Pin1 WW Domain Ligand Library Synthesized with an Easy Solid-Phase Phosphorylating Reagent.

Cell cycle regulatory enzyme Pin1 both catalyzes pSer/Thr--Pro isomerization and binds the same motif separately in its WW domain. To better understand the function of Pin1, a way to separate these activities is needed. An unnatural peptide library, RCO-pSer-Pro-NHR, was designed to identify ligands specific for the Pin1 WW domain.

Interdomain interactions support interdomain communication in human Pin1.

Pin1 is an essential mitotic regulator consisting of a peptidyl-prolyl isomerase (PPIase) domain flexibly tethered to a smaller Trp-Trp (WW) binding domain. Communication between these domains is important for Pin1 in vivo activity; however, the atomic basis for this communication has remained elusive. Our previous nuclear magnetic resonance (NMR) studies of Pin1 functional dynamics suggested that weak interdomain contacts within Pin1 enable allosteric communication between the domain interface and the distal active site of the PPIase domain.

Oxandrolone for the treatment of bone marrow failure in Fanconi anemia.

Background: A majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization.

Expanding the Repertoire of Target Sites for Zinc Finger Nuclease-mediated Genome Modification.

Recent studies have shown that zinc finger nucleases (ZFNs) are powerful reagents for making site-specific genomic modifications. The generic structure of these enzymes includes a ZF DNA-binding domain and nuclease domain (Fn) are separated by an amino acid "linker" and cut genomic DNA at sites that have a generic structure (site1)-(spacer)-(site2) where the "spacer" separates the two binding sites. In this work, we compare the activity of ZFNs with different linkers on target sites with different spacer lengths.

Design and Development of Artificial Zinc Finger Transcription Factors and Zinc Finger Nucleases to the hTERT Locus.

The ability to direct human telomerase reverse transcriptase (hTERT) expression through either genetic control or tunable regulatory factors would advance not only our understanding of the transcriptional regulation of this gene, but also potentially produce new strategies for addressing telomerase-associated disease. In this work, we describe the engineering of artificial zinc finger transcription factors (ZFTFs) and ZF nucleases (ZFNs) to target sequences within the hTERT promoter and exon-1. We were able to identify several active ZFTFs that demonstrate a broadly tunable response when screened by a cell-based transcriptional reporter assay.

Attentional biases for threat in at-risk daughters and mothers with lifetime panic disorder.

Children of parents with panic disorder (PD) have high risk for developing anxiety disorders. However, the mechanisms involved in transmission of risk are uncertain. Cognitive models of anxiety propose that information-processing biases underlie anxiety vulnerability; in particular, attentional biases for threat.

Stereospecific gating of functional motions in Pin1.

Pin1 is a modular enzyme that accelerates the cis-trans isomerization of phosphorylated-Ser/Thr-Pro (pS/T-P) motifs found in numerous signaling proteins regulating cell growth and neuronal survival. We have used NMR to investigate the interaction of Pin1 with three related ligands that include a pS-P substrate peptide, and two pS-P substrate analogue inhibitors locked in the cis and trans conformations. Specifically, we compared the ligand binding modes and binding-induced changes in Pin1 side-chain flexibility.

Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.

Background: Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex.

Methods: Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study.

Toward flexibility-activity relationships by NMR spectroscopy: dynamics of Pin1 ligands.

Drug design involves iterative ligand modifications. For flexible ligands, these modifications often entail restricting conformational flexibility. However, defining optimal restriction strategies can be challenging if the relationship between ligand flexibility and biological activity is unclear.

Patient motivation for participating in clinical trials for depression: validation of the motivation for clinical trials inventory-depression.

The motivation for clinical trials inventory-depression (MCTI-D) was developed and evaluated for assessing motivations to participate in clinical trials on depression. Sixty-four participants completed the MCTI-D: 40 individuals expressing interest in participating in a randomized clinical trial (RCT); and 24 clinic patients receiving traditional care for depression. Content validity was supported by feedback derived from a panel of experts in depression research and respondents completing the measure.

Mindfulness and rumination: does mindfulness training lead to reductions in the ruminative thinking associated with depression?

The purpose of this study was to investigate the impact of mindfulness-based stress reduction (MBSR; Kabat-Zinn, 1982, 1990) training on a self-selected adult community sample in the areas of mindfulness, rumination, depressive symptomatology and overall well-being. Targeting rumination was considered particularly important because a tendency toward rumination in nondepressed populations has been found to be predictive of subsequent onset of depression. As hypothesized, completers of the MBSR class showed increases in mindfulness and overall wellbeing, and decreases in rumination and symptoms of depression.

Transcription of ENOD8 in Medicago truncatula nodules directs ENOD8 esterase to developing and mature symbiosomes.

In Medicago truncatula nodules, the soil bacterium Sinorhizobium meliloti reduces atmospheric dinitrogen into nitrogenous compounds that the legume uses for its own growth. In nitrogen-fixing nodules, each infected cell contains symbiosomes, which include the rhizobial cell, the symbiosome membrane surrounding it, and the matrix between the bacterium and the symbiosome membrane, termed the symbiosome space. Here, we describe the localization of ENOD8, a nodule-specific esterase.

Puberty and gender interact to predict social anxiety symptoms in early adolescence.

This study examines direct and interactive effects of puberty and gender on social anxiety symptoms in early adolescence. One hundred-six participants were assessed at ages 9.5 and 11 years.

Preferential loss of central (trunk) adiposity in adolescents and young adults after laparoscopic gastric bypass.

Background: An increasing number of young people are developing severe obesity with adult-like co-morbidities and undergoing bariatric surgery. Although a number of studies have described major weight loss after bariatric surgery, none have examined the proportions of lean body and fat mass lost or the potentially more important issue of changes in regional fat mass distribution after laparoscopic gastric bypass surgery.

Methods: Five morbidly obese females (mean age 18) were evaluated by standard anthropometric measures and dual energy x-ray absorptiometry at baseline and 1 year after bariatric surgery.

The developmental psychopathology of social anxiety in adolescents.

To evaluate a developmental psychopathology approach for understanding adolescent social anxiety, parent-reported predictors of social anxiety were examined in a nonclinical sample of adolescents. Structured diagnostic interviews were obtained from biological parents of 770 participants. Potential risk factors assessed included child characteristics: negative affect, shyness, separation anxiety disorder, and childhood chronic illness, as well as parent characteristics: major depression, panic disorder, and agoraphobia.

Anxiety sensitivity: a missing piece to the agoraphobia-without-panic puzzle.

This article reviews the controversy surrounding the diagnosis of agoraphobia without panic attacks and proposes a key role for anxiety sensitivity in explaining agoraphobic avoidance among those who have never experienced panic. Although rare in clinical samples, agoraphobia without panic is commonly observed in population-based surveys, including more recent studies in which misclassification bias is addressed. Differential treatment seeking may partially explain these discrepant findings; however, it remains unclear why agoraphobic avoidance develops in the absence of panic.

Lifetime prevalence and pseudocomorbidity in psychiatric research.

Context: Comorbidity is the rule rather than the exception with psychiatric disorders and is consequently of great interest to both researchers and clinicians. However, many studies of psychiatric comorbidity have been based on lifetime prevalence with mixed-age samples, a practice that (1) biases the assessment of epidemiologic comorbidity and (2) creates the appearance of comorbidity even when disorders are randomly associated. This bias is what we refer to as pseudocomorbidity.

Cognitive therapy for obsessive-compulsive disorder.

A multiple baseline across subjects design was used to test the efficacy of cognitive therapy for obsessive-compulsive disorder (OCD). Six people with OCD received 10-18 sessions of weekly, outpatient cognitive therapy. Assessment included both structured interviews and diary data.

Unique contributions of anxiety sensitivity to avoidance: a prospective study in adolescents.

Examination of the prospective relation between anxiety sensitivity (AS) and behavioral avoidance is largely absent from the literature. In a longitudinal study of a community sample of 2246 adolescents, participants completed the Anxiety Sensitivity Index (ASI; Reiss, Peterson, Gursky, & McNally (1986). Behaviour Research & Therapy, 24, 1-8), State-Trait Anxiety Inventory (STAI; Spielberger (1983).

A prospective evaluation of agoraphobia and depression symptoms following panic attacks in a community sample of adolescents.

In a community sample of high schoolers who experienced their first panic attack, we examined the prospective relationships among pre-panic vulnerabilities, panic attack severity, and post-panic agoraphobia and depression symptoms. Students were evaluated yearly over 4 years to test the following four hypotheses: (1) pre-panic anxiety sensitivity, negative affect, and childhood behavioral inhibition will serve as vulnerabilities that predict agoraphobia and depression symptoms following a panic attack; (2) these vulnerabilities will lead to more severe panic attacks; (3) severe and spontaneous panic attacks will predict subsequent agoraphobia and depressive symptoms; and (4) the interaction between panic severity and vulnerabilities will be associated with worse outcomes following a panic attack. Results supported the first three hypotheses, but no evidence emerged for an interactive effect.

Changes in caffeine consumption as a signal of pregnancy.

Objectives: The purpose of this prospective study was to examine caffeine consumption and other signals of early pregnancy.

Study Design: One hundred and five pregnant, nonsmoking, coffee drinkers ages 18-40 were enrolled by the ninth week after their last menstrual period (LMP). Participants kept daily diaries of beverage and caffeine consumption and symptoms.

Parent-reported predictors of adolescent panic attacks.

Objective: To identify parent-reported risk factors for adolescent panic attacks.

Method: Structured diagnostic interviews were obtained from 770 parents of participants in a school-based risk factor study for adolescent panic. Parent-reported risk factors assessed included characteristics of the child (negative affect, separation anxiety disorder [SAD], childhood chronic illness, and childhood loss) as well as characteristics of the parent (parental panic disorder or agoraphobia [PDA], parental major depression, and parental chronic illness).

Connections among symptoms of obsessive-compulsive disorder and posttraumatic stress disorder: a case series.

Theoretical, clinical, and empirical implications of the functional connections between symptoms of obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) are abundant. As such, four cases are presented here of men and women who met criteria for comorbid OCD and PTSD. All had been diagnosed with treatment-resistant OCD and were seeking treatment from an OCD specialty clinic or institute, all reported a history of traumatic experiences prior to the onset of OCD, and all appeared to demonstrate negative treatment outcomes.

Marital interaction of agoraphobic women: a controlled, behavioral observation study.

Married couples with a female agoraphobic spouse (n = 22) were compared with demographically similar community control couples (n = 21) on self-report and observational measures of marital interaction. Consistent with hypotheses, husbands of agoraphobic women were more critical of their wives than were control husbands, and clinical couples were less likely to engage in positive problem solution than control couples. Contrary to hypothesis, clinical husbands were not less supportive than control husbands.