A Novel Statistical Algorithm for Gene Expression Analysis Helps Differentiate Pregnane X Receptor-Dependent and Independent Mechanisms of Toxicity

Genome-wide gene expression profiling has become standard for assessing potential liabilities as well as for elucidating mechanisms of toxicity of drug candidates under development. Analysis of microarray data is often challenging due to the lack of a statistical model that is amenable to biological variation in a small number of samples. Here we present a novel non-parametric algorithm that requires minimal assumptions about the data distribution. Our method for determining differential expression consists of two steps: 1) We apply a nominal threshold on fold change and platform p-value to designate whether a gene is differentially expressed in each treated and control sample relative to the averaged control pool, and 2) We compared the number of samples satisfying criteria in step 1 between the treated and control groups to estimate the statistical significance based on a null distribution established by sample permutations. The method captures group effect without being too sensitive to anomalies as it allows tolerance for potential non-responders in the treatment group and outliers in the control group. Performance and results of this method were compared with the Significant Analysis of Microarrays (SAM) method. These two methods were applied to investigate hepatic transcriptional responses of wild-type (PXR+/+) and pregnane X receptor-knockout (PXR−/−) mice after 96 h exposure to CMP013, an inhibitor of β-secretase (β-site of amyloid precursor protein cleaving enzyme 1 or BACE1). Our results showed that CMP013 led to transcriptional changes in hallmark PXR-regulated genes and induced a cascade of gene expression changes that explained the hepatomegaly observed only in PXR+/+ animals. Comparison of concordant expression changes between PXR+/+ and PXR−/− mice also suggested a PXR-independent association between CMP013 and perturbations to cellular stress, lipid metabolism, and biliary transport

Women and power: a theoretical approach using the example of copreneurial businesses

Despite the gradual recognition of strategic issues related to the integration of women into the economy, female entrepreneurship continues to receive little attention. Family business research attributes this situation to a lack of recognition given to the (decisive) role of women in these organizations. However, there is one type of family governance that formally acknowledges the man/woman combination: the copreneurial company. Copreneurs are couples who run a business together. This theoretical article highlights the role of women in the copreneurial context by distinguishing between formal and informal power- the latter being primarily held by women, but which is no less influential. The distribution of power reduces opposition costs between partners and the social costs of non-compliance, and improves the clarity of the entrepreneurial structure. Moreover, it increases satisfaction and a feeling of equality between the partners. These results can be generalized and shed light on the role of women in other entrepreneurial and social contexts. This article is published as part as part of a collection on the role of women in management and business

The Paducah Post

Weekly newspaper from Paducah, Texas that includes local, state, and national news along with advertising

Strategic planning for the family business: parallel planning to unify the family and business

Family business planning has traditionally centered on two issues - estate planning and succession. These goals are far too limited for today's family firm. Business families want to turn the business into not only a tool for profit, but for self-expression, innovation and legacy. The authors introduce the new concept of the Parallel Planning Process, explaining how to integrate the needs and expectations of the family and business systems in order to create an organic and entrepreneurial unit. Planning and decision making templates are included as well as studies of well-known family businesses

Strength of minority ties: the role of homophily and group composition in a weighted social network

Homophily describes a fundamental tie-formation mechanism in social networks in which connections between similar nodes occur at a higher rate than among dissimilar ones. In this article, we present an extension of the weighted social network (WSN) model that, under an explicit homophily principle, quantifies the emergence of attribute-dependent properties of a social system. To test our model, we make use of empirical association data of a group of free-ranging spider monkeys in Yucatan, Mexico. Our homophilic WSN model reproduces many of the properties of the empirical association network with statistical significance, specifically, the average weight of sex-dependent interactions (female-female, female-male, male-male), the weight distribution function, as well as many weighted macro properties (node strength, weighted clustering, and weighted number of modules), even for different age group combinations (adults, subadults, and juveniles). Furthermore, by performing simulations with fitted parameters, we show that one of the main features of a spider monkey social system, namely, stronger male-male interactions over female-female or female-male ones, can be accounted for by an asymmetry in the node-type composition of a bipartisan network, independently of group size. The reinforcement of connections among members of minority groups could be a general structuring mechanism in homophilic social networks