Individuals with psychometric schizotypy show similar social but not physical anhedonia to patients with schizophrenia

Very few studies have examined physical and social anhedonia across the spectrum of schizophrenia. In the present study, we recruited three groups of participants (n=84 in each group): patients with schizophrenia, schizotypy and non-schizotypy as assessed by the Schizotypal Personality Questionnaire (SPQ). All participants completed the self-reported trait anhedonia scales (the Revised Physical Anhedonia Scale and the Social Anhedonia Scale). The clinical symptoms of schizophrenia patients were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessment of Negative Symptoms (SANS). We found that the three groups differed in both physical and social anhedonia. The schizotypy group reported higher levels of physical anhedonia than the non-schizotypy group, and the patient group reported higher levels of physical anhedonia than the schizotypy group. For social anhedonia, the non-schizotypy group differed significantly from both the schizotypy and the patient group, while no significant difference was found between the last two groups. Our findings show that individuals with schizotypy exhibits similar social but not physical anhedonia compared with patients with schizophrenia, which further suggests that decreased pleasure experiences in the social environment may be a valuable target for identification and early intervention in high-risk populations, (C) 2014 Elsevier Ireland Ltd. All rights reserved

Fine Mapping of the NRG1 Hirschsprung's Disease Locus

The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ∼350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR

Novel Association Strategy with Copy Number Variation for Identifying New Risk Loci of Human Diseases

Copy number variations (CNV) are important causal genetic variations for human disease; however, the lack of a statistical model has impeded the systematic testing of CNVs associated with disease in large-scale cohort.Here, we developed a novel integrated strategy to test CNV-association in genome-wide case-control studies. We converted the single-nucleotide polymorphism (SNP) signal to copy number states using a well-trained hidden Markov model. We mapped the susceptible CNV-loci through SNP site-specific testing to cope with the physiological complexity of CNVs. We also ensured the credibility of the associated CNVs through further window-based CNV-pattern clustering. Genome-wide data with seven diseases were used to test our strategy and, in total, we identified 36 new susceptible loci that are associated with CNVs for the seven diseases: 5 with bipolar disorder, 4 with coronary artery disease, 1 with Crohn's disease, 7 with hypertension, 9 with rheumatoid arthritis, 7 with type 1 diabetes and 3 with type 2 diabetes. Fifteen of these identified loci were validated through genotype-association and physiological function from previous studies, which provide further confidence for our results. Notably, the genes associated with bipolar disorder converged in the phosphoinositide/calcium signaling, a well-known affected pathway in bipolar disorder, which further supports that CNVs have impact on bipolar disorder.Our results demonstrated the effectiveness and robustness of our CNV-association analysis and provided an alternative avenue for discovering new associated loci of human diseases

Deleted in Liver Cancer 1 (DLC1) Negatively Regulates Rho/ROCK/MLC Pathway in Hepatocellular Carcinoma

Aims: Deleted in liver cancer 1 (DLC1), a member of RhoGTPase activating protein (GAP) family, is known to have suppressive activities in tumorigenicity and cancer metastasis. However, the underlying molecular mechanisms of how DLC1 suppresses cell motility have not been fully elucidated. Rho-kinase (ROCK) is an immediate down-stream effector of RhoA in mediating cellular cytoskeletal events and cell motility. In the present study, we aimed to investigate the effects of DLC1 on Rho/ROCK signaling pathway in hepatocellular carcinoma (HCC). Methodology/Principal Findings: We demonstrated that DLC1 negatively regulated ROCK-dependent actomyosin contractility. From immumofluorescence study, we found that ectopic expression of DLC1 abrogated Rho/ROCK-mediated cytoskeletal reorganization including formation of stress fibers and focal adhesions. It also downregulated cortical phosphorylation of myosin light chain 2 (MLC2). These inhibitory events by DLC1 were RhoGAP-dependent, as RhoGAP-deficient mutant of DLC1 (DLC1 K714E) abolished these inhibitory events. In addition, from western study, DLC1 inhibited ROCK-related myosin light chain phosphatase targeting unit 1 (MYPT1) phosphorylation at Threonine 853. By examining cell morphology under microscope, we found that ectopic expression of dominant-active ROCK released cells from DLC1-induced cytoskeletal collapse and cell shrinkage. Conclusion: Our data suggest that DLC1 negatively regulates Rho/ROCK/ MLC2. This implicates a ROCK-mediated pathway of DLC1 in suppressing metastasis of HCC cells and enriches our understanding in the molecular mechanisms involved in the progression of hepatocellular carcinoma. © 2008 Wong et al.published_or_final_versio

RET Mutational Spectrum in Hirschsprung Disease: Evaluation of 601 Chinese Patients

Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial)

Potential for Hepatitis C Virus Resistance to Nitazoxanide or Tizoxanide▿

Nitazoxanide and its primary metabolite, tizoxanide, inhibit hepatitis C virus (HCV) replication in HCV replicon systems. To study the potential for resistance, we subjected Huh7 cells harboring HCV replicons to serial passage in 250 μM G418 and increasing concentrations of nitazoxanide or tizoxanide. Passage of the replicon-containing cell lines in either compound resulted in increases in the 50% effective concentrations (EC50s) (7- to 13-fold), EC90s (14- to 36-fold), and 50% cytotoxic concentrations (2- to 4-fold) of both compounds. Serial passage in either compound did not alter the susceptibility of HCV replicons to ribavirin or 2′-C-methylcytidine. Interestingly, serial passage in nitazoxanide or tizoxanide resulted in increased sensitivity to alpha interferon 2b: EC50s and EC90s were reduced three- and eightfold, respectively. Replicons isolated from these cell lines had no greater ability to confer tizoxanide resistance, or increased susceptibility to alpha interferon, than replicons isolated from the parental cell line that had not previously been exposed to nitazoxanide or tizoxanide. These findings are indicative of a cell-mediated activity differing from that of other anti-HCV drugs but complementary with interferon and are consistent with the enhanced response rates observed clinically when nitazoxanide is combined with pegylated interferon therapy. Finally, unlike data for other compounds in advanced clinical development for HCV, these data are consistent with resistance in HCV replicon-containing cell lines conferred by changes in the host and not by mutations in the virus

Deficits in maintenance and interference control of working memory in major depression: evidence from the visuospatial change detection task

Introduction: Recent theories in cognitive psychology suggest that working memory (WM) processing involves a set of specific functions, in particular the WM functions of maintenance and interference control. Previous findings on WM impairments in patients with major depressive disorder (MDD) had been inconsistent, partly because earlier studies did not take into account these two different functions of WM. Method: Forty-two participants with MDD and 39 controls completed the visuospatial change detection task. We estimated the WM function of maintenance, based on performance in trials using the targets only, and the WM function of interference control, based on performance in trials with distractor rectangles. Results: Our results showed that participants with MDD had poorer WM function of maintenance and interference control than controls. However, the results of filtering efficiency did not show significant group difference, thus patients with MDD showed comparable impairments in WM function of maintanance as well as in WM function of interference control. Conclusion: Our findings suggested that patients with MDD appear to show generalised impairments on visuospatial WM function of maintenance and interference control. Future studies should use refined paradigms to assess the different functions of WM and their distinctive contributions to symptomatology of depression

Experiential pleasure deficits in different stages of schizophrenia

Prior research has found dampened anticipatory pleasure but relatively intact consummatory pleasure in people with first-episode and more chronic schizophrenia, but no study has examined anticipatory and consummatory pleasure across the schizophrenia spectrum. To confirm the factor structure of the Chinese version of the Temporal Experience Pleasure Scale (TEPS), which measures four components of anhedonia, we recruited 364 people with schizophrenia for confirmatory factor analysis. To examine anhedonia in people across the schizophrenia spectrum, we recruited people with first-episode (n = 76) and chronic schizophrenia (n = 45), people with schizotypal traits (n = 210), first-degree relatives (n = 45) of people with schizophrenia and healthy controls. Deficit in abstract anticipatory pleasure appeared to be most severe in people with chronic schizophrenia, while dampened abstract consummatory pleasure was observed in people with schizotypal personality features and in people with chronic schizophrenia. In addition, both abstract anticipatory and abstract consummatory pleasure were negatively correlated with negative schizotypal personality features and schizophrenia symptoms. Our results suggest that deficits in anticipatory pleasure are present across the schizophrenia spectrum, particularly in the abstract domain. (C) 2015 Elsevier B.V. All rights reserved