Efficient heuristics for the design of ring networks

In telecommunications, the Ring Design Problem (RDP) lies at the heart ofmetropolitan area network design. We propose an integer programming formulation for the RDP, as well as several ring construction and post-optimization heuristics. These heuristics are tested and compared on a series of test problems.     

Enhancement of eicosaenoic acid lipoxygenation in human platelets by 12-hydroperoxy derivative of arachidonic acid

Human platelet lipoxygenase activity toward several eicosaenoic acids was measured in intact cells as well as in subcellular fractions (cytosol and membranes). In whole platelets, the lipoxygenation of eicosaenoic acids was enhanced greatly by high concentrations of aspirin, which partially inhibit the peroxidase activity associated with the pathway. The lipoxygenation also was increased by arachidonic acid (AA) or its lipoxygenase product, 12-hydroxyperoxy-eicosatetraenoic acid (12-HPETE). Similarly, prostanoid precursors, dihomogammalinolenic (DHLA) and eicosapentaenoic (EPA) acids also were better converted by cyclooxygenase in the presence of AA or 12-HPETE. Among the eicosaenoic acids tested, EPA oxygenation was affected most. Using cytosol or membranes as the lipoxygenase source instead of whole cells led to completely different results. AA exerted a competitive inhibition upon the other eicosaenoic acid oxygenation except that of EPA, for which a dual effect of AA was observed. This makes questionable the use of platelet subfractions for investigating lipoxygenase activity. We conclude that platelet lipoxygenation of eicosaenoic acids appears peroxide-dependent, especially for apparent poor substrates like EPA. This might be relevant in respect to 12-HPETE, which is the main hydroperoxy derivative to be produced during platelet activation.     

Coagulation Factor XIIIa and Activated Protein C Activate Platelets via GPVI and PAR1

Platelet and coagulation activation are highly reciprocal processes driven by multi-molecular interactions. Activated platelets secrete several coagulation factors and expose phosphatidylserine, which supports the activation of coagulation factor proteins. On the other hand, the coagulation cascade generates known ligands for platelet receptors, such as thrombin and fibrin. Coagulation factor (F)Xa, (F)XIIIa and activated protein C (APC) can also bind to platelets, but the functional consequences are unclear. Here, we investigated the effects of the activated (anti)coagulation factors on platelets, other than thrombin. Multicolor flow cytometry and aggregation experiments revealed that the ‘supernatant of (hirudin-treated) coagulated plasma’ (SCP) enhanced CRP-XL-induced platelet responses, i.e., integrin α_IIbβ₃ activation, P-selectin exposure and aggregate formation. We demonstrated that FXIIIa in combination with APC enhanced platelet activation in solution, and separately immobilized FXIIIa and APC resulted in platelet spreading. Platelet activation by FXIIIa was inhibited by molecular blockade of glycoprotein VI (GPVI) or Syk kinase. In contrast, platelet spreading on immobilized APC was inhibited by PAR1 blockade. Immobilized, but not soluble, FXIIIa and APC also enhanced in vitro adhesion and aggregation under flow. In conclusion, in coagulation, factors other than thrombin or fibrin can induce platelet activation via GPVI and PAR receptors.     

In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators

ABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the ABCB11 gene cause a spectrum of rare liver diseases. The most severe form is progressive familial intrahepatic cholestasis type 2 (PFIC2). Current medical treatments have limited efficacy. Here, we report the in vitro study of Abcb11 missense variants identified in PFIC2 patients and their functional rescue using cystic fibrosis transmembrane conductance regulator potentiators. Three ABCB11 disease-causing variations identified in PFIC2 patients (i.e., A257V, T463I and G562D) were reproduced in a plasmid encoding an Abcb11-green fluorescent protein. After transfection, the expression and localization of the variants were studied in HepG2 cells. Taurocholate transport activity and the effect of potentiators were studied in Madin–Darby canine kidney (MDCK) clones coexpressing Abcb11 and the sodium taurocholate cotransporting polypeptide (Ntcp/Slc10A1). As predicted using three-dimensional structure analysis, the three variants were expressed at the canalicular membrane but showed a defective function. Ivacaftor, GLP1837, SBC040 and SBC219 potentiators increased the bile acid transport of A257V and T463I and to a lesser extent, of G562D Abcb11 missense variants. In addition, a synergic effect was observed when ivacaftor was combined with SBC040 or SBC219. Such potentiators could represent new pharmacological approaches for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the function of the transporter.     

RAB10 Interacts with ABCB4 and Regulates Its Intracellular Traffic

ABCB4 (ATP-binding cassette subfamily B member 4) is an ABC transporter expressed at the canalicular membrane of hepatocytes where it ensures phosphatidylcholine secretion into bile. Genetic variations of ABCB4 are associated with several rare cholestatic diseases. The available treatments are not efficient for a significant proportion of patients with ABCB4-related diseases and liver transplantation is often required. The development of novel therapies requires a deep understanding of the molecular mechanisms regulating ABCB4 expression, intracellular traffic, and function. Using an immunoprecipitation approach combined with mass spectrometry analyses, we have identified the small GTPase RAB10 as a novel molecular partner of ABCB4. Our results indicate that the overexpression of wild type RAB10 or its dominant-active mutant significantly increases the amount of ABCB4 at the plasma membrane expression and its phosphatidylcholine floppase function. Contrariwise, RAB10 silencing induces the intracellular retention of ABCB4 and then indirectly diminishes its secretory function. Taken together, our findings suggest that RAB10 regulates the plasma membrane targeting of ABCB4 and consequently its capacity to mediate phosphatidylcholine secretion.     

A new continuous-flow recycle microwave reactor for homogeneous and heterogeneous chemical reactions

A new continuous-flow recycle microwave reactor suitable for organic synthesis has been developed to handle 0.51 quantities of reagents. The apparatus, which is designed for laboratory use, operates at atmospheric pressure in open- or closed-loop mode. It is fitted with a temperature control system. We describe this novel reactor and illustrate its efficiency with examples of organic syntheses carried out using both homogeneous and heterogeneous reactions.     

Clients Who Stalk Psychologists: Prevalence, Methods, and Motives.

There is emerging recognition that psychologists are susceptible to various forms of intrusiveness by clients, including stalking. Information regarding the contexts in which stalking emerges and the behaviors to which clinicians are subjected is limited. A random sample of Australian psychologists (N = 1,750) was surveyed to ascertain the prevalence, nature, and occupational impact of stalking by clients. Of the 830 respondents, 19.5% had been stalked for 2 weeks or more. Psychologists typically perceived the stalking to be motivated by resentment (42%) or infatuation (19%). Most practitioners altered their professional practice as a consequence of the harassment and 29% considered leaving the profession. Stalking by clients is a salient professional issue that requires greater attention to better manage conduct that is potentially damaging to both therapists and clients. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hemispheric Specialization in the Primary Auditory Area of Awake and Anesthetized Starlings (Sturnus vulgaris).

Although evidence exists for a lateralization of song production, few studies have focused on the perceptual aspect of lateralization in songbirds. In the present study, the authors recorded neuronal responses to a variety of species-specific and artificial, nonspecific stimuli in both hemispheres of awake and anesthetized male starlings (Sturnus vulgaris). Recordings were made in the primary auditory area of the songbird brain, the Field L complex. The right hemisphere exhibited significantly more responsive units than the left hemisphere in awake birds, and this difference was significantly reduced in anesthetized birds. Furthermore, clear hemispheric specialization toward categories of behaviorally relevant stimuli and precise parameters of these stimuli were found. The main auditory area of the starling's brain thus appears to show some degree of lateralization. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Solar operated water-Amonia absorption heat pump for air-conditioning: Modelling and simulation

This study is devoted to the mathematical modelling of an ammoniawater absorption heat pump adapted to solar air-conditioning and including refrigerant and solution storages. Mathematical simulation permits the prediction of the performance of the system during a 24-h period and allows one to estimate its energetic performance, which is compared with those of systems using water-lithium bromide.