Structural Variations of the Cell Wall Precursor Lipid II and Their Influence on Binding and Activity of the Lipoglycopeptide Antibiotic Oritavancin

Oritavancin is a semisynthetic derivative of the glycopeptide antibiotic chloroeremomycin with activity against Gram-positive pathogens, including vancomycin-resistant staphylococci and enterococci. Compared to vancomycin, oritavancin is characterized by the presence of two additional residues, a hydrophobic 4′-chlorobiphenyl methyl moiety and a 4-epi-vancosamine substituent, which is also present in chloroeremomycin. Here, we show that oritavancin and its des-N-methylleucyl variant (des-oritavancin) effectively inhibit lipid I- and lipid II-consuming peptidoglycan biosynthesis reactions in vitro. In contrast to that for vancomycin, the binding affinity of oritavancin to the cell wall precursor lipid II appears to involve, in addition to the d-Ala-d-Ala terminus, other species-specific binding sites of the lipid II molecule, i.e., the crossbridge and d-isoglutamine in position 2 of the lipid II stem peptide, both characteristic for a number of Gram-positive pathogens, including staphylococci and enterococci. Using purified lipid II and modified lipid II variants, we studied the impact of these modifications on the binding of oritavancin and compared it to those of vancomycin, chloroeremomycin, and des-oritavancin. Analysis of the binding parameters revealed that additional intramolecular interactions of oritavancin with the peptidoglycan precursor appear to compensate for the loss of a crucial hydrogen bond in vancomycin-resistant strains, resulting in enhanced binding affinity. Augmenting previous findings, we show that amidation of the lipid II stem peptide predominantly accounts for the increased binding of oritavancin to the modified intermediates ending in d-Ala-d-Lac. Corroborating our conclusions, we further provide biochemical evidence for the phenomenon of the antagonistic effects of mecA and vanA resistance determinants in Staphylococcus aureus, thus partially explaining the low frequency of methicillin-resistant S. aureus (MRSA) acquiring high-level vancomycin resistance.     

Uric Acid and Cardiovascular Events: A Mendelian Randomization Study

Obesity and diets rich in uric acid–raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid–regulating single nucleotide polymorphisms. Causal odds ratios and causal hazard ratios (HRs) were calculated using a two-stage regression estimate with the GRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death.     

Designing and Testing an Inventory for Measuring Social Media Competency of Certified Health Education Specialists

Background

Social media can promote healthy behaviors by facilitating engagement and collaboration among health professionals and the public. Thus, social media is quickly becoming a vital tool for health promotion. While guidelines and trainings exist for public health professionals, there are currently no standardized measures to assess individual social media competency among Certified Health Education Specialists (CHES) and Master Certified Health Education Specialists (MCHES).

Objective

The aim of this study was to design, develop, and test the Social Media Competency Inventory (SMCI) for CHES and MCHES.

Methods

The SMCI was designed in three sequential phases: (1) Conceptualization and Domain Specifications, (2) Item Development, and (3) Inventory Testing and Finalization. Phase 1 consisted of a literature review, concept operationalization, and expert reviews. Phase 2 involved an expert panel (n=4) review, think-aloud sessions with a small representative sample of CHES/MCHES (n=10), a pilot test (n=36), and classical test theory analyses to develop the initial version of the SMCI. Phase 3 included a field test of the SMCI with a random sample of CHES and MCHES (n=353), factor and Rasch analyses, and development of SMCI administration and interpretation guidelines.

Results

Six constructs adapted from the unified theory of acceptance and use of technology and the integrated behavioral model were identified for assessing social media competency: (1) Social Media Self-Efficacy, (2) Social Media Experience, (3) Effort Expectancy, (4) Performance Expectancy, (5) Facilitating Conditions, and (6) Social Influence. The initial item pool included 148 items. After the pilot test, 16 items were removed or revised because of low item discrimination (r<.30), high interitem correlations (Ρ>.90), or based on feedback received from pilot participants. During the psychometric analysis of the field test data, 52 items were removed due to low discrimination, evidence of content redundancy, low R-squared value, or poor item infit or outfit. Psychometric analyses of the data revealed acceptable reliability evidence for the following scales: Social Media Self-Efficacy (alpha=.98, item reliability=.98, item separation=6.76), Social Media Experience (alpha=.98, item reliability=.98, item separation=6.24), Effort Expectancy(alpha =.74, item reliability=.95, item separation=4.15), Performance Expectancy (alpha =.81, item reliability=.99, item separation=10.09), Facilitating Conditions (alpha =.66, item reliability=.99, item separation=16.04), and Social Influence (alpha =.66, item reliability=.93, item separation=3.77). There was some evidence of local dependence among the scales, with several observed residual correlations above |.20|.

Conclusions

Through the multistage instrument-development process, sufficient reliability and validity evidence was collected in support of the purpose and intended use of the SMCI. The SMCI can be used to assess the readiness of health education specialists to effectively use social media for health promotion research and practice. Future research should explore associations across constructs within the SMCI and evaluate the ability of SMCI scores to predict social media use and performance among CHES and MCHES.     

Attention interference for emotional stimuli in cardiac interoceptive awareness

Previous research has shown that individuals with good perception of cardiac signals, referred to as cardiac interoceptive awareness, experience emotions more intensely. To investigate if emotional experience in high cardiac interoceptive awareness arises from biases in attention, we compared the performance of participants with high versus regular cardiac interoceptive awareness in an emotional Stroop task. Participants with high cardiac interoceptive awareness showed attention interference for negative words, whereas participants with regular cardiac interoceptive awareness showed attention facilitation for positive words. Our data provide further evidence for the emotion information process associated with cardiac interoceptive awareness. The results support the notion that better access to cardiac changes accompanying negative emotional conditions results in automatic vigilance for negative information and may interfere with cognitive processing.     

Human stem cell models of neurodegeneration: a novel approach to study mechanisms of disease development

The number of patients with neurodegenerative diseases is increasing significantly worldwide. Thus, intense research is being pursued to uncover mechanisms of disease development in an effort to identify molecular targets for therapeutic intervention. Analysis of postmortem tissue from patients has yielded important histological and biochemical markers of disease progression. However, this approach is inherently limited because it is not possible to study patient neurons prior to degeneration. As such, transgenic and knockout models of neurodegenerative diseases are commonly employed. While these animal models have yielded important insights into some molecular mechanisms of disease development, they do not provide the opportunity to study mechanisms of neurodegeneration in human neurons at risk and thus, it is often difficult or even impossible to replicate human pathogenesis with this approach. The generation of patient-specific induced pluripotent stem (iPS) cells offers a unique opportunity to overcome these obstacles. By expanding and differentiating iPS cells, it is possible to generate large numbers of functional neurons in vitro, which can then be used to study the disease of the donating patient. Here, we provide an overview of human stem cell models of neurodegeneration using iPS cells from patients with Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, spinal muscular atrophy and other neurodegenerative diseases. In addition, we describe how further refinements of reprogramming technology resulted in the generation of patient-specific induced neurons, which have also been used to model neurodegenerative changes in vitro.