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

Use of bisulfite processing to generate high-β-O-4 content water-soluble lignosulfonates

This work was supported by EPSRC grants (EP/1518175), the Industrial Biotechnology Innovation Centre (IBioIC) (DMB Ph.D. studentship) and an EPSRC Doctoral Prize Fellowship (CSL).With lignin-first biorefineries likely to become a reality, controlled depolymerization of high-quality lignin streams to high value products has become a priority. Using bisulfite chemistry, access to a high-β-O-4 content water-soluble lignosulfonate has been achieved, allowing follow-on procedures in water to be conducted. We show that phenolic β-O-4 units preferential-ly react under acidic bisulfite conditions, whilst non-phenolic β-O-4 units react much more slowly. Exploiting this improved chemical understanding and inherent selectivity, a softwood lignosulfonate has been prepared in which phenolic β-O-4 α-sulfonation has occurred leaving significant native β-O-4 content. Use of an O-benzoylation protocol with lignin coupled with advanced 2D NMR methods has allowed detailed analysis of this and other commercial and industrial lignosulfonates. Conversion of the native β-O-4 to benzylic- oxidized β-O-4 units was followed by a selective reductive cleavage to give a premium aromatic monomer in pure form.Publisher PDFPeer reviewe

Discussions and Reviews : Theorizing about theory in international politics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66906/2/10.1177_002200276000400405.pd

Reserves and trade jointly determine exposure to food supply shocks

While a growing proportion of global food consumption is obtained through international trade, there is an ongoing debate on whether this increased reliance on trade benefits or hinders food security, and specifically, the ability of global food systems to absorb shocks due to local or regional losses of production. This paper introduces a model that simulates the short-term response to a food supply shock originating in a single country, which is partly absorbed through decreases in domestic reserves and consumption, and partly transmitted through the adjustment of trade flows. By applying the model to publicly-available data for the cereals commodity group over a 17 year period, we find that differential outcomes of supply shocks simulated through this time period are driven not only by the intensification of trade, but as importantly by changes in the distribution of reserves. Our analysis also identifies countries where trade dependency may accentuate the risk of food shortages from foreign production shocks; such risk could be reduced by increasing domestic reserves or importing food from a diversity of suppliers that possess their own reserves. This simulation-based model provides a framework to study the short-term, nonlinear and out-of-equilibrium response of trade networks to supply shocks, and could be applied to specific scenarios of environmental or economic perturbations

Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome

Background The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. Methods We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. Results The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combinationtherapy group (P\u3c0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combinationtherapy group (46.0%, P\u3c0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group. Conclusions Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861.

Finding a moral homeground: appropriately critical religious education and transmission of spiritual values

Values-inspired issues remain an important part of the British school curriculum. Avoiding moral relativism while fostering enthusiasm for spiritual values and applying them to non-curricular learning such as school ethos or children's home lives are challenges where spiritual, moral, social and cultural (SMSC) development might benefit from leadership by critical religious education (RE). Whether the school's model of spirituality is that of an individual spiritual tradition (schools of a particular religious character) or universal pluralistic religiosity (schools of plural religious character), the pedagogy of RE thought capable of leading SMSC development would be the dialogical approach with examples of successful implementation described by Gates, Ipgrave and Skeie. Marton's phenomenography, is thought to provide a valuable framework to allow the teacher to be appropriately critical in the transmission of spiritual values in schools of a particular religious character as evidenced by Hella's work in Lutheran schools

JWST Reveals Excess Cool Water near the Snow Line in Compact Disks, Consistent with Pebble Drift

Previous analyses of mid-infrared water spectra from young protoplanetary disks observed with the Spitzer-IRS found an anticorrelation between water luminosity and the millimeter dust disk radius observed with ALMA. This trend was suggested to be evidence for a fundamental process of inner disk water enrichment proposed decades ago to explain some properties of the solar system, in which icy pebbles drift inward from the outer disk and sublimate after crossing the snow line. Previous analyses of IRS water spectra, however, were uncertain due to the low spectral resolution that blended lines together. We present new JWST-MIRI spectra of four disks, two compact and two large with multiple radial gaps, selected to test the scenario that water vapor inside the snow line is regulated by pebble drift. The higher spectral resolving power of MIRI-MRS now yields water spectra that separate individual lines, tracing upper level energies from 900 to 10,000 K. These spectra clearly reveal excess emission in the low-energy lines in compact disks compared to large disks, demonstrating an enhanced cool component with T ≈ 170–400 K and equivalent emitting radius R eq ≈ 1–10 au. We interpret the cool water emission as ice sublimation and vapor diffusion near the snow line, suggesting that there is indeed a higher inward mass flux of icy pebbles in compact disks. Observation of this process opens up multiple exciting prospects to study planet formation chemistry in inner disks with JWST

Water-Rich Disks around Late M-stars Unveiled: Exploring the Remarkable Case of Sz114

We present an analysis of the JDISC JWST/MIRI-MRS spectrum of Sz~114, an accreting M5 star surrounded by a large dust disk with a shallow gap at $\sim 39$ au. The spectrum is molecular-rich: we report the detection of water, CO, CO$_2$, HCN, C$_2$H$_2$, and H$_2$. The only identified atomic/ionic transition is from [NeII] at 12.81 micron. A distinct feature of this spectrum is the forest of water lines with the 17.22 micron emission surpassing that of most mid-to-late M-star disks by an order of magnitude in flux and aligning instead with disks of earlier-type stars. Moreover, flux ratios of C$_2$H$_2$/H$_2$O and HCN/H$_2$O in Sz~114 also resemble those of earlier-type disks, with a slightly elevated CO$_2$/H$_2$O ratio. While accretional heating can boost all infrared lines, the unusual properties of Sz~114 could be explained by the young age of the source, its formation under unusual initial conditions (a large massive disk), and the presence of dust substructures. The latter delays the inward drift of icy pebbles and help preserve a lower C/O ratio over an extended period. In contrast, mid-to-late M-star disks--which are typically faint, small in size, and likely lack significant substructures--may have more quickly depleted the outer icy reservoir and already evolved out of a water-rich inner disk phase. Our findings underscore the unexpected diversity within mid-infrared spectra of mid-to-late M-star disks, highlighting the need to expand the observational sample for a comprehensive understanding of their variations and thoroughly test pebble drift and planet formation models.Comment: 16 pages, 8 figures, accepted by ApJ

Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease