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PubMed1996

Vaccinia virus replication is independent of cellular HSP72 expression which is induced during virus infection.

HSP72 is dramatically induced in the ovaries of vaccinia virus (VV)-infected mice and associates with VV proteins. In order to investigate the role of HSP72 during vaccinia virus replication, we have constructed a recombinant vaccinia virus encoding the major inducible cellular HSP72 (VV-HSP72+) and examined the replication characteristics of this virus. VV-HSP72+ exhibited growth kinetics identical to and peak titers very similar to those of control viruses, both in vitro and in vivo. In particular, replication of VV-HSP72+ was identical to that of control viruses in the HSP72-negative cell line Y3.Ag.1.2.3, and overexpression of HSP72 had no effect on the virulence of VV infection in normal or immunocompromised mice. We conclude that while VV infection results in the induction of the major inducible 72-kDa HSP, VV replication proceeds normally in the absence of this protein. It is unclear whether another celluar chaperone is required to facilitate virus replication in place of HSP72 in Y3.Ag.1.2.3 cells or whether HSP expression plays no role in virus replication, but is simply a component of the generalized stress response to virus infection.

Animals↗
PubMed1983

The use of ligament efficiency to model fenestrations in the internal elastic lamina of cerebral arteries. I--modelling scheme.

The spatial geometry of fenestrations (windows) in the internal elastic lamina from human cerebral arteries is being characterized by a single parameter termed 'ligament efficiency', which is a ratio of the solid band of material to the centre-to-centre spacing between two or more holes. As a result, the apparent random distribution of fenestrations with variable diameters may be represented as a uniform array of holes with a single diameter. The actual arrangement of fenestrations from three separate tissue specimens were replicated in thin latex sheets by transposing the image of the fenestrations from photomicrographs obtained with the scanning electron microscope. In a similar manner, the uniform array of holes with an equivalent ligament efficiency are modelled in latex sheets. The tensile (stress-strain) properties of the latex sheets representing the replication and model configurations were comparable for all three specimens, even though their individual ligament efficiencies were different. The close similarity between the elastic characteristics for the two configurations, verifies the application of ligament efficiency to represent the spatial geometry of a perforated material such as the fenestrated internal elastic lamina.

Biomechanical Phenomena↗
PubMed2002

Psychophysiology of post-traumatic stress disorder.

In general, the results of psychophysiologic research on PTSD support the presence of a variety of autonomic, sensory, and cognitive processing differences between individuals with and without the disorder. The findings are diverse and include heightened responsiveness to trauma reminders; exaggerated startle; increased conditionability and autonomic responsiveness to aversive, high-intensity stimuli; and elevated tonic or baseline physiologic activity. Increased sensitivity of the central nervous system is suggested by electrophysiologic evidence for a failure to habituate to redundant information, over-responsiveness to novel information, and reduced cortical responsiveness to overstimulation. Cognitive processing abnormalities are suggested by electrophysiologic evidence for a reduced ability to attend to task-relevant information and increased attention to task-irrelevant, trauma-related information in individuals with PTSD. Some findings, such as the heightened physiologic and P300 response amplitude responses to trauma-related stimuli and increased HR response to loud tones, have been highly replicable and appear to be as reliable as any biologic finding in the psychiatric literature. Other findings, such as increased eye-blink startle responses and tonic or baseline physiologic activity, have been less consistently replicated and have led investigators to explore how stressful or threatening experimental contexts might produce phasic alterations in the psychophysiology of individuals with PTSD. We hope that the broad range of psychophysiologic investigations and findings in PTSD will inspire others to consider possible applications of these methodologies to their own clinical and research endeavors.

Arousal↗
PubMed2004

Retinol improves development of bovine oocytes compromised by heat stress during maturation.

The objectives of this study were to evaluate: 1) effects of a physiologically relevant elevated temperature on in vitro development of maturing oocytes, 2) effects of retinol on in vitro development of maturing oocytes, and 3) effects of retinol to improve development of oocytes compromised by an elevated temperature. Bovine oocytes were matured for 24 h at 38.5 or 41.0 degrees C (first 12 h) in 0 or 5 microM retinol. After insemination, cleavage and blastocyst development were assessed on d 3 and 8, respectively. Temperature, retinol, and their interaction were included in the statistical model. Culture of oocytes at 41.0 degrees C decreased the proportion of 8- to 16-cell embryos and increased that of 2-cell embryos. In addition, culture at 41.0 degrees C decreased the ability of oocytes to develop to the blastocyst stage. Blastocysts derived from oocytes cultured at 41.0 degrees C had fewer total nuclei. In 3 of the 7 experimental replicates, effects of 41.0 degrees C to reduce blastocyst development were minimal (difference in the development of the control vs. heat stress group was <20%). To provide a more precise test of our hypothesis (retinol administration may improve development of oocytes compromised by heat stress), data were analyzed, including only those replicates (n = 4) in which heat stress reduced development to blastocyst >20%. When this was done, a significant temperature x retinol interaction was noted. The addition of retinol to the maturation medium prevented heat-induced reductions in development of oocytes to blastocyst stage. Results indicate that retinol may protect oocytes from some of the deleterious effects of heat stress.

Animals↗
PubMed2006

Proper control of genetic background with precise allele substitution: a comment on Coyne and Elwyn.

Coyne and Elwyn report that, using Drosophila stocks provided by us, they were unable to replicate our experiments measuring the effects of desaturase-2 on stress tolerance. In this note, we provide evidence that these authors did not properly control for the differences in genetic background between the lines. Their experiments are thus not meaningful replications of our previous ones. We discuss ways of circumventing this problem in studies involving induced mutations in single genes.

Animals↗
PubMed2003

Mnsod overexpression extends the yeast chronological (G(0)) life span but acts independently of Sir2p histone deacetylase to shorten the replicative life span of dividing cells.

Studies in Drosophila and Caenorhabditis elegans have shown increased longevity with the increased free radical scavenging that accompanies overexpression of oxidant-scavenging enzymes. This study used yeast, another model for aging research, to probe the effects of overexpressing the major activity protecting against superoxide generated by the mitochondrial respiratory chain. Manganese superoxide dismutase (MnSOD) overexpression increased chronological life span (optimized survival of stationary (G(0)) yeast over time), showing this is a survival ultimately limited by oxidative stress. In contrast, the same overexpression dramatically reduced the replicative life span of dividing cells (the number of daughter buds produced by each newly born mother cell). This reduction in the generational life span by MnSOD overexpression was greater than that generated by loss of the major redox-responsive regulator of the yeast replicative life span, NAD+-dependent Sir2p histone deacetylase. It was also independent of the latter activity. Expression of a mitochondrially targeted green fluorescent protein in the MnSOD overexpressor revealed that the old mother cells of this overexpressor, which had divided for a few generations, were defective in segregation of the mitochondrion from the mother to daughter. Mitochondrial defects are, therefore, the probable reason that MnSOD overexpression shortens replicative life span.

Cell Division↗
PubMed2001

Corticosterone differentially modulates expression of corticotropin releasing factor and arginine vasopressin mRNA in the hypothalamic paraventricular nucleus following either acute or repeated restraint stress.

Exposing rats to repeated restraint stress induces well-characterized adaptations in the expression of either corticotropin-releasing factor (CRF) or arginine-vasopressin (AVP) mRNA in the parvocellular neurons of the hypothalamic paraventricular nucleus (PVN). The effects of regulating corticosterone levels on this adaptation was studied in male rats. In intact rats, acute restraint stress increased the expression of CRF mRNA whilst AVP mRNA expression was no different to control. Repeated exposure resulted in habituation of CRF expression, whereas AVP mRNA increased above that seen in either non stressed or acutely stressed animals. In adrenalectomised rats with replacement pellets of corticosterone that replicated blood levels approximating to the daily trough (mean levels 37--65 ng/mL), basal CRF expression levels were raised, but the response to acute stress was still observed. However, the habituation seen in normal animals that had been repeatedly stressed was prevented, so that CRF mRNA levels continued to be raised after repeated stress. By contrast, the AVP response to both acute and repeated stress was unaltered in these low-dose corticosterone-treated rats compared with controls. Higher dose pellets, which resulted in blood levels around those of the daily maximum (mean 118--141 ng/mL) had the opposite effects. There was no change compared to intact rats in the expression of CRF mRNA following either acute or repeated stress, but the expected increase in AVP following repeated restraint was prevented. These experiments show that corticosterone has important modulating effects on the adaptive pattern of both CRF and AVP mRNA expression in the parvocellular PVN. The 'set-point' of corticosterone differs; for CRF, experiencing higher levels is necessary for subsequent adaptation to repeated restraint to occur, whereas for AVP a return to lower levels is necessary to allow this peptide to respond to repeated stress.

Acute Disease↗
PubMed2006

Rates and factors associated with suicide in Kaniyambadi Block, Tamil Nadu, South India, 2000-2002.

BACKGROUND: Inefficient civil registration systems, non-report of deaths, variable standards in certifying death and the legal and social consequences of suicide are major obstacles to investigating suicide in the developing world. OBJECTIVE: The aim of this study was to prospectively determine the suicide rate in Kaniyambadi Block, Tamil Nadu, South India, for the years 2000-2002 using verbal autopsies. METHOD: The setting for the study was a comprehensive community health programme in a development block in rural South India. The main outcome measure was death by suicide, diagnosed by a detailed verbal autopsy and census, and birth and death data to identify the population base. RESULTS: The average suicide rate was 92.1 per 100,000. The ratio of male to female suicides was 1:0.66. The age-specific suicide rate for men increased with age while that for women showed two peaks: 15-24 years and over 65 years of age. Hanging (49%) and poisoning with organo-phosphorus compounds (40.5%) were the commonest methods of committing suicide. Acute and/or chronic stress was elicited for nearly all subjects. More men suffered from chronic stress while more women had acute precipitating events (chi2 = 4.58; p < 0.04). People less than 44 years of age had more acute precipitating events before death while older subjects reported more chronic stress (chi2 = 17.38; p < 0.001). CONCLUSION: The study replicates findings of an earlier study from the area. The suicide rate documented in this study is very high and is a major public health concern. There is a need for sentinel centres in India and in developing countries to monitor trends and to develop innovative strategies to reduce deaths by suicide.

Adolescent↗
PubMed1996

Identification and characterization of the Yersinia enterocolitica gsrA gene, which protectively responds to intracellular stress induced by macrophage phagocytosis and to extracellular environmental stress.

Yersinia enterocolitica is able to resist the microbicidal mechanisms of macrophages and to grow within phagocytic cells. Some bacteria including Y. enterocolitica have been shown to respond to the hostile environment in macrophages by producing a set of stress proteins which are also induced by environmental stresses. To understand the role of stress proteins in intracellular survival of bacteria, we identified and cloned a Y. enterocolitica gene, called gsrA (global stress requirement). The gsrA gene was identified because its insertional inactivation by a transposon resulted in the inability of the organism to grow at an elevated temperature and to survive within macrophages after phagocytosis. The gsrA gene was sequenced and shown to encode a basic, 49,500-Da protein. The GsrA protein shows significant amino acid sequence homology to the HtrA stress protein which was originally identified in Escherichia coli. Furthermore, the genetically defined Y. enterocolitica gsrA mutant was constructed and characterized. The insertional mutation of gsrA resulted in inhibition of growth at temperatures above 39 degrees C and greatly increased susceptibility to oxidative and osmotic stresses. The mutant additionally lost the ability to survive and replicate within macrophages. These results, taken together, indicate that the gsrA gene is an essential component of the protection mechanism employed by Y. enterocolitica, allowing it to respond to the intracellular stress in macrophages as well as extracellular environmental stress.

Amino Acid Sequence↗
PubMed2005

Overexpression of MsrA protects WI-38 SV40 human fibroblasts against H2O2-mediated oxidative stress.

Proteins are modified by reactive oxygen species, and oxidation of specific amino acid residues can impair their biological functions, leading to an alteration in cellular homeostasis. Oxidized proteins can be eliminated through either degradation or repair. Repair is limited to the reversion of a few modifications such as the reduction of methionine oxidation by the methionine sulfoxide reductase (Msr) system. However, accumulation of oxidized proteins occurs during aging, replicative senescence, or neurological disorders or after an oxidative stress, while Msr activity is impaired. In order to more precisely analyze the relationship between oxidative stress, protein oxidative damage, and MsrA, we stably overexpressed MsrA full-length cDNA in SV40 T antigen-immortalized WI-38 human fibroblasts. We report here that MsrA-overexpressing cells are more resistant than control cells to hydrogen peroxide-induced oxidative stress, but not to ultraviolet A irradiation. This MsrA-mediated resistance is accompanied by a decrease in intracellular reactive oxygen species and is partially abolished when cells are cultivated at suboptimal concentration of methionine. These results indicate that MsrA may play an important role in cellular defenses against oxidative stress, by catalytic removal of oxidant through the reduction of methionine sulfoxide, and in protection against death by limiting, at least in part, the accumulation of oxidative damage to proteins.

Aging↗
PubMedDate not supplied

Human skeletal muscle satellite cells: aging, oxidative stress and the mitotic clock.

Normal satellite cell cultures, isolated from human skeletal muscle, have a limited proliferative capacity and inevitably reach replicative senescence. In this study, we have focused on the consequences of a single oxidative stress by hydrogen peroxide (H(2)O(2)) on both proliferative capacity and myogenic characteristics. Treatment with 1mM H(2)O(2) for 30 min causes a small decrease in the viability and lifespan while the number of cells which are able to proliferate, decreases dramatically. This premature arrest of the cells in a non-proliferative state was not due to spontaneous differentiation since there was no increase in the number of myogenin positive cells. This stress did not affect the myogenicity of the cells or their ability to differentiate and fuse to form multinucleated myotubes. In addition, the mitotic clock does not seem to be modified by oxidative stress treatment since the rate of telomere shortening was similar in H(2)O(2)-treated and control cells. This could be the consequence of the high level of oxygen consumption with an even higher level of ROS being produced in skeletal muscle than in other tissues which would be counteracted by an increase in the antioxidant defense system.

Cell Division↗
PubMed2006

Shrinkage stress in light-cured composite resins: influence of material and photoactivation mode.

OBJECTIVES: The aim of this study was to record the effect of composite type and photoactivation mode on the stresses resulting from polymerization of five established composite resins: packable (Solitaire, Solitaire 2), micro-hybrid (Aelitefil, Z100) and hybrid (Clearfil AP-X). METHODS: A mechanical testing machine was used to record the polymerization contraction stress (MPa) of cylindrical composite specimens (d=5mm; h=2mm; C-factor=1.25) at 0.1s intervals over a period of 400s. The samples were photopolymerized using a halogen light curing device under two types of light exposure: group 1, Standard (800mW.cm(-2)x60s); group 2, Exponential (logarithmic increase from 150 to 800mW.cm(-2) over 15s+800mW.cm(-2)x45s). The stress rate (SR: slope(MPa>0-60s)) and the maximum shrinkage stress (MSS: MPa(400s)) of each material (five replications) were statistically analysed by one-way ANOVA/Scheffe's test and Pearson's correlation procedure (alpha=0.05). Finally, Student's t-test (two matched series) enabled the assessment of the effect of the irradiation method on the results. RESULTS: For group 1, in decreasing order, the MSS was 1.51+/-0.07MPa (Solitaire) statistically equivalent to 1.45+/-0.06MPa (Aelitefil), 1.29+/-0.08MPa (Solitaire 2), and 1.04+/-0.03MPa (Z100) statistically equivalent to 0.92+/-0.05MPa (Clearfil AP-X). Z100 showed the highest SR (0.045+/-6x10(-3)) and Solitaire, the lowest (0.017+/-2x10(-3)). There was no correlation between SR and MSS (r<-0.33, p<0.05). For group 2, the MSS and SR values were distributed in a similar way to those from group 1. There was a negative correlation between SR and MSS (r<-0.43 and p<0.01). The exponential ramp successfully reduced the MSS (-3.9%) and SR (-11%) values. SIGNIFICANCE: There is no relationship between composite resin type, stress rate and shrinkage stress levels. The slower stress rate development, resulting from ramped light intensity, helped slightly to reduce the maximum polymerization stress.

Analysis of Variance↗
PubMed2003

Identification of Friend murine retrovirus-infected immune cells and studies of the effects of sex and steroid hormones in the early phase of infection.

Male mice are more susceptible than female mice to the murine retrovirus FIS-2. We previously reported that sex-related factors influence early virus replication via mechanisms involving a glucocorticoid response element (GRE) in the long terminal repeat (LTR) enhancer region. In the present study, we investigated further the influence of sex and steroid hormones on early murine retrovirus dissemination and immune functions. In male mice we found a correlation between an early expansion of the CD8+ cell subset and rapid infection of lymphocytes, including CD8+ cells. Virus load in blood declined faster in females than in males, and the postpeak declines coincided with more rapidly generation of antibodies against virus-positive cells. Moreover, female-derived T-cells responded better to in vitro mitogen stimuli than male-derived T-cells. Physiological concentrations of progesterone and dexamethasone induced a dose-dependent inhibition of T-cell proliferation. Administration of progestin in vivo did not modify early FIS-2 production in female mice. Male castrated mice, who were notably less involved in aggressive behaviour and fighting compared to male control mice, had a significant delay of virus dissemination. We suggest that testosterone-dependent aggression, with successive enhanced stress hormone levels, may influence both FIS-2 replication and immune responses during infection.

3T3 Cells↗
PubMedDate not supplied

[The effect of surgical stress on DNA synthesis in liver and brain cells].

Distinct alterations in the rate of DNA synthesis (an increase in the rate of reparation and a decrease in the rate of replication in nuclei and mitochondria) were detected in liver and brain cells during the stress caused by surgical operation. Within 8-10 hrs after the operation the rate of DNA reparation was increased by 40-50% in nuclei of liver cells and by 31-35% in brain cell nuclei. Replication of nuclear DNA was decreased immediately after the operation--by 33% in liver cells and by 50% in brain cells. Within a day after the operation the rate of replication was restored up to the control level in liver cells, while it was still decreased by 30% in brain cells. The rate of mitochondrial DNA synthesis was slightly decreased within the first 12 hrs after the operation: by 12-14% in liver cells and by 18-20% in brain cells. The stress, and particularly postoperative stress, exhibited pronounced action on structure and various systems of DNA synthesis in cells of various tissues.

Animals↗
PubMed2000

Productive replication of adeno-associated virus can occur in human papillomavirus type 16 (HPV-16) episome-containing keratinocytes and is augmented by the HPV-16 E2 protein.

We used a sensitive assay to test whether an adeno-associated virus (AAV) productive replication cycle can occur in immortalized human keratinocytes carrying episomal human papillomavirus type 16 (HPV-16) DNA. Following transfection with cloned AAV DNA, infectious AAV was produced, and the infectivity was blocked by anti-AAV antiserum. The HPV-16 E2 protein substantially increased the yield of AAV. Other HPV early proteins did not, in our experiments, show this ability. E2 has been shown to be able to affect p53 levels and to block cell cycle progression at mitosis. We tested the effect of changes in p53 expression on AAV replication and found that large differences in the level of p53 did not alter AAV DNA replication. In extension of this, we found that cellular help for AAV in response to stress was also independent of p53. To test if a mitotic block could trigger AAV DNA replication, we treated the cells with the mitotic inhibitor nocodazole. AAV DNA replication was stimulated by the presence of nocodazole in these and a number of other cell types tested. Yields of infectious virus, however, were not increased by this treatment. We conclude that the HPV-16 E2 protein stimulates AAV multiplication in these cells and propose that this occurs independently of the effects of E2 on p53 and cell cycle progression. Since the effect of E2 was not seen in keratinocytes lacking the HPV-16 episome, we suggest that E2 can help AAV by working in concert with other HPV-16 proteins.

Animals↗
PubMed1991

On the origins of genetic variants.

Two contrasting mechanisms responsible for the creation of genetic variants are described: one is the manifestation of the limited accuracy of the cellular machinery for DNA replication, the other results from the ability of cells to repair damaged DNA. Replication-dependent variants and those caused by episodical DNA damage enhance the probability that a small fraction of a cell population may survive a sudden (physical or biological) change of environmental conditions. Replication-independent variants arise during persistent but not immediately lethal stress (e.g. starvation) of a non-dividing population. The variants observed under these conditions are of selective advantage because they are able to cope with the particular stress situation. The molecular basis of their creation is a matter of intensive debate.

Biological Evolution↗
PubMed2000

Prolonged reduction of salivary immunoglobulin A (sIgA) after a major academic exam.

OBJECTIVE: In a previous study we observed a continuous reduction of salivary IgA concentration ([sIgA]) during a period of academic stress. This reduction of sIgA concentration exceeded the stress period by at least 1 week. The present study aimed to replicate and extend our previous finding. In particular, we wanted to examine the time of recovery of [sIgA] alterations associated with academic stress. METHOD: Twenty-seven participants in a major medical exam and 27 controls not participating in any exam during the study provided daily saliva samples (immediately after awakening), from the 6th day prior to their last exam until the 14th day afterwards, for analysis of salivary IgA. Data were averaged for the last weeks of exams and the first and second week after exams, respectively. RESULTS: A prolonged reduction of sIgA in exam students as compared to controls was observed. Fourteen days post-stress sIgA concentrations of exam students were still significantly lower than control levels (P=0.004). No recovery was observable. At the same time exam students and controls did not differ in terms of self-reported stress and recovery. CONCLUSIONS: Psychological and immunological stress effects may be dissociated, the latter considerably exceeding the stress period. A closer look at the temporal dynamics of stress-induced immune alterations might increase our understanding of psychoimmuno relationships.

Adult↗
PubMed2004

Direct evidence from siRNA-directed "knock down" that p16(INK4a) is required for human fibroblast senescence and for limiting ras-induced epithelial cell proliferation.

The selective pressure for disruption of the cyclin-dependent kinase inhibitor p16(INK4a) in human cancer has been postulated to reflect its role in mediating growth arrest, both in response to telomere erosion (replicative senescence) and to oncogene-induced and other "stress" signals. Given the known species-specific differences in regulation of senescence, we have tested this hypothesis in human, as opposed to rodent, cells by designing a small interfering RNA (siRNA) to knock down p16(INK4a) expression. Transfection of this siRNA into late-passage normal human diploid fibroblasts allowed at least temporary escape from entry into replicative senescence. Furthermore, in our in vitro model of early-stage, RAS-induced thyroid tumorigenesis, sequential transfections with this siRNA allowed outgrowth of small clusters of proliferating epithelial cells, consistent with escape from the spontaneous "senescence", which normally curtails their proliferative response to mutant RAS. These data provide the first direct evidence that p16(INK4a) is necessary for the initiation of both telomere-dependent and telomere-independent senescence in human cells.

Cell Division↗