Rapid uptake of calcium, ATP, and inositol 1,4,5-trisphosphate via cation and anion channels into surface-derived vesicles from HIT cells containing the inositol 1,4,5-trisphosphate-sensitive calcium store

AbstractIn a previous study [K. Lange and U. Brandt (1993) FEBS Lett. 320, 183-188], we showed that the bulk of the ATP-dependent IP3-sensitive Ca2+ store of the hamster insulinoma cell line, HIT-T15, resides in cell surface-derived vesicles most likely of microvillar origin. The origin and orientation of these vesicles suggested that Ca2+ storage is not due to a membrane-located Ca2+ pumping ATPase but rather to ATP-dependent Ca2+-binding within the vesicles. In this case, Ca2+, ATP and IP3 should have free access to the vesicle lumen. This hypothesis was tested. ATP-independent Ca2+ uptake occurred with biphasic kinetics. An initial rapid uptake, which was complete within 30 s, was followed by a slow linear uptake lasting about 10 min. The rapid component was shown by efflux experiments to have an equilibration half-time of about 4 s. This rapid Ca2+ efflux pathway was inhibited by externally applied La3+ (0.1 mM). A similar rapidly equilibrating La3+-sensitive Ca2+ pool was also present in vesicles which had been actively loaded with Ca2+ in the presence of ATP. The intravesicular distribution space of this labile Ca2+ pool was identical with that of the non-metabolizable hexose analogue 3-O-methyl-D-glucose, demonstrating that rapid Ca2+ uptake occurs into a true vesicular water space and is not due to binding. ATP and IP3 were also shown to enter the vesicles by an energy-independent pathway which is inhibited by the anion channel inhibitor, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; 0.5 mM). Both ATP-dependent Ca2+ uptake and IP3-induced Ca2+ release from preloaded vesicles were inhibited by DIDS. These findings clearly demonstrate that (1) the vesicle membrane is permeable to ATP and IP3 via anion channels, and (2) Ca2+ uptake into as well as IP3-induced Ca2+ release from the vesicles occur by passive diffusion through a cation channel which is not regulated by IP3. Consequently, the mechanisms for Ca2+ storage and IP3-induced Ca2+ release must be located in the vesicle lumen. Moreover, the microvillar diffusion-barrier concept, originally proposed for the regulation of hexose transport may also be valid for the receptor-operated regulation of cation and anion influx pathways. Functional coupling of the microvillar Ca2+ stores with the associated cation influx pathway is also strongly supported by the previously demonstrated microvillar shape changes accompanying depletion of the Ca2+ stores by bombesin or thapsigargin in HIT cells [K. Lange and U. Brandt (1992) FEBS Lett. 320, 183-188]

Activation of G12/G13 Results in Shape Change and Rho/Rho-Kinase–mediated Myosin Light Chain Phosphorylation in Mouse Platelets

Platelets respond to various stimuli with rapid changes in shape followed by aggregation and secretion of their granule contents. Platelets lacking the α-subunit of the heterotrimeric G protein Gq do not aggregate and degranulate but still undergo shape change after activation through thromboxane-A2 (TXA2) or thrombin receptors. In contrast to thrombin, the TXA2 mimetic U46619 led to the selective activation of G12 and G13 in Gαq-deficient platelets indicating that these G proteins mediate TXA2 receptor-induced shape change. TXA2 receptor-mediated activation of G12/G13 resulted in tyrosine phosphorylation of pp72syk and stimulation of pp60c-src as well as in phosphorylation of myosin light chain (MLC) in Gαq-deficient platelets. Both MLC phosphorylation and shape change induced through G12/G13 in the absence of Gαq were inhibited by the C3 exoenzyme from Clostridium botulinum, by the Rho-kinase inhibitor Y-27632 and by cAMP-analogue Sp-5,6-DCl-cBIMPS. These data indicate that G12/G13 couple receptors to tyrosine kinases as well as to the Rho/Rho-kinase–mediated regulation of MLC phosphorylation. We provide evidence that G12/G13-mediated Rho/Rho-kinase–dependent regulation of MLC phosphorylation participates in receptor-induced platelet shape change

Rezensionen

Rezension zu: 1) Arnold, Rolf; Gieseke, Wiltrud; Zeuner, Christine (Hrsg.): Bildungsberatung im Dialog. Bd. 1, Theorie - Empirie – Reflexion. Baltmannsweiler: Schneider Verl. Hohengehren 2009. ISBN 978-3-8340-0556-4. 2) Knoll, Jörg: Lern- und Bildungsberatung: professionell beraten in der Weiterbildung. Bielefeld: W. Bertelsmann Verl. 2008. ISBN 978-3-7639-1956-7. 3) Schiersmann, Christiane; Bachmann, Miriam; Dauner, Alexander; Weber, Peter: Qualität und Professionalität in Bildungs- und Berufsberatung. Bielefeld: W. Bertelsmann Verl. 2009. ISBN 978-3-7639-4200-8. 4) Alheit, Peter; Felden, Heide von (Hrsg.): Lebenslanges Lernen und erziehungswissenschaftliche Biographieforschung: Konzepte und Forschung im europäischen Diskurs. Wiesbaden: VS Verl. f. Sozialwissenschaften 2009. ISBN 978-3-531-15600-2. 5) Dehnbostel, Peter: Berufliche Weiterbildung - Grundlagen aus arbeitnehmerorientierter Sicht. Berlin: Ed. Sigma 2008. ISBN 978-3-89404-562-3. 6) Kortendieck, Georg; Summen, Frank (Hrsg.): Betriebswirtschaftliche Kompetenz in der Erwachsenenbildung. Bielefeld: W. Bertelsmann Verl. 2008. ISBN 978-3-7639-3652-6. 7) Müller-Commichau, Wolfgang: Identitätslernen: jüdische Erwachsenenbildung in Deutschland vom Kaiserreich bis zur Berliner Republik. Baltmannsweiler: Schneider Verl. Hohengehren 2009. ISBN 978-3-8340-0583-0. 8) Müller-Ruckwitt, Anne: „Kompetenz“ - Bildungstheoretische Untersuchungen zu einem aktuellen Begriff. Würzburg: Ergon Verl. 2008. ISBN 978-3-89913-615-9. 9) Salman, Yvonne: Bildungseffekte durch Lernen im Arbeitsprozess: Verzahnung von Lern- und Arbeitsprozessen zwischen ökonomischer Verwertbarkeit und individueller Entfaltung am Beispiel des IT-Weiterbildungssystems. Bielefeld: W. Bertelsmann Verl. 2009. ISBN 3-7639-1123-5. 10) Schmidt-Lauff, Sabine: Zeit für Bildung im Erwachsenenalter: interdisziplinäre und empirische Zugänge. Münster: Waxmann 2008. ISBN 978-3-8309-2020-5. 11) Strauch, Anne: Kompetenzbilanzierung im Betriebskontext - eine Fallstudie. Baltmannsweiler: Schneider Verl. Hohengehren 2008. ISBN 978-3-8340-0468-0. 12) Wolf, Frieder: Bildungsfinanzierung in Deutschland. Wiesbaden: VS Verl. f. Sozialwissenschaften 2008. ISBN 978-3-531-16055-9

A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density.

INTRODUCTION: Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density. METHODS: The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (P int) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density. RESULTS: No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02). CONCLUSIONS: The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-015-0625-

Cardiac rehabilitation in Austria: long term health-related quality of life outcomes

<p>Abstract</p> <p>Background</p> <p>The goal of cardiac rehabilitation programs is not only to prolong life but also to improve physical functioning, symptoms, well-being, and health-related quality of life (HRQL). The aim of this study was to document the long-term effect of a 1-month inpatient cardiac rehabilitation intervention on HRQL in Austria.</p> <p>Methods</p> <p>Patients (N = 487, 64.7% male, age 60.9 ± 12.5 SD years) after myocardial infarction, with or without percutaneous interventions, coronary artery bypass grafting or valve surgery underwent inpatient cardiac rehabilitation and were included in this long-term observational study (two years follow-up). HRQL was measured with both the MacNew Heart Disease Quality of Life Instrument [MacNew] and EuroQoL-5D [EQ-5D].</p> <p>Results</p> <p>All MacNew scale scores improved significantly (p < 0.001) and exceeded the minimal important difference (0.5 MacNew points) by the end of rehabilitation. Although all MacNew scale scores deteriorated significantly over the two year follow-up period (p < .001), all MacNew scale scores still remained significantly higher than the pre-rehabilitation values. The mean improvement after two years in the MacNew social scale exceeded the minimal important difference while MacNew scale scores greater than the minimal important difference were reported by 40-49% of the patients.</p> <p>Two years after rehabilitation the mean improvement in the EQ-5D Visual Analogue Scale score was not significant with no significant change in the proportion of patients reporting problems at this time.</p> <p>Conclusion</p> <p>These findings provide a first indication that two years following inpatient cardiac rehabilitation in Austria, the long-term improvements in HRQL are statistically significant and clinically relevant for almost 50% of the patients. Future controlled randomized trials comparing different cardiac rehabilitation programs are needed.</p

Combined Forward-Backward Asymmetry Measurements in Top-Antitop Quark Production at the Tevatron

The CDF and D0 experiments at the Fermilab Tevatron have measured the asymmetry between yields of forward- and backward-produced top and antitop quarks based on their rapidity difference and the asymmetry between their decay leptons. These measurements use the full data sets collected in proton-antiproton collisions at a center-of-mass energy of $\sqrt s =1.96$ TeV. We report the results of combinations of the inclusive asymmetries and their differential dependencies on relevant kinematic quantities. The combined inclusive asymmetry is $A_{\mathrm{FB}}^{t\bar{t}} = 0.128 \pm 0.025$. The combined inclusive and differential asymmetries are consistent with recent standard model predictions

Reduced parahippocampal and lateral temporal GABA(A)-[C-11]flumazenil binding in major depression: preliminary results

Purpose: Major depressive disorder (MDD) has been related to both a dysfunctional γ-amino butyric acid (GABA) system and to hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA). Although GABA has been suggested to inhibit HPA axis activity, their relationship has never been studied at the level of the central GAB

Moderne Lernumgebungen für den Campus von morgen. Das Projekt ITSI

Wie verändern sich virtuelle und physische Lernumgebungen vor dem Hintergrund mobiler Technologien und der stetigen Weiterentwicklung von Informations- und Kommunikationsmedien? Zusammen mit internen und externen ExpertInnen hat das LearnTechNet, das Kompetenznetzwerk für neue Medien in Studium und Lehre der Universität Basel, die Anforderungen an künftige Lernumgebungen im Rahmen des Projekts ITSI identifiziert und Umsetzungsmöglichkeiten aufgezeigt. Dabei wurden Schwerpunkte auf die Themen Lernen, Lehre, Prüfungen, Austausch und Innovation gelegt. Der vorliegende Beitrag beschreibt sowohl die konzeptionelle und methodische Herangehensweise als auch zentrale Ergebnisse aus dem Projekt, und leitet abschliessend Thesen für den Weg zum Campus von morgen ab. (DIPF/Orig.