Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and hearts

Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. To date, the contribution of microRNAs (miRNAs) in DS has not been investigated. Bioinformatic analyses demonstrate that human chromosome 21 (Hsa21) harbors five miRNA genes; miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. MiRNA expression profiling, miRNA RT-PCR, and miRNA in situ hybridization experiments demonstrate that these miRNAs are overexpressed in fetal brain and heart specimens from individuals with DS when compared with age- and sex-matched controls. We hypothesize that trisomic 21 gene dosage overexpression of Hsa21-derived miRNAs results in the decreased expression of specific target proteins and contribute, in part, to features of the neuronal and cardiac DS phenotype. Importantly, Hsa21-derived miRNAs may provide novel therapeutic targets in the treatment of individuals with DS.     

Genetic control of endosperm proteins in wheat

Summary Total endosperm proteins extracted from both several common wheat cultivars and some intervarietal substitution lines derived from them were fractionated according to their molecular weight in a high resolution one-dimensional gel electrophoresis. The four donor cultivars and the recipient one — Chinese Spring, possessed differentially migrating protein bands in the fractions of high molecular weight (HMW) glutenins and gliadins. Several of these bands were identified for the first time in this study. By utilizing intervarietal substitution lines the control of the HMW glutenins and gliadins by chromosomes of homoeologous group 1 was either reaffirmed or, for the new bands, established. Several HMW gliadin subunits showed a considerable variation in their staining intensity in the intervarietal substitution lines indicating that their expression was dependent on the genetic background.This paper is based on a portion of a dissertation to be submitted by G. Galili in partial fulfilment of the Ph.D. requirements of the Feinberg Graduate School, The Weizmann Institute of Science, RehovotThe Marshall and Edith Korshak Professor of Plant Cytogenetics     

Effects of Diet Composition on Postprandial Energy Availability during Weight Loss Maintenance

Background

The major circulating metabolic fuels regulate hunger, and each is affected by dietary composition. An integrated measure of postprandial energy availability from circulating metabolic fuels may help inform dietary recommendations for weight maintenance after weight loss.

Aim

We examined the effect of low-fat (LF, 60% of energy from carbohydrate, 20% fat, 20% protein), low-glycemic index (LGI, 40%–40%-20%), and very low-carbohydrate (VLC, 10%–60%-30%) diets on total postprandial metabolic fuel energy availability (EA) during weight loss maintenance.

Methods

Eight obese young adults were fed a standard hypocaloric diet to produce 10–15% weight loss. They were then provided isocaloric LF, LGI, and VLC diets in a randomized crossover design, each for a 4-week period of weight loss maintenance. At the end of each dietary period, a test meal representing the respective diet was provided, and blood samples were obtained every 30 minutes for 5 hours. The primary outcome was EA, defined as the combined energy density (circulating level×relative energy content) of glucose, free fatty acids, and β-hydroxybutyrate. Secondary outcomes were individual metabolic fuels, metabolic rate, insulin, glucagon, cortisol, epinephrine, and hunger ratings. Respiratory quotient was a process measure. Data were analyzed by repeated-measures analysis of variance, with outcomes compared in the early (30 to 150 min) and late (180 to 300 min) postprandial periods.

Results

EA did not differ between the test meals during the early postprandial period (p = 0.99). However, EA in the late postprandial period was significantly lower after the LF test meal than the LGI (p<0.0001) and VLC (p<0.0001) test meals. Metabolic rate also differed in the late postprandial period (p = 0.0074), with higher values on the VLC than LF (p = 0.0064) and LGI (p = 0.0066) diets.

Conclusion

These findings suggest that an LF diet may adversely affect postprandial EA and risk for weight regain during weight loss maintenance.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00315354","term_id":"NCT00315354"}}NCT00315354     

Phylogenetic analysis reveals that Rhabdopleura is an extant graptolite

A phylogenetic analysis of morphological data from modern pterobranch hemichordates (Cephalodiscus, Rhabdopleura) and representatives of each of the major graptolite orders reveals that Rhabdopleura nests among the benthic, encrusting graptolite taxa as it shares all of the synapomorphies that unite the graptolites. Therefore, rhabdopleurids can be regarded as extant members of the Subclass Graptolithina (Class Pterobranchia). Combined with the results of previous molecular phylogenetic studies of extant deuterostomes, these results also suggest that the Graptolithina is a sister taxon to the Subclass Cephalodiscida. The Graptolithina, as an important component of Early–Middle Palaeozoic biotas, provide data critical to our understanding of early deuterostome phylogeny. This result allows one to infer the zooid morphology, mechanics of colony growth and palaeobiology of fossil graptolites in direct relation to the living members of the clade. The Subdivision Graptoloida (nom. transl.), which are all planktic graptolites, is well supported in this analysis. In addition, we recognize the clade Eugraptolithina (nov.). This clade comprises the Graptoloida and all of the other common and well‐known graptolites of the distinctive Palaeozoic fauna. Most of the graptolites traditionally regarded as tuboids and dendroids appear to be paraphyletic groups within the Eugraptolithina; however, Epigraptus is probably not a member of this clade. The Eugraptolithina appear to be derived from an encrusting, Rhabdopleura‐like species, but the available information is insufficient to resolve the phylogeny of basal graptolites. The phylogenetic position of Mastigograptus and the status of the Dithecoidea and Mastigograptida also remain unresolved. □ Biodiversity, Cambrian, Hemichordata, Deuterostomia, Ordovician.     

An ordered arrangement of chromosomes in the somatic nucleus of common wheat Triticum aestivum L.

Spatial relationships between chromosomes of the same genome, both homologous and non-homologous, were studied in root-tip cells of common wheat, Triticum aestivum (2n = 6x = 42). Mean distance between members of all the 21 homologous pairs (seven in each of the three genomes) and of 45 out of the 63 possible non-homologous combinations of two (21 in each genome) were determined. To minimize disruption of nuclear chromosomal arrangement, the cells were pretreated with cold temperature either in tap water or in a physiological medium (White solution) and distances between cytologically marked chromosomes were measured at metaphase. Comparison of distances for homologues with those for non-homologues indicated clearly that, within each genome, the homologous chromosomes were significantly closer to one another than were the non-homologues. Distances between homologues were similar in all three genomes, as were distances between non-homologues. The data are consistent with the hypothesis that the chromosomes of each genome of common wheat are arranged in the somatic nucleus in a highly specific ordered pattern. In this hypothetical arrangement, homologous chromosomes are closely associated, while the nonhomologues occupy definite positions with respect to one another. The universality of the phenomenon and its cellular mechanism and biological significance are discussed.     

Comparison of the catalytic oxidation of cysteine and o-dianisidine by cupric ion and ceruloplasmin

Several features of the catalytic oxidation of cysteine by ceruloplasmin and nonenzymic Cu(II) at pH 7 have been compared. The oxidation of cysteine by ceruloplasmin has several properties in common with the Cu(II) catalyzed oxidation of cysteine: pH maxima, thiol specificity, lack of inhibition by anions, and high sensitivity to inhibition by copper complexing reagents. These two catalysts differed in their molecular activity, in their ability to oxidize penicillamine and thioglycolate, and in that H₂O₂ was produced as a primary product only during Cu(II) oxidation. The oxidation of cysteine by ceruloplasmin was compared also with the ceruloplasmin catalyzed oxidation of o-dianisidine, a classical pH 5.5 substrate. The mechanism of the oxidation of cysteine by ceruloplasmin at pH 7 differed from that of o-dianisidine oxidation because the latter substrate was inhibited by anions but not by copper complexing agents. Spectral and other data suggest that during the ceruloplasmin reaction with cysteine there is a one electron transfer from cysteine to ceruloplasmin resulting in the specific reduction of type lb Cu(II).     

Adenosine(5')tetraphospho(5')adenosine-binding protein of calf thymus

An adenosine(5')tetraphospho(5')adenosine (Ap4A) binding protein has been purified from calf thymus. The protein is comprised of a single polypeptide of Mr 54000 and is capable of high-affinity (Kd = 13 microM) binding of Ap4A with great substrate specificity. The Ap4A binding protein has been isolated in two forms: a 'free', or non-polymerase-bound, form which predominates, and a similar form which copurifies with DNA polymerase alpha, but which can be resolved from it. The free form of Ap4A binding protein contains associated adenosine(5')tetraphospho(5')adenosine phosphohydrolase (Ap4Aase) activity, while the form resolved from DNA polymerase alpha contains no such activity. The Ap4Aase activity, which catalyzes the phosphohydrolysis of Ap4A to ATP and AMP, is strongly inhibited by low levels (50-100 microM) of Zn2+ without any effect on the Ap4A binding protein activity. This difference in associated Ap4Aase activity between free and polymerase-bound forms of the protein, plus the copurification mentioned above, indicate a specific association between Ap4A binding protein and DNA polymerase alpha.     

Effect of estradiol-17β on glucose and proline uptake in plasma membrane vesicles from the R3230AC rat mammary carcinoma

Purified plasma membrane vesicles isolated from R3230AC rat mammary tumors displayed carrier-mediated and stereospecific uptake. Uptake was shown to be proportional to protein concentration, sensitive to increasing osmolarity, and inhibited only by substrates entering by the same carrier. Carrier-mediated glucose uptake was inhibited rapidly by estradiol-17β and phloretin in a dose-dependent manner, whereas proline uptake was not affected by estradiol-17β. The data suggest that the inhibition of glucose by estradiol and phloretin, originally observed in whole cells, occurs by an interaction of the steroid with a component on the plasma membrane. In contrast, the lack of effects of estradiol on proline transport into vesicles implies that intracellular components may have mediated the estrogen-induced effects observed in whole cells.     

Biogeography of body size in terrestrial isopods (Crustacea: Oniscidea)

This study tries to unveil the contribution of climatic shift in shaping the extreme body size diversity in terrestrial isopods (Oniscidea). Trying to explain size variation at an interspecific level, we test five hypotheses: (1) Bergmann's Rule and the temperature‐size rule postulate large size in cold areas; (2) The metabolic cold adaptation theory postulates small animal sizes in cold environments; (3) The primary productivity hypothesis predicts size increase in resource‐rich areas; (4) The aridity resistance hypothesis predicts large size in arid regions; and (5). The acidosis hypothesis predicts smaller size with decreasing soil pH. Globally, Bergmann's rule and the aridity hypothesis are weakly supported. Among families and genera, results are variable and idiosyncratic. Conglobating species sizes provide weak support for the acidosis hypothesis. Overall, size is strongly affected by familial affiliation. Isopod size evolution seems to be mainly affected by phylogenetically constrained life‐history traits.     

Gut Hormone Pharmacology of a Novel GPR119 Agonist (GSK1292263), Metformin,and Sitagliptin in Type 2 Diabetes Mellitus: Results from Two Randomized Studies

GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25–800 mg; n = 45) or multiple doses (100–600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼five-fold compared with placebo, reaching peak concentrations of ∼50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides.

Trial Registration:

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01119846","term_id":"NCT01119846"}}NCT01119846 Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01128621","term_id":"NCT01128621"}}NCT01128621