High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis.

Background: The only available tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), has variable efficacy. New vaccines are therefore urgently needed. Why BCG fails is incompletely understood, and the tools used for early assessment of new vaccine candidates do not account for BCG variability. Taking correlates of risk of TB disease observed in human studies and back-translating them into mice to create models of BCG variability should allow novel vaccine candidates to be tested early in animal models that are more representative of the human populations most at risk. Furthermore, this could help to elucidate the immunological mechanisms leading to BCG failure. We have chosen the monocyte to lymphocyte (ML) ratio as a correlate of risk of TB disease and have back-translated this into a mouse model. Methods: Four commercially available, inbred mouse strains were chosen. We investigated their baseline ML ratio by flow cytometry; extent of BCG-mediated protection from M ycobacterium tuberculosis infection by experimental challenge; vaccine-induced interferon gamma (IFNγ) response by ELISPOT assay; and tissue distribution of BCG by plating tissue homogenates. Results: The ML ratio varied significantly between A/J, DBA/2, C57Bl/6 and 129S2 mice. A/J mice showed the highest BCG-mediated protection and lowest ML ratio, while 129S2 mice showed the lowest protection and higher ML ratio. We also found that A/J mice had a lower antigen specific IFNγ response than 129S2 mice. BCG tissue distribution appeared higher in A/J mice, although this was not statistically significant. Conclusions: These results suggest that the ML ratio has an impact on BCG-mediated protection in mice, in alignment with observations from clinical studies. A/J and 129S2 mice may therefore be useful models of BCG vaccine variability for early TB vaccine testing. We speculate that failure of BCG to protect from TB disease is linked to poor tissue distribution in a ML high immune environment

Affective Awareness in Parenting of Fathers with Co-Occurring Substance Abuse and Intimate Partner Violence

Purpose: Few studies have examined the parenting of fathers with co-occurring Substance Abuse (SA) and Intimate Partner Violence (IPV) problems. None have specifically interviewed men with these co-occurring issues using qualitative methods about their reflective functioning in relation to their children. This qualitative study was designed to provide evidence of the reflective capacity of fathers with co-occurring SA and IPV. Approach: To assess this, men were asked to describe examples of negative emotions they experienced as parents and how they perceived their children responded to those emotions. Forty fathers with co-occurring SA and IPV were interviewed using the Revised Parent Development Interview. Interviews were coded for reflective functioning and for themes that emerged related to angry and guilty feelings these fathers experienced as parents. Findings: Overall, fathers in the sample had a very limited capacity to think about the thoughts and feelings of their children. The desire to spend more time with their child and an inability to provide financially were two common themes. Anger toward the child’s mother for not providing adequate care and a focus on shielding the child from his anger were also reported frequently. Fathers did not report feelings of guilt related to their substance use or aggression in their relationships. Originality: This paper is one of the first to explore reflective functioning of fathers with co-occurring IPV and SA. These findings are discussed in relation to their implications for intervention with fathers with co-occurring SA and IPV issues

Searching for salvation: An analysis of US religious searching on the World Wide Web

The goals of this research were to answer three questions. How predominant is religious searching online? How do people interact with Web search engines when searching for religious information? How effective are these interactions in locating relevant information? Specifically, referring to a US demographic, we analyzed five data sets from Web search engine, collected between 1997 and 2005, of over a million queries each in order to investigate religious searching on the Web. Results point to four key findings. First, there is no evidence of a decrease in religious Web-searching behaviors. Religious interest is a persistent topic of Web searching. Second, those seeking religious information on the Web are becoming slightly more interactive in their searching. Third, there is no evidence for a move away from mainstream religions toward non-mainstream religions since the majority of the search terms are associated with established religions. Fourth, our work does not support the hypothesis that traditional religious affiliation is associated with lower adoption of or sophistication with technology. These factors point to the Web as a potentially usefully communication medium for a variety of religious organizations. © 2009 Elsevier Ltd. All rights reserved

The regulation of mDia1 by autoinhibition and its release by Rho•GTP

Formins induce the nucleation and polymerisation of unbranched actin filaments via the formin-homology domains 1 and 2. Diaphanous-related formins (Drfs) are regulated by a RhoGTPase-binding domain situated in the amino-terminal (N-terminal) region and a carboxy-terminal Diaphanous-autoregulatory domain (DAD), whose interaction stabilises an autoinhibited inactive conformation. Binding of active Rho releases DAD and activates the catalytic activity of mDia. Here, we report on the interaction of DAD with the regulatory N-terminus of mDia1 (mDia(N)) and its release by Rho•GTP. We have defined the elements required for tight binding and solved the three-dimensional structure of a complex between an mDia(N) construct and DAD by X-ray crystallography. The core DAD region is an α-helical peptide, which binds in the most highly conserved region of mDia(N) using mainly hydrophobic interactions. The structure suggests a two-step mechanism for release of autoinhibition whereby Rho•GTP, although having a partially nonoverlapping binding site, displaces DAD by ionic repulsion and steric clashes. We show that Rho•GTP accelerates the dissociation of DAD from the mDia(N)•DAD complex