The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

Transglutaminase activity in equine strongyles and its potential role in growth and development

Transglutaminases (E.C. 2.3.3.13) are a family of Ca2+-dependent enzymes that stabilize protein structure by catalyzing the formation of isopeptide bonds. A novel form of transglutaminase has been identified and characterized that seem to play an important role in growth, development, and molting in adult and larval stages of filarial nematodes. The aim of this study was to identify the ubiquitous nature of this enzyme in other nematodes and to measure its significance to larval growth, molting, and development. For this purpose, equine Strongylus spp. were used. Activity of this enzyme was identified in extracts of larvae and adults of Strongylus vulgaris, S. edentatus, Parascaris equorum and Cylicocyclus insigne. The significance of transglutaminase in the early growth and development of Strongylus vulgaris, S. edentatus and S. equinus was tested by adding specific inhibitors, monodansylcadaverine (MDC) or cystamine (CS), to in vitro cultures of third (L3) and fourth stage larvae (L4). The viability, molting and growth of these nematode species were affected by both inhibitors. Cystamine promoted abnormal development of Strongylus edentatus L3, resulting in an aberrant expansion of the anterior end. Addition of these inhibitors to cultures of L4 also reduced growth of the three species. The results indicated that transglutaminase is present in a wide array of nematode parasites and may be important in growth and development of their larval stages

Eficácia de vermífugos à base de avermectinas e milbemicinas utilizados há cinco anos em uma criação de eqüinos Efficacy of avermectins and milbemicins anthelmintics derivatives being used for five years in an equine farm

Avaliou-se a eficácia do controle parasitário com anti-helmínticos (AH) de largo espectro usados há mais de cinco anos, em um plantel eqüino da raça puro-sangue inglês, sob manejo semi-intensivo. Os animais foram tratados com Ivermectin (Eqvalan®) e Moxidectin (Equest®), por via oral. Durante o estudo, o número de ovos por grama de fezes (opg) manteve-se zero na maioria dos animais.<br>The efficacy of parasite control with broad spectrum anthelmintics, used for over five years on a Thoroughbred herd was evaluated. The animals were kept on semi-intensive pasture regimen. During this study the horses received Ivermectin (Eqvalan®) and Moxidectin (Equest®); both treatments were given orally. The epg number was zero for most animals troughout the trial

Prevalence of anthelmintic resistant cyathostomes on horse farms

Objective-To determine prevalence of anthelmintic resistance in cyathostome nematodes of horses in the southern United States. Design-Cross-sectional study. Animals-786 horses on 44 farms and stables in Georgia, South Carolina, Florida, Kentucky, and Louisiana. Procedure-Fecal egg count (FEC) reduction tests were performed on 44 large farms and stables. Horses on each farm were treated with an oral paste formulation of fenbendazole, oxibendazole, pyrantel pamoate, or ivermectin at recommended label dosages. A mixed linear model was fitted to the percentage reduction in FEC, accounting for differences among farms, states, ages, treatments, and treatment by state interactions. Results-By use of a conservative measure of resistance (< 80% reduction), the percentage of farms with anthelmintic-resistant cyathostomes was 977%, 0%, 53.5%, and 40.5% for fenbendazole, ivermectin, oxibendazole, and pyrantel pamoate, respectively. Mean percentage reductions in FEC for all farms were 24.8%, 99.9%, 73.8%, and 78.6% for fenbendazole, ivermectin, oxibendazole, and pyrantel pamoate, respectively. Pairwise contrasts between states for each treatment revealed that in almost all instances, there were no significant differences in results between states. Conclusions and Clinical Relevance-The prevalence of resistance found in this study was higher than that reported previously, suggesting that anthelmintic resistance in equine cyathostomes is becoming a major problem. Furthermore, data from these 5 southern states, which are geographically and physiographically distinct, were remarkably similar. This suggests that drug resistance in cyathostomes is highly prevalent throughout the entire southern United States and probably nationwide