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PubMed2006

Assembly of nuclear matrix-bound protein complexes involved in non-homologous end joining is induced by inhibition of DNA topoisomerase II.

Topoisomerases maintain the DNA structure by relieving the torsional stress and alleviating other topological problems occurring in DNA during transcription and replication. Topoisomerase II appears to have a close association with the family of proteins involved in the organization of chromatin in a series of loops on the proteinaceous chromosomal matrix. Beyond its physiological functions, topoisomerase II is the target for some of the most active anticancer drugs. Inhibition of the topoisomerase II function can result in DNA double-strand breaks (DSBs) and, thus, lead to chromosomal translocations. The earliest event during DSB repair is phosphorylation of histone H2AX at S139 (so-called gammaH2AX) which is believed to serve as a focal point for the assembly of repair proteins at the DSB. In this work, we have demonstrated the formation of gammaH2AX foci in two human cell lines--K562 and HeLa--after suppression of topoisomerase II activity with etoposide. Furthermore, these foci remained visible at nuclear matrices and colocalized with the major components of non-homologous end joining (NHEJ) system of DSBs repair. Thus, inhibition of topoisomerase II activity triggers assembly of NHEJ complexes at the nuclear matrix.

Antigens, Nuclear↗
PubMed1980

Tail pinch facilitation of self-stimulation in the rat--dependence upon dopamine and independence of opiates.

We have previously demonstrated that adult male Sprague-Dawley rats which are chronically maintained upon a schedule of intracranial reward (ICS) show elevated rates of response after a mild tail pinch. Both dopamine and opiates have been implicated in the mediation of other stress induced behavioral alterations, and may therefore also possibly be involved in the ICS effect. The present report replicated the initial finding of tail pinch induced facilitation of ICS, and further demonstrated that while opiate blockade failed to affect the ICS response dopaminergic blockage in fact inhibited it. These findings suggest neuropharmacological specificity for stress related behavioral change, and further implicate dopamine in stress responses.

Animals↗
PubMed2002

Depletion of mitochondrial DNA in the skeletal muscle of two cirrhotic patients with severe asthenia.

Qualitative and quantitative alterations of mitochondrial DNA (mtDNA) in the skeletal muscle from two patients with cirrhosis and severe asthenia have been studied. The 4977 bp (mtDNA(4977)) and the 7436 bp (mtDNA(7436)) mtDNA deletions, as well as other mtDNA deletions, revealed by long extension PCR (LX-PCR), were found in the two patients, whereas the 10,422 bp (mtDNA(10,422)) mtDNA deletion was absent. Altogether, the qualitative alterations of mtDNA in cirrhotic patients with severe asthenia were comparable to those of age-matched healthy individuals. The mtDNA content, on the contrary, was substantially decreased in both patients with respect to control. Such mtDNA depletion might be explained by an increased, disease-related, oxidative damage to mtDNA, which probably affects the replication of the mitochondrial genome as already suggested in other oxidative stress-associated diseases.

Asthenia↗
PubMed2002

Molecular gerontology.

Evolutionary theory and empirical evidence from many lines of research suggest that ageing is a process of gradual accumulation of damage in cells and tissues of the body, leading eventually to frailty and increased risk from a spectrum of age-associated diseases. There are multiple kinds of damage that affect cells, ranging from mutations in DNA to oxidative attack on proteins by chemical by-products of normal cellular metabolism. In some ways the surprising thing is not that we age, but that we live as long as we do. The key to understanding longevity lies in the network of cell maintenance systems that cooperate to slow the accumulation of damage. Research has shown that long-lived species carry out cellular maintenance better than short-lived species, suggesting that enhancement of the body's natural maintenance systems may postpone aspects of ageing. Recognition that ageing results from accumulation of damage also points to a role for lifestyle interventions (e.g. nutrition and exercise) to help prevent damage or promote repair.

Aging↗
PubMed2005

Cell death in HIV dementia.

Many patients infected with human immunodeficiency virus type-1 (HIV-1) suffer cognitive impairment ranging from mild to severe (HIV dementia), which may result from neuronal death in the basal ganglia, cerebral cortex and hippocampus. HIV-1 does not kill neurons by infecting them. Instead, viral proteins released from infected glial cells, macrophages and/or stem cells may directly kill neurons or may increase their vulnerability to other cell death stimuli. By binding to and/or indirectly activating cell surface receptors such as CXCR4 and the N-methyl-D-aspartate receptor, the HIV-1 proteins gp120 and Tat may trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations. Membrane lipid metabolism and inflammation may also play important roles in determining whether neurons live or die in HIV-1-infected patients. Drugs and diets that target oxidative stress, excitotoxicity, inflammation and lipid metabolism are in development for the treatment of HIV-1 patients.

AIDS Dementia Complex↗
PubMed2003

DNA polymerase stabilization at stalled replication forks requires Mec1 and the RecQ helicase Sgs1.

To ensure proper replication and segregation of the genome, eukaryotic cells have evolved surveillance systems that monitor and react to impaired replication fork progression. In budding yeast, the intra-S phase checkpoint responds to stalled replication forks by downregulating late-firing origins, preventing spindle elongation and allowing efficient resumption of DNA synthesis after recovery from stress. Mutations in this pathway lead to high levels of genomic instability, particularly in the presence of DNA damage. Here we demonstrate by chromatin immunoprecipitation that when yeast replication forks stall due to hydroxyurea (HU) treatment, DNA polymerases alpha and epsilon are stabilized for 40-60 min. This requires the activities of Sgs1, a member of the RecQ family of DNA helicases, and the ATM-related kinase Mec1, but not Rad53 activation. A model is proposed whereby Sgs1 helicase resolves aberrantly paired structures at stalled forks to maintain single-stranded DNA that allows RP-A and Mec1 to promote DNA polymerase association.

DNA Helicases↗
PubMed1982

Rifampicin treatment of cutaneous leishmaniasis.

In a small-scale preliminary trial of oral rifampicin treatment was considered successful in six out of eight cutaneous leishmaniasis patients and probably effective in a seventh. The in vitro effect of rifampicin on leishmania organisms concerns inhibition of mitochondrial function or replication. The need for protozoological control in the assessment of treatment is stressed.

Adolescent↗
PubMed1999

Induction of heat shock protein expression in cervical epithelial cells by human semen.

OBJECTIVE: The 70kD heat shock protein (Hsp70), induced when cells are subjected to environmental stress, prevents the denaturation and incorrect folding of polypeptides and may expedite replication and transmission of DNA and RNA viruses. We analyzed whether messenger RNA (mRNA) for Hsp70 was expressed following exposure of a cultured human cervical cell line (HeLa cells) to human semen or in cervical cells from sexually active women. STUDY DESIGN: HeLa cells were co-cultured with a 1:50 dilution of semen from four men or with purified spermatozoa or cell-free seminal fluid. Endocervical swabs were acquired at mid-cycle from 53 women. Heat shock protein 70 mRNA was detected by a reverse transcriptase-polymerase chain reaction utilizing specific primer pairs and analysis on agarose gels. In cervical cells Hsp70 mRNA was measured identically followed by hybridization with an Hsp70-specific internal probe and detection by enzyme-linked immunosorbent assay (ELISA). Cervical immunoglobulin A (IgA) antibodies to the human Hsp70 were determined by ELISA. RESULTS: HeLa cell-semen co-culture resulted in the induction of Hsp70 mRNA. In addition, cell-free seminal plasma and motile sperm incubated individually with HeLa cells also induced this mRNA. Heat shock protein 70 mRNA was detected in 28 (52.8%) of 53 endocervical samples obtained from women at various time points following intercourse. The percentage of samples expressing this mRNA was 37.5% at less than 10 hours, 64.3% at 10 hours, 70% at 11 hours, and between 36% and 50% at later times after semen exposure. The detection of cervical IgA antibodies to the Hsp70 was highly associated with Hsp70 gene transcription. CONCLUSION: Human semen induces transcription of Hsp70 in cervical epithelial cells.

Cervix Uteri↗
PubMed2006

The fission yeast DNA structure checkpoint protein Rad26ATRIP/LCD1/UVSD accumulates in the cytoplasm following microtubule destabilization.

BACKGROUND: DNA structure checkpoints are conserved eukaryotic signal transduction pathways that help preserve genomic integrity. Upon detecting checkpoint signals such as stalled replication forks or double-stranded DNA breaks, these pathways coordinate appropriate stress responses. Members of the PI-3 kinase related kinase (PIKK) family are essential elements of DNA structure checkpoints. In fission yeast, the Rad3 PIKK and its regulatory subunit Rad26 coordinate the detection of checkpoint signals with pathway outputs. RESULTS: We found that untreated rad26Delta cells were defective for two microtubule-dependent processes: chromosome segregation and morphogenesis. Interestingly, cytoplasmic accumulation of Rad26-GFP occurred following treatment with microtubule destabilizing drugs, but not during treatment with the genotoxic agent Phleomycin. Cytoplasmic accumulation of Rad26-GFP depended on Rad24, a 14-3-3 protein also required for DNA structure checkpoints and morphogenesis. Results of over expression and epistasis experiments confirm that Rad26 and Rad24 define a response to microtubule destabilizing conditions. CONCLUSION: Two DNA structure checkpoint proteins with roles in morphogenesis define a response to microtubule destabilizing conditions.

Actins↗
PubMed2003

The construction and use of bacterial DNA microarrays based on an optimized two-stage PCR strategy.

BACKGROUND: DNA microarrays are a powerful tool with important applications such as global gene expression profiling. Construction of bacterial DNA microarrays from genomic sequence data using a two-stage PCR amplification approach for the production of arrayed DNA is attractive because it allows, in principal, the continued re-amplification of DNA fragments and facilitates further utilization of the DNA fragments for additional uses (e.g. over-expression of protein). We describe the successful construction and use of DNA microarrays by the two-stage amplification approach and discuss the technical challenges that were met and resolved during the project. RESULTS: Chimeric primers that contained both gene-specific and shared, universal sequence allowed the two-stage amplification of the 3,168 genes identified on the genome of Synechocystis sp. PCC6803, an important prokaryotic model organism for the study of oxygenic photosynthesis. The gene-specific component of the primer was of variable length to maintain uniform annealing temperatures during the 1st round of PCR synthesis, and situated to preserve full-length ORFs. Genes were truncated at 2 kb for efficient amplification, so that about 92% of the PCR fragments were full-length genes. The two-stage amplification had the additional advantage of normalizing the yield of PCR products and this improved the uniformity of DNA features robotically deposited onto the microarray surface. We also describe the techniques utilized to optimize hybridization conditions and signal-to-noise ratio of the transcription profile. The inter-lab transportability was demonstrated by the virtual error-free amplification of the entire genome complement of 3,168 genes using the universal primers in partner labs. The printed slides have been successfully used to identify differentially expressed genes in response to a number of environmental conditions, including salt stress. CONCLUSIONS: The technique detailed here minimizes the cost and effort to replicate a PCR-generated DNA gene fragment library and facilitates several downstream processes (e.g. directional cloning of fragments and gene expression as affinity-tagged fusion proteins) beyond the primary objective of producing DNA microarrays for global gene expression profiling.

Cyanobacteria↗
PubMed2005

Mitochondrial transcription factor A in the maintenance of mitochondrial DNA: overview of its multiple roles.

Mitochondria have their own genome, which is essential for proper oxidative phosphorylation needed for a large part of ATP production in a cell. Although mitochondrial DNA-less (rho0) cells can survive under special conditions, the integrity of the mitochondrial genome is critical for survival of multicellular organisms. Mitochondrial transcription factor A (TFAM), originally cloned as transcription factor, is essential for the maintenance of mtDNA. Recently, it has become known that TFAM plays critical roles in multiple aspects to maintain the integrity of mitochondrial DNA: transcription, replication, nucleoid formation, damage sensing, and DNA repair. The effects of TFAM in these aspects are intimately related to each other and to function as a whole for the purpose of maintenance of mtDNA.

Animals↗
PubMedDate not supplied

[The mechanism of specific cleavage of supercoiled DNA by human DNA topoisomerase I: the effect of ligand structure on the catalytic step of reaction].

Eukaryotic DNA topoisomerase I (Topo) regulates the topological state of cell DNA and plays an important part in replication, transcription, repair, and recombination. Factors affecting the specific recognition of topologically stressed DNA were analyzed on the basis of the thermodynamic and kinetic data on the Topo-DNA interaction and the X-ray data on human Topo. A model was advanced for possible structural changes occurring in the ligand after initial recognition. The effect of conformational changes in specific DNA on the catalytic stage of the reaction was analyzed.

Catalysis↗
PubMedDate not supplied

Dimensions of client control.

The purposes of this study were to identify activities that give patients a sense of control during their hospitalization and to characterize the kinds of people who find control in various ways. Bandura's (1977) social learning theory and the relationship between control and stress formed the theoretical framework; Q methodology was central to implementation and replication of the descriptive design. Consistent with Q methodology, major and replication samples were purposively selected, each consisting of 30 medical-surgical inpatients of both sexes, ranging from 24 to 75 years of age. Instruments used were the Client Control Q Set, Health Opinion Survey (HOS), a demographic data form, and a semi-structured interview. Q factor analysis and the construction of factor arrays resulted in three dimensions of client control in the original data set which replicated and were supported by interview and HOS data. These orthogonal dimensions were: knowing and fulfilling the patient role, being involved in making decisions, and directing interpersonal and environmental components. A theme common to all dimensions was the importance patients attached to having cognitive control over diagnostic tests, surgery, and treatment and to understanding concomitant life-style implications. Identification of the kinds of people who find control in various ways remains elusive, although patients hospitalized for diagnosis and/or treatment of cancer were predominant among those who wanted to be involved in making decisions.

Adult↗
PubMed1983

Intrinsic noise and the design of the genetic machinery.

Darwinian theory envisages 'selection pressure' as a stress imposed on the genotype by the environment. However, noise in the replicative and translational mechanisms in itself imposes a significant 'pressure' on the adaptive fitness of the organism. We propose that the biosphere has been shaped by both extrinsic (environmental) and intrinsic (noise-generated) factors. Because noise has been a remorseless and ever-present background to the evolutionary process, adaptations to this intrinsic pressure include not only a variety of familiar genetic mechanisms but also many anatomical and life-style characteristics that focus on the transmission of information between generations.

Animals↗
PubMed2001

[Characterization of the expression and function of SigM an ECF sigma factor in mycobacteria].

The survival of M. tuberculosis within the macrophage depends on its ability to respond to oxidative stress, and the ECF subfamily of sigma factors likely play an important role. We studied SigM, a sigma factor whose gene is located near the origin of DNA replication. In both M. smegmatis and M. bovis BCG, the expression of sigM was induced at high temperature and in stationary phase. Mutants of M. smegmatis without an intact sigM were defective for survival in oxidative stress and also for the induction of thioredoxin reductase activity in oxidative stress. The thioredoxin system reduces disulfide bonds that are formed in oxidative stress. SigM thus appears to regulate thioredoxins and forms part of the bacteria's complex protective responses.

DNA Replication↗
PubMed1998

A confirmatory factor analysis of posttraumatic stress symptoms.

Investigators have recently identified a two-factor structure underlying posttraumatic stress symptoms through the use of exploratory factor analysis. [Taylor et al. (1988). The structure of posttraumatic stress symptoms. Journal of Abnormal Psychology, 107, 154-160]. These two factors, which were labeled as Intrusion and Avoidance, and Hyperarousal and Numbing, are consistent with current theoretical models of posttraumatic stress disorder--PTSD [e.g. Foa et al. (1992). Uncontrollability and unpredictability in post-traumatic stress disorder: An animal model. Psychological Bulletin, 112, 218-238]. However, the authors of the Taylor et al. study issued caution in interpreting their findings because there has yet to be a systematic replication of their results. This paper presents a confirmatory factor analysis of the two-factor structure of posttraumatic stress symptoms in 217 survivors of serious motor vehicle accidents with varying degrees of PTSD symptoms. A hierarchical, confirmatory-factor analysis conducted with a structural equation modeling statistics package confirmed that the model proposed by Taylor et al. can adequately account for the presentation of PTSD symptoms in this sample of motor vehicle accident survivors. The implications for the assessment and diagnosis of PTSD are discussed.

Accidents, Traffic↗
PubMed1988

Race and cardiovascular reactivity. A replication.

In a previous study, we reported that black children demonstrated greater cardiovascular reactivity than did white children to the psychological stress of a television video game. Reliance on urban volunteers and the wide age range of the children may have limited conclusions concerning the generalizability of those results. In the present study, 481 of 484 children enrolled in the third grade of the public schools of an entire rural county in Tennessee were examined with the same video game procedure used previously. Results indicated greater heart rate and blood pressure reactivity among black children than among white children. Thus, the previous results were replicated. The greater prevalence of hypertension among black adults may relate to the greater reactivity among black children; reactivity may be either a marker or a mechanism in the development of hypertension.

Age Factors↗