Alterations in Platelet Alpha-Granule Secretion and Adhesion on Collagen under Flow in Mice Lacking the Atypical Rho GTPase RhoBTB3

Typical Rho GTPases, such as Rac1, Cdc42, and RhoA, act as molecular switches regulating various aspects of platelet cytoskeleton reorganization. The loss of these enzymes results in reduced platelet functionality. Atypical Rho GTPases of the RhoBTB subfamily are characterized by divergent domain architecture. One family member, RhoBTB3, is expressed in platelets, but its function is unclear. In the present study we examined the role of RhoBTB3 in platelet function using a knockout mouse model. We found the platelet count, size, numbers of both alpha and dense granules, and surface receptor profile in these mice were comparable to wild-type mice. Deletion of Rhobtb3 had no effect on aggregation and dense granule secretion in response to a range of agonists including thrombin, collagen, and adenosine diphosphate (ADP). By contrast, alpha-granule secretion increased in mice lacking RhoBTB3 in response to thrombin, collagen related peptide (CRP) and U46619/ADP. Integrin activation and spreading on fibrinogen and collagen under static conditions were also unimpaired; however, we observed reduced platelet accrual on collagen under flow conditions. These defects did not translate into alterations in tail bleeding time. We conclude that genetic deletion of Rhobtb3 leads to subtle alterations in alpha-granule secretion and adhesion to collagen without significant effects on hemostasis in vivo

Atherogenic Lipid Stress Induces Platelet Hyperactivity Through CD36-Mediated Hyposensitivity To Prostacyclin-; The Role Of Phosphodiesterase 3A

Prostacyclin (PGI2) controls platelet activation and thrombosis through a cyclic adenosine monophosphate (cAMP) signalling cascade. However, in patients with cardiovascular diseases this protective mechanism fails for reasons that are unclear. Using both pharmacological and genetic approaches we describe a mechanism by which oxidised low density lipoproteins (oxLDL) associated with dyslipidaemia promote platelet activation through impaired PGI2 sensitivity and diminished cAMP signalling. In functional assays using human platelets, oxLDL modulated the inhibitory effects of PGI2, but not a PDE-insensitive cAMP analogue, on platelet aggregation, granule secretion and in vitro thrombosis. Examination of the mechanism revealed that oxLDL promoted the hydrolysis of cAMP through the phosphorylation and activation of phosphodiesterase 3A (PDE3A), leading to diminished cAMP signalling. PDE3A activation by oxLDL required Src family kinases, Syk and protein kinase C. The effects of oxLDL on platelet function and cAMP signalling were blocked by pharmacological inhibition of CD36, mimicked by CD36-specific oxidised phospholipids and ablated in CD36-/- murine platelets. The injection of oxLDL into wild type mice strongly promoted FeCl3 induced carotid thrombosis in vivo, which was prevented by pharmacological inhibition of PDE3A. Furthermore, blood from dyslipidaemic mice was associated with increased oxidative lipid stress, reduced platelet sensitivity to PGI2 ex vivo and diminished PKA signalling. In contrast, platelet sensitivity to a PDE-resistant cAMP analogue remained normal. Genetic deletion of CD36, protected dyslipidaemic animals from PGI2 hyposensitivity and restored PKA signalling. These data suggest that CD36 can translate atherogenic lipid stress into platelet hyperactivity through modulation of inhibitory cAMP signalling.  

The pharmaceutical use of permethrin: Sources and behavior during municipal sewage treatment

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 Springer Science+Business Media, LLC.Permethrin entered use in the 1970s as an insecticide in a wide range of applications, including agriculture, horticultural, and forestry, and has since been restricted. In the 21st century, the presence of permethrin in the aquatic environment has been attributed to its use as a human and veterinary pharmaceutical, in particular as a pedeculicide, in addition to other uses, such as a moth-proofing agent. However, as a consequence of its toxicity to fish, sources of permethrin and its fate and behavior during wastewater treatment are topics of concern. This study has established that high overall removal of permethrin (approximately 90%) was achieved during wastewater treatment and that this was strongly dependent on the extent of biological degradation in secondary treatment, with more limited subsequent removal in tertiary treatment processes. Sources of permethrin in the catchment matched well with measured values in crude sewage and indicated that domestic use accounted for more than half of the load to the treatment works. However, removal may not be consistent enough to achieve the environmental quality standards now being derived in many countries even where tertiary treatment processes are applied.United Utilities PL

Sodium Chloride Inhibits the Growth and Infective Capacity of the Amphibian Chytrid Fungus and Increases Host Survival Rates

The amphibian chytrid fungus Batrachochytrium dendrobatidis is a recently emerged pathogen that causes the infectious disease chytridiomycosis and has been implicated as a contributing factor in the global amphibian decline. Since its discovery, research has been focused on developing various methods of mitigating the impact of chytridiomycosis on amphibian hosts but little attention has been given to the role of antifungal agents that could be added to the host's environment. Sodium chloride is a known antifungal agent used routinely in the aquaculture industry and this study investigates its potential for use as a disease management tool in amphibian conservation. The effect of 0–5 ppt NaCl on the growth, motility and survival of the chytrid fungus when grown in culture media and its effect on the growth, infection load and survivorship of infected Peron's tree frogs (Litoria peronii) in captivity, was investigated. The results reveal that these concentrations do not negatively affect the survival of the host or the pathogen. However, concentrations greater than 3 ppt significantly reduced the growth and motility of the chytrid fungus compared to 0 ppt. Concentrations of 1–4 ppt NaCl were also associated with significantly lower host infection loads while infected hosts exposed to 3 and 4 ppt NaCl were found to have significantly higher survival rates. These results support the potential for NaCl to be used as an environmentally distributed antifungal agent for the prevention of chytridiomycosis in susceptible amphibian hosts. However, further research is required to identify any negative effects of salt exposure on both target and non-target organisms prior to implementation

A novel regulatory circuit specifies cell fate in the Arabidopsis root epidermis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75165/1/j.1399-3054.2006.00606.x.pd

Integrating modes of policy analysis and strategic management practice : requisite elements and dilemmas

There is a need to bring methods to bear on public problems that are inclusive, analytic, and quick. This paper describes the efforts of three pairs of academics working from three different though complementary theoretical foundations and intervention backgrounds (i.e., ways of working) who set out together to meet this challenge. Each of the three pairs had conducted dozens of interventions that had been regarded as successful or very successful by the client groups in dealing with complex policy and strategic problems. One approach focused on leadership issues and stakeholders, another on negotiating competitive strategic intent with attention to stakeholder responses, and the third on analysis of feedback ramifications in developing policies. This paper describes the 10 year longitudinal research project designed to address the above challenge. The important outcomes are reported: the requisite elements of a general integrated approach and the enduring puzzles and tensions that arose from seeking to design a wide-ranging multi-method approach

Massive Spin-2 States as the Origin of the Top Quark Forward-Backward Asymmetry

We show that the anomalously large top quark forward-backward asymmetry observed by CDF and D\O\, can naturally be accommodated in models with flavor-violating couplings of a new massive spin-2 state to quarks. Regardless of its origin, the lowest-order couplings of a spin-2 boson to fermions are analogous to the coupling of the graviton to energy/momentum, leading to strong sensitivity of the effects associated with its virtual exchange to the energy scales at hand. Precisely due to this fact, the observed dependence of the asymmetry on the $t\bar t$ invariant mass fits nicely into the proposed framework. In particular, we find a vast parameter space which can lead to the central value for the observed forward-backward asymmetry in the high mass bin, while being in accord with all of the existing experimental constraints.Comment: added discussion of differential observables at the LHC, matches version accepted for publication in JHE

Konstruktivistische Ansätze in der Erwachsenenbildung und Weiterbildung

Theoretical approaches in the field of further education and advanced vocational training have to face multifaceted demands: the analysis of knowledge aquisition and knowledge transfer and its instructional support as well as the revealment of the mechanisms which influence further education on an organisational level in companies. This article describes, that herefore especially moderate constructivistic approaches are useful. After an introduction to the philosophical tradition of these approaches and important characteristics of adult learning, two examples of constructivistic models are being described particularly: The theory of situated learning environments and career counseling. Concluding it is shown, that a moderate constructive perspective fulfils important criteria for the theoretic modelling of further education processes.Theoretische Ansätze in der Erwachsenen- und insbesondere in der beruflichen Weiterbildung müssen sich vielfältigen Ansprüchen stellen: der Analyse des Wissenserwerbs und Wissenstransfers und seiner instruktionalen Unterstützung ebenso wie der Aufdeckung der Mechanismen, die in den Betrieben auf organisatorischer Ebene die Weiterbildung beeinflussen. In diesem Beitrag wird die Auffassung vertreten, daß dafür insbesondere liberalisierte konstruktivistische Ansätze gut geeignet sind. Nach einer Einführung in die philosophische Tradition dieser Ansätze und wichtiger Merkmale des Lernens im Erwachsenenalter werden zwei Beispiele konstruktivistischer Modelle genauer beschrieben: die Theorie situierter Lernumgebungen und das career counseling. Abschließend wird gezeigt, daß eine liberalisierte konstruktivistische Perspektive wichtige Kriterien für die theoretische Modellierung von Weiterbildungsprozessen erfüllt