higgs bosons; and c) charged Higgs bosons in $e\gamma$ collisions.We investigate the potential for detecting and studying Higgs bosons in $\gamma\gamma$ and $e\gamma$ collisions at future linear colliders with energies below a TeV. Our study incorporates realistic $\gamma\gamma$ spectra based on available laser technology, and NLC and CLIC acceleration techniques. Results include detector simulations. We study the cases of: a) a SM-like Higgs boson based on a devoted low energy machine with $\sqrt{s_{ee}}\le 200$ GeV; b) the heavy MSSM Higgs bosons; and c) charged Higgs bosons in $e\gamma$ collisions

Preventing foot ulceration in diabetes:systematic review and meta-analyses of RCT data

Aims/hypothesis: Foot ulceration is a serious complication for people with diabetes that results in high levels of morbidity for individuals and significant costs for health and social care systems. Nineteen systematic reviews of preventative interventions have been published, but none provides a reliable numerical summary of treatment effects. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to make the best possible use of the currently available data. Methods: We conducted a systematic review and meta-analysis of RCTs of preventative interventions for foot ulceration. OVID MEDLINE and EMBASE were searched to February 2019 and the Cochrane Central Register of Controlled Trials to October 2018. RCTs of interventions to prevent foot ulcers in people with diabetes who were free from foot ulceration at trial entry were included. Two independent reviewers read the full-text articles and extracted data. The quality of trial reporting was assessed using the Cochrane Risk of Bias tool. The primary outcome of foot ulceration was summarised using pooled relative risks in meta-analyses. Results: Twenty-two RCTs of eight interventions were eligible for analysis. One trial of digital silicone devices (RR 0.07 [95% CI 0.01, 0.55]) and meta-analyses of dermal infrared thermometry (RR 0.41 [95% CI 0.19, 0.86]), complex interventions (RR 0.59 [95% CI 0.38, 0.90], and custom-made footwear and offloading insoles (RR 0.53 [95% CI 0.33, 0.85]) showed beneficial effects for these interventions. Conclusions/interpretation: Four interventions were identified as being effective in preventing foot ulcers in people with diabetes, but uncertainty remains about what works and who is most likely to benefit

Between Antagonism and Eros: The Feud as Couple Form and Netflix’s GLOW

A feud is an antagonism that is continuous and extended; “a state of prolonged mutual hostility” (OED). Historically, feuds take place between families or communities, or result from failed couples. Considered as a couple form in its own right, however, the feud is associated with aesthetic forms often coded as camp, queer, or feminized. In such popular, serialized forms, the feud must be open ended and of unforeseen futurity, for resolution brings an end to the feud as such and dissolves the couple. Thus, feuds reject normative modes of coupling (such as the nuclear family) that center harmonious or happy feelings. The article begins with the political economy of the feud through an examination of the pre-modern form of the blood feud and continues with its late-modern presence in popular culture. We rehearse the idea of the feud as it emerges from anthropology and philosophy, especially as it impacts notions of debt and alternative economies, before thinking through the contemporary “coupling” of the feud in popular culture, fandom, and, via the performance form of professional wrestling and Netflix’s GLOW

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Maternal Condition Effects Methylation Status of Infants

Background: Rates of diabetes and obesity are continually increasing in the united states, including rates among pregnant women. An estimated 30.3 million people of all ages in the U.S. have diabetes mellitus, and approximately 12.7 million children and adolescents in the U.S. are obese (Ogden, Carroll et al. 2014, CDC 2017). Objective: The objective of this research is to determine if maternal obesity or diabetes mellitus during pregnancy results in a change in infant DNA methylation. Additionally, if that change in DNA methylation is associated with genes related to obesity or diabetes mellites (DM) disease pathways, pathways related to comorbidities of DM and obesity, or associated with complications known to be related to fetal exposure to obesity and/or DM. Design/Methods: A total of 69 infant/mother couplets (23 diabetes (DM), 23 obese (OB), 23 healthy weight non-diabetic (NT)) were enrolled, and cord blood samples were collected at University Health System from 2016 to 2018. DNA was purified from agranular leukocytes, treated through bisulfite conversion, and processed on an Illumina Infinium MethylationEPIC BeadChip to analyze over 850,000 different probe sites to determine methylation on a site specific basis. Data were analyzed with a R Bioconductor workflow including Probe wise analysis, and Peak wise detection (Bumphunter). Results: 15 genes and 23 probes were identified as significantly differentially methylated between DM or obese groups and healthy weight non-diabetic groups. These genes are: CCDC110, KALRN, PAG1, GNRH1, SLC2A9, CSRP2BP, HIVEP1, RALGDS, DHX37, SCNN1D, HOOK2, LCE3C, TMEM63B, LTF, and DUSP22. Genes ranged in apparent involvement in disease pathology of interest, with HOOK2, and SLC2A9 being the most related to the conditions DM and obesity based on current research. Conclusion(s): Maternal condition causes differential methylation of DNA near, or within, certain genes. Genes located by comparison between groups with DM or obesity, and healthy weight non-diabetic groups showed promising relatedness to several pathways and diseases which may be considered to be related to DM, obesity, and associated complications of in utero exposure to diabetic and/or obese maternal conditions

Tight junction channel regulation by interclaudin interference

Peer reviewe