Eliciting the Low-Activity Aldehyde Dehydrogenase Asian Phenotype by an Antisense Mechanism Results in an Aversion to Ethanol

A mutation in the gene encoding for the liver mitochondrial aldehyde dehydrogenase (ALDH2–2), present in some Asian populations, lowers or abolishes the activity of this enzyme and results in elevations in blood acetaldehyde upon ethanol consumption, a phenotype that greatly protects against alcohol abuse and alcoholism. We have determined whether the administration of antisense phosphorothioate oligonucleotides (ASOs) can mimic the low-activity ALDH2–2 Asian phenotype. Rat hepatoma cells incubated for 24 h with an antisense oligonucleotide (ASO-9) showed reductions in ALDH2 mRNA levels of 85% and ALDH2 (half-life of 22 h) activity of 55% equivalent to a >90% inhibition in ALDH2 synthesis. Glutamate dehydrogenase mRNA and activity remained unchanged. Base mismatches in the oligonucleotide rendered ASO-9 virtually inactive, confirming an antisense effect. Administration of ASO-9 (20 mg/kg/day for 4 d) to rats resulted in a 50% reduction in liver ALDH2 mRNA, a 40% inhibition in ALDH2 activity, and a fourfold (P < 0.001) increase in circulating plasma acetaldehyde levels after ethanol (1 g/kg) administration. Administration of ASO-9 to rats by osmotic pumps led to an aversion (−61%, P < 0.02) to ethanol. These studies provide a proof of principle that specific inhibition of gene expression can be used to mimic the protective effects afforded by the ALDH2–2 phenotype

More than Body Composition: A Darwinian Theory of Somatotype, Applied to a DII Track and Field Outdoor Season

International Journal of Exercise Science 17(4): 1-12, 2024. This study presents somatotype data on a team sport with chronic and diverse sporting demands. The aims were to (1) characterize a somatotype profile for Division II (DII) track and field athletes (n=54) by sex, class, and events; (2) determine if somatotype changed across the season; (3) determine if changes differed based on class or sex; and, (4) assess potential differences in somatotype between sexes. Methods: Anthropometrics (height, weight, body composition, somatotype) were evaluated after a competitive indoor season and immediately before the outdoor conference championships (41 days). Body measurements were assessed using a bioelectrical impedance analysis device, skinfold assessment, boney breadths, and limb girths. Descriptive statistics are provided as well as results from two-way ANOVAs which evaluate differences in actual and change scores across sex and class. Results: Our DII track and field athletes were primarily endomorphic (scores displayed as ENDO, MESO, ECTO, respectively). Males were found to be primarily ENDO-MESO somatotypes (4.7, 4.1, 3.0), while females were dominantly ENDO (7.7, 2.9, 2.9). Upperclass were more ENDO-MESO balanced compared with lowerclass (5.8, 3.8, 2.8 vs 6.0, 3.5, 3.0). When investigated based on sex, class level, and event, the groups were similar. There was no meaningful change to ECTO scores across the season for males or females. Female athletes improved ENDO scores (-0.89%) and males and females improved MESO scores (14.29% and 5.29%, respectively), indicating adaptations can be accomplished despite the chronic demands of a competitive season. Conclusion: Our research offers practitioners information about the potential changes they may expect across a competitive track and field season

Correlates of Depressive and Anxiety Symptoms in Young Adults with Spina Bifida *

Objective Based on social ecological theory, this study was designed to examine the unique relationships between multi-level ecological factors and psychological symptoms in young adults with spina bifida (SB). Method A sample of 61 individuals with SB, 18–25 years of age, completed standardized self-report measures of attitude toward SB, satisfaction with family functioning, Chronic Care Model (CCM) services, and depressive and anxiety symptoms. A chart review yielded SB clinical data. Results High rates of depressive and anxiety symptoms were found. Hierarchical regression analysis identified the proximal individual (attitude toward SB) and family (satisfaction with family functioning) factors as more strongly related to depressive symptoms than the distal healthcare system factor (CCM services). Self-reported pain was the only ecological factor associated with anxiety symptoms. Conclusions Study findings provide a potential foundation for multi-factor screening of young adults with SB at risk for psychological symptoms

The Major Yolk Protein Vitellogenin Interferes with the Anti-Plasmodium Response in the Malaria Mosquito Anopheles gambiae

Functional gene analysis in malaria mosquitoes reveals molecules underpinning the trade-off between efficient reproduction and the antiparasitic response

Interaction of Macrolide Antibiotics with Intestinally Expressed Human and Rat Organic Anion-Transporting Polypeptides

The macrolide antibiotics azithromycin and clarithromycin are large molecular weight compounds that exhibit moderate to excellent oral bioavailability in preclinical species and humans. Previous concomitant dosing studies in rats using rifamycin SV, a general organic anion-transporting polypeptide (OATP) inhibitor, suggested that the high oral absorption of azithromycin and clarithromycin may be caused by facilitative uptake by intestinal Oatps. In this study, we used OATP/Oatp-expressing cells to investigate the interaction of macrolides with rat Oatp1a5, human OATP1A2, and human/rat OATP2B1/Oatp2b1. These experiments showed that azithromycin and clarithromycin were potent inhibitors of rat Oatp1a5-mediated taurocholate uptake with apparent inhibitor constant (Ki) values of 3.3 and 2.4 μM, respectively. The macrolides functioned as noncompetitive inhibitors but were not transport substrates for rat Oatp1a5, as assessed by direct uptake measurements of radiolabeled azithromycin and clarithromycin. cis-Inhibition and direct uptake studies further showed that azithromycin and clarithromycin were only very weak inhibitors and not substrates for human OATP1A2 and human/rat OATP2B1/Oatp2b1. In summary, these results indicate that the macrolides azithromycin and clarithromycin potently inhibit rat Oatp1a5 but do not significantly interact with OATP1A2 and OATP2B1/Oatp2b1. These intestinally expressed OATP/Oatp(s) are not responsible for the postulated facilitative uptake of azithromycin and clarithromycin, and alternative facilitative pathways must exist for their intestinal absorption

Ectromelia Virus Disease Characterization in the BALB/c Mouse: A Surrogate Model for Assessment of Smallpox Medical Countermeasures

In 2007, the United States– Food and Drug Administration (FDA) issued guidance concerning animal models for testing the efficacy of medical countermeasures against variola virus (VARV), the etiologic agent for smallpox. Ectromelia virus (ECTV) is naturally-occurring and responsible for severe mortality and morbidity as a result of mousepox disease in the murine model, displaying similarities to variola infection in humans. Due to the increased need of acceptable surrogate animal models for poxvirus disease, we have characterized ECTV infection in the BALB/c mouse. Mice were inoculated intranasally with a high lethal dose (125 PFU) of ECTV, resulting in complete mortality 10 days after infection. Decreases in weight and temperature from baseline were observed eight to nine days following infection. Viral titers via quantitative polymerase chain reaction (qPCR) and plaque assay were first observed in the blood at 4.5 days post-infection and in tissue (spleen and liver) at 3.5 days post-infection. Adverse clinical signs of disease were first observed four and five days post-infection, with severe signs occurring on day 7. Pathological changes consistent with ECTV infection were first observed five days after infection. Examination of data obtained from these parameters suggests the ECTV BALB/c model is suitable for potential use in medical countermeasures (MCMs) development and efficacy testing