Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs

Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double-mutant viruses, HIV-1 (Ile 100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM.     

Child maltreatment moderates the association of MAOA with symptoms of depression and antisocial personality disorder.

There is a growing body of data indicating that Gene × Child Maltreatment interactions at monoamine oxidase A (MAOA) play a role in vulnerability to symptoms of antisocial personality disorder (ASPD) but not major depression (MD). Using a sample of 538 participants from the Iowa Adoption Studies, we introduce a conceptual model that highlights two distinct pathways from child maltreatment to symptoms of MD, suggesting that maltreatment has different effects depending on genotype and highlighting the importance of including the indirect pathway through ASPD. As predicted by the model, high activity alleles predispose to symptoms of MD in the context of child maltreatment whereas low activity alleles predispose to symptoms of ASPD. We conclude that the Gene × Environment interplay at this locus (MAOA) contributes to both symptoms of ASPD and MD and that careful specification of child maltreatment may be essential if genetic association research is to produce replicable results. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Locating eating pathology within an empirical diagnostic taxonomy: Evidence from a community-based sample.

Existing structural models of psychopathology need to be expanded to include additional diagnostic constructs beyond mood, anxiety, substance use, and antisocial behavior disorders. The goal of this study was to locate eating disorders within a hierarchical structural model of psychopathology that is anchored by broad Internalizing and Externalizing factors. Participants were female adolescent twins (N = 1,434) from the Minnesota Twin Family Study. The authors compared the fit of 4 models in which eating disorders (a) defined their own diagnostic class, (b) represented a subclass within Internalizing, (c) formed a subclass within Externalizing, and (d) were allowed to cross-load on both Internalizing and Externalizing. In the best fitting model, eating disorders formed a subfactor within Internalizing. These findings underscore the value of developing more comprehensive empirically based models of psychopathology to increase researchers' understanding of diverse mental disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sabbatical leave: Who gains and how much?

A rigorous quasi-experiment tested the ameliorative effects of a sabbatical leave, a special case of respite from routine work. We hypothesized that (a) respite increases resource level and well-being and (b) individual differences and respite features moderate respite effects. A sample of 129 faculty members on sabbatical and 129 matched controls completed measures of resource gain, resource loss, and well-being before, during, and after the sabbatical. Among the sabbatees, resource loss declined and resource gain and well-being rose during the sabbatical. The comparison group showed no change. Moderation analysis revealed that those who reported higher respite self-efficacy and greater control, were more detached, had a more positive sabbatical experience, and spent their sabbatical outside their home country enjoyed more enhanced well-being than others. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavior analysis in intellectual and developmental disabilities.

Individuals with intellectual and developmental disabilities (IDD) have deficits in adaptive behavior, slow rates of learning, and behavior disorders that interfere with learning or place them or others at risk. Since the 1960s, researchers and clinicians in the field of applied behavior analysis have used methods based on principles of learning to increase adaptive behavior and decrease the occurrence of behavior disorders of individuals with IDD. This article provides an overview of assessment and treatment strategies used in behavior analysis to effect positive changes in the quality of life for individuals with IDD and presents an illustrative case study. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Breaking the mold: The impact of working in a gender-congruent versus gender-incongruent role on self-reported sources of stress, organizational commitment, and health in U.K. universities.

We present an analysis of archive data collected using the ASSET (Cartwright & Cooper, 2002) from a stratified sample of employees (N = 2,005) working in higher education institutions in the United Kingdom in 2003. We hypothesized that employees working in gender-incongruent roles would report higher levels of work-related stress, poorer health, and lower organizational commitment compared with those working in gender-congruent roles. Interpreted in accordance with the role strain hypotheses, we found that women working in gender-incongruent roles reported significantly higher (p > .01) levels of stress, higher levels of minor ill-health problems, and lower levels of perceived commitment from their organizations compared with all other employees. Conversely, men who worked in gender-incongruent roles often reported the lowest levels of stress. The implications of these findings are discussed with reference to women’s progression in U.K. higher education. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gatekeeping or gate slippage? A national survey of counseling educators in Australian undergraduate and postgraduate academic training programs.

Counseling educators fulfill a complex and demanding role as gatekeepers. The role serves a quality control function and involves ethical and educational responsibilities; it also interfaces with a confounding array of issues. This study was undertaken to establish how counseling educators view and experience the gatekeeping function, and to identify the mechanisms implemented by training programs to facilitate educators in the gatekeeping process. Educators from across Australia involved in counseling training at the bachelor's degree or higher award level were surveyed (n = 63, response rate = 34%). Findings suggested that educators are highly motivated by their sense of responsibility toward the counseling profession when assessing students. Nevertheless, their gatekeeping efforts are often compromised having been predominantly impeded by a lack of clear evidence of the problematic issues and leniency biases within their programs. In addition, gatekeeping efforts have not been generally supported by program initiatives, such as written policy and procedures, which are recognized to be facilitative of the gatekeeping process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral Phenotype of the Reeler Mutant Mouse: Effects of Reln Gene Dosage and Social Isolation.

Reeler (rl/rl) and reeler/wild-type (+/rl) mice synthesize Reln at subnormal rates, as do patients with schizophrenia, bipolar disorder, and autism, thereby forming the basis for a Reln hypothesis for vulnerability to these psychopathologies and justifying attention to the behavioral phenotypes of Reln-deficient mice. Tests of gait, emotionality, social aggression, spatial working memory, novel-object detection, fear conditioning, and sensorimotor reflex modulation revealed the behavioral phenotype of rl/rl, but not +/rl, mice to be different from that of wild-type (+/+) mice. These results reveal no effect of Reln gene dosage and provide significant challenges to both the Reln and the neurodevelopmental hypotheses of the etiology of major psychopathologies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)