Ablation of Cytochrome c in Adult Forebrain Neurons Impairs Oxidative Phosphorylation Without Detectable Apoptosis.

Cytochrome c (Cyt c), a heme-containing mitochondrial protein, has a critical function in both respiration and apoptosis. Consistent with these vital functions, somatic Cyt c mouse knockout is embryonic lethal. In order to investigate the sensitivity of postnatal neurons to Cyt c depletion, we developed a neuron-specific conditional knockout model.

Using the BioAssay Ontology for analyzing high-throughput screening data.

High-throughput screening (HTS) is the main starting point for hit identification in drug discovery programs. This has led to a rapid increase of available screening data both within pharmaceutical companies and the public domain. We have used the BioAssay Ontology (BAO) 2.

Metadata Standard and Data Exchange Specifications to Describe, Model, and Integrate Complex and Diverse High-Throughput Screening Data from the Library of Integrated Network-based Cellular Signatures (LINCS).

The National Institutes of Health Library of Integrated Network-based Cellular Signatures (LINCS) program is generating extensive multidimensional data sets, including biochemical, genome-wide transcriptional, and phenotypic cellular response signatures to a variety of small-molecule and genetic perturbations with the goal of creating a sustainable, widely applicable, and readily accessible systems biology knowledge resource. Integration and analysis of diverse LINCS data sets depend on the availability of sufficient metadata to describe the assays and screening results and on their syntactic, structural, and semantic consistency. Here we report metadata specifications for the most important molecular and cellular components and recommend them for adoption beyond the LINCS project.

An Overview of the Challenges in Designing, Integrating, and Delivering BARD: A Public Chemical-Biology Resource and Query Portal for Multiple Organizations, Locations, and Disciplines.

Recent industry-academic partnerships involve collaboration among disciplines, locations, and organizations using publicly funded "open-access" and proprietary commercial data sources. These require the effective integration of chemical and biological information from diverse data sources, which presents key informatics, personnel, and organizational challenges. The BioAssay Research Database (BARD) was conceived to address these challenges and serve as a community-wide resource and intuitive web portal for public-sector chemical-biology data.

Crack-tip strain field mapping and the toughness of metallic glasses.

We have used high-energy x-ray scattering to map the strain fields around crack tips in fracture specimens of a bulk metallic glass under load at room temperature and below. From the measured strain fields we can calculate the components of the stress tensor as a function of position and determine the size and shape of the plastic process zone around the crack tip. Specimens tested at room temperature develop substantial plastic zones and achieve high stress intensities ((K(If) = 76 MPa m(1/2)) prior to fracture.

CLO: The cell line ontology.

Background: Cell lines have been widely used in biomedical research. The community-based Cell Line Ontology (CLO) is a member of the OBO Foundry library that covers the domain of cell lines. Since its publication two years ago, significant updates have been made, including new groups joining the CLO consortium, new cell line cells, upper level alignment with the Cell Ontology (CL) and the Ontology for Biomedical Investigation, and logical extensions.

GPCR ontology: development and application of a G protein-coupled receptor pharmacology knowledge framework.

Motivation: Novel tools need to be developed to help scientists analyze large amounts of available screening data with the goal to identify entry points for the development of novel chemical probes and drugs. As the largest class of drug targets, G protein-coupled receptors (GPCRs) remain of particular interest and are pursued by numerous academic and industrial research projects.

Results: We report the first GPCR ontology to facilitate integration and aggregation of GPCR-targeting drugs and demonstrate its application to classify and analyze a large subset of the PubChem database.

Formalization, annotation and analysis of diverse drug and probe screening assay datasets using the BioAssay Ontology (BAO).

Huge amounts of high-throughput screening (HTS) data for probe and drug development projects are being generated in the pharmaceutical industry and more recently in the public sector. The resulting experimental datasets are increasingly being disseminated via publically accessible repositories. However, existing repositories lack sufficient metadata to describe the experiments and are often difficult to navigate by non-experts.

BioAssay Ontology (BAO): a semantic description of bioassays and high-throughput screening results.

Background: High-throughput screening (HTS) is one of the main strategies to identify novel entry points for the development of small molecule chemical probes and drugs and is now commonly accessible to public sector research. Large amounts of data generated in HTS campaigns are submitted to public repositories such as PubChem, which is growing at an exponential rate. The diversity and quantity of available HTS assays and screening results pose enormous challenges to organizing, standardizing, integrating, and analyzing the datasets and thus to maximize the scientific and ultimately the public health impact of the huge investments made to implement public sector HTS capabilities.

BioAssay ontology annotations facilitate cross-analysis of diverse high-throughput screening data sets.

High-throughput screening data repositories, such as PubChem, represent valuable resources for the development of small-molecule chemical probes and can serve as entry points for drug discovery programs. Although the loose data format offered by PubChem allows for great flexibility, important annotations, such as the assay format and technologies employed, are not explicitly indexed. The authors have previously developed a BioAssay Ontology (BAO) and curated more than 350 assays with standardized BAO terms.

Lack of cytochrome c in mouse fibroblasts disrupts assembly/stability of respiratory complexes I and IV.

Cytochrome c (cyt c) is a heme-containing protein that participates in electron transport in the respiratory chain and as a signaling molecule in the apoptotic cascade. Here we addressed the effect of removing mammalian cyt c on the integrity of the respiratory complexes in mammalian cells. Mitochondria from cyt c knockout mouse cells lacked fully assembled complexes I and IV and had reduced levels of complex III.

Mouse models of oxidative phosphorylation dysfunction and disease.

Oxidative phosphorylation (OXPHOS) deficiency results in a number of human diseases, affecting at least one in 5000 of the general population. Altering the function of genes by mutations are central to our understanding their function. Prior to the development of gene targeting, this approach was limited to rare spontaneous mutations that resulted in a phenotype.

Mouse models of oxidative phosphorylation defects: powerful tools to study the pathobiology of mitochondrial diseases.

Defects in the oxidative phosphorylation system (OXPHOS) are responsible for a group of extremely heterogeneous and pleiotropic pathologies commonly known as mitochondrial diseases. Although many mutations have been found to be responsible for OXPHOS defects, their pathogenetic mechanisms are still poorly understood. An important contribution to investigate the in vivo function of several mitochondrial proteins and their role in mitochondrial dysfunction, has been provided by mouse models.

Role of cytochrome C in apoptosis: increased sensitivity to tumor necrosis factor alpha is associated with respiratory defects but not with lack of cytochrome C release.

Although the role of cytochrome c in apoptosis is well established, details of its participation in signaling pathways in vivo are not completely understood. The knockout for the somatic isoform of cytochrome c caused embryonic lethality in mice, but derived embryonic fibroblasts were shown to be resistant to apoptosis induced by agents known to trigger the intrinsic apoptotic pathway. In contrast, these cells were reported to be hypersensitive to tumor necrosis factor alpha (TNF-alpha)-induced apoptosis, which signals through the extrinsic pathway.

A consensus RNA signal that directs germ layer determinants to the vegetal cortex of Xenopus oocytes.

RNA localization is an important mechanism for generating cellular diversity and polarity in the early embryo. In Xenopus, the correct localization of the RNA encoding the T-box transcription factor VegT is essential for the correct spatial organization and identity of endoderm and mesoderm. Although localization signals in the 3' UTR have been identified for many localized RNAs, insight into what constitutes an RNA localization signal remains elusive.

Isolation and characterization of a transforming growth factor-beta Type II receptor cDNA from Xenopus laevis.

Transforming Growth Factor-beta (TGF-beta) and their receptors have been characterized from many organisms. Two TGF-beta signaling receptors called Type I and II have been described for various ligands of the superfamily from organisms ranging from Drosophila to humans. In Xenopus laevis, TGF-beta2 and 5 have been reported and presumably, play important roles during early development.

Transforming growth factor-beta5 expression during early development of Xenopus laevis.

Members of the transforming growth factor-beta (TGF-beta) superfamily play various roles during development in both vertebrates and invertebrates. Two isoforms, TGF-beta2 and -beta5, have been isolated from Xenopus laevis. We describe here the localization of TGF-beta5 mRNA in early embryos of X.

Molecular organization of the gene encoding Xenopus laevis transforming growth factor-beta 5.

Transforming growth factor-beta s (TGF-beta s) are multifunctional polypeptides, known to influence proliferation and differentiation of many cell types. TGF-beta 5 cDNA was cloned from Xenopus laevis and this isoform is unique to the amphibians. Here, we report the isolation and characterization of the TGF-beta 5 genomic clones to determine the structure of TGF-beta 5 gene.

Characterization of the 5' flanking region of the Xenopus laevis transforming growth factor-beta 5 (TGF-beta 5) gene.

Transforming growth factors-beta are potent regulators of cellular proliferation, differentiation and morphogenesis. 2.41 kb of the 5' flanking region of the transforming growth factor-beta 5 (TGF-beta 5) gene has been isolated from a Xenopus laevis genomic library and sequenced.