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PubMed2003

The stress-inducible immediate-early responsive gene IEX-1 is activated in cells infected with herpes simplex virus 1, but several viral mechanisms, including 3' degradation of its RNA, preclude expression of the gene.

The accumulation of cellular transcripts from cells infected with herpes simplex virus 1 (HSV-1) as measured with the aid of Affymetrix microchips has been reported elsewhere. Among these transcripts were genes that respond to stress and that could have a noxious effect on viral replication. We have selected the stress-inducible cellular gene encoding the immediate-early response protein IEX-1 to verify and determine the significance of the accumulation of these transcripts in infected cells. We report that we verified the increase in accumulation of IEX-1 transcripts after infection by Northern analyses and real-time PCR. These transcripts reach peak levels between 3 and 7 h after infection and decrease thereafter. However, IEX-1 protein was detected in cells 1 h after infection but not at later intervals. Studies designed to elucidate the failure of IEX-1 protein to be synthesized revealed the following points. (i) IEX-1 RNA transported to the cytoplasm after 1 h of infection consisted of at least two populations, a partially degraded population and a population consisting of unspliced IEX-1 RNA. Neither of these RNAs could translate the authentic IEX-1 protein. (ii) The partially degraded IEX-1 RNA was not detected in the cytoplasm of cells infected with a mutant virus lacking the U(L)41 gene encoding the virion host shutoff protein (vhs). Although degradation of RNA mediated by vhs was reported to be 5' to 3', the partially degraded IEX-1 RNA lacked the 3' sequences rather than the 5' sequences. (iii) The unspliced pre-RNA form containing the IEX-1 intron sequences was detected in the cytoplasm of cell infected with wild-type virus but not in those infected with a mutant lacking the alpha27 gene encoding the infected cell protein No. 27. (iv) Overexpression of IEX-1 protein by transduction of the gene prior to infection with 1 PFU of HSV-1 per cell had no effect on the accumulation of late genes and virus yield. We conclude that the failure of IEX-1 to express its protein reflects the numerous mechanisms by which the virus thwarts the cells from expressing its genes after infection.

3' Untranslated Regions↗

PubMed2007

Physiological deterioration associated with breeding in female mice: a model for the study of senescence and aging.

Longevity is a complex and dynamic process influenced by a diversity of factors. Amongst other, gestation and lactation contribute to organismal decline because they represent a great energetic investment in mammals. Here we compared the rate of senescence onset observed in primary fibroblast obtained from the lungs of retired female breeder mice (12 months old), with the senescence arrival observed in fibroblasts derived from age-matched nulliparous mice. Two-month-old animals were also used as controls of young, fully-developed adults. Cell proliferation, DNA synthesis, and expression of senescence-associated beta-galactosidase activity were evaluated as senescent parameters. In order to test differences in energetic competence at a systemic level, mitochondrial respiration was also evaluated in mitochondria isolated from the livers of the same animals used for the primary cultures. Our data indicated that the cells derived from female mice subjected to the physiological stress of breeding onset into replicative senescence prior than the cells from female mice age-matched without that particular stress. Thus validating the use of retired breeders as a model to study aging and senescence at the cellular level.

Aging↗

PubMed1994

Long-term monitoring of psychosocial stress and symptomatology in inflammatory bowel disease.

Eleven subjects with inflammatory bowel disease (IBD) participated in a longterm self-monitoring investigation of the relationship between psychosocial stress and IBD symptomatology. Two measurement instruments, the IBD Symptom Diary and the Psychosocial Stress Diary, were completed by each subject for 7 consecutive days each month for one year. Pooled time-series analysis of the influence of daily stress on IBD activity revealed a significant effect. A positive concurrent relationship was found between both daily and monthly psychosocial stress and IBD activity. Investigations of temporal relationship among variables revealed a negative effect of previous month stress on IBD. Results suggest a monthly rebound effect whereby IBD symptom severity is negatively responsive to the severity of the previous month stress. The effects of stress upon IBD were not found to be modified by behavioral coping strategies. These results support the prevailing impression that psychosocial stress contributes to the clinical course of IBD, and specifically suggest an influential role of daily and monthly stress. A pattern matching IBD's characteristic waxing and waning clinical course emerges when the association between stress and IBD is examined from a monthly viewpoint. Refinement of our knowledge of the IBD-stress model calls for replication and explanation of the monthly rebound effect as well as investigations into type of stressor and coping strategy that may influence IBD activity.

Adaptation, Psychological↗

PubMed2003

Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts.

In addition to replicative senescence, normal diploid fibroblasts undergo stress-induced premature senescence (SIPS) in response to DNA damage caused by oxidative stress or ionizing radiation (IR). SIPS is not prevented by telomere elongation, indicating that, unlike replicative senescence, it is triggered by nonspecific genome-wide DNA damage rather than by telomere shortening. ATM, the product of the gene mutated in individuals with ataxia telangiectasia (AT), plays a central role in cell cycle arrest in response to DNA damage. Whether ATM also mediates signaling that leads to SIPS was investigated with the use of normal and AT fibroblasts stably transfected with an expression vector for the catalytic subunit of human telomerase (hTERT). Expression of hTERT in AT fibroblasts resulted in telomere elongation and prevented premature replicative senescence, but it did not rescue the defect in G(1) checkpoint activation or the hypersensitivity of the cells to IR. Despite these remaining defects in the DNA damage response, hTERT-expressing AT fibroblasts exhibited characteristics of senescence on exposure to IR or H(2)O(2) in such a manner that triggers SIPS in normal fibroblasts. These characteristics included the adoption of an enlarged and flattened morphology, positive staining for senescence-associated beta-galactosidase activity, termination of DNA synthesis, and accumulation of p53, p21(WAF1), and p16(INK4A). The phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which mediates signaling that leads to senescence, was also detected in both IR- or H(2)O(2)-treated AT and normal fibroblasts expressing hTERT. These results suggest that the ATM-dependent signaling pathway triggered by DNA damage is dispensable for activation of p38 MAPK and SIPS in response to IR or oxidative stress.

Ataxia Telangiectasia↗

PubMed1998

The effects of stress on memory and the hippocampus throughout the life cycle: implications for childhood development and aging.

Studies in animals showing hippocampal atrophy and associated memory deficits in stress and aging have implications for stress and aging in humans. Clinical studies in traumatized human populations with posttraumatic stress disorder (PTSD) have replicated studies in animals, showing reduction in volume of the hippocampus measured with magnetic resonance imaging and associated memory deficits. Trauma at different stages of development (early childhood abuse versus trauma in later life due to combat) may influence the nature of memory deficits and hippocampal atrophy. Studies in aging human subjects are consistent with animal studies, although future research is needed in this area. The similarities between biological findings related to cortisol and the hippocampus in stress and aging in both animal and human studies raises the question of whether PTSD can be seen as a form of accelerated aging. Evidence that stress affects the hippocampus and the capacity for learning has broad implications for public health policy, underlying the need for additional resources in this important area and a reexamination of our understanding of factors influencing academic achievement.

Adult↗

PubMed2006

The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice.

After liver injury, parenchymal regeneration occurs through hepatocyte replication. However, during regenerative stress, oval cells (OCs) and small hepatocyte like progenitor cells (SHPCs) contribute to the process. We systematically studied the intra-hepatic and extra-hepatic sources of liver cell replacement in the hepatitis B surface antigen (HBsAg-tg) mouse model of chronic liver injury. Female HBsAg-tg mice received a bone marrow (BM) transplant from male HBsAg-negative mice, and half of these animals received retrorsine to block indigenous hepatocyte proliferation. Livers were examined 3 and 6 months post-BM transplantation for evidence of BM-derived hepatocytes, OCs, and SHPCs. In animals that did not receive retrorsine, parenchymal regeneration occurred through hepatocyte replication, and the BM very rarely contributed to hepatocyte regeneration. In mice receiving retrorsine, 4.8% of hepatocytes were Y chromosome positive at 3 months, but this was frequently attributable to cell fusion between indigenous hepatocytes and donor BM, and their frequency decreased to 1.6% by 6 months, as florid OC reactions and nodules of SHPCs developed. By analyzing serial sections and reconstructing a 3-dimensional map, continuous streams of OCs could be seen that surrounded and entered deep into the nodules of SHPCs, connecting directly with SHPCs, suggesting a conversion of OCs into SHPCs. In conclusion, during regenerative stress, the contribution to parenchymal regeneration from the BM is minor and frequently attributable to cell fusion. OCs and SHPCs are of intrinsic hepatic origin, and OCs can form SHPC nodules.

Animals↗

PubMed2005

The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity.

Prion diseases are transmissible neurodegenerative disorders characterized by extensive neuronal apoptosis and accumulation of misfolded prion protein (PrP(SC)). Recent reports indicate that PrP(SC) induces neuronal apoptosis via activation of the endoplasmic reticulum (ER) stress pathway and activation of the ER resident caspase-12. Here, we investigate the relationship between prion replication and induction of ER stress during different stages of the disease in a murine scrapie model. The first alteration observed consists of the upregulation of the ER chaperone of the glucose-regulated protein Grp58, which was detected during the presymptomatic phase and followed closely the formation of PrP(SC). An increase in Grp58 expression correlated with PrP(SC) accumulation at all stages of the disease in different brain areas, suggesting that this chaperone may play an important role in the cellular response to prion infection. Indeed, in vitro studies using N2a neuroblastoma cells demonstrated that inhibition of Grp58 expression with small interfering RNA led to a significant enhancement of PrP(SC) toxicity. Conversely, overexpression of Grp58 protected cells against PrP(SC) toxicity and decreased the rate of caspase-12 activation. Grp58 and PrP were shown to interact by coimmunoprecipitation, observing a higher interaction in cells infected with scrapie prions. Our data indicate that expression of Grp58 is an early cellular response to prion replication, acting as a neuroprotective factor against prion neurotoxicity. Our findings suggest that targeting Grp58 interaction may have applications for developing novel strategies for treatment and early diagnosis of prion diseases.

Analysis of Variance↗

PubMed1982

Further analysis of the specificity of a novel animal model of depression--effects of an antihistaminic, antipsychotic and anxiolytic compound.

In previous papers we reported that chronic stress elicited reductions in selected forms of open field activity resembled endogenomorphic depression upon behavioral, motivational, neuroendocrine, and neuropharmacological grounds. In particular, the loss of acute stress elicited activity proved to be exclusively reversible by antidepressant treatments. Insofar as clinically ineffective compounds were tested, the deficit proved refractory to treatment, further suggesting the model reflected just those processes which were disrupted in depression. A number of ineffective compounds are known to yield false positives upon other related tests, but have yet to be examined in the present model. Three such compounds, an antihistamine (tripelennamine), a neuroleptic (haloperidol), and an anxiolytic (oxazepam) were examined for their behavioral and neuroendocrine effects. Although other stress related phenomena were replicated, none of the above compounds was effective in restoring the activation deficit or in eliminating the endocrine abnormality. This suggests the depression model is relatively selective pharmacologically and not critically dependent upon receptor blocking properties of the above drugs.

Animals↗

PubMed1995

Failure of all-ceramic fixed partial dentures in vitro and in vivo: analysis and modeling.

Hertzian cone cracks visible at the loading site of 20 all-ceramic fixed partial dentures (FPDs), tested in vitro, led to the hypotheses that failure was due to the propagation of localized contact damage crack systems (Hertzian stress state) and that such damage was an unlikely clinical failure mode. Fractographic analysis of the 20 laboratory-failed and nine clinically-failed all-ceramic FPDs allowed for definitive testing of these hypotheses and a comparison between in vitro and in vivo failure behavior. In all cases, failure occurred in the FPD connectors (none from contact damage), with approximately 70 to 78% originating from the interface between the core and veneer ceramics. The coincidence between failure origins provides strong evidence that the in vitro test modeled aspects of structural behavior having clinical importance. The fractographic observations, coupled with the in vitro failure load data, furnished very specific boundary conditions which were applied to constrain mathematical models of FPD connector failure. Finite element analysis (FEA) of the laboratory FPDs found that maximum principal tensile stresses would occur at locations consistent with the fractographic observations only if: (1) there were appropriate elastic moduli differences between the ceramics; and (2) a small amount of abutment rotation was allowed. Weibull failure probability (Pf) calculations, incorporating FEA stress profiles, very closely replicated the laboratory failure distribution only when: (1) the veneer ceramic was much weaker than the core ceramic; and (2) the Weibull modulus of the core-veneer interface was much lower than that for the free veneer surface (i.e., the interface is of lower quality with regard to defects).(ABSTRACT TRUNCATED AT 250 WORDS)

Ceramics↗

PubMed2005

Drug-induced mitochondrial toxicity.

Mitochondria play a critical role in generating most of the cell's energy as ATP. They are also involved in other metabolic processes such as urea generation, haem synthesis and fatty acid beta-oxidation. Disruption of mitochondrial function by drugs can result in cell death by necrosis or can signal cell death by apoptosis (e.g., following cytochrome c release). Drugs that injure mitochondria usually do so by inhibiting respiratory complexes of the electron chain; inhibiting or uncoupling oxidative phosphorylation; inducing mitochondrial oxidative stress; or inhibiting DNA replication, transcription or translation. It is important to test for mitochondrial toxicity early in drug development as impairment of mitochondrial function can induce various pathological conditions that are life threatening or can increase the progression of existing mitochondrial diseases.

Animals↗

PubMed2004

Abnormal response to metabolic stress in schizophrenia: marker of vulnerability or acquired sensitization?

BACKGROUND: Previous work suggests that individuals with schizophrenia display an altered homovanillic acid (HVA) response to metabolic stress. The present study replicated and extended this paradigm, including individuals with elevated genetic risk for schizophrenia. METHOD: Patients with psychosis (n = 50), non-psychotic first-degree relatives of patients with psychosis (n = 51) and controls without psychosis (n = 50) underwent, in randomized order, double-blind administration of placebo and the glucose analogue 2-deoxy-D-glucose (2DG), which induces a mild, transient clinical state of glucoprivation. Plasma HVA and cortisol were assessed twice before the start of the 2DG/placebo infusion (baseline values), as well as four times post infusion. Data were analysed using multi-level random regression techniques. RESULTS: During the stress condition, significant increases in plasma HVA and cortisol were found. The increase in plasma HVA level during the stress condition was significantly stronger in patients than in controls, whereas this was not the case in relatives v. controls. The increase in plasma cortisol during the stress condition was significantly less in patients than controls, but no significant difference in the increase of plasma cortisol during stress was found in the comparison between relatives and controls. CONCLUSIONS: Patients with psychosis, but not their non-psychotic first-degree relatives, show an altered neurobiological response to metabolic stress, suggesting that this dysregulation is not a genetically transmitted vulnerability, but an illness-related effect, possibly reflecting acquired sensitization of neuroendocrine systems by repeated environmental stressors or repeated stimulation with agonistic drugs.

Adolescent↗

PubMed1996

Response of two heat shock genes to selection for knockdown heat resistance in Drosophila melanogaster.

To identify genes involved in stress resistance and heat hardening, replicate lines of Drosophila melanogaster were selected for increased resistance to knockdown by a 39 degrees heat stress. Two selective regimes were used, one with and one without prior hardening. Mean knockdown times were increased from approximately 5 min to > 20 min after 18 generations. Initial realized heritabilities were as high as 10% for lines selected without hardening, and crosses between lines indicated simple additive gene effects for the selected phenotypes. To survey allelic variation and correlated selection responses in two candidate stress genes, hsr-omega and hsp68, we applied denaturing gradient gel electrophoresis to amplified DNA sequences from small regions of these genes. After eight generations of selection, allele frequencies at both loci showed correlated responses for selection following hardening, but not without hardening. The hardening process itself was associated with a hsp68 frequency change in the opposite direction to that associated with selection that followed hardening. These stress loci are closely linked on chromosome III, and the hardening selection established a disequilibrium, suggesting an epistatic effect on resistance. The data indicate that molecular variation in both hsr-omega and.hsp68 contribute to natural heritable variation for hardened heat resistance.

Alcohol Dehydrogenase↗

PubMed2002

Use of stress echocardiography to predict mortality in patients with diabetes and known or suspected coronary artery disease.

OBJECTIVE: This study sought to determine whether stress echocardiography using exercise (when feasible) or dobutamine echo could be used to predict mortality in patients with diabetes. RESEARCH DESIGN AND METHODS: Stress echo was performed in 937 patients with diabetes (aged 59 +/- 13 years, 529 men) for symptom evaluation (42%) and follow-up of known coronary artery disease (CAD) (58%). Stress echocardiography using exercise was performed in 333 patients able to exercise maximally, and dobutamine echo using a standard dobutamine stress was used in 604 patients. Patients were followed for < or = 9 years (mean 3.9 +/- 2.3) for all-cause mortality. RESULTS: Normal studies were obtained in 567 (60%) patients; 29% had resting left ventricular (LV) dysfunction, and 25% had ischemia. Abnormalities were confined to one territory in 183 (20%) patients and to multiple territories in 187 (20%) patients. Death (in 275 [29%] patients) was predicted by referral for pharmacologic stress (hazard ratio [HR] 3.94, P < 0.0001), ischemia (1.77, P < 0.0001), age (1.02, P = 0.002), and heart failure (1.54, P = 0.01). The risk of death in patients with a normal scan was 4% per year, and this was associated with age and selection for pharmacologic stress testing. In stepwise models replicating the sequence of clinical evaluation, the predictive power of independent clinical predictors (age, selection for pharmacologic stress, previous infarction, and heart failure; model chi(2) = 104.8) was significantly enhanced by addition of stress echo data (model chi(2) = 122.9). CONCLUSIONS: The results of stress echo are independent predictors of death in diabetic patients with known or suspected CAD. Ischemia adds risk that is incremental to clinical risks and LV dysfunction.

Cohort Studies↗

PubMed2005

The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication.

CONTEXT: Prior evidence from twin studies suggested genetic moderation of the depressogenic effects of stressful life events (SLEs). Can the specific genes involved in this effect be identified? OBJECTIVE: To replicate and extend a recent study that a functional variant in the serotonin transporter (5-HTT) might in part explain these findings. DESIGN: Characterizing risk for major depression and generalized anxiety syndrome in the last year as a function of 5-HTT genotype, sex, and the occurrence of SLEs and ratings of the SLE-associated level of threat. SETTING: A population-based sample of adult twins. PARTICIPANTS: Five hundred forty-nine male and female twins with a mean age at participation of 34.9 years (SD 9.1). MAIN OUTCOME MEASURE: Episodes of major depression and generalized anxiety syndrome in the last year with onset measured to the nearest month. RESULTS: Individuals with 2 short (S) alleles at the 5-HTT locus were more sensitive to the depressogenic effects of all SLEs than were those with 1 or 2 long (L) alleles. When level of SLE-associated threat was examined, the interaction between genotype and SLE resulted from an increased sensitivity of SS individuals to the depressogenic effects of common low-threat events. These events had little impact on risk for those possessing the SL and LL genotypes. The 5-HTT genotype did not modify the effects of SLEs on risk for generalized anxiety syndrome. CONCLUSION: Variation at the 5-HTT moderates the sensitivity of individuals to the depressogenic effects of SLEs largely by producing, in SS individuals, an increased sensitivity to the impact of mild stressors. Replication of these intriguing results is needed.

Adult↗

PubMed2002

From heart attacks to melanoma: do common sense models of somatization influence symptom interpretation for female victims?

Common sense models regarding gender and stress influenced how laypeople responded to information about symptoms in 3 experiments. In Study 1, medical intervention was perceived to be less important for female targets reporting chest pain and stressful events than for male targets experiencing identical symptoms and stressors. In addition, chest pain was less likely to be attributed to cardiac causes for female targets. This gender-based stress-discounting effect was replicated for symptoms of gallstones and melanoma in Study 2, where participants again were less likely to recommend medical care for female than for male targets. Recognition memory for information about a somatizing target was tested in Study 3; results suggested that laypeople hold stereotypes associating somatization with female gender. The authors' findings provide insight into the naive theories that shape symptom interpretation and self-referral behavior.

Adolescent↗

PubMed2006

Phylogenetic comparisons of bacterial communities from serpentine and nonserpentine soils.

I present the results of a culture-independent survey of soil bacterial communities from serpentine soils and adjacent nonserpentine comparator soils using a variety of newly developed phylogenetically based statistical tools. The study design included site-based replication of the serpentine-to-nonserpentine community comparison over a regional scale ( approximately 100 km) in Northern California and Southern Oregon by producing 16S rRNA clone libraries from pairs of samples taken on either side of the serepentine-nonserpentine edaphic boundary at three geographical sites. At the division level, the serpentine and nonserpentine communities were similar to each other and to previous data from forest soils. Comparisons of both richness and Shannon diversity produced no significant differences between any of the libraries, but the vast majority of phylogenetically based tests were significant, even with only 50 sequences per library. These results suggest that most samples were distinct, consisting of a collection of lineages generally not found in other samples. The pattern of results showed that serpentine communities tended to be more similar to each other than they were to nonserpentine communities, and these differences were at a lower taxonomic scale. Comparisons of two nonserpentine communities generally showed differences, and some results suggest that the geographical site may control community composition as well. These results show the power of phylogenetic tests to discern differences between 16S rRNA libraries compared to tests that discard DNA data to bin sequences into operational taxonomic units, and they stress the importance of replication at larger scales for inferences regarding microbial biogeography.

Bacteria↗

PubMed2006

Circadian tempo: a paradigm for genome stability?

Circadian clocks are molecular time-keeping systems that underlie daily biological rhythms in anticipation of the changing light and dark cycles. These clocks mediate daily rhythms in physiology and behavior that are thought to confer an adaptive advantage for organisms. It is hypothesized that cell cycle checkpoints are gated to an intrinsic circadian clock to protect DNA from diurnal exposure to mutagens (e.g.; UV radiation peaks with daylight and dissolved genotoxins that fluctuate with feeding periods). It is proposed that DNA replication arrest in response to genotoxic stress is a likely basis for the evolution of circadian-gated DNA replication. This protective mechanism is highly conserved and can be traced along the evolutionary time-line to the early prokaryotes, unicellular eukaryotes and viruses. Peak DNA repair capacity is normally synchronous to the crest of mutagenic stress as they oscillate with respect to time. Mutator phenotypes with increased vulnerability to genotoxic stress may therefore develop when the circadian pattern of cell cycle control, DNA repair or apoptotic response are phase-shifted relative to the rhythm of mutagenic stress. The accumulating mutations would lead to accelerated aging, genome instability and neoplasia. The proposed model delineates areas of research with potentially profound implications for carcinogenesis.

Aging↗

PubMed2005

Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism unresponsive to dopaminergic therapy, cerebellar ataxia, and dysautonomia. Neuropathology shows a characteristic neuronal multisystem degeneration that is associated with widespread oligodendroglial alpha-synuclein (alpha-SYN) inclusions. Presently no animal model completely replicates the specific neuropathology of MSA. Here we investigated the behavioral and pathological features resulting from oligodendroglial alpha-SYN overexpression in transgenic mice exposed to mitochondrial inhibition by 3-nitropropionic acid. In transgenic mice 3-nitropropionic acid induced or augmented motor deficits that were associated with MSA-like pathology including striatonigral degeneration and olivopontocerebellar atrophy. Widespread astrogliosis and microglial activation were also observed in the presence of alpha-SYN in oligodendrocytes. Our results indicate that combined mitochondrial inhibition and overexpression of oligodendroglial alpha-SYN generates a novel model of MSA that may be useful for evaluating both pathogenesis and treatment strategies.

Animals↗