Expanding the Membership of a Stem Cell-Related Blood Transcriptional Module Containing Biomarkers of Cardiovascular Function by a Novel “Bottom-up” Bioinformatics Approach

Background: The circulating stem/progenitor cells (CSPCs) system comprises a variety of rare cells with mixed primitive and differentiation characteristics. So far, this system has eluded traditional methods of characterization. We recently showed that quantitative real-time PCR, the most sensitive and reliable gene expression analysis tool available, consistently detects a comprehensive battery of gene markers in all tested peripheral blood mononuclear cell samples from adult human subjects. Moreover, network representation of these genes’ co-variation across samples organizes them into two modules of the hierarchical transcriptional network. One module, termed the ‘cardiovascular module’ (CVM), was inversely related with the age, vascular stiffness and blood pressure of healthy blood donors, and highly depressed (but paradoxically more compact) in hypertensive patients. However, the targeted definition of CVM composition required an expansion to include more potential members. These could be extracted from high-throughput, unbiased methods such as gene microarrays. Approach and Results: We verified the ability of Affymetrix gene chips, available on public databases, to sense the CVM-associated rare transcripts, and found that only two (out of 15) were detectable. This oriented us towards gene chips hybridized with samples from children, where the frequency of CSPCs is known to be higher, and found that 5 CVM members were detectable. Implementing the ‘guilt-by-association’ (GBA) principle, we used these markers as ‘seed genes’ to generate co-variation lists. These were organized as network ‘neighborhoods’ which were then fused in increasingly higher gene communities that maintained their modular organization around their hub (i.e., ‘seed’) gene. This ‘bottom-up’ approach to reconstitute a network is both original and promising, as it reveals a large crop of candidate genes with meaningful known roles in the cardiovascular field (currently being validated by qRT-PCR). We also compared our method with the traditional “top-down” Weighted Gene Correlation Network Analysis (WGCNA) method, as well as a direct ‘Clique Mining’ protocol applied to an expanded list of stemness genes. Neither method produced modules enriched in CVM genes, even when the source data were blood samples from patients recovering from burn injury, a condition expected to stimulate CSPC release from bone marrow. However, the latter method did suggest the existence of a module containing the CVM gene Notch4 as being mobilized in burn patients, and one organized around OLR1/oxidized LDL receptor with a more widespread occurrence. Conclusions: Here, we demonstrate a new method to expand a transcriptional network by detection of candidate members with particular relevance for the analysis of rare transcripts, such as CSPC markers. This method has the potential to be applied for cell isolation, diagnostic, prognostic, and treatment purposes in a variety of CSPC and other cell-dependent medical conditions.No embargoAcademic Major: Biolog

The Right to Stay Put: City Garden Montessori School and Neighborhood Change

This report presents findings from the Listening Project. A collaboration among St. Louis’ Forest Park Southeast Neighborhood Association, the Brown School of Social Work, and the Sam Fox School of Design and Visual Arts at Washington University, the project engaged underrepresented voices in the Forest Park Southeast, Botanical Heights, Tiffany, and Shaw neighborhoods neighborhood to identify priorities for community improvement

Nonverbal Synchrony Between Dyads as a Function of Protective Versus Acquisitive Self-Monitoring

Synchrony is coordinated nonverbal behavior between two individuals (Ramseyer & Tschacher, 2006). Dispositional differences in self-monitoring involves responsivity to others (Fuglestad & Snyder, 2010). Acquisitive self-monitoring entails responsivity for gain social/nonsocial rewards, whereas protective self-monitoring entails responsivity for avoiding social/nonsocial losses (Wilmot, 2015). We explored the connection between self-monitoring and nonverbal synchrony. Pairs of participants had 5-minute conversation on a non-controversial topic to control for the influence of affect on synchrony (Tschacher et al., 2014). We utilized Motion Energy Analysis and Windowed Crossed Correlation software to quantify nonverbal synchrony. Participants completed the 25-item Self-Monitoring Scale (Snyder, 1974), and responses were score or protective and acquisitive impression management motives (Wilmot et al, 2017). Dyad self-monitoring was calculated as the product of partners’ self-monitoring scores. Controlling for self-reported partner familiarity, separate regression analyses revealed that protective, β=+.21, p = .048, but not acquisitive, β=+.11, p = .287, self-monitoring reliably predicted nonverbal synchrony. These findings extend the literature on (a) synchrony by identifying individual differences in this process and (b) self-monitoring by illuminating the two-dimensional nature of this individual difference variable. Future research should further extend these literatures by examining moderator (e.g., relationship closeness) and mediating (e.g., state anxiety) variables

A Bioinformatics-Based Bottom-up Network Reconstruction Approach to Detect Stem Cell-Related Blood Biomarkers of Cardiovascular Damage and Repair

Health Professions - Laboratory/Cellular: 3rd Place (The Ohio State University Denman Undergraduate Research Forum)In peripheral blood there are very rare circulating stem/progenitor cells (CSPCs) with primitive characters and the capacity to differentiate into cardiovascular and other lineages. These cells are promising biomarkers of the organism’s resilience and of its ability to repair injuries. However, because of its complexity, the system of CSPCs has not yet been described by traditional methods in a coherent and simple enough manner to be clinically useful. In response to this limitation, we proposed the CSPC system could be directly assessed by gene expression analysis of peripheral blood mononuclear cells (PBMCs). Initially, 45 genes representing the most used markers of primitivity and differentiation were tested. Among these, 15 genes were organized as a module of the blood transcriptional network which inversely depended on age, blood pressure, and vascular stiffness of donors, as expected from CSPCs. To identify more members of this module, we analyzed 503 Affymetrix microarrays from public databases hybridized with RNA of normal human PBMCs from children (where the primitive genes were better expressed), adults, and burn victims (a response to an injury condition that is preferable to actual cardiovascular patients because of the lack of other risk factors which complicate the interpretation). Normalized data was analyzed by the bioinformatics co-variation method known as “guilt-by-association”. This approach identified 107 potential candidates from data collected from microarrays on healthy children, many having known roles associated with stemness, differentiation, angiogenesis, and/or cardiovascular diseases or repair. A larger study on adults was conducted, as well as studies involving burn injury (that induces massive mobilization of CSPCs) and pregnant women suffering from preeclampsia (a condition due to deficiencies in CSPCs), for comparison. In conclusion, we show how to expand a new, collective, systemic biomarker for the elusive CSPCs that could be used to track their response to injury and to identify patients at risk for developing, or already experiencing, cardiovascular diseases.Arts and Sciences Honors Undergraduate Research ScholarshipAcademic Major: BiologyAcademic Major: Electrical and Computer EngineeringAcademic Major: Neuroscienc

Racial Disparities in Student Debt: Evidence From the Refund to Savings Initiative

This brief provides evidence that low- and moderate-income (LMI) Black households accumulate significantly more debt in pursuit of a higher education than do LMI White students, even after using rigorous methods to account for race- and debt-related confounders. Using data from the Refund to Savings experiment, the authors find that LMI Black households accrued $7,721 more in student loan debt than their White counterparts did. This finding is crucial in light of the financial vulnerability of this population both before and after college. That vulnerability potentially contributes to diminished returns and exacerbates racial disparities in educational outcomes and wealth accumulation. The brief discusses policy remedies that can continue to enhance access to college for low-income minorities while ensuring equitable outcomes during and after college

Genetic Evaluation of Cardiomyopathy - a Heart Failure Society of America Practice Guideline

This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), this guidance has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, as high throughput sequencing is now feasible for clinical testing, and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to manage secondary and incidental sequence findings as recommended by the ACMG is provided

Is there a potential of misuse for venlafaxine and bupropion?

© 2018 Schifano and Chiappini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Objective: Traditionally, studies on the nonmedical use of pharmaceutical products have focused on controlled substances; e.g. opiates/opioids; and benzodiazepines. Although both bupropion and venlafaxine have been reported as being misused, only anecdotal reports have been made available so far. Hence, the European Monitoring Agency (EMA) Adverse Drug Reactions (ADRs), misuse/abuse/dependence and withdrawal, venlafaxine- and bupropion-related, database was here analyzed. Methods: All EMA spontaneous reports relating to venlafaxine (2005-2016) and bupropion (2003-2016) notifications were here analyzed, to provide a descriptive analysis by source, gender, age, and type of report. The UK-based, 2000-2016, Yellow Card Scheme pharmacovigilance database, bupropion and venlafaxine withdrawal reports were compared as well with those pertaining to fluoxetine and paroxetine. Results: Out of 20,720 (bupropion) and 47,516 (venlafaxine) total number of ADRs, some 2,232 (10.8%), and 4,071 (8.5%) misuse/abuse/dependence ADRs were respectively associated with bupropion and venlafaxine. Conversely, bupropion withdrawal-related ADRs were here reported in 299/20,720 (1.44%) cases and in 914/47,516 (1.92%) cases for venlafaxine. Overall, all bupropion and venlafaxine misuse-/abuse-/dependence- and withdrawal-ADRs were related to a respective number of 264 and 447 patients. According to the Proportional Reporting Ratio (PRR) computation, in comparison with venlafaxine bupropion resulted to be more frequently misused/abused (PRR: 1.50), but less frequently associated with both dependence (PRR: 0.92) and withdrawal (PRR: 0.77) issues. Yellow Card Scheme data suggested that paroxetine and venlafaxine, in comparison with fluoxetine and bupropion, were associated with higher number of withdrawal-related reports. Conclusions: The dopaminergic, stimulant-like, bupropion activities may be associated with its possible recreational value. Present data may confirm that the occurrence of a withdrawal syndrome may be a significant issue for venlafaxine-treated patients.Peer reviewedFinal Published versio

Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu-Natal, South Africa: implications for future treatment options

Article approval pendingDrug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy