mGluR5-Antagonist Mediated Reversal of Elevated Stereotyped, Repetitive Behaviors in the VPA Model of Autism

Autism spectrum disorders (ASD) are highly disabling developmental disorders with a population prevalence of 1–3%. Despite a strong genetic etiology, there are no current therapeutic options that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of glutamatergic signaling, in particular through metabotropic glutamate receptor 5 (mGluR5) receptors, may contribute to phenotypic deficits and may be appropriate targets for pharmacologic intervention. This study assessed the therapeutic potential of 2-methyl-6-phenylethyl-pyrididine (MPEP), an mGluR5-receptor antagonist, on repetitive and anxiety-like behaviors in the valproic acid (VPA) mouse model of autism. Mice were exposed prenatally on day E13 to VPA and assessed for repetitive self-grooming and marble burying behaviors as adults. Anxiety-like behavior and locomotor activity were measured in an open-field. VPA-exposed mice displayed increased repetitive and anxiety-like behaviors, consistent with previously published results. Across both marble burying and self-grooming assays, MPEP significantly reduced repetitive behaviors in VPA-treated mice, but had no effect on locomotor activity. These results are consistent with emerging preclinical literature that mGluR5-antagonists may have therapeutic efficacy for core symptoms of autism

APX001 Is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis.

Invasive pulmonary aspergillosis (IPA) due to Aspergillus fumigatus is a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high, and new treatments are needed. The novel antifungal APX001A targets the conserved Gwt1 enzyme required for the localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of APX001A against A. fumigatus and the in vivo activity of its prodrug APX001 in an immunosuppressed mouse model of IPA. APX001A inhibited the growth of A. fumigatus with a minimum effective concentration of 0.03 μg/ml. The use of 50 mg/kg 1-aminobenzotriazole (ABT), a suicide inhibitor of cytochrome P450 enzymes, enhanced APX001A exposures (area under the time-concentration curve [AUC]) 16- to 18-fold and enhanced serum half-life from ∼1 to 9 h, more closely mimicking human pharmacokinetics. We evaluated the efficacy of APX001 (with ABT) in treating murine IPA compared to posaconazole treatment. Treatment of mice with 78 mg/kg once daily (QD), 78 mg/kg twice daily, or 104 mg/kg QD APX001 significantly enhanced the median survival time and prolonged day 21 postinfection overall survival compared to the placebo. Furthermore, administration of APX001 resulted in a significant reduction in lung fungal burden (4.2 to 7.6 log10 conidial equivalents/g of tissue) versus the untreated control and resolved the infection, as judged by histopathological examination. The observed survival and tissue clearance were comparable to a clinically relevant posaconazole dose. These results warrant the continued development of APX001 as a broad-spectrum, first-in-class treatment of invasive fungal infections

Generic Model Refactorings

Many modeling languages share some common concepts and principles. For example, Java, MOF, and UML share some aspects of the concepts\ud of classes, methods, attributes, and inheritance. However, model\ud transformations such as refactorings specified for a given language\ud cannot be readily reused for another language because their related\ud metamodels may be structurally different. Our aim is to enable a\ud flexible reuse of model transformations across various metamodels.\ud Thus, in this paper, we present an approach allowing the specification\ud of generic model transformations, in particular refactorings, so\ud that they can be applied to different metamodels. Our approach relies\ud on two mechanisms: (1) an adaptation based mainly on the weaving\ud of aspects; (2) the notion of model typing, an extension of object\ud typing in the model-oriented context. We validated our approach by\ud performing some experiments that consisted of specifying three well\ud known refactorings (Encapsulate Field, Move Method, and Pull Up Method)\ud and applying each of them onto three different metamodels (Java,\ud MOF, and UML)

Functional and Crystal Structure Analysis of Active Site Adaptations of a Potent Anti-Angiogenic Human tRNA Synthetase

SummaryHigher eukaryote tRNA synthetases have expanded functions that come from enlarged, more differentiated structures that were adapted to fit aminoacylation function. How those adaptations affect catalytic mechanisms is not known. Presented here is the structure of a catalytically active natural splice variant of human tryptophanyl-tRNA synthetase (TrpRS) that is a potent angiostatic factor. This and related structures suggest that a eukaryote-specific N-terminal extension of the core enzyme changed substrate recognition by forming an active site cap. At the junction of the extension and core catalytic unit, an arginine is recruited to replace a missing landmark lysine almost 200 residues away. Mutagenesis, rapid kinetic, and substrate binding studies support the functional significance of the cap and arginine recruitment. Thus, the enzyme function of human TrpRS has switched more to the N terminus of the sequence. This switch has the effect of creating selective pressure to retain the N-terminal extension for functional expansion

Efecto de procesos de ahumado frío y caliente y la adición de extracto polifenólico natural de Dunaliella salina sobre la calidad bioquímica y la vida útil de filetes de Sander lucioperca almacenados durante 90 días

The effects of cold and hot smoking and the addition of Dunaliella salina polyphenol extract on the biochemical quality and shelf-life of Sander lucioperca fillets after storage for 90 days at 0-4 °C were examined. The results showed a significant increase in protein, lipid, free fatty acid, and 1,1-diphenyl-2-picrylhydrazyl contents, and a decrease in peroxide and thiobarbituric acid reactive substances, and volatile base nitrogen levels in cold (CSF) and hot (HSF) smoked fillets covered with or without extract and stored for 1, 20, and 90 days compared to fresh fillets (FF). Saturated and monounsaturated fatty acids exhibited a significant increase in FF and CSF and HSF covered with or without extract. The total polyunsaturated fatty acids revealed a significant decrease in FF and CSF and HSF with or without extract. Therefore, cold and hot smoking and polyphenol extract improved the biochemical quality and storage shelf-life of fillets for 90 days at 0-4 °C.Se examinaron los efectos del ahumado en frío y en caliente y la adición de extracto de polifenoles de Dunaliella salina sobre la calidad bioquímica y la vida útil de filetes de Sander lucioperca almacenados durante 90 días a 0-4 °C. Los resultados mostraron un aumento significativo en los contenidos de proteínas, lípidos, ácidos grasos libres y 1,1-difenil-2-picrilhidrazilo, y una disminución en las sustancias reactivas de peróxido y ácido tiobarbitúrico, y los niveles de nitrógeno básico volátil en frío (LCR) y caliente (HSF) de filetes ahumados cubiertos con o sin extracto y almacenados durante 1, 20 y 90 días en comparación con los filetes frescos (FF). Los ácidos grasos saturados y monoinsaturados exhibieron un aumento significativo en FF y LCR y HSF cubiertos con o sin extracto. Los ácidos grasos poliinsaturados totales revelaron una disminución significativa en FF y CSF y HSF con o sin extracto. Por lo tanto, el ahumado en frío y en caliente y el extracto de polifenoles mejoraron la calidad bioquímica y la vida útil durante el almacenamiento de los filetes durante 90 días a 0-4 °C

Anthropometric and physical characteristics allow differentiation of young female volleyball players according to playing position and level of expertise

The aim of our study was to determine the differences in some anthropometric and physical performance variables of young Croatian female volleyball players (aged 13 to 15) in relation to playing position (i.e., independent variable) and performance level within each position (i.e., independent variable). Players were categorized according to playing position (i.e., role) as middle blockers (n=28), opposite hitters (n=41), passer-hitters (n=54), setters (n=30), and liberos (n=28). Within each position, players were divided into a more successful group and a less successful group according to team ranking in the latest regional championship and player quality within the team. Height and body mass, somatotype by the Heath-Carter method, and four tests of lower body power, speed, agility and upper body power (i.e., dependent variables) were assessed. Players in different positions differed significantly in height and all three somatotype components, but no significant differences were found in body mass, body mass index or measured physical performance variables. Players of different performance level differed significantly in both anthropometric and physical performance variables. Generally, middle blockers were taller, more ectomorphic, less mesomorphic and endomorphic, whereas liberos were shorter, less ectomorphic, more mesomorphic and endomorphic than players in other positions. More successful players in all positions had a lower body mass index, were less mesomorphic and endomorphic, and more ectomorphic than less successful players. Furthermore, more successful players showed better lower body power, speed, agility and upper body power. The results of this study can potentially provide coaches with useful indications about the use of somatotype selection and physical performance assessment for talent identification and development

Rezultati dela Ambulante za bolezni dojk pri Splošni bolnišnici Trbovlje

V članku avtorji prikazujejo rezultate dela Ambulante za bolezni dojk pri ginekološko-porodniškem oddelku Splošne bolnišnice Trbovlje. V devetih letih dela ambulante za bolezni dojk so opravili več kot 10.000 pregledov. Na dodatne preglede so napotili 171 pregledanih žensk. Pri 78 (47 %) napotenih ženskah je bil potrjen rak dojke. Pri 15 (19,2 %) je bil rak dojke v začetnem, neinvazivnem stadiju, pri 63 (80,7 %) pa v invazivnem stadiju bolezni. Pri 24 (30,7 %) so bile metastaze že v regionalnih bezgavkah, pri 48 (61,54 %) bolnicah pa takih metastaz niso ugotovili. Za 5 (6,4 %) bolnic ni podatkov, ugotovili so en primer vnetnega raka. Ugotavljajo 9 intervalnih rakov, kar je 0,09 % od vseh pregledanih žensk oz. 11,3 % ugotovljenih rakov. Ugotavljajo, da je v prikazanem vzorcu rak dojke zelo pogost že pred 50. letom starosti28,2 % primerov je bilo v starostni skupini 30–49 let, v skupini 50–69 let pa 47,4 % vseh za rakom na dojki obolelih žensk. To pomeni, da je v starostni skupini 30–69 let za rakom dojke zbolelo 75,6 % vseh obolelih. Ugotavljajo tudi pomanjkljivo povezavo med družinskimi zdravniki, Onkološkim inštitutom in ambulanto za bolezni dojk