Novel Feature for Catalytic Protein Residues Reflecting Interactions with Other Residues

Owing to their potential for systematic analysis, complex networks have been widely used in proteomics. Representing a protein structure as a topology network provides novel insight into understanding protein folding mechanisms, stability and function. Here, we develop a new feature to reveal correlations between residues using a protein structure network. In an original attempt to quantify the effects of several key residues on catalytic residues, a power function was used to model interactions between residues. The results indicate that focusing on a few residues is a feasible approach to identifying catalytic residues. The spatial environment surrounding a catalytic residue was analyzed in a layered manner. We present evidence that correlation between residues is related to their distance apart most environmental parameters of the outer layer make a smaller contribution to prediction and ii catalytic residues tend to be located near key positions in enzyme folds. Feature analysis revealed satisfactory performance for our features, which were combined with several conventional features in a prediction model for catalytic residues using a comprehensive data set from the Catalytic Site Atlas. Values of 88.6 for sensitivity and 88.4 for specificity were obtained by 10fold crossvalidation. These results suggest that these features reveal the mutual dependence of residues and are promising for further study of structurefunction relationship

Barriers to formal healthcare utilisation among poor older people under the livelihood empowerment against poverty programme in the Atwima Nwabiagya District of Ghana

Abstract: Background: Even though there is a growing literature on barriers to formal healthcare use among older people, little is known from the perspective of vulnerable older people in Ghana. Involving poor older people under the Livelihood Empowerment Against Poverty (LEAP) programme, this study explores barriers to formal healthcare use in the Atwima Nwabiagya District of Ghana. Methods: Interviews and focus group discussions were conducted with 30 poor older people, 15 caregivers and 15 formal healthcare providers in the Atwima Nwabiagya District of Ghana. Data were analysed using the thematic analytical framework, and presented based on an a posteriori inductive reduction approach. Results: Four main barriers to formal healthcare use were identified: physical accessibility barriers (poor transport system and poor architecture of facilities), economic barriers (low income coupled with high charges, and non-comprehensive nature of the National Health Insurance Scheme [NHIS]), social barriers (communication/language difficulties and poor family support) and unfriendly nature of healthcare environment barriers (poor attitude of healthcare providers). Conclusions: Considering these barriers, removing them would require concerted efforts and substantial financial investment by stakeholders. We argue that improvement in rural transport services, implementation of free healthcare for poor older people, strengthening of family support systems, recruitment of language translators at the health facilities and establishment of attitudinal change programmes would lessen barriers to formal healthcare use among poor older people. This study has implications for health equity and health policy framework in Ghana

A Low T Regulatory Cell Response May Contribute to Both Viral Control and Generalized Immune Activation in HIV Controllers

HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127dim), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV-infected “non-controllers” with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (P = 0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (P≤0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion

Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy

RATIONALE: Pro-cognitive agents for chronic psychotic disorders (CPDs) might be detected via experimental medicine models, in which neural targets engaged by the drug predict sensitivity to the drug’s pro-cognitive effects. OBJECTIVE: This study aims to use an experimental medicine model to test the hypothesis that “target engagement” predicts pro-cognitive effects of the NMDA antagonist, memantine (MEM), in CPDs. METHODS: MATRICS Consensus Cognitive Battery (MCCB) performance was assessed in CPD (n = 41) and healthy subjects (HS; n = 41) in a double-blind, randomized cross-over design of acute (single dose) MEM (placebo vs. 10 or 20 mg p.o.). Measures of prepulse inhibition (PPI) and mismatch negativity previously reported from this cohort substantiated target engagement. Biomarkers predicting MEM neurocognitive sensitivity were assessed. RESULTS: Testing confirmed MCCB deficits associated with CPD diagnosis, age, and anticholinergic exposure. MEM (20 mg p.o.) reduced MCCB performance in HS. To control for significant test order effects, an “order-corrected MEM effect” (OCME) was calculated. In CPD subjects, greater age, positive MEM effects on PPI, and SNP rs1337697 (within the ionotropic NMDA receptor gene, GRIN3A) predicted greater positive OCME with 20 mg MEM. CONCLUSIONS: An experimental medicine model to assess acute pro-cognitive drug effects in CPD subjects is feasible but not without challenges. A single MEM 20 mg dose had a negative impact on neurocognition among HS. In CPD patients, age, MEM effects on PPI, and rs1337697 predicted sensitivity to the neurocognitive effects of MEM. Any potential clinical utility of these predictive markers for pro-cognitive effects of MEM in subgroups of CPD patients cannot be inferred without a validating clinical trial