A Genome-Wide Linkage Scan for Distinct Subsets of Schizophrenia Characterized by Age at Onset and Neurocognitive Deficits

As schizophrenia is genetically and phenotypically heterogeneous, targeting genetically informative phenotypes may help identify greater linkage signals. The aim of the study is to evaluate the genetic linkage evidence for schizophrenia in subsets of families with earlier age at onset or greater neurocognitive deficits.Patients with schizophrenia (n  =  1,207) and their first-degree relatives (n  =  1,035) from 557 families with schizophrenia were recruited from six data collection field research centers throughout Taiwan. Subjects completed a face-to-face semi-structured interview, the Continuous Performance Test (CPT), the Wisconsin Card Sorting Test, and were genotyped with 386 microsatellite markers across the genome.A maximum nonparametric logarithm of odds (LOD) score of 4.17 at 2q22.1 was found in 295 families ranked by increasing age at onset, which had significant increases in the maximum LOD score compared with those obtained in initial linkage analyses using all available families. Based on this subset, a further subsetting by false alarm rate on the undegraded and degraded CPT obtained further increase in the nested subset-based LOD on 2q22.1, with a score of 7.36 in 228 families and 7.71 in 243 families, respectively.We found possible evidence of linkage on chromosome 2q22.1 in families of schizophrenia patients with more CPT false alarm rates nested within the families with younger age at onset. These results highlight the importance of incorporating genetically informative phenotypes in unraveling the complex genetics of schizophrenia

Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression

<p>Abstract</p> <p>Purpose</p> <p>Cell division cycle 20 (CDC20) homolog is an anaphase-promoting complex activator that is essential for cell division, but whether its expression in pancreatic ductal adenocarcinoma (PDAC) is significant is unknown. In this retrospective study, we determined whether aberrant CDC20 expression can be used as a biomarker in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and whether its expression reflects clinical progression.</p> <p>Experimental design</p> <p>We compared CDC20 expression levels in normal, cancerous, and inflamed pancreatic tissues from stage II PDAC patients with clinical outcomes and determined CDC20 levels in seven PDAC cell lines. CDC20 was identified using a cDNA microarray database containing gene expression profiles for PDAC tissues and cell lines and chronic pancreatitis and normal pancreas tissues. Its expression was confirmed by real-time quantitative reverse-transcriptase-polymerase chain reaction (qRT-PCR). An immunohistochemical analysis of tissue microarrays from resected PDAC tumors and paired benign pancreatic tissues was done and CDC20 levels were correlated with clinical outcome.</p> <p>Results</p> <p>Fifty-six patients were included in this study. A microarray analysis revealed 5-fold higher CDC20 expression in PDAC tissue than in chronic pancreatitis tissue. A qRT-PCR analysis confirmed a mean 20-fold higher CDC20 level in PDAC tissue than in normal pancreas and pancreatitis tissue. RNA and protein CDC20 expression was detected in several PDAC cell lines. An immunohistochemical analysis revealed higher CDC20 protein expression levels in PDAC tissue than in normal pancreas tissue, and high CDC20 expression was associated with poor differentiation (<it>P </it>= 0.020) and a significantly lower 5-year recurrence-free survival rate (<it>P </it>= 0.039); we also found a trend toward a shorter overall survival duration.</p> <p>Conclusions</p> <p>Aberrant CDC20 expression may play an important role in PDAC tumorigenesis and progression and may thus be useful as a marker of disease progression and prognosis and as a therapeutic target.</p

Shaping immune responses through the activation of dendritic cells–P2 receptors

Dendritic cells (DCs) activate and shape the adaptive immune response by capturing antigens, migrating to peripheral lymphoid organs where naïve T cells reside, expressing high levels of MHC and costimulatory molecules and secreting cytokines and chemokines. DCs are endowed with a high degree of functional plasticity and their functions are tightly regulated. Besides initiating adaptive immune responses, DCs play a key role in maintaining peripheral tolerance toward self-antigens. On the basis of the information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. A wide variety of signals from neighbouring cells affecting DC functional activity have been described. Here we will discuss the complex role of extracellular nucleotides in the regulation of DC function and the role of P2 receptors as possible tools to manipulate immune responses

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Morphological study of early-stage lung cancer using synchrotron radiation

In the present study the feasibility of applying synchrotron radiation to the morphological study of early-stage lung cancer has been investigated. Lewis lung cancer was implanted and grown in a nude mouse for different periods, and imaged using phase-contrast synchrotron X-rays. Morphological differences were clearly shown between the normal lung and cancerous tissues at this early stage. Irregular and tortuous angiogenesis were found in the periphery region of the developing lung cancer. Results from this study indicate that synchrotron X-rays can be used for imaging cancer development and progression with minimal invasion. (C) 2008 International Union of Crystallography.open111214sciescopu

Enhanced x-ray irradiation-induced cancer cell damage by gold nanoparticles treated by a new synthesis method of polyethylene glycol modification

We explored a very interesting gold nanoparticle system-pegylated gold in colloidal solution-and analyzed its uptake by mice colorectal adenocarcinoma CT26 tumor cells and the impact on the cell&apos;s response to x-ray irradiation. We found that exposure to polyethylene glycol ( PEG) modified (&apos;pegylated&apos;) 4.7 +/- 2.6 nm gold nanoparticles synthesized by a novel synchrotron-based method enhances the response of CT26 cells to x-ray irradiation. Transmission electron microscopy (TEM) and confocal microscopy revealed that substantial amounts of such nanoparticles are taken up and absorbed by the cells and this conclusion is supported by quantitative induced coupled plasma (ICP) results. Standard tests indicated that the internalized particles are highly biocompatible but strongly enhance the cell damage induced by x-ray irradiation. Synchrotron radiation Fourier transform infrared (SR-FTIR) spectromicroscopy analyzed the chemical aspects of this phenomenon: the appearance of C = O stretching bond spectral features could be used as a marker for cell damage and confirmed the enhancement of the radiation-induced toxicity for cells.X1169sciescopu

The experiences of women of reproductive age regarding health-promoting behaviours: A qualitative study

<p>Abstract</p> <p>Background</p> <p>Health promotion is critical for community and family health. Health-promoting behaviours provide solutions for maintaining and promoting health. Although several studies have addressed the frequency and different types of health-promoting behaviours in women, little information is available about their experiences. This study aimed to explore the experiences of women of reproductive age regarding health-promoting behaviours.</p> <p>Methods</p> <p>In the present study, which was conducted in Tehran, Iran, 15 females, who were selected purposefully, participated in individual in-depth, semi-structured interviews. The interviews were recorded, transcribed verbatim, and analysed using conventional content analysis.</p> <p>Results</p> <p>Nine main categories were derived from the analysis, including establishing an appropriate eating pattern, establishing a balanced rest/activity pattern, spirituality, stress management, personal sensitivity and responsibility, establishing an appropriate pattern of social interactions, practicing safe and healthy recreations, feeling improvement in physical-functional health, and feeling improvement in emotional and psychological health. The first 7 categories represent the nature and types of real health-promoting behaviours in women of reproductive age, whereas the last 2 constitute feeling and understanding of the implementation of these behaviours.</p> <p>Conclusion</p> <p>The study findings show that the women experience improvement in physical-functional, emotional, and psychological health by implementing health-promoting behaviours. It is therefore necessary to introduce strategies in the context of the community culture for improving different aspects of health-promoting behaviours in women of reproductive age to maintain and improve their overall health.</p