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Fernandez M.A.,University of Valladolid | Rueda C.,University of Valladolid | Peddada S.D.,National Institute of Environmental Health science NIEHS
Nucleic Acids Research | Year: 2012

A cell division cycle is a well-coordinated process in eukaryotes with cell cycle genes exhibiting a periodic expression over time. There is considerable interest among cell biologists to determine genes that are periodic in multiple organisms and whether such genes are also evolutionarily conserved in their relative order of time to peak expression. Interestingly, periodicity is not well-conserved evolutionarily. A conservative estimate of a number of periodic genes common to fission yeast (Schizosaccharomyces pombe) and budding yeast (Saccharomyces cerevisiae) ('core set FB') is 35, while those common to fission yeast and humans (Homo sapiens) ('core set FH') is 24. Using a novel statistical methodology, we discover that the relative order of peak expression is conserved in ∼80 of FB genes and in ∼40 of FH genes. We also discover that the order is evolutionarily conserved in six genes which are potentially the core set of signature cell cycle genes. These include ace2 (a transcription factor) and polo-kinase plo1, which are well-known hubs of early M-phase clusters, cdc18 a key component of pre-replication complexes, mik1 which is critical for the establishment and maintenance of DNA damage check point, and histones hhf1 and hta2. © 2011 The Author(s). Source

Sharma N.K.,The New School | Sharma N.K.,Dr D Y Patil Biotechnology And Bioinformatics Institute | Lebedeva M.,Yale University | Thomas T.,The New School | And 5 more authors.
DNA Repair | Year: 2014

Ataxia Telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer. A-T is caused by mutations in the kinase ATM, a master regulator of the DNA double-strand break response. In addition to DNA-damage signaling defects, A-T cells display mitochondrial dysfunction that is thought to contribute to A-T pathogenesis. However, the molecular mechanism leading to mitochondrial dysfunction in A-T remains unclear. Here, we show that lack of ATM leads to reduced mitochondrial DNA (mtDNA) integrity and mitochondrial dysfunction, which are associated to defective mtDNA repair. While protein levels of mtDNA repair proteins are essentially normal, in the absence of ATM levels specifically of DNA ligase III (Lig3), the only DNA ligase working in mitochondria is reduced. The reduction of Lig3 is observed in different A-T patient cells, in brain and pre-B cells derived from ATM knockout mice as well as upon transient or stable knockdown of ATM. Furthermore, pharmacological inhibition of Lig3 in wild type cells phenocopies the mtDNA repair defects observed in A-T patient cells. As targeted deletion of LIG3 in the central nervous system causes debilitating ataxia in mice, reduced Lig3 protein levels and the consequent mtDNA repair defect may contribute to A-T neurodegeneration. A-T is thus the first disease characterized by diminished Lig3. © 2013. Source

Caballero M.T.,Alianza INFANT Argentina Brazil | Serra M.E.,Alianza INFANT Argentina Brazil | Acosta P.L.,Alianza INFANT Argentina Brazil | Acosta P.L.,CONICET | And 48 more authors.
Journal of Clinical Investigation | Year: 2015

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention. Source

Harper M.,U.S. National Institute for Occupational Safety and Health | Weis C.,National Institute of Environmental Health science NIEHS | Pleil J.D.,U.S. Environmental Protection Agency | Blount B.C.,Centers for Disease Control and Prevention | And 3 more authors.
Journal of Exposure Science and Environmental Epidemiology | Year: 2015

Exposure science is a holistic concept without prejudice to exposure source. Traditionally, measurements aimed at mitigating environmental exposures have not included exposures in the workplace, instead considering such exposures to be an internal affair between workers and their employers. Similarly, occupational (or industrial) hygiene has not typically accounted for environmental contributions to poor health at work. Many persons spend a significant amount of their lifetime in the workplace, where they maybe exposed to more numerous chemicals at higher levels than elsewhere in their environment. In addition, workplace chemical exposures and other exogenous stressors may increase epigenetic and germline modifications that are passed on to future generations. We provide a brief history of the development of exposure science from its roots in the assessment of workplace exposures, including an appendix where we detail current resources for education and training in exposure science offered through occupational hygiene organizations. We describe existing successful collaborations between occupational and environmental practitioners in the field of exposure science, which may serve as a model for future interactions. Finally, we provide an integrated vision for the field of exposure science, emphasizing interagency collaboration, the need for complete exposure information in epidemiological studies, and the importance of integrating occupational, environmental, and residential assessments. Our goal is to encourage communication and spur additional collaboration between the fields of occupational and environmental exposure assessment. Providing a more comprehensive approach to exposure science is critical to the study of the "exposome", which conceptualizes the totality of exposures throughout a person's life, not only chemical, but also from diet, stress, drugs, infection, and so on, and the individual response. © 2015 Nature America, Inc. Source

Kufareva I.,University of California at San Diego | Katritch V.,Scripps Research Institute | Biggin P.,University of Oxford | Kim M.,Korea University | And 116 more authors.
Structure | Year: 2014

Despite tremendous successes of GPCR crystallography, the receptors with available structures represent only a small fraction of human GPCRs. An important role of the modeling community is to maximize structural insights for the remaining receptors and complexes. The community-wide GPCR Dock assessment was established to stimulate and monitor the progress in molecular modeling and ligand docking for GPCRs. The four targets in the present third assessment round presented new and diverse challenges for modelers, including prediction of allosteric ligand interaction and activation states in 5-hydroxytryptamine receptors 1B and 2B, and modeling by extremely distant homology for smoothened receptor. Forty-four modeling groups participated in the assessment. State-of-the-art modeling approaches achieved close-to-experimental accuracy for small rigid orthosteric ligands and models built by close homology, and they correctly predicted protein fold for distant homology targets. Predictions of long loops and GPCR activation states remain unsolved problems. © 2014 Elsevier Ltd All rights reserved. Source

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