Novel HIV therapeutic strategies.
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Animals↗
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Role of RAS2 in recovery from chronic stress: effect on yeast life span.
The replicative life span of Saccharomyces cerevisiae was previously shown to be modulated by the homologous signal transducers Ras1p and Ras2p in a reciprocal manner. We have used thermal stress as a life span modulator in order to uncover functional differences between the RAS genes that may contribute to their divergent effects on life span. Chronic exposure of cells throughout life to recurring heat shocks at sublethal temperatures decreased their replicative life span. ras2 mutants, however, suffered the largest decrease compared to wild-type and ras1 mutant cells. The decrease was correlated with a substantial delay in resumption of budding upon recovery from these heat shocks, indicating an impaired renewal of cell cycling. Detailed analysis of gene expression showed that, during recovery, ras2 mutants were selectively impaired in down-regulation of stress-responsive genes and up-regulation of growth-promoting genes. Our results suggest that one of the functions of RAS2 in maintaining life span, for which RAS1 does not substitute, is to ensure renewal of growth and cell division after bouts of stress that cells encounter during their life. This activity of RAS2 is effected by the cyclic AMP pathway. Overexpression of RAS2, but not RAS2(ser42) which is deficient in the activation of adenylate cyclase, completely reversed the effect of chronic stress on life span. Thus, RAS2 is limiting for longevity in the face of chronic stress. Since RAS2 is known to down-regulate stress responses, this demonstrates that for longevity the ability to recover from stress is at least as important as the ability to mount a stress response.
Blotting, Northern↗
Disappearance of the telomere dysfunction-induced stress response in fully senescent cells.
Replicative senescence is a natural barrier to cellular proliferation that is triggered by telomere erosion and dysfunction. Here, we demonstrate that ATM activation and H2AX-gamma nuclear focus formation are sensitive markers of telomere dysfunction in primary human fibroblasts. Whereas the activated form of ATM and H2AX-gamma foci were rarely observed in early-passage cells, they were readily detected in late-passage cells. The ectopic expression of telomerase in late-passage cells abrogated ATM activation and H2AX-gamma focus formation, suggesting that these stress responses were the consequence of telomere dysfunction. ATM activation was induced in quiescent fibroblasts by inhibition of TRF2 binding to telomeres, indicating that telomere uncapping is sufficient to initiate the telomere signaling response; breakage of chromosomes with telomeric associations is not required for this activation. Although ATM activation and H2AX-gamma foci were readily observed in late-passage cells, they disappeared once cells became fully senescent, indicating that constitutive signaling from dysfunctional telomeres is not required for the maintenance of senescence.
Ataxia Telangiectasia Mutated Proteins↗
Repeated psychological stress testing in stimulant-dependent patients.
Decreasing response to stress has been one goal of interventions aimed at reducing relapse to substances of abuse. A laboratory stress test that can be repeated would be helpful in testing the efficacy of interventions in decreasing the response to stress before more extensive trials are begun. The effects of two types of psychological stress tests, the Trier Social Stress Test (TSST) and a stress imagery test, on psychological, physiological, and hormonal responses (salivary cortisol and DHEA) were examined when each test was given twice to cocaine- or methamphetamine-dependent human subjects, 24 of whom completed at least one session. The stress imagery test produced significant changes in several of the subjective response measures in both first and second sessions, including several measures of negative affect and a craving measure. The TSST produced significant changes only in the second session. The stress imagery protocol showed better replicability across two sessions. Cocaine users and methamphetamine users did not respond similarly in their craving responses. Reported craving for methamphetamine after stress testing showed decreases or much smaller increases compared to that for cocaine. Neither stress test significantly increased salivary cortisol or DHEA, and changes in hormone concentrations were not related to subjective responses. These results suggest that stress imagery testing procedures may be useful as provocative tests of stress-induced affect and stimulant drug craving. Although less convincing because of the heterogeneity of the subjects, they also suggest that HPA axis responsivity is not clearly linked to acute stress-induced stimulant craving or affective response.
Affect↗
Role of lymphocyte multidrug resistance protein 1 in HIV infection: expression, function, and consequences of inhibition.
The multidrug resistance protein 1 (MRP1) is a drug transporter that protects cells from oxidative stress, which increases HIV-1 replication. The aim of this study was to characterize the expression, function, and role of lymphocyte MRP1 in HIV-1 infection and its modulation by antiretroviral drugs such as the protease inhibitors (PIs). Peripheral blood mononuclear cells (PBMCs) from HIV-positive individuals do not show significant alterations of MRP1 expression despite highly active antiretroviral therapy and HIV plasma viral load levels; however, they exhibit different intracellular MRP1 expression as compared with healthy subjects. By contrast, MRP efflux function is increased in subjects with primary HIV infection and becomes defective in later stages of the infection. PI- and probenecid (PBCD)-mediated inhibition of MRP lowers the in vitro stress-induced response of lymphoid cells by reducing the level of the specific reactive oxygen species superoxide anion and hydrogen peroxide. Finally, the blockade of MRP by PBCD and PIs down-modulates HIV-1 replication by a mechanism independent of inhibition of the HIV-1 protease. Our results are consistent with a model wherein HIV replication is favored by the MRP1-related oxidative stress and inhibition of MRP1 may contribute to the antiviral activity of PIs.
Acquired Immunodeficiency Syndrome↗
Low urinary cortisol excretion in patients with posttraumatic stress disorder.
In the present study, we replicated and extended our previous findings of low urinary free-cortisol levels in PTSD. Cortisol was measured in 16 male patients (nine inpatients, seven outpatients) with posttraumatic stress disorder (PTSD) and in 16 nonpsychiatric control subjects. The mean cortisol level in the PTSD group was significantly lower, and the range narrower, than that observed in control subjects. Low cortisol in PTSD did not seem to be related to the presence or absence of major depressive disorder or to overall psychiatric symptomatology as assessed by the sum Brief Psychiatric Rating Scale score. In the outpatient group, there was a relationship between PTSD symptomatology and cortisol levels. The findings suggests a physiological adaptation of the hypothalamic-pituitary-adrenal axis to chronic stress.
Adult↗
Dietary cation-anion balance and cation source effects on production and acid-base status of heat-stressed cows.
Two 4 x 4 replicated Latin square studies, each containing 8 lactating Holstein cows, were conducted simultaneously in south Georgia during the summer. The effects of dietary cation source (Na or K) and increasing dietary cation-anion balance (milliequivalents of Na + K - Cl per kilogram of feed DM) within cation source (control = 120.4 meq/kg of feed DM; Na source = 219.7, 347.8, 464.1 meq/kg of feed DM; K source = 231.2, 352.6, 456.0 meq/kg of feed DM) were determined on performance and acid-base chemistry during hot, humid weather. Cow body temperatures were elevated by environmental conditions but were not affected by dietary cation-anion balance. Differences in body temperature from dietary cation source probably were related to differences in cow BW. Intake of DM increased linearly, but yields of milk and FCM did not change with increasing dietary cation-anion balance, and cation source had no effect. Milk fat and protein percentages were not altered by dietary cation-anion balance, and greater milk fat and protein percentages from cows offered the Na versus K source diets probably were due to differences between cows in the two Latin squares. Alterations in blood acid-base chemistry with increasing dietary cation-anion balance were as expected. Greater blood buffering capacity, indicated by blood base excess and bicarbonate content, may be responsible for the improved feed intake.
Acid-Base Equilibrium↗
Brown widow (Latrodectus geometricus) major ampullate silk protein and its material properties.
Major ampullate (dragline) silk is the main web component as well as the silk that spiders use for a lifeline when they fall. This silk has a breaking stress of 4.6 GPa, which is similar to that of Kevlar. The majority of the previous mechanical testing studies involved the major ampullate silk from orb-weaving spiders. To date, there have been no reports on dragline silk mechanical properties from a cob-weaver, brown widow Latrodectus geometricus. L. geometricus dragline was found to be composed of MaSp1, MaSp2, and MaSp-like proteins all of which have highly conserved amino acid motifs, especially the GGX, GA and poly A for MaSp1 and GPGGX and poly A for MaSp2. These sequences are the same as those found in the silks of orb-weaving spiders. To determine if protein sequences influence the material properties of the silk, mechanical testing was performed on single strands of silk fibers from adult female L. geometricus spiders. The 3 cm long silk fibers were tested for breaking stress and strain with a MTS Synergie 100 mechanical testing system using a 50 g load cell with the cross-head speed set at 10 mm/min. The breaking stress and strain were measured for 20 replicate samples and averaged. The values of 0.83 +/- 0.19 GPa for stress and 0.14 +/- 0.06 for strain shows that brown widow dragline is weaker than the orb-weaving spiders.
Animals↗
Phosphorylation of Rad55 on serines 2, 8, and 14 is required for efficient homologous recombination in the recovery of stalled replication forks.
DNA damage checkpoints coordinate the cellular response to genotoxic stress and arrest the cell cycle in response to DNA damage and replication fork stalling. Homologous recombination is a ubiquitous pathway for the repair of DNA double-stranded breaks and other checkpoint-inducing lesions. Moreover, homologous recombination is involved in postreplicative tolerance of DNA damage and the recovery of DNA replication after replication fork stalling. Here, we show that the phosphorylation on serines 2, 8, and 14 (S2,8,14) of the Rad55 protein is specifically required for survival as well as for normal growth under genome-wide genotoxic stress. Rad55 is a Rad51 paralog in Saccharomyces cerevisiae and functions in the assembly of the Rad51 filament, a central intermediate in recombinational DNA repair. Phosphorylation-defective rad55-S2,8,14A mutants display a very slow traversal of S phase under DNA-damaging conditions, which is likely due to the slower recovery of stalled replication forks or the slower repair of replication-associated DNA damage. These results suggest that Rad55-S2,8,14 phosphorylation activates recombinational repair, allowing for faster recovery after genotoxic stress.
Adenosine Triphosphatases↗
Herpesvirus quiescence in neuronal cells: antiviral conditions not required to establish and maintain HSV-2 quiescence.
We previously described a novel in vitro model of a non-productive herpes simplex virus type 1 (HSV-1) infection in neurally differentiated (ND)-PC12 cells that allows for inducible virus replication upon forskolin and heat stress (HS) treatment. In this research, we further characterized the model with respect to HSV-2 strain 333. We found that: (i) ND-PC12 cells are non-permissive to HSV-2 replication; (ii) HSV-2 can establish a quiescent infection, like HSV-1, in ND-PC12 cells with the transient use of acycloguanosine (ACV); however unlike HSV-1, anti-viral conditions are not obligatory to establish and maintain a quiescent state; (iii) the quiescent state is maintained in the presence of Vero cell cocultivation indicating that such cultures are free of infectious virus; and (iv) a high percentage of quiescently infected (QIF)-PC12 cell cultures (80 - 100%) produce HSV-2 in response to forskolin and HS (43 degrees C, 3 h) treatment for as long as 4 weeks post infection. These findings indicate that ND-PC12 cells can harbor HSV-2 in a cryptic and non-productive state that is reversible. This model has appealing features for studying gene expression during the establishment, maintenance and reactivation phases of the HSV-2 quiescent state in cell culture.
Acyclovir↗
A model integrating risk variables involved in the development of the schizophrenia spectrum.
A theoretical model of the etiology of schizophrenia, the schizophrenia spectrum, and normal development is proposed. This model is based upon replicated research. A selected review of the literature on the etiology of schizophrenia indicated that schizophrenia may be a developmental disorder of the quality of attachment interacting with the development of the reticulothalamocortical system, beginning in the earliest months of life. A genotype, phenocopy, and stress are specified, based upon replicated research results. We hypothesize that schizophrenia results from a continuing malforming transaction, beginning at birth, between a temperament genotype of a sensitive, easily aroused to high peaks of arousal baby and an environmental stress of an unempathic/insensitive, physically rejecting, noncontingent mother. This results in a classical conditioning paradigm wherein people become an aversive stimulus for an anxiously/avoidant attached infant. This anxious/avoidant response may have permanent biochemical and structural effects. It is also hypothesized that the same genotype interacting with an empathic, sensitive, physically affectionate, contingent mother may also account for artistically or musically creative superphrenics.
Adolescent↗
Predeployment personality traits and exposure to trauma as predictors of posttraumatic stress symptoms: a prospective study of former peacekeepers.
OBJECTIVE: The authors' goal was to study the contribution of predeployment personality traits and exposure to traumatic events during deployment to the development of symptoms of posttraumatic stress disorder (PTSD) in individuals involved in military peacekeeping activities. METHOD: Five hundred seventy-two male veterans who participated in the United Nations Protection Force mission in the former Yugoslavia completed a short form of the Dutch MMPI before deployment. Following deployment, they participated in a survey of all Dutch military veterans who had been deployed in the years 1990-1995 and completed the Self-Rating Inventory for PTSD. RESULTS: Exposure to traumatic events during deployment had the highest unique contribution to the prediction of PTSD symptom severity, followed by the personality traits of negativism and psychopathology, followed by age. CONCLUSIONS: Both pretrauma vulnerabilities and exposure to traumatic events were found to be important factors in the etiology of posttraumatic stress symptoms. The current study replicates in a non-American sample of peacekeepers findings obtained among American Vietnam veterans. Particularly, there is accumulating evidence for an etiological role of the personality trait of psychoneuroticism in the development of posttraumatic stress symptoms.
Adolescent↗
[Effects of baisong tablets on the behavior and levels of norepinephrine and dopamine in the brain of stress rats].
OBJECTIVE: To explore the effects of baisong tablets on the behavior and contents of norepinephrine and dopamine in the brain of stress rats. METHODS: Forty adult Sprague-Dawley male rats were randomly divided into 4 groups: the control group, the depression model group, the baisong tablet group and the fluoxetine group. The depression model was replicated by chronic unpredictable mild stress and single house in 21 days. Ten rats as a group were treated with baisong tablets or fluoxetine hydrochloride. Changes of behaviors were observed by open-field test and the volume of sugar-solution the rat drank in 24 hours. The weight increase was also observed. The levels of norepinephrine and dopamine in the brain in each group were detected with high-pergomance liquid chromatography. RESULTS: Compared with the model group, baisong tablets could improve the depressive behaviors significantly, and increase the levels of norepinephrine and dopamine in the rat brain. CONCLUSION: Baisong tablets can improve the depressive behaviors and increase the levels of 5-hydroxytryptaimne and dopamine in the brain of stress rats.
Animals↗
Signal transduction in H2O2-induced senescence-like phenotype in human diploid fibroblasts.
A stress-induced senescence-like phenotype is induced by exposure of human diploid fibroblasts to subcytotoxic H2O2 stress. Previous studies showed that TGF-beta1 is responsible for the induction of several biomarkers of replicative senescence within 72 h after stress: senescence-like morphology, senescence-associated beta-galactosidase activity, and an increase in the mRNA steady state level of four senescence-associated genes. Other studies showed that the retinoblastoma protein is responsible for the appearance of these biomarkers in the same conditions. Here we show that sustained p38(MAPK) phosphorylation is responsible for both H2O2-induced overexpression of TGF-beta 1 and subsequent TGF-beta 1-induced appearance of these biomarkers. p38(MAPK) phosphorylation is shown to be necessary for a self-sustained TGF-beta 1 overexpression after H2O2 stress through the activation of ATF-2 transcription factor, thereby creating a regulatory loop between sustained p38(MAPK) activation and sustained TGF-beta 1 overexpression after stress. p38(MAPK) activation is also shown to be responsible in part for the growth arrest observed in stress-induced senescence-like phenotype. At 48 h after stress, ATF-2 starts to interact with hypophosphorylated Rb, which allows the biomarkers of stress-induced senescence-like phenotype to appear. This report gives an overall explanation of how a senescence-like phenotype is established after subcytotoxic H2O2 stress.
Activating Transcription Factor 2↗
Effect of a single ethanol exposure on HIV replication in human lymphocytes.
BACKGROUND: Alcoholism is known to cause perturbations in cellular and humoral immunity, and some data suggest that acute alcohol ingestion enhances HIV replication in the lymphocytes of drinkers. METHODS: To study the acute effects of alcohol ingestion on HIV replication, oral ethanol (1 g/kg) was administered to 12 healthy volunteers in a controlled clinical setting. In vitro replication of HIV in the subjects' cultured lymphocytes and changes in lymphocyte phenotypes were evaluated. RESULTS: Statistically significant increases in peripheral lymphocytes and natural killer cell numbers were identified after the initial ethanol trial. HIV replication also increased in the isolated lymphocytes of some subjects after ethanol ingestion, but most subjects in the second trial showed essentially no changes in any of these parameters. CONCLUSIONS: Our results are consistent with either a subtle, study-induced stress-related enhancement in HIV replication or significant individual variation in response to ethanol. The results do not provide evidence for a general increase in HIV replication in the lymphocytes of subjects following a single in vivo ethanol dose of 1 g/kg.
Adult↗
Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway.
Hepatitis C virus (HCV) replicates from a ribonucleoprotein (RNP) complex that is associated with the endoplasmic reticulum (ER) membrane. The replication activities of the HCV subgenomic replicon are shown here to induce ER stress. In response to this stress, cells expressing HCV replicons induce the unfolded protein response (UPR), an ER-to-nucleus intracellular signaling pathway. The UPR is initiated by the proteolytic cleavage of a transmembrane protein, ATF6. The resulting cytoplasmic protein fragment of ATF6 functions as a transcription factor in the nucleus and activates selective genes required for an ER stress response. ATF6 activation leads to increased transcriptional levels of GRP78, an ER luminal chaperone protein. However, the overall level of GRP78 protein is decreased. While ER stress is also known to affect translational attenuation, cells expressing HCV replicons have lower levels of phosphorylation of the alpha subunit of eukaryotic initiation factor 2. Interestingly, cap-independent internal ribosome entry site-mediated translation directed by the 5' noncoding region of HCV and GRP78 is activated in cells expressing HCV replicons. These studies provide insight into the effects of HCV replication on intracellular events and the mechanisms underlying liver pathogenesis.
Activating Transcription Factor 6↗
Microsatellite diversity correlated with ecological-edaphic and genetic factors in three microsites of wild emmer wheat in North Israel.
This study was conducted to test the effects of internal (genetic) and external factors on allelic diversity at 27 dinucleotide microsatellite (simple sequence repeat [SSR]) loci in three Israeli natural populations of Triticum dicoccoides from Ammiad, Tabigha, and Yehudiyya, north of the Sea of Galilee. The results demonstrated that SSR diversity is correlated with the interaction of ecological and genetic factors. Genetic factors, including genome (A vs. B), chromosome, motif, and locus, affected average repeat number (ARN), variance in repeat number (sigma), and number of alleles (NA) of SSRs, but the significance of some factors varied among populations. Genome effect on SSR variation may result from different motif types, particularly compound (or imperfect) versus perfect motifs, which may be related to different evolutionary histories of genomes A and B. Ecological factors significantly affected SSR variation. Soil-unique and soil-specific alleles were found in two edaphic groups dwelling on terra rossa and basalt soils across macro- and microgeographical scales. The largest contributions of genetic and ecological effects were found for diversity of ARN and NA, respectively. Multiple regression indicated that replication slippage and unequal crossing over could be important mutational mechanisms, but their significance varied among motifs. Edaphic stresses may affect the probability of replication errors and recombination intermediates and thus control diversity level and divergence of SSRs. The results may indicate that SSR diversity is adaptive, channeled by natural selection and influenced by both internal and external factors and their interactions.
Dinucleotide Repeats↗
[New insights into the molecular mechanisms of evolution: stress increases genetic diversity].
The mechanisms of stress-induced mutagenesis in prokaryotes and realization of reserved (preaccumulated) genetic variation in eukaryotes are considered. In prokaryotes, replication becomes error-prone in stress because of the induction of the SOS response and the inactivation of the mismatch repair system; stress also increases the transposition rate and the efficiency of interspecific gene transfer. In eukaryotes, chaperone HSP90, which restores the native folding of mutant proteins (e.g., signal transduction and morphogenetic proteins) in normal conditions, fails to do so in stress, which leads to abrupt expression of multiple mutations earlier reserved in the corresponding genes. The role of these mechanisms in the evolution of prokaryotes and eukaryotes is discussed.
Adaptation, Physiological↗