Angiotensin II Triggers NLRP3 Inflammasome Activation by a Ca2+ Signaling-Dependent Pathway in Rat Cardiac Fibroblast Ang-II by a Ca2+-Dependent Mechanism Triggers NLRP3 Inflammasome in CF.

Angiotensin II (Ang-II) is a widely studied hypertensive, profibrotic, and pro-inflammatory peptide. In the heart, cardiac fibroblasts (CF) express type 1 angiotensin II receptors (AT1R), Toll-like receptor-4 (TLR4), and the NLRP3 inflammasome complex, which play important roles in pro-inflammatory processes. When activated, the NLRP3 inflammasome triggers proteolytic cleavage of pro-IL-1, resulting in its activation. However, in CF the mechanism by which Ang-II assembles and activates the NLRP3 inflammasome remains not fully known. To elucidate this important point, we stimulated TLR4 receptors in CF and evaluated the signaling pathways by which Ang-II triggers the assembly and activity. In cultured rat CF, pro-IL-1ß levels, NLRP3, ASC, and caspase-1 expression levels were determined by Western blot. NLRP3 inflammasome complex assembly was analyzed by immunocytochemistry, whereas by ELISA, we analyzed NLRP3 inflammasome activity and [Formula: see text] release. In CF, Ang-II triggered NLRP3 inflammasome assembly and caspase-1 activity; and in LPS-pretreated CF, Ang-II also triggered [Formula: see text] secretion. These effects were blocked by losartan (AT1R antagonist), U73221 (PLC inhibitor), 2-APB (IP3R antagonist), and BAPTA-AM (Ca2+ chelator) indicating that the AT1R/PLC/IP3R/Ca2+ pathway is involved. Finally, bafilomycin A1 prevented Ang-II-induced [Formula: see text] secretion, indicating that a non-classical protein secretion mechanism is involved. These findings suggest that in CF, Ang-II by a Ca2+-dependent mechanism triggers NLRP3 inflammasome assembly and activation leading to [Formula: see text] secretion through a non-conventional protein secretion mechanism.

Reliability of professional judgments in forensic child sexual abuse evaluations: unsettled or unsettling science?

In the absence of photographic or DNA evidence, a credible eyewitness, or perpetrator confession, forensic evaluators in cases of alleged child sexual abuse must rely on psychosocial or "soft" evidence, often requiring substantial professional judgment for case determination. This article offers a three-part rebuttal to Herman's (2009 ) argument that forensic decisions based on psychosocial evidence are fundamentally unreliable and that this conclusion represents settled science. The article also discusses the potentially adverse consequences of Herman's proposed reforms to forensic practice on child protection and prosecution efforts.

Forensic child sexual abuse evaluations: assessing subjectivity and bias in professional judgements.

OBJECTIVES: Evaluators examining the same evidence often arrive at substantially different conclusions in forensic assessments of child sexual abuse (CSA). This study attempts to identify and quantify subjective factors that contribute to such disagreements so that interventions can be devised to improve the reliability of case decisions. METHODS: Participants included 1106 professionals in the field of child maltreatment representing a range of professional positions or job titles and years of experience. Each completed the Child Forensic Attitude Scale (CFAS), a 28-item survey assessing 3 forensic attitudes believed to influence professional judgments about CSA allegations: emphasis-on-sensitivity (i.e., a focus on minimizing false negatives or errors of undercalling abuse); emphasis-on-specificity (i.e., a focus on minimizing false positives or errors of overcalling abuse); and skepticism toward child and adolescent reports of CSA. A subset of 605 professionals also participated in 1 of 3 diverse decision exercises to assess the influence of the 3 forensic attitudes on ratings of case credibility. RESULTS: Exploratory factor analysis identified 4 factors or attitude subscales that corresponded closely with the original CFAS scales: 2 subscales for emphasis-on-sensitivity and 1 each for emphasis-on-specificity and skepticism. Attitude subscale scores differed significantly by sample source (in-state trainings vs. national conferences), gender, years of experience, and professional position, with Child Protective Service workers unexpectedly more concerned about overcalling abuse and more skeptical of child disclosures than other professionals-a pattern of scores associated with an increased probability of disbelieving CSA allegations. The 3 decision exercises offered validation of the attitude subscales as predictors of professional ratings of case credibility, with adjusted R(2)s for the three exercises ranging from .06 to .24, suggesting highly variable effect sizes. CONCLUSIONS: Evaluator disagreements about CSA allegations can be explained, in part, by individual differences in 3 attitudes related to forensic decision-making: emphasis-on-sensitivity, emphasis-on-specificity, and skepticism toward child reports of abuse. These attitudes operate as predispositions or biases toward viewing CSA allegations as likely true or likely false. Several strategies for curbing the influence of subjective factors are highlighted including self-awareness of personal biases and team approaches to assessment.