Ontogeny of purinergic receptor-regulated Ca2+ signaling in mouse cortical collecting duct epithelium

Changes in ATP-induced increase in {[}Ca2+], during collecting duct ontogeny were studied in primary monolayer cultures of mouse ureteric bud (UB) and cortical collecting duct (CCD) cells by Fura-PE3 fluorescence ratio imaging. In UB (embryonic day E14 and postnatal day P1) the ATIP-stimulated increase (EC50 approximate to 1 muM) in fluorescence ratio (DeltaR(ATP)) was independent of extracellular Ca2+ and insensitive to the P2 purinoceptor-antagonist suramin (1 mM). From day P7 onward when CCD morphogenesis had been completed DeltaR(ATP) increased and became dependent on extracellular Ca2+. This ATP-stimulated Ca2+ entry into CCD cells was non-capacitative and suramin (11 mM)insensitive, but sensitive to nifedipine (30 muM) and enhanced by Bay K8644 (15 muM), a blocker and an agonist of L-type Ca2+ channels, respectively. Quantitative RT-PCR demonstrated similar mRNA expression of L-type Ca2+ channel alpha1-subunit, P2Y(1), P2Y(2), and P2X(4b) purinoceptors in UB and CCD monolayers while the abundance of P2X(4) mRNA increased with CCD morphogenesis. In conclusion, both embryonic and postnatal cells express probably P2Y(2)-stimulated Ca2+ release from intracellular stores. With development, the CCD epithelium acquires ATP-stimulated Ca2+ entry via L-type Ca2+ channels. This pathway might by mediated by the increasing expression of P2X(4)-receptors resulting in an increasing ATP-dependent membrane depolarization and activation of L-type Ca2+ channels. Copyright (C) 2002 S. Karger AG, Basel

Intersection between metabolic dysfunction, high fat diet consumption, and brain aging

Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high‐fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high‐fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age‐related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.Fil: Uranga, Romina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bruce Keller, Annadora J.. State University of Louisiana; Estados UnidosFil: Morrison, Christopher D.. State University of Louisiana; Estados UnidosFil: Fernandez Kim, Sun Ok. State University of Louisiana; Estados UnidosFil: Ebenezer, Philip J.. State University of Louisiana; Estados UnidosFil: Zhang, Le. State University of Louisiana; Estados UnidosFil: Dasuri, Kalavathi. State University of Louisiana; Estados UnidosFil: Keller, Jeffrey N.. State University of Louisiana; Estados Unido

Altered fasting and postprandial plasma ghrelin levels in patients with liver failure are normalized after liver transplantation

[Abstract] Context Anorexia is a problem of paramount importance in patients with advanced liver failure. Ghrelin has important actions on feeding and weight homeostasis. Experimental data exist, which suggest that ghrelin could protect hepatic tissue. Both fasting and post-oral glucose tolerance test (OGTT) ghrelin concentrations are controversial in liver cirrhosis and are unknown after liver transplantation. Objective Our aim was to study fasting ghrelin concentrations and their response to an OGTT in liver failure patients before and after liver transplantation. Design and methods We included 21 patients with severe liver failure studied before (pretransplantation, PreT) and 6 months after liver transplantation (posttransplantation, PostT), and 10 age- and body mass index-matched healthy or overweight subjects as the control group (Cont). After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, and ghrelin were obtained at baseline and at times 30, 60, 90, and 120 min. Results Fasting ghrelin (median and range, pg/ml) levels were lower in PreT: 539 (309–1262) than in Cont: 643 (523–2163), P=0.045. Fasting ghrelin levels increased after liver transplantation, 539 (309–1262) vs 910 (426–3305), for PreT and PostT respectively, P=0.001. The area under the curve (AUC) of ghrelin (pg/ml min) was lower in PreT: 63 900 (37 260–148 410) than in Cont: 76 560 (56 160–206 385), P=0.027. The AUC of ghrelin increased in PostT, 63 900 (37 260–148 410) vs 107 595 (59 535–357 465), for PreT and PostT respectively, P=0.001. Fasting levels and the AUC of ghrelin were similar in PosT and Cont. Conclusions Decreased fasting and post-OGTT ghrelin levels in liver failure patients were normalized after liver transplantation.Instituto de Salud Carlos III; PI051024Instituto de Salud Carlos III; PI070413Xunta de Galicia; PS07/12Galicia. Consellería de Innovación, Industria e Comercio; PGIDT05PXIC91605PNGalicia. Consellería de Economía e Industria; INCITE08ENA916110E

Prediction of Mechanical Properties of Polymers With Various Force Fields

The effect of force field type on the predicted elastic properties of a polyimide is examined using a multiscale modeling technique. Molecular Dynamics simulations are used to predict the atomic structure and elastic properties of the polymer by subjecting a representative volume element of the material to bulk and shear finite deformations. The elastic properties of the polyimide are determined using three force fields: AMBER, OPLS-AA, and MM3. The predicted values of Young s modulus and shear modulus of the polyimide are compared with experimental values. The results indicate that the mechanical properties of the polyimide predicted with the OPLS-AA force field most closely matched those from experiment. The results also indicate that while the complexity of the force field does not have a significant effect on the accuracy of predicted properties, small differences in the force constants and the functional form of individual terms in the force fields determine the accuracy of the force field in predicting the elastic properties of the polyimide

Ghrelin

This work was supported by grants from the NIH (DP2DK105570-01 and 2P30DK046200 to MLA, DK21397 to HJG, K01DK098319 to KMH, K01MH091222 to LH, DK093848 to RJS, R01DK082590 to LS, R01DK097550 to JT, RO1 DK 076037 to MOT, R01DA024680 and R01MH085298 to JMZ, R01AG019230 and R01AG029740 to RGS) The Wellcome Trust (MK), Science Foundation Ireland (12/YI/B2480 to CWL), the Alexander von Humboldt Foundation (MHT), the Deutsches Zentrum für Diabetesforschung (MHT), the Helmholtz Alliance ICEMED e Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association (MHT), and the Helmholtz cross-program topic “Metabolic Dysfunction” (MHT). Allan Geliebter was sponsored by NIH grants R01DK80153; R01DK074046; R03DK068603; P30DK26687

CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction

Funding This work was supported by the BBSRC and Diabetes UK.Peer reviewedPublisher PD

RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS

Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels

Changes in appetite, energy intake, body composition and circulating ghrelin constituents during an incremental trekking ascent to high altitude

Purpose Circulating acylated ghrelin concentrations are associated with altitude-induced anorexia in laboratory environments, but have never been measured at terrestrial altitude. This study examined time course changes in appetite, energy intake, body composition, and ghrelin constituents during a high-altitude trek. Methods Twelve participants [age: 28(4) years, BMI 23.0(2.1) kg m−2] completed a 14-day trek in the Himalayas. Energy intake, appetite perceptions, body composition, and circulating acylated, des-acylated, and total ghrelin concentrations were assessed at baseline (113 m, 12 days prior to departure) and at three fixed research camps during the trek (3619 m, day 7; 4600 m, day 10; 5140 m, day 12). Results Relative to baseline, energy intake was lower at 3619 m (P = 0.038) and 5140 m (P = 0.016) and tended to be lower at 4600 m (P = 0.056). Appetite perceptions were lower at 5140 m (P = 0.027) compared with baseline. Acylated ghrelin concentrations were lower at 3619 m (P = 0.046) and 4600 m (P = 0.038), and tended to be lower at 5140 m (P = 0.070), compared with baseline. Des-acylated ghrelin concentrations did not significantly change during the trek (P = 0.177). Total ghrelin concentrations decreased from baseline to 4600 m (P = 0.045). Skinfold thickness was lower at all points during the trek compared with baseline (P ≤ 0.001) and calf girth decreased incrementally during the trek (P = 0.010). Conclusions Changes in plasma acylated and total ghrelin concentrations may contribute to the suppression of appetite and energy intake at altitude, but differences in the time course of these responses suggest that additional factors are also involved. Interventions are required to maintain appetite and energy balance during trekking at terrestrial altitudes

Assessing the complex sponge microbiota: core, variable and species-specific bacterial communities in marine sponges

Marine sponges are well known for their associations with highly diverse, yet very specific and often highly similar microbiota. The aim of this study was to identify potential bacterial sub-populations in relation to sponge phylogeny and sampling sites and to define the core bacterial community. 16S ribosomal RNA gene amplicon pyrosequencing was applied to 32 sponge species from eight locations around the world's oceans, thereby generating 2567 operational taxonomic units (OTUs at the 97% sequence similarity level) in total and up to 364 different OTUs per sponge species. The taxonomic richness detected in this study comprised 25 bacterial phyla with Proteobacteria, Chloroflexi and Poribacteria being most diverse in sponges. Among these phyla were nine candidate phyla, six of them found for the first time in sponges. Similarity comparison of bacterial communities revealed no correlation with host phylogeny but a tropical sub-population in that tropical sponges have more similar bacterial communities to each other than to subtropical sponges. A minimal core bacterial community consisting of very few OTUs (97%, 95% and 90%) was found. These microbes have a global distribution and are probably acquired via environmental transmission. In contrast, a large species-specific bacterial community was detected, which is represented by OTUs present in only a single sponge species. The species-specific bacterial community is probably mainly vertically transmitted. It is proposed that different sponges contain different bacterial species, however, these bacteria are still closely related to each other explaining the observed similarity of bacterial communities in sponges in this and previous studies. This global analysis represents the most comprehensive study of bacterial symbionts in sponges to date and provides novel insights into the complex structure of these unique associations

Ghrelin Modulates the fMRI BOLD Response of Homeostatic and Hedonic Brain Centers Regulating Energy Balance in the Rat

The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A) are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI) within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin’s BOLD effect in a region specific manner. In females, the estradiol milieu does not influence the BOLD response to ghrelin