Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach

Utility of Hemoglobin A1c for Diagnosing Prediabetes and Diabetes in Obese Children and Adolescents

OBJECTIVE-Hemoglobin A(1c) (A1C) has emerged as a recommended diagnostic tool for identifying diabetes and subjects at risk for the disease. This recommendation is based on data in adults showing the relationship between A1C with future development of diabetes and microvascular complications. However, studies in the pediatric population are lacking. RESEARCH DESIGN AND METHODS-We studied a multiethnic cohort of 1,156 obese children and adolescents without a diagnosis of diabetes (male, 40%/female, 60%). All subjects underwent an oral glucose tolerance test (OGTT) and A1C measurement. These tests were repeated after a follow-up time of similar to 2 years in 218 subjects. RESULTS-At baseline, subjects were stratified according to A1C categories: 77% with normal glucose tolerance (A1C 6.5%). In the at risk for diabetes category, 47% were classified with prediabetes or diabetes, and in the diabetes category, 62% were classified with type 2 diabetes by the OGTT. The area under the curve receiver operating characteristic for A1C was 0.81 (95% Cl 0.70-0.92). The threshold for identifying type 2 diabetes was 5.8%, with 78% specificity and 68% sensitivity. In the subgroup with repeated measures, a multivariate analysis showed that the strongest predictors of 2-h glucose at follow-up were baseline A1C and 2-h glucose, independently of age, ethnicity, sex, fasting glucose, and follow-up time. CONCLUSIONS-The American Diabetes Association suggested that an A1C of 6.5% underestimates the prevalence of prediabetes and diabetes in obese children and adolescents. Given the low sensitivity and specificity, the use of A1C by itself represents a poor diagnostic tool for prediabetes and type 2 diabetes in obese children and adolescents

Identification of candidate genes for drought tolerance in coffee by high-throughput sequencing in the shoot apex of different Coffea arabica cultivars.

BACKGROUND: Drought is a widespread limiting factor in coffee plants. It affects plant development, fruit production, bean development and consequently beverage quality. Genetic diversity for drought tolerance exists within the coffee genus. However, the molecular mechanisms underlying the adaptation of coffee plants to drought are largely unknown. In this study, we compared the molecular responses to drought in two commercial cultivars (IAPAR59, drought-tolerant and Rubi, drought-susceptible) of Coffea arabica grown in the field under control (irrigation) and drought conditions using the pyrosequencing of RNA extracted from shoot apices and analysing the expression of 38 candidate genes. RESULTS: Pyrosequencing from shoot apices generated a total of 34.7 Mbp and 535,544 reads enabling the identification of 43,087 clusters (41,512 contigs and 1,575 singletons). These data included 17,719 clusters (16,238 contigs and 1,575 singletons) exclusively from 454 sequencing reads, along with 25,368 hybrid clusters assembled with 454 sequences. The comparison of DNA libraries identified new candidate genes (n = 20) presenting differential expression between IAPAR59 and Rubi and/or drought conditions. Their expression was monitored in plagiotropic buds, together with those of other (n = 18) candidates genes. Under drought conditions, up-regulated expression was observed in IAPAR59 but not in Rubi for CaSTK1 (protein kinase), CaSAMT1 (SAM-dependent methyltransferase), CaSLP1 (plant development) and CaMAS1 (ABA biosynthesis). Interestingly, the expression of lipid-transfer protein (nsLTP) genes was also highly up-regulated under drought conditions in IAPAR59. This may have been related to the thicker cuticle observed on the abaxial leaf surface in IAPAR59 compared to Rubi. CONCLUSIONS: The full transcriptome assembly of C. arabica, followed by functional annotation, enabled us to identify differentially expressed genes related to drought conditions. Using these data, candidate genes were selected and their differential expression profiles were confirmed by qPCR experiments in plagiotropic buds of IAPAR59 and Rubi under drought conditions. As regards the genes up-regulated under drought conditions, specifically in the drought-tolerant IAPAR59, several corresponded to orphan genes but also to genes coding proteins involved in signal transduction pathways, as well as ABA and lipid metabolism, for example. The identification of these genes should help advance our understanding of the genetic determinism of drought tolerance in coffee

Late Cretaceous (Maastrichtian) shallow water hydrocarbon seeps from Snow Hill and Seymour Islands, James Ross Basin, Antarctica

Fossil hydrocarbon seeps are present in latest Cretaceous (Maastrichtian) volcaniclastic shallow shelf sediments exposed on Snow Hill and Seymour Islands, James Ross Basin, Antarctica. The seeps occur in the Snow Hill Island Formation on Snow Hill Island and are manifest as large-sized, cement-rich carbonate bodies, containing abundant thyasirid bivalves and rarer ammonites and solemyid bivalves. These bodies have typical seep cement phases, with δ13C values between 20.4 and 10.7‰ and contain molecular fossils indicative of terrigenous organic material and the micro-organisms involved in the anaerobic oxidation of methane, including methanotrophic archaea and sulphate-reducing bacteria. On Seymour Island the seeps occur as micrite-cemented burrow systems in the López de Bertodano Formation and are associated with thyasirid, solemyid and lucinid bivalves, and background molluscan taxa. The cemented burrows also have typical seep cement phases, with δ13C values between 58.0 and 24.6‰. There is evidence from other data that hydrocarbon seepage was a common feature in the James Ross Basin throughout the Maastrichtian and into the Eocene. The Snow Hill and Seymour Island examples comprise the third known area of Maastrichtian hydrocarbon seepage. But compared to most other ancient and modern seep communities, the James Ross Basin seep fauna is of very low diversity, being dominated by infaunal bivalves, all of which probably had thiotrophic chemosymbionts, but which were unlikely to have been seep obligates. Absent from the James Ross Basin seep fauna are ‘typical’ obligate seep taxa from the Cretaceous and the Cenozoic. Reasons for this may have been temporal, palaeolatitudinal, palaeobathymetric, or palaeoecological

Middle Lutetian climate in the Paris Basin: Implications for a marine hotspot of paleobiodiversity

International audienceThe present study reports the evolution of environmental conditions and seawater temperatures during the establishment of a marine hotspot of paleobiodiversity that took place in the Paris Basin during the Lutetian. The stable isotope compositions (δ 18O and δ 13C) of three species of molluscs (two bivalves: Cubitostrea plicata and Venericardia imbricata, and one gastropod: Sigmesalia multisulcata) collected along the reference section of Grignon (Falunière) are used for paleoenvironmental and paleoclimatic reconstructions. Additional high-resolution analyses on one specimen of Haustator imbricatarius allow the documentation of seasonal changes for temperature. The high-resolution profiles of the δ 18O signatures of S. multisulcata reveal that these gastropods mineralized their shell during the warm months of the year, as did V. imbricata, which probably had a short life span (less than 1 year). These two species thus only yield temperatures for the summer period, from 22 to 30 °C. The δ 18O of C. plicata shells indicate mean annual sea surface temperatures ranging between 15 and 23 °C during the Middle Lutetian, with minimal temperatures probably reflecting greater depth at the base of the section. The seasonal contrasts reconstructed in the upper part of the section, from the large gastropod H. imbricatarius, ranged between 18 and 30 °C. Comparison of the isotopic values of the species indicates that the δ 13C of the three taxa seems to be mostly influenced by ecological features, leading to differences between endobenthic (V. imbricata) and epibenthic species (C. plicata); or the food habits. The paleoclimatic reconstructions show that the Lutetian climate was relatively stable in the Paris Basin with long-term cooling of the mean annual sea-surface temperatures. Nevertheless, this study shows that despite a context of colder conditions compared to the Early Eocene, the climate provided a favorable context for the increase of marine biodiversity in the Paris Basin during the Middle Lutetian. © 2012 Springer-Verlag

The triglyceride-to-HDL cholesterol ratio: association with insulin resistance in obese youths of different ethnic backgrounds

OBJECTIVE: We evaluated whether the triglyceride-to-HDL cholesterol (TG/HDL-C) ratio is associated with insulin resistance (IR) in a large multiethnic cohort of obese youths. RESEARCH DESIGN AND METHODS: Obese youths (1,452) had an oral glucose tolerance test and a fasting lipid profile. Insulin sensitivity was estimated using the whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA)-IR and evaluated, in a subgroup of 146 obese youths, by the hyperinsulinemic-euglycemic clamp. The cohort was divided by ethnicity (612 whites, 357 Hispanics, and 483 African Americans) and then stratified into ethnicity-specific tertiles of TG/HDL-C ratio. Differences across tertiles were evaluated, and the association between the TG/HDL-C ratio and insulin sensitivity (WBISI) was defined by a multiple stepwise linear regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was determined to calculate the TG/HDL-C ratio cutoff to identify insulin-resistant subjects by ethnicity. RESULTS: In each ethnic group and across rising tertiles of TG/HDL-C ratio, insulin sensitivity (WBISI) progressively decreased, whereas 2-h glucose and the AUC-glucose progressively increased. The cutoff for TG/HDL-C ratio was 2.27, and the odds of presenting with IR, in youths with TG/HDL-C ratio higher than the cutoff, was 6.023 (95% CI 2.798–12.964; P < 0.001) in white girls and boys, whereas for both Hispanics and African Americans the AUC-ROCs were not significant, thus not allowing the calculation of an optimal cutoff TG/HDL-C value. CONCLUSIONS: The TG/HDL-C ratio is associated with IR mainly in white obese boys and girls and thus may be used with other risk factors to identify subjects at increased risk of IR-driven morbidity

Most Earth-surface calcites precipitate out of isotopic equilibrium

International audienceOxygen-isotope thermometry played a critical role in the rise of modern geochemistry and remains extensively used in (bio-)geoscience. Its theoretical foundations rest on the assumption that 18 O/ 16 O partitioning among water and carbonate minerals primarily reflects thermodynamic equilibrium. However, after decades of research, there is no consensus on the true equilibrium 18 O/ 16 O fractionation between calcite and water (18 α cc/w). Here, we constrain the equilibrium relations linking temperature, 18 α cc/w , and clumped isotopes (Δ 47) based on the composition of extremely slow-growing calcites from Devils Hole and Laghetto Basso (Corchia Cave). Equilibrium 18 α cc/w values are systematically~1.5‰ greater than those in biogenic and synthetic calcite traditionally considered to approach oxygen-isotope equilibrium. We further demonstrate that subtle disequilibria also affect Δ 47 in biogenic calcite. These observations provide evidence that most Earth-surface calcites fail to achieve isotopic equilibrium, highlighting the need to improve our quantitative understanding of non-equilibrium isotope fractionation effects instead of relying on phenomenological calibrations