Real-time imaging of Rab3a and Rab5a reveals differential roles in presynaptic function

We investigated the roles of two Rab-family proteins, Rab3a and Rab5a, in hippocampal synaptic transmission using real-time fluorescence imaging. During synaptic activity, Rab3a dissociated from synaptic vesicles and dispersed into neighbouring axonal regions. Dispersion required calcium-dependent exocytosis and was complete before the entire vesicle pool turned over. In contrast, even prolonged synaptic activity produced limited dispersion of Rab5a. A GTPase-deficient mutant, Rab3a (Q81L), dispersed more slowly than wild-type Rab3a, and decreased the rate of exocytosis and the size of the recycling pool of vesicles. While overexpression of Rab3a did not affect vesicle recycling, overexpression of Rab5a reduced the recycling pool size by 50%. We propose that while Rab3a preferentially associates with recycling synaptic vesicles and modulates their trafficking, Rab5a is largely excluded from recycling vesicles.     

Who Can I Ask? Who Would I Tell? An Egocentric Network Analysis Among a Sample of Women At-Risk to Explore Anticipated Advice Seeking and Disclosure Around Pre-exposure Prophylaxis (PrEP)

AIDS and Behavior - Pre-Exposure Prophylaxis (PrEP) health campaigns invite women to talk with their provider, partner, and peers about PrEP, though they do not offer specific guidance about who...     

Cognitive-behavioral therapy versus other therapies: Redux

Despite the evidence suggesting that all treatments intended to be therapeutic are equally efficacious, the conjecture that one form of treatment, namely cognitive-behavioral therapy (CBT), is superior to all other treatment persists. The purpose of the current study was to (a) reanalyze the clinical trials from an earlier meta-analysis that compared CBT to ‘other therapies’ for depression and anxiety (viz., Tolin, 2010) and (b) conduct a methodologically rigorous and comprehensive meta-analysis to determine the relative efficacy of CBT and bona fide non-CBT treatments for adult anxiety disorders. Although the reanalysis was consistent with the earlier meta-analysis' findings of small to medium effect sizes for disorder-specific symptom measures, the reanalysis revealed no evidence for the superiority of CBT for depression and anxiety for outcomes that were not disorder-specific. Following the reanalysis, a comprehensive anxiety meta-analysis that utilized a survey of 91 CBT experts from the Association of Behavioral and Cognitive Therapists (ABCT) to consensually identify CBT treatments was conducted. Thirteen clinical trials met the inclusion criteria. There were no differences between CBT treatments and bona fide non-CBT treatments across disorder-specific and non-disorder specific symptom measures. These analyses, in combination with previous meta-analytic findings, fail to provide corroborative evidence for the conjecture that CBT is superior to bona fide non-CBT treatments.     

Cyclin-dependent kinase inhibitors p21 and p27 function as critical regulators of liver regeneration following 90% hepatectomy in the rat

BACKGROUNDLiver reduction is the main curative treatment for primary liver cancer, but its use remains limited as liver regeneration requires a minimum of 30% functional parenchyma. AIMTo study the dynamics of the liver regeneration process and consequent behavior of cell cycle regulators in rats after extended hepatectomy (90%) and postoperative glucose infusions.METHODSPost-hepatectomy liver failure was triggered in 84 Wistar rats by reducing their liver mass by 90%. The animals received a post-operative glucose infusion and were randomly assigned to two groups: One to investigate the survival rate and the other for biochemical analyses. Animals that underwent laparotomy or 70% hepatectomy were used as controls. Blood and liver samples were collected on postoperative days 1 to 7. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, and western blotting. RESULTSPostoperative mortality after major resection reached 20% and 55% in the first 24 h and 48 h, respectively, with an overall total of 70% 7 d after surgery. No apparent signs of apoptotic cell death were detected in the extended hepatectomy rat livers, but hepatocytes displaying a clear cytoplasm and an accumulation of hyaline material testified to changes affecting their functional activities. Liver regeneration started properly, as early events initiating cell proliferation occurred within the first 3 h, and the G1 to S transition was detected in less than 12 h. However, a rise in p27 (Kip1) followed by p21 (Waf1/Cip1) cell cycle inhibitor levels led to a delayed S phase progression and mitosis. Overall, liver regeneration in rats with a 90% hepatectomy was delayed by 24 h and associated with a delayed onset and lower peak magnitude of hepatocellular deoxyribonucleic acid synthesis. CONCLUSIONThis work highlights the critical importance of the cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family in regulating the liver regeneration timeline following extended hepatectomy.     

Telomere maintenance and telomerase activity are differentially regulated in asexual and sexual worms

In most sexually reproducing animals, replication and maintenance of telomeres occurs in the germ line and during early development in embryogenesis through the use of telomerase. Somatic cells generally do not maintain telomere sequences, and these cells become senescent in adults as telomeres shorten to a critical length. Some animals reproduce clonally and must therefore require adult somatic mechanisms for maintaining their chromosome ends. Here we study the telomere biology of planarian flatworms with apparently limitless regenerative capacity fueled by a population of highly proliferative adult stem cells. We show that somatic telomere maintenance is different in asexual and sexual animals. Asexual animals maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual animals only achieve telomere elongation through sexual reproduction. We demonstrate that this difference is reflected in the expression and alternate splicing of the protein subunit of the telomerase enzyme. Asexual adult planarian stem cells appear to maintain telomere length over evolutionary timescales without passage through a germ-line stage. The adaptations we observe demonstrate indefinite somatic telomerase activity in proliferating stem cells during regeneration or reproduction by fission, and establish planarians as a pertinent model for studying telomere structure, function, and maintenance.     

Influence of antithymocyte globulin treatment of brain‐dead organ donor on inflammatory response in cardiac grafts: an experimental study in mice

The expression of proinflammatory cytokines in donor hearts after antithymocyte globulin (ATG) treatment given prior to organ removal was evaluated to analyze changes in inflammatory response. Adult female OF‐1 mice were randomized into brain death (BD) groups (BD Control, BD ATG) with or without treatment, and Controls (Control, ATG). BD induction was performed through gradual inflation of an intracranial positioned balloon catheter. At the end of a 6‐h observation period, ATG (1 mg/kg BW) was given intravenously. After 45 min, the donor hearts were removed. Proinflammatory markers IL‐2 and IL‐6 were examined using ELISA and immunohistochemistry staining. After single administration of ATG, the inflammatory reaction in the myocardium showed a significant reduction in IL‐2 expression (BD Control vs. BD ATG, P = 0.033). Our investigation showed expected increase in proinflammatory mediators after BD. This increase was abolished by single infusion of ATG, indicated by significant reduction in IL‐2 levels in the myocardium. We observed a reduction of IL‐6 deposition in media cells in ATG‐treated specimens. Further research is necessary to evaluate the role of ATG in donor management considering a potentially positive effect of ATG on IL‐2‐directed inflammatory response and possible reduction of IL‐6‐mediated vascular changes.     

Women's Perspectives on Female-Initiated Barrier Methods for the Prevention of HIV in the Context of Methamphetamine Use and Partner Violence

BackgroundFemale-initiated barrier methods for the prevention of HIV may be an effective alternative for drug-using women who are unable to negotiate safe sex, often as a result of physical and/or sexual partner violence.MethodsUtilizing a SAVA (substance abuse, violence, and AIDS) syndemic framework, we qualitatively examined perspectives on female condoms and vaginal microbicides among 18 women with histories of methamphetamine abuse and partner violence in San Diego, California.FindingsMost women were not interested in female condoms owing to perceived discomfort, difficulty of insertion, time-intensive effort, and unappealing appearance. Alternatively, most women viewed vaginal microbicides as a useful method. Positive aspects included convenience, ability to disguise as a lubricant, and a sense of control and empowerment. Concerns included possible side effects, timing of application, and unfavorable characteristics of the gel. Acceptability of female-initiated barrier methods was context dependent (i.e., partner type, level of drug use and violence that characterized the sexual relationship).ConclusionsFindings indicate that efforts are needed to address barriers identified for vaginal microbicides to increase its uptake in future HIV prevention trials and marketing of future Food and Drug Administration-approved products. Strategies should address gender-based inequalities (e.g., partner violence) experienced by drug-using women and promote female empowerment. Education on female-initiated barrier methods is also needed for women who use drugs, as well as health care providers and other professionals providing sexual health care and contraception to women with histories of drug use and partner violence.     

IL-9 exerts biological function on antigen-experienced murine T cells and exacerbates colitis induced by adoptive transfer

IL-9 is involved in various T cell-dependent inflammatory models including colitis, encepahlitis, and asthma. However, the regulation and specificity of IL-9 responsiveness by T cells during immune responses remains poorly understood. Here, we addressed this question using two different models: experimental colitis induced by transfer of naive CD4⁺CD45RB^high T cells into immunodeficient mice, and OVA-specific T cell activation. In the colitis model, constitutive IL-9 expression exacerbated inflammation upon transfer of CD4⁺CD45RB^high T cells from WT but not from Il9r^−/− mice, indicating that IL-9 acts directly on T cells. Suprisingly, such naïve CD4⁺CD45RB^high T cells failed to express the Il9r or respond to IL-9 in vitro, in contrast with CD4⁺CD45RB^low T cells. By using OVA-specific T cells, we observed that T cells acquired the capacity to respond to IL-9 along with CD44 upregulation, after long-lasting (5 to 12 days) in vivo antigenic stimulation. Il9r expression was associated with Th2 and Th17 phenotypes. Interestingly, in contrast to the IL-2 response, antigen restimulation downregulated IL-9 responsiveness. Taken together, our results demonstrate that IL-9 does not act on naïve T cells but that IL-9 responsiveness is acquired by CD4⁺ T cells after in vivo activation and acquisition of memory markers such as CD44.     

Dietary Quality of Women of Reproductive Age in Low-Income Settings: A Cross-Sectional Study in Kyrgyzstan

Dietary diversity and adequate nutrient intake are essential for conducting a healthy life. However, women in low-income settings often face difficulties in ensuring dietary quality. This research assessed relationships between the dietary diversity, nutrient adequacy, and socio-economic factors among women of reproductive age (WRA) in Kyrgyzstan. A cross-sectional study was undertaken in four locations, including two rural and two urban areas in the north and south of Kyrgyzstan. A survey with pre-coded and open-ended questions was employed during the interviews of 423 WRAs aged 18–49. Data collection was conducted in March–May 2021. The average value body mass index (BMI) of WRA was 24.2 ± 4.6 kg/m². The dietary diversity score (DDS) was higher among rural women (common language effect size) cles = 0.67, adjusted p < 0.001) in the northern region (cles = 0.61, p < 0.05) who have cropland (cles = 0.60, p < 0.001) and a farm animal (cles = 0.60, p < 0.05). Mean nutrient adequacy ratio (NAR) was below 1 in most micronutrients, whereas thiamine, riboflavin, vitamins B6 and C, folic acid, calcium, and magnesium were even lower than 0.5. Women with a kitchen garden or a cropland had better NAR energy (cles = 0.57), NAR carbohydrate (cles = 0.60), NAR fiber (cles = 0.60), NAR vitamin B1 (cles = 0.53), and NAR folic acid (cles = 0.54). Respondents who receive remittances and a farm animal have better NARs for energy, carbohydrates, fiber, vitamin B1, folic acid, iron, zinc, and mean adequacy ratio for 16 nutrients (MAR 16) than those who do not. Education and income have a negative correlation with dietary quality. This study contributes to the limited literature on the quality of diets in Kyrgyzstan. Hidden hunger and undernutrition are a severe problem among WRA in low-income settings. Recommendations are including study programs in nutrition, teaching households farming practices, and raising awareness on adequate nutrition.