Construction of endophenotypes for complex diseases in the presence of heterogeneity

Endophenotypes such as behavior disorders have been increasingly adopted in genetic studies for complex traits. For efficient gene mapping, it is essential that an endophenotype is associated with the disease of interest and is inheritable or co-segregating within families. In this study, we proposed a strategy to construct endophenotypes to analyze the Genetic Analysis Workshop 14 simulated dataset. Initially, generalized estimating equation models were employed to identify phenotypes that were correlated to the disease (affected status) in combination with the family structures in data. Endophenotypes were then constructed with consideration of heterogeneity as functions of the identified phenotypes. Genome scans on the constructed endophenotypes were carried out using family-based association analysis. For comparison, genome scans were also performed with the original affected status. The family-based association analysis using the endophenotypes correctly identified the same susceptible gene in about 80 of the 100 replicates

An integrated analysis tool for analyzing hybridization intensities and genotypes using new-generation population-optimized human arrays

The cross-sample plot of the multipoint LOH/LCSH analyses of the three samples used in Fig. 5. The plot comprises four panels: (a) The top-left panel is a cross-sample and cross-chromosome plot. The vertical axis is the index of study samples, and the horizontal axis is the physical position (Mb) on each of the 23 chromosomes. The blue and red bars represent SNPs without and with LOH/LSCH, respectively. (b) The top-right panel is a histogram of cross-chromosome aberration frequency. The vertical axis is the index of study samples, and the horizontal axis is the cross-chromosome aberration frequency of the corresponding samples. The pink (skyblue) background represents that the genetic gender of a sample is female (male). The histogram represents the aberration frequency of LOH/LCSH SNPs across the chromosomes of the corresponding samples. (c) The bottom-left panel is a histogram of the cross-sample aberration frequency. The vertical axis is the cross-sample aberration frequency of a SNP, and the horizontal axis is the physical position (Mb) on each of the 23 chromosomes. The purple line represents the aberration proportion of samples carrying the SNPs with LOH/LCSH. (d) The bottom-right panel is the legend of the genetic gender that is used in panel (b), where the pink (skyblue) background represents that the genetic gender of a sample is female (male). (TIFF 1656 kb

Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity

<p>Abstract</p> <p>Background</p> <p>Influenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.</p> <p>Methods</p> <p>We searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.</p> <p>Results</p> <p>The 50% effective inhibitory concentration (IC₅₀) of BPR1P0034 was 0.42 ± 0.11 μM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.</p> <p>Conclusions</p> <p>To the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-μM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.</p

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10−13), ALDH2/MYL2 (rs671, P = 3.40 × 10−11; rs12229654, P = 4.56 × 10−9), ITIH4 (rs2535633, P = 1.77 × 10−10) and NT5C2 (rs11191580, P = 3.83 × 10−8) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10−8) and an additional 14 at P < 1.0 × 10−3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity

Starch Synthesis in Arabidopsis Is Achieved by Spatial Cotranscription of Core Starch Metabolism Genes1[W][OA]

Starch synthesis and degradation require the participation of many enzymes, occur in both photosynthetic and nonphotosynthetic tissues, and are subject to environmental and developmental regulation. We examine the distribution of starch in vegetative tissues of Arabidopsis (Arabidopsis thaliana) and the expression of genes encoding core enzymes for starch synthesis. Starch is accumulated in plastids of epidermal, mesophyll, vascular, and root cap cells but not in root proper cells. We also identify cells that can synthesize starch heterotrophically in albino mutants. Starch synthesis in leaves is regulated by developmental stage and light. Expression of gene promoter-β-glucuronidase fusion constructs in transgenic seedlings shows that starch synthesis genes are transcriptionally active in cells with starch synthesis and are inactive in root proper cells except the plastidial phosphoglucose isomerase. In addition, ADG2 (for ADPG PYROPHOSPHORYLASE2) is not required for starch synthesis in root cap cells. Expression profile analysis reveals that starch metabolism genes can be clustered into two sets based on their tissue-specific expression patterns. Starch distribution and expression pattern of core starch synthesis genes are common in Arabidopsis and rice (Oryza sativa), suggesting that the regulatory mechanism for starch metabolism genes may be conserved evolutionarily. We conclude that starch synthesis in Arabidopsis is achieved by spatial coexpression of core starch metabolism genes regulated by their promoter activities and is fine-tuned by cell-specific endogenous and environmental controls

Intake of phthalate-tainted foods alters thyroid functions in Taiwanese children.

BACKGROUND: On April-May, 2011, two Taiwan chemical companies were found to have intentionally added phthalates, Di-(2-ethylhexyl) phthalate (DEHP) and/or Di-isononyl phthalate, as a substitute of emulsifier to many foodstuffs. This study aimed to investigate whether exposure to these foods altered endocrine functions in children aged ≤10 years and, if so, whether those changes could be reversed by stopping exposure. METHODS: One Phthalates Clinic for Children was established in southern Taiwan between May 31 and June 17, 2011. All eligible children had their exposure information, blood and/or urine specimens collected. Endocrine functions were assessed in serum. The exposure groups were categorized into three (High, >500 ppm, Low, 1-500 ppm, and No, <1 ppm of DEHP). After six months, some children were followed up for the selected endocrine hormones. RESULTS: Sixty children were eligible in this study; all were Tanner stage 1 with no pubic hair. Compared to non-exposed group, both high and low exposure groups had significantly lower serum thyroid-stimulating hormone (TSH) levels (P = 0.001 and 0.024). At six months follow-up, serum triiodothyronine (T3) levels was significantly changed (P = 0.034) in high exposure group (n = 13). For serum estradiol (E2), the detectable rate (≥8 pg/mL) decreased from 76.9% (10/13) to 30.8% (4/13) (P = 0.070). CONCLUSIONS: This study shows that serum TSH levels can be altered when children were exposed to high concentrations of phthalate-tainted foodstuffs. Serum E2 and T3 may be partially recovered after stopping exposure

Analysis and Construction of Genetic Network for Mice Brain Microarray Datasets

This paper intends to find out target genes about memory and learning via microarray analysis. Microarrays are often used to store and manage large amounts of data; however, there is no consensus as to how to best analyze microarray data. This paper uses computational algorithms to analyze gene samples from mice with various calcium channel phenotypes. Min-max normalization was used first to normalize the data. Then, analysis of variance was applied to detect genetic differences among the genes. Finally, Pearson correlation coefficients were calculated to identify the regulatory network of the genes. This analysis model can be applied to efficiently analyze complicated gene expression data. It can also be used to examine the biological functions and regulations of target genes

Blood Pressure Variations Real-Time Reflect the Conditioned Fear Learning and Memory

<div><p>The conditioned fear learning and memory occurs when a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US). This process is critically dependent on the amygdala and inevitably involves blood pressure (BP) alterations. We hypothesized that BP variations could instantaneously reveal individual steps during conditioned fear learning and memory. An implanted telemetric probe was used to monitor the BP real-time in rats during training and testing sessions of the fear-potentiated startle. Our results showed that (i) the conditioned fear learning during the training sessions was reflected by light (CS)-induced rapid BP elevations and by electric shock (US)-evoked sympathetic tone elevations; (ii) these two BP-related parameters were not only negatively correlated with each other but also coupled to each other in the training session trials; (iii) both parameters closely predicted the performance of fear-potentiated startle on the next day; and (iv) although local blocking of one of the two fear-conditioned pathways in the training session partially inhibited fear learning, the fear memory retrieval still used both pathways. Altogether, real-time blood pressure variations faithfully revealed the critical steps involved in conditioned fear learning and memory, and our results supported a coupling between the cued learning and the post-shock calmness.</p> </div