Despite heightened awareness of the clinical significance of social phobia, information is still lacking about putative subtypes, functional impairment, and treatment-seeking. New epidemiologic data ...on these topics are presented from the National Comorbidity Survey Replication (NCS-R).
The NCS-R is a nationally representative household survey fielded in 2001-2003. The World Health Organization (WHO) Composite International Diagnostic Interview Version 3.0 (CIDI 3.0) was used to assess 14 performance and interactional fears and DSM-IV social phobia.
The estimated lifetime and 12-month prevalence of social phobia are 12.1% and 7.1% respectively. Performance and interactional fears load onto a single latent factor, and there is little evidence for distinct subtypes based either on the content or the number of fears. Social phobia is associated with significant psychiatric co-morbidity, role impairment, and treatment-seeking, all of which have a dose-response relationship with number of social fears. However, social phobia is the focus of clinical attention in only about half of cases where treatment is obtained. Among non-co-morbid cases, those with the most fears were least likely to receive social phobia treatment.
Social phobia is a common, under-treated disorder that leads to significant functional impairment. Increasing numbers of social fears are associated with increasingly severe manifestations of the disorder.
Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that ...citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.
Cytotoxic T lymphocytes (CTLs) kill infected and cancerous cells. We detected transfer of cytotoxic multiprotein complexes, called supramolecular attack particles (SMAPs), from CTLs to target cells. ...SMAPs were rapidly released from CTLs and were autonomously cytotoxic. Mass spectrometry, immunochemical analysis, and CRISPR editing identified a carboxyl-terminal fragment of thrombospondin-1 as an unexpected SMAP component that contributed to target killing. Direct stochastic optical reconstruction microscopy resolved a cytotoxic core surrounded by a thrombospondin-1 shell of ~120 nanometer diameter. Cryo-soft x-ray tomography analysis revealed that SMAPs had a carbon-dense shell and were stored in multicore granules. We propose that SMAPs are autonomous extracellular killing entities that deliver cytotoxic cargo targeted by the specificity of shell components.
Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales ...based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem.
Expert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives.
Stepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance area under the receiver operating characteristic curve (AUC) was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9-38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ2 1 = 0.0-2.9, p = 0.09-0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81-0.86, sensitivity 68.0-80.2%, specificity 90.1-98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR- is 0.1 or less at informative thresholds for all diagnoses.
CIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.
Introduced species offer unique opportunities to study evolution in new environments, and some provide opportunities for understanding the mechanisms underlying macroecological patterns. We sought to ...determine how introduction history impacted genetic diversity and differentiation of the house sparrow (Passer domesticus), one of the most broadly distributed bird species. We screened eight microsatellite loci in 316 individuals from 16 locations in the native and introduced ranges. Significant population structure occurred between native than introduced house sparrows. Introduced house sparrows were distinguished into one North American group and a highly differentiated Kenyan group. Genetic differentiation estimates identified a high magnitude of differentiation between Kenya and all other populations, but demonstrated that European and North American samples were differentiated too. Our results support previous claims that introduced North American populations likely had few source populations, and indicate house sparrows established populations after introduction. Genetic diversity also differed among native, introduced North American, and Kenyan populations with Kenyan birds being least diverse. In some cases, house sparrow populations appeared to maintain or recover genetic diversity relatively rapidly after range expansion (<50 years; Mexico and Panama), but in others (Kenya) the effect of introduction persisted over the same period. In both native and introduced populations, genetic diversity exhibited large‐scale geographic patterns, increasing towards the equator. Such patterns of genetic diversity are concordant with two previously described models of genetic diversity, the latitudinal model and the species diversity model.
The stress sensitization theory hypothesizes that individuals exposed to childhood adversity will be more vulnerable to mental disorders from proximal stressors. We aimed to test this theory with ...respect to risk of 30-day major depressive episode (MDE) and generalized anxiety disorder (GAD) among new US Army soldiers.
The sample consisted of 30 436 new soldier recruits in the Army Study to Assess Risk and Resilience (Army STARRS). Generalized linear models were constructed, and additive interactions between childhood maltreatment profiles and level of 12-month stressful experiences on the risk of 30-day MDE and GAD were analyzed.
Stress sensitization was observed in models of past 30-day MDE (χ2 8 = 17.6, p = 0.025) and GAD (χ2 8 = 26.8, p = 0.001). This sensitization only occurred at high (3+) levels of reported 12-month stressful experiences. In pairwise comparisons for the risk of 30-day MDE, the risk difference between 3+ stressful experiences and no stressful experiences was significantly greater for all maltreatment profiles relative to No Maltreatment. Similar results were found with the risk for 30-day GAD with the exception of the risk difference for Episodic Emotional and Sexual Abuse, which did not differ statistically from No Maltreatment.
New soldiers are at an increased risk of 30-day MDE or GAD following recent stressful experiences if they were exposed to childhood maltreatment. Particularly in the military with an abundance of unique stressors, attempts to identify this population and improve stress management may be useful in the effort to reduce the risk of mental disorders.
Hypoxia is a common feature of locally advanced breast cancers that is associated with increased metastasis and poorer survival. Stabilisation of hypoxia-inducible factor-1α (HIF1α) in tumours causes ...transcriptional changes in numerous genes that function at distinct stages of the metastatic cascade. We demonstrate that expression of RIOK3 (RIght Open reading frame kinase 3) was increased during hypoxic exposure in an HIF1α-dependent manner. RIOK3 was localised to distinct cytoplasmic aggregates in normoxic cells and underwent redistribution to the leading edge of the cell in hypoxia with a corresponding change in the organisation of the actin cytoskeleton. Depletion of RIOK3 expression caused MDA-MB-231 to become elongated and this morphological change was due to a loss of protraction at the trailing edge of the cell. This phenotypic change resulted in reduced cell migration in two-dimensional cultures and inhibition of cell invasion through three-dimensional extracellular matrix. Proteomic analysis identified interactions of RIOK3 with actin and several actin-binding factors including tropomyosins (TPM3 and TPM4) and tropomodulin 3. Depletion of RIOK3 in cells resulted in fewer and less organised actin filaments. Analysis of these filaments showed reduced association of TPM3, particularly during hypoxia, suggesting that RIOK3 regulates actin filament specialisation. RIOK3 depletion reduced the dissemination of MDA-MB-231 cells in both a zebrafish model of systemic metastasis and a mouse model of pulmonary metastasis. These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis.
The U.S. Army uses universal preventives interventions for several negative outcomes (e.g. suicide, violence, sexual assault) with especially high risks in the early years of service. More intensive ...interventions exist, but would be cost-effective only if targeted at high-risk soldiers. We report results of efforts to develop models for such targeting from self-report surveys administered at the beginning of Army service.
21 832 new soldiers completed a self-administered questionnaire (SAQ) in 2011-2012 and consented to link administrative data to SAQ responses. Penalized regression models were developed for 12 administratively-recorded outcomes occurring by December 2013: suicide attempt, mental hospitalization, positive drug test, traumatic brain injury (TBI), other severe injury, several types of violence perpetration and victimization, demotion, and attrition.
The best-performing models were for TBI (AUC = 0.80), major physical violence perpetration (AUC = 0.78), sexual assault perpetration (AUC = 0.78), and suicide attempt (AUC = 0.74). Although predicted risk scores were significantly correlated across outcomes, prediction was not improved by including risk scores for other outcomes in models. Of particular note: 40.5% of suicide attempts occurred among the 10% of new soldiers with highest predicted risk, 57.2% of male sexual assault perpetrations among the 15% with highest predicted risk, and 35.5% of female sexual assault victimizations among the 10% with highest predicted risk.
Data collected at the beginning of service in self-report surveys could be used to develop risk models that define small proportions of new soldiers accounting for high proportions of negative outcomes over the first few years of service.
Traumatic life experiences are associated with alcohol use problems, an association that is likely to be moderated by genetic predisposition. To understand these interactions, we conducted a ...gene-by-environment genome-wide interaction study (GEWIS) of alcohol use problems in two independent samples, the Army STARRS (STARRS, N=16 361) and the Yale-Penn (N=8084) cohorts. Because the two cohorts were assessed using different instruments, we derived separate dimensional alcohol misuse scales and applied a proxy-phenotype study design. In African-American subjects, we identified an interaction of PRKG1 rs1729578 with trauma exposure in the STARRS cohort and replicated its interaction with trauma exposure in the Yale-Penn cohort (discovery-replication meta-analysis: z=5.64, P=1.69 × 10
). PRKG1 encodes cyclic GMP-dependent protein kinase 1, which is involved in learning, memory and circadian rhythm regulation. Considering the loci identified in stage-1 that showed same effect directions in stage-2, the gene ontology (GO) enrichment analysis showed several significant results, including calcium-activated potassium channels (GO:0016286; P=2.30 × 10
), cognition (GO:0050890; P=1.90 × 10
), locomotion (GO:0040011; P=6.70 × 10
) and Stat3 protein regulation (GO:0042517; P=6.4 × 10
). To our knowledge, this is the largest GEWIS performed in psychiatric genetics, and the first GEWIS examining risk for alcohol misuse. Our results add to a growing body of literature highlighting the dynamic impact of experience on individual genetic risk.
Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for ...these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.
Small but mighty: A new class of inhibitor was discovered that is highly potent towards the histone lysine demethylases (KDMs) KDM2A/7A. A modular synthetic approach was used to explore chemical space and accelerate the investigation of key structure–activity relationships, which led to the development of a small molecule with more than 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.
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