Microarray analysis of androgen-regulated gene expression in testis: the use of the androgen-binding protein (ABP)-transgenic mouse as a model

BACKGROUND: Spermatogenesis is an androgen-dependent process, yet the molecular mechanisms of androgens' actions in testis are poorly understood. Transgenic mice overexpressing rat androgen-binding protein (ABP) in their testes have reduced levels of intratesticular androgens and, as a result, show a progressive impairment of spermatogenesis. We used this model to characterize changes in global gene expression in testis in response to reduced bioavailability of androgens. METHODS: Total RNA was extracted from testes of 30-day old transgenic and wild-type control mice, converted to cRNA, labeled with biotin, and hybridized to oligonucleotide microarrays. Microarray results were confirmed by real-time reverse transcription polymerase chain reaction. RESULTS: Three-hundred-eighty-one genes (3.05% of all transcripts represented on the chips) were up-regulated and 198 genes (1.59%) were down-regulated by at least a factor of 2 in the androgen-deficient animals compared to controls. Genes encoding membrane proteins, intracellular signaling molecules, enzymes, proteins participating in the immune response, and those involved in cytoskeleton organization were significantly overrepresented in the up-regulated group. Among the down-regulated transcripts, those coding for extracellular proteins were overrepresented most dramatically, followed by those related to proteolysis, cell adhesion, immune response, and growth factor, cytokine, and ion channel activities. Transcripts with the greatest potential impact on cellular activities included several transcription factors, intracellular signal transducers, secreted signaling molecules and enzymes, and various cell surface molecules. Major nodes in the up-regulated network were IL-6, AGT, MYC, and A2M, those in the down-regulated network were IL-2, -4, and -10, MAPK8, SOCS1, and CREB1. CONCLUSION: Microarray analysis followed by gene ontology profiling and connectivity analysis identified several functional groups of genes and individual genes responding to sustained reduction of androgen levels in the mouse testis. These include genes whose products function as transcription factors, cell surface molecules including ion channels, extra- and intracellular signaling molecules, and secreted enzymes with the potential of regulating cell-to-cell attachment. The transcription factors CREB1 (down-regulated) and MYC (up-regulated) may mediate the most important initial phases of the testicular response to reduced levels of androgens. These results suggest specific avenues for further research that will lead to a better understanding of how androgens regulate spermatogenesis

Comparative analysis of inter population genetic diversity in Puntius filametosus using restriction fragment length polymorphism (RFLP) analysis

The genetic variation in different population of the freshwater cyprinid Puntius filamentosus was studied using restriction fragment length polymorphism (RFLP) analysis. Samples were collected fromfive different locations of southern Western Ghats, India. The morphometric characters of population from Alancholai showed little variation when compared with other population. The genomic size of the different population of P. filamentosus found between 3.45 and 3.80 ng/mg. The result of RFLP analysis showed that the population from Alancholai had distinct fragment length and scored high band volume (12.430 nmoles). The result of cluster analysis showed that Alancholai population had distinct genetic structure and it did not cluster with other population. The study inferred that the population from Alancholai appeared to be unique among the other population of P. filamentosus

Applications of Clustering with Mixed Type Data in Life Insurance

Death benefits are generally the largest cash flow item that affects financial statements of life insurers where some still do not have a systematic process to track and monitor death claims experience. In this article, we explore data clustering to examine and understand how actual death claims differ from expected, an early stage of developing a monitoring system crucial for risk management. We extend the $k$-prototypes clustering algorithm to draw inference from a life insurance dataset using only the insured's characteristics and policy information without regard to known mortality. This clustering has the feature to efficiently handle categorical, numerical, and spatial attributes. Using gap statistics, the optimal clusters obtained from the algorithm are then used to compare actual to expected death claims experience of the life insurance portfolio. Our empirical data contains observations, during 2014, of approximately 1.14 million policies with a total insured amount of over 650 billion dollars. For this portfolio, the algorithm produced three natural clusters, with each cluster having a lower actual to expected death claims but with differing variability. The analytical results provide management a process to identify policyholders' attributes that dominate significant mortality deviations, and thereby enhance decision making for taking necessary actions.Comment: 25 pages, 6 figures, 5 table

Multidisciplinary design of a more electric regional aircraft including certification constraints

The use of electrified on-board systems is increasingly more required to reduce aircraft complexity, polluting emissions, and its life cycle cost. However, the more and all-electric aircraft configurations are still uncommon in the civil aviation context and their certifiability has yet to be proven in some aircraft segments. The aim of the present paper is to define a multidisciplinary design problem which includes some disciplines pertaining to the certification domain. In particular, the study is focused on the preliminary design of a 19 passengers small regional turboprop aircraft. Different on-board systems architectures with increasing electrification levels are considered. These architectures imply the use of bleedless technologies including electrified ice protection and environmental control systems. The use of electric actuators for secondary surfaces and landing gear are also considered. The aircraft design, which includes aerodynamic, structural, systems and propulsion domains, is then assessed by some certification disciplines. In particular, minimum performance, external noise and safety assessments are included in the workflow giving some insights on the aircraft certifiability. The results show a reduction of 3% of MTOM and 3% of fuel mass depending on the systems architecture selected. From the certification side, the design has proven to be certifiable and the margins with the certification constraint can be controlled to improve the overall design

Complex expression dynamics and robustness in C. elegans insulin networks

Gene families expand by gene duplication and resulting paralogs diverge through mutation. Functional diversification can include neo-functionalization as well as sub-functionalization of ancestral functions. In addition, redundancy in which multiple genes fulfill overlapping functions is often maintained. Here, we use the family of 40 Caenorhabditis elegans insulins to gain insight into the balance between specificity and redundancy. The insulin/insulin-like growth factor (IIS) pathway comprises a single receptor, DAF-2. To date, no single insulin-like peptide recapitulates all DAF-2-associated phenotypes, likely due to redundancy between insulin-like genes. To provide a first-level annotation of potential patterns of redundancy, we comprehensively delineate the spatiotemporal and conditional expression of all 40 insulins in living animals. We observe extensive dynamics in expression that can explain the lack of simple patterns of pair-wise redundancy. We propose a model in which gene families evolve to attain differential alliances in different tissues and in response to a range of environmental stresses

A meta-analytic structural equation model for understanding social commerce adoption

YesSocial commerce (s-commerce) has gained prominence with advances in social media and social networking technologies over the last decade. Prior research has employed diverse theoretical perspectives to understand and explain consumer behavior within s-commerce but has also produced inconsistent results. This study integrates different theoretical perspectives including trust, social support, and social presence. The research portrays an integrated research model involving factors that impact behavioral intention and use behavior of s-commerce consumers whilst synthesizing prior empirical findings. A meta-analytic structural equation modeling (MASEM) method was used to synthesize 189 findings reported in 68 s-commerce studies and to analyze the structural model. Our findings show that trust and informational support have positive effects on behavioral intention while trust and emotional support have positive effects on use behavior. Furthermore, our findings highlight that behavioral intention influences use behavior and mediates the effect of trust and informational support on use behavior. The implications for research and practice are discussed in detail

Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer

GBO-006 was shown to be a highly specific and selective PLK2 inhibitor that promoted mitotic arrest in various cancer cell lines, subsequently resulting in their apoptotic death. Intraperitoneal alternate day dosing of GBO-006 using 100 % DMSO as formulation showed significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies necessitated the development of a suitable and GRAS (generally considered as safe) preformulation for pharmacokinetic and efficacy studies. GBO-006 possesses challenging physicochemical and biopharmaceutical properties like poor solubility in aqueous media, low permeability and a crystalline nature. Different methods like cosolvency, complexation and micellar solubilization were employed to improve the solubility of GBO-006. A strategy of co-solvency is used to solubilize the GBO-006 up to 10 mg/mL. A formulation with 20 % DMSO, 40 % PEG 400, 30 % of 100 mM citrate buffer (pH 3.0) and 10 % solutol displayed clear solution without any visual precipitation of the drug even after 2 weeks of storage. GBO-006 showed moderate clearance in rat and high systemic clearance in mouse and dog. It showed poor oral bioavailability across all species. Intraperitoneal dosing of GBO-006 demonstrated the linear exposure. GBO-006 showed significant inhibition of tumor progression

Why is it difficult to implement e-health initiatives? A qualitative study

<b>Background</b> The use of information and communication technologies in healthcare is seen as essential for high quality and cost-effective healthcare. However, implementation of e-health initiatives has often been problematic, with many failing to demonstrate predicted benefits. This study aimed to explore and understand the experiences of implementers - the senior managers and other staff charged with implementing e-health initiatives and their assessment of factors which promote or inhibit the successful implementation, embedding, and integration of e-health initiatives.<p></p> <b>Methods</b> We used a case study methodology, using semi-structured interviews with implementers for data collection. Case studies were selected to provide a range of healthcare contexts (primary, secondary, community care), e-health initiatives, and degrees of normalization. The initiatives studied were Picture Archiving and Communication System (PACS) in secondary care, a Community Nurse Information System (CNIS) in community care, and Choose and Book (C&B) across the primary-secondary care interface. Implementers were selected to provide a range of seniority, including chief executive officers, middle managers, and staff with 'on the ground' experience. Interview data were analyzed using a framework derived from Normalization Process Theory (NPT).<p></p> <b>Results</b> Twenty-three interviews were completed across the three case studies. There were wide differences in experiences of implementation and embedding across these case studies; these differences were well explained by collective action components of NPT. New technology was most likely to 'normalize' where implementers perceived that it had a positive impact on interactions between professionals and patients and between different professional groups, and fit well with the organisational goals and skill sets of existing staff. However, where implementers perceived problems in one or more of these areas, they also perceived a lower level of normalization.<p></p> <b>Conclusions</b> Implementers had rich understandings of barriers and facilitators to successful implementation of e-health initiatives, and their views should continue to be sought in future research. NPT can be used to explain observed variations in implementation processes, and may be useful in drawing planners' attention to potential problems with a view to addressing them during implementation planning