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PubMed2003

Community outreach as an iterative dialogue among scientists and communities in the Texas gulf coast region.

In response to significant environmental health challenges in Southeast Texas, a National Institute for Environmental Health Sciences Center at the University of Texas Medical Branch at Galveston was created to promote and conduct inter-disciplinary research in the areas of: (1) the molecular biology of DNA repair, replication and mutagenesis, (2) asthma pathogenesis in response to oxidative stress and viral exposures, and (3) environmental toxicant biotransformation. In addition, the NIEHS Center maintains close ties with neighboring communities through an active Community Outreach & Education Program (COEP) that develops and disseminates translational materials for use in environmental health awareness outreach, toxicology consultation, K-12 curriculum enrichment and in developing site-specific Community Partnership projects. The COEP core service divisions include: Environmental Arts & Sciences, Asthma Outreach & Education, Theater Outreach & Education, and Public Forum & Toxics Assistance. Public Forums focus on the use of Augusto Boal's Forum Theater dramaturgy to include the voices and local knowledge of communities within the process of Participatory Research. Forums create the preconditions for significant partnerships that link the hazardous risk perceptions and environmental health needs of communities with the expertise of NIEHS Center investigators and translational services provided through COEP outreach programs. The Forum process also creates leadership cores within environmentally challenged communities that facilitate the ongoing translational process and maintain the vital linkage between the health needs of communities and the analytic tools and the field and clinical technologies of the environmental sciences.

Community-Institutional Relations↗
PubMed2003

The response regulator LetA regulates the stationary-phase stress response in Legionella pneumophila and is required for efficient infection of Acanthamoeba castellanii.

In order to identify a potential regulator of virulence gene expression in Legionella pneumophila, the L. pneumophila homologue of the response regulator GacA, LetA, was identified and cloned, facilitating the generation of a L. pneumophila letA insertion mutant. The L. pneumophila letA insertion mutant was more sensitive to oxidative and acid stress than the wild-type. The letA mutant exhibited reduced infectivity and was defective for intracellular growth within Acanthamoeba castellanii. Transcription of the rpoS and dotA genes was reduced in the letA mutant. Our data indicate that the response regulator LetA functions as a regulator of the stationary-phase stress response in L. pneumophila and is required for efficient replication within A. castellanii.

Acanthamoeba↗
PubMed2001

Changes in behaviour, cortisol and lymphocyte types during isolation and group confinement of sheep.

This experiment compared changes in complex behaviour patterns, adrenal corticosteroid secretion and the numbers of various types of lymphocytes in sheep that were subjected to the stress of confinement. Grazing Merino ewes (n=80 in five replicated experiments) were confined either in groups of four per pen or in total isolation from other sheep. The percentage of CD4+ lymphocytes increased while the percentage of CD8+ lymphocytes decreased over the experimental period. This result was more pronounced in isolated sheep than in grouped sheep. The increase in CD4:CD8 was greater for isolated sheep than for grouped sheep and greater for 2 week sheep than for 3 week sheep. The percentage of CD5+ cells also increased, less so in isolated than in grouped animals. Interpreting these changes as a recovery of immune competence following introduction of a stressor, it is apparent that isolation impaired immune system recovery more severely than group confinement. Physiological and behavioural adaptation over the period were characterized by a decline in the adrenocortical response, resumption of the normal pattern of flocking behaviour and a reduction in motor activity during the test. These findings add to the evidence pointing to the possible correspondence between critical features of the psychoneural, neuroendocrine and immune systems.

Animals↗
PubMed2000

Activation of nuclear factor kappaB and induction of apoptosis by tumor necrosis factor-alpha in the mouse uterine epithelial WEG-1 cell line.

In order to better understand how tumor necrosis factor (TNF)-alpha may contribute to the local regulation of uterine cell death, cultures of mouse uterine epithelial WEG-1 cells were exposed to TNF-alpha and observed at different time intervals. Earliest decrease in cell viability was observed after 31 h of exposure to 50 ng/ml mouse TNF-alpha and was associated with the expression of several markers of apoptosis. Treatment with human TNF-alpha or addition of a neutralizing antibody against TNF-alpha receptor protein 80 to mouse TNF-alpha resulted in attenuated induction of apoptosis, suggesting that coengagement of the two TNF-alpha receptor types is required for maximal impact. Ceramide analogs failed to replicate the effect of TNF-alpha and the stress-activated protein kinase signaling pathway was not activated by the cytokine. Treatment with mouse TNF-alpha resulted in an increase in nuclear factor (NF)kappaB activity that receded after 24 h. The impact of human TNF-alpha on NFkappaB activation was more moderate. Addition of either one of three different inhibitors of NFkappaB (SN50, PDTC, and A771726) to mouse TNF-alpha sensitized WEG-1 cells to the toxicity of the cytokine. Our data suggest that WEG-1 cells initiate their response to TNF-alpha with an increase in NFkappaB activation that may have transiently biased these cells toward cell death resistance.

Aniline Compounds↗
PubMed2000

Nutrition, HIV, and drug abuse: the molecular basis of a unique role for selenium.

HIV-infected injection drug users (IDUs) often suffer from serious nutritional deficiencies. This is a concern because plasma levels of micronutrients such as vitamin B12, zinc, and selenium have been correlated with mortality risk in HIV-positive populations. Injection drug use also increases lipid peroxidation and other indicators of oxidative stress, which, combined with antioxidant deficiencies, can stimulate HIV-1 replication through activation of NF-kappaB transcription factors, while weakening immune defenses. As detailed herein, these prooxidant stimuli can also increase the pathogenic effects of HIV-1 by another mechanism, involving viral selenoproteins. Overlapping the envelope coding region, HIV-1 encodes a truncated glutathione peroxidase (GPx) gene (see #6 in reference list). Sequence analysis and molecular modeling show that this viral GPx (vGPx) module has highly significant structural similarity to known mammalian GPx, with conservation of the catalytic triad of selenocysteine (Sec), glutamine, and tryptophan. In addition to other functions, HIV-1 vGPx may serve as a negative regulator of proviral transcription, by acting as an NF-kappaB inhibitor (a known property of cellular GPx). Another potential selenoprotein coding function of HIV-1 is associated with the 3' end of the nef gene, which terminates in a conserved UGA (potential Sec) codon in the context of a sequence (Cys-Sec) identical to the C-terminal redox center of thioredoxin reductase, another cellular regulator of NF-kappaB. Thus, in combination with known cellular mechanisms involving Se, viral selenoproteins may represent a unique mechanism by which HIV-1 monitors and exploits an essential micronutrient to optimize its replication relative to the host.

Amino Acid Sequence↗
PubMed2002

Redox regulation of adenovirus-induced AP-1 activation by overexpression of manganese-containing superoxide dismutase.

Adenovirus gene therapy is a promising tool in the clinical treatment of many genetic and acquired diseases. However, it has also caused pathogenic effects in organs such as the liver. The redox-sensitive transcription factors AP-1 and NF-kappaB have been implicated in these effects. To study the mechanisms of adenovirus-mediated AP-1 and NF-kappaB activation and the possible involvement of oxidative stress in adenovirus transduction, rats were injected with either replication-defective recombinant adenovirus with DNA containing the cytomegalovirus promoter region only (AdCMV), adenovirus containing human manganese-containing superoxide dismutase (MnSOD) cDNA (AdMnSOD), or vehicle. Compared to vehicle and AdCMV transduction, MnSOD gene transfer yielded a fivefold increase in liver MnSOD activity 7 days postinjection. Gel shift assay showed that AdCMV transduction induced DNA binding activity for AP-1 but not NF-kappaB. MnSOD overexpression abolished this activation. Western blotting analysis of c-Fos and c-Jun suggested that up-regulation of c-fos and c-jun gene expression does not directly contribute to the induction of AP-1 activation. Glutathione/glutathione disulfide ratios were decreased by adenovirus transduction and restored by MnSOD overexpression. The AP-1 binding activity that was induced by AdCMV was decreased by immunoprecipitation of Ref-1 protein. Ref-1 involvement was confirmed by restoration of AP-1 binding activity after the immunoprecipitated Ref-1 protein had been added back. AP-1 DNA binding activity was also elevated in control and AdMnSOD-injected rats after addition of the immunoprecipitated Ref-1 protein. These data indicate that cellular transduction by recombinant adenovirus stimulates AP-1 DNA binding activity. Furthermore, our results suggest that MnSOD overexpression decreases AP-1 DNA binding activity by regulating intracellular redox status, with the possible involvement of Ref-1 in this redox-sensitive pathway.

Adenoviridae↗
PubMed2006

Environmental stress and lesion-bypass DNA polymerases.

In nature, microbes live under a variety of harsh conditions, such as excess DNA damage, starvation, pH shift, or high temperatures. Microbial cells respond to such stressful conditions mostly by switching global patterns of gene expression to relieve the environmental stress. The SOS response, which is induced by DNA damage, is one such global network of gene expression that plays a crucial role in balancing the genomic stability and flexibility that are necessary to adapt to harsh environments. Here, I review the roles of SOS-inducible and noninducible lesion-bypass DNA polymerases in mutagenesis induced by environmental stress, and discuss how these polymerases are coordinated for the replication of damaged chromosomes. Possible contributions of lesion-bypass DNA polymerase in hyperthermophilic archaea, e.g., Sulfolobus solfataricus, to genome maintenance are also discussed.

Archaea↗
PubMed1999

Modelling method comparison data.

We explore a range of linear regression models that might be useful for either: (a) the relative calibration of two or more methods or (b) to evaluate their precisions relative to each other. Ideally, one should be able to use a single data set to carry out the jobs (a) and (b) together. Throughout this review we consider the constraints (assumptions) needed to attain identifiability of the models and the possible pitfalls to the unwary in having to introduce them. We also pay particular attention to the possible problems arising from the presence of random matrix effects (reproducible random measurement 'errors' that are characteristic of a given method when being used on a given specimen or sample, i.e. specimen specific biases or subject by method interactions). Finally, we stress the importance of a fully-informative design (using replicate measurements on each subject using at least three independent methods) and large sample sizes.

Clinical Laboratory Techniques↗
PubMed2004

Functional aging and gradual senescence in zebrafish.

Zebrafish (Danio rerio) has been recognized as a powerful model for genetic studies in developmental biology. Recently, the zebrafish system also has given insights into several human diseases such as neurodegenerative, hematopoietic, and cardiovascular disease, and cancer. Because aging processes affect these and various other human disorders, it is important to compare zebrafish and mammalian senescence. However, the aging process of zebrafish remains largely unexplored, and little is known about functional aging and senescence in zebrafish. In our initial studies to assess aging phenotypes in zebrafish, we have identified several potential aging biomarkers in an ongoing search for suitable ones on zebrafish aging. In aging zebrafish, we detected senescence-associated beta-galactosidase activity in skin and oxidized protein accumulation in muscle. On the other hand, we did not observe lipofuscin granules (aging pigments), which accumulate in postmitotic cells, in muscle of zebrafish with advancing age. Consistently, there were continuously proliferating myocytes that incorporated BrdU in muscle tissues of the aged fish. Moreover, we demonstrated that zebrafish have constitutively abundant telomerase activity in adult somatic tissues implicating unlimited replicative ability of cells throughout their lives. Although some stress-associated markers are upregulated and minor histological changes are observed during the aging process of zebrafish, our studies together with other evidence of remarkable reproductive and regenerative abilities suggest that zebrafish show very gradual senescence. By using those biological and biochemical aging markers already characterized in normal zebrafish, transgenic fish analyses and genetic mutant fish screens can be readily performed. These efforts will help to elucidate the role and molecular mechanisms of common or different pathways of aging among vertebrates from fish to humans and also will contribute to the discovery of potential drugs applicable to age-associated diseases in the future.

Aging↗
PubMed2006

Genomic convergence toward diploidy in Saccharomyces cerevisiae.

Genome size, a fundamental aspect of any organism, is subject to a variety of mutational and selection pressures. We investigated genome size evolution in haploid, diploid, and tetraploid initially isogenic lines of the yeast Saccharomyces cerevisiae. Over the course of approximately 1,800 generations of mitotic division, we observed convergence toward diploid DNA content in all replicate lines. This convergence was observed in both unstressful and stressful environments, although the rate of convergence was dependent on initial ploidy and evolutionary environment. Comparative genomic hybridization with microarrays revealed nearly euploid DNA content by the end of the experiment. As the vegetative life cycle of S. cerevisiae is predominantly diploid, this experiment provides evidence that genome size evolution is constrained, with selection favouring the genomic content typical of the yeast's evolutionary past.

Chromosomes, Fungal↗
PubMed1998

Stressful life events and loss of hair among adult women, a case-control study.

A case-control design was used to compare stress (as measured with the Social Readjustment Rating Scale) in the lives of 25 women who had experienced recent, unexplained hair loss with that of 25 women with no hair loss. High stress was reported by 22 of the women experiencing hair loss and 10 not experiencing hair loss. An odds ratio of 11 suggests that women who experience high stress are 11 times more likely to experience hair loss. Replication is encouraged.

Adult↗
PubMed1999

Failure to activate transcription factor NF-kappaB in corneal stromal cells (keratocytes).

PURPOSE: Freshly isolated cultures of corneal stromal cells (keratocytes) are incompetent to synthesize the tissue remodeling proteinase, collagenase, in response to agents such as cytochalasin B (CB) or phorbol myristate acetate (PMA), which are strong stimulators of collagenase expression in subcultured fibroblasts of all types, including those from corneal stroma. Incompetence is due to failure to activate an autocrine interleukin (IL)1alpha feedback loop required to mediate cell response. The goal of the present study was to investigate the mechanism for this failure. METHODS: A cell culture model of freshly isolated corneal stromal cells and subcultured stromal fibroblasts from rabbits was used for these studies. RESULTS: Competence to synthesize collagenase in response to CB was acquired as a differentiation property by corneal stromal cells placed in culture, and did not require subculture. Competence acquisition correlated with transition to a fibroblastic spindle shape, assembly of actin stress fibers, and the acquired capacity to collapse in response to CB. It was demonstrated that competence could be more precisely defined as the capacity to express IL-1alpha in response to IL-1, making possible activation of the feedback loop. Investigation into the signaling pathway for IL-1alpha expression in response to IL-1 revealed a requirement for reactive oxygen species and activity of the transcription factor nuclear factor (NF)kappaB. Importantly, freshly isolated stromal cells were found to be relatively incompetent to activate NF-kappaB in comparison to subcultured stromal fibroblasts. CONCLUSIONS: Failure to activate NF-kappaB explains incompetence for expression of IL-1alpha in corneal stromal cells. Because NF-kappaB regulates many cell functions with potential to disturb corneal structure, including expression of inflammatory, stress, and degradative proteinase genes; protection against apoptosis; and cell replication; this seems likely to be an important mechanism protecting corneal stasis and preserving function.

Animals↗
PubMed2001

Identification of causal relationships among traits related to drought resistance in Stylosanthes scabra using QTL analysis.

Previous studies have shown that a negative relationship exists between transpiration efficiency (TE) and carbon isotope discrimination (Delta) and between TE and specific leaf area (SLA) in Stylosanthes scabra. A glasshouse experiment was conducted to confirm these relationships in an F(2) population and to study the causal nature of these relationships through quantitative trait loci (QTL) analysis. One hundred and twenty F(2) genotypes from a cross between two genotypes within S. scabra were used. Three replications for each genotype were maintained through vegetative propagation. Water stress was imposed by maintaining plants at 40% of field capacity for about 45 d. To facilitate QTL analysis, a genetic linkage map consisting of 151 RAPD markers was developed. Results from this study show that Delta was significantly and negatively correlated with TE and biomass production. Similarly, SLA showed significant negative correlation with TE and biomass production. Most of the QTL for TE and Delta were present on linkage groups 5 and 11. Similarly, QTL for SLA, transpiration and biomass productivity traits were clustered on linkage groups 13 and 24. One unlinked marker was also associated with these traits. There were several markers coincident between different traits. At all the coincident QTL, the direction of QTL effects was consistent with phenotypic data. At the coincident markers between TE and Delta, high alleles of TE were associated with low alleles of Delta. Similarly, low alleles of SLA were associated with high alleles of biomass productivity traits and transpiration. At the coincident markers between trans-4-hydroxy-N:-methyl proline (MHP) and relative water content (RWC), low alleles of MHP were associated with high alleles of RWC. This study suggests the causal nature of the relationship between TE and Delta. Phenotypic data and QTL data show that SLA was more closely associated with biomass production than with TE. This study also shows that a cause-effect relationship may exist between SLA and biomass production.

Alleles↗
PubMed1980

Viscoelasticity of dog spinal cord.

Longitudinal viscoelastic behavior of dog spinal cord was investigated by means of the stress-relaxation curve for various conditions. A 40-mm formalin-fixed piece showed little relaxation or relatively high elasticity. A freshly removed piece of cord displayed slightly longer relaxation at 5-20 degrees C than at 39-50 degrees C. The stress-relaxation curve for a 20-g load could be replicated several times with return to original length (viscous behavior). A 20-g load repeatedly applied before relaxation was complete or a 60-g load rapidly applied caused the 40-mm piece to elongate to twice its original length with no return to that length (plastic flow). The viscous coefficient was calculated for an average 20-g load at 39 degrees C from eta = epsilon tau = 3.54 x 10(7) poise. Histological examination of the tissue after rupture suggested that much of the viscoelasticity was due to glycosaminoglycans rather than axons.

Animals↗
PubMed1998

Infectious agents in coronary artery disease: viral infection, aspirin, and gene expression in human coronary smooth muscle cells.

We and others have observational evidence that human cytomegalovirus (HCMV) may be a pathogen in human atherosclerosis and restenosis. We have experimental evidence that HCMV infects human coronary smooth muscle cells and initiates viral replication. Vascular cells generate reactive oxygen species in response to stress (such as infection or reperfusion) and this leads to increased transcription of atherosclerosis-related cellular and viral genes, and to reactivation of latent HCMV. Finally, we found that aspirin can attenuate this augmented gene transcription via direct and indirect effects.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

[Oxidative stress and heart failure].

The excessive reactive oxygen species (ROS), produced by the electron leak in mitochondria of failing myocardium, play an important role in development and progression of heart failure (HF) and cardiac remodeling, which is associated with induction of myocyte hypertrophy and apoptosis and activation of matrix metalloproteinases. Furthermore, ROS can damage mitochondrial DNA(mtDNA), and thus lead to mitochondrial dysfunction and additional ROS generation. Recently, we found that the overexpression of mitochondrial transcription factor A (TFAM), which is essential for mtDNA transcription and replication, ameliorates cardiac remodeling and failure. Therefore, the regulation of mitochondrial oxidative stress or manipulation of TFAM protein may provide a novel therapeutic strategy of HF.

Animals↗