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Mitochondrial DNA replication, nucleoside reverse-transcriptase inhibitors, and AIDS cardiomyopathy.

Nucleoside reverse-transcriptase inhibitors (NRTIs) in combination with other antiretrovirals (HAART) are the cornerstones of current AIDS therapy, but extensive use brought mitochondrial side effects to light. Clinical experience, pharmacological, cell, and molecular biological evidence links altered mitochondrial (mt-) DNA replication to the toxicity of NRTIs in many tissues, and conversely, mtDNA replication defects and mtDNA depletion in target tissues are observed. Organ-specific pathological changes or diverse systemic effects result from and are frequently attributed to HAART in which NRTIs are included. The shared features of mtDNA depletion and energy depletion became key observations and related the clinical and in vivo experimental findings to inhibition of mtDNA replication by NRTI triphosphates in vitro. Subsequent to those findings, other observations suggested that mitochondrial energy deprivation is concomitant with or the result of mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself.

Acquired Immunodeficiency Syndrome↗

PubMed2005

A novel in vitro and numerical analysis of shear-induced drug release from extended-release tablets in the fed stomach.

PURPOSE: To design an in vitro apparatus that could simulate the in vivo range of surface shear stresses relevant for the human stomach under fed conditions. METHODS: Computer simulations were combined with in vitro experiments to quantify tablet erosion rate vs. surface shear stress. From two separate computer models, of tablets in the fed stomach and of tablets in vitro, we first estimated the intragastric range of surface stress and Reynolds number (Re), and then designed a dissolution apparatus and parameter space to replicate the in vivo conditions. The in vitro tablet erosion was determined by a new rotating beaker apparatus that provided predictable surface shear on tablets. Tablet mass erosion rates were measured for two different extended-release tablets at a range of in vivo relevant surface shear stresses obtained by varying viscosity of test media and rotation rate of the beaker. RESULTS: Mass erosion rate and surface shear were found to be highly correlated. Erosion rate increased with surface shear more rapidly at "low" stresses (<35 dyne/cm2) independent of tablet material. At higher surface stress, erosion was strongly material dependent. CONCLUSIONS: Shear force effects on drug release from matrix tablets relevant for fed state are for the first time possible to predict by in vitro dissolution testing.

Algorithms↗

PubMed1986

Nuclear patterns of cyclin (PCNA) antigen distribution subdivide S-phase in cultured cells--some applications of PCNA antibodies.

Immunofluorescence studies using PCNA autoantibodies specific for the proliferation-sensitive protein cyclin have revealed dramatic changes in the nuclear distribution of this protein during the S-phase of normal and transformed cells. Patterns of cyclin antigen distribution subdivide S-phase and have provided new cell cycle landmarks. Some of these (nucleolar exclusion or staining), mimic topographical patterns of DNA synthesis thus arguing for a role of this protein in some specific aspect of DNA replication. Cells outside S-phase (G0 included) stain only weakly with PCNA antibodies, stressing the usefulness of this reagent for identifying proliferating cells (S-phase cells) of both normal and malignant origins.

Animals↗

PubMed1991

Negative affectivity as the underlying cause of correlations between stressors and strains.

The extent to which negative affectivity (NA), the tendency to experience a wide range of negative emotions, inflated correlations between chronic job stressors and strains was examined in this study. NA was found to account for a large proportion of shared variance between stressors and physical strains (as indicated by absence, doctor visits, and physical symptoms). Contrary to the results of Brief, Burke, George, Robinson, and Webster (1988), NA did not account for much of the variance shared by stressors and affective strains (job satisfaction, anger, and feelings of stress and frustration). Reasons for the failure of this and several earlier studies to successfully replicate Brief et al.'s results are explored.

Adolescent↗

PubMed2026

Distinct STRIPAK subunits drive conserved and subunit-specific signaling programs in Cryptococcus neoformans.

The striatin-interacting phosphatase and kinase (STRIPAK) complex is a conserved protein phosphatase 2A (PP2A)-associated signaling hub that integrates kinase-phosphatase networks, yet its roles in human fungal pathogens remain poorly defined. Here, we dissected STRIPAK functions in the opportunistic pathogen Cryptococcus neoformans by combining genetic, genomic, virulence, and phosphoproteomic analyses across mutants lacking individual STRIPAK subunits. Loss of the core STRIPAK components via PPH22, FAR8, FAR9, or FAR11 mutations caused severe defects in growth, stress adaptation, cell cycle progression, and morphogenesis, accompanied by widespread aneuploidy and genome instability. In murine infection models, far11Δ strains were avirulent, whereas far9Δ mutants caused delayed but ultimately fatal disease and underwent host-associated genome remodeling, with recovered isolates exhibiting chromosome 11 amplification despite no consistent in vitro fitness advantage. In contrast, deletion of MOB3 produced a hypervirulent phenotype. mob3Δ cells exhibited enhanced transmigration across an in vitro blood-brain barrier model, increased survival in macrophages, and generated small-cell morphotypes, features associated with increased dissemination. Phosphoproteomic profiling revealed extensive and overlapping phosphorylation changes among core STRIPAK mutants, affecting pathways involved in signaling, cytoskeletal, cell cycle control, chromatin regulation, RNA metabolism, and stress responses. Conversely, mob3Δ mutants displayed a smaller, largely distinct phosphoproteomic signature. Network and functional enrichment analyses highlighted STRIPAK-dependent regulation of TORC2-associated signaling, MAPK/GTPase signaling, autophagy, nuclear transport, RNA processing, DNA replication, and ribosome biogenesis. Together, these findings establish STRIPAK as a coordinator of genome stability, morphological plasticity, stress adaptation, and virulence in C. neoformans, and demonstrate that individual STRIPAK subunits drive shared yet divergent signaling outputs that shape host-pathogen interactions.IMPORTANCEFungal pathogens must rapidly adapt their growth, morphology, and stress responses to survive within the host, requiring precise coordination of cellular signaling pathways. The conserved striatin-interacting phosphatase and kinase (STRIPAK) complex controls key developmental programs in eukaryotes, but its roles in fungal pathogenesis are not fully defined. We previously showed that STRIPAK is important for genome stability, development, and virulence in the opportunistic human fungal pathogen Cryptococcus neoformans. Here, we define how individual STRIPAK subunits differentially regulate fungal morphogenesis, genome plasticity, host adaptation, and virulence, revealing both shared and subunit-specific functions within this conserved signaling complex. Core STRIPAK mutants exhibit severe growth and stress-response defects and attenuation of virulence, whereas loss of the Mob3 subunit promotes hypervirulence by enhancing dissemination and persistence within the host. Phosphoproteomic profiling reveals that individual STRIPAK components exert shared yet distinct control over phosphorylation networks that shape host-pathogen interactions, establishing STRIPAK as a central signaling hub and a potential target for antifungal intervention.

Cryptococcus neoformans↗

PubMed2026

Distinct STRIPAK subunits drive conserved and subunit-specific signaling programs in Cryptococcus neoformans.

The striatin-interacting phosphatase and kinase (STRIPAK) complex is a conserved PP2A-associated signaling hub that integrates kinase-phosphatase networks, yet its roles in human fungal pathogens remain poorly defined. Here, we dissected STRIPAK functions in the opportunistic pathogen Cryptococcus neoformans by combining genetic, genomic, virulence, and phosphoproteomic analyses across mutants lacking individual STRIPAK subunits. Loss of the core STRIPAK components via PPH22, FAR8, FAR9, or FAR11 mutations caused severe defects in growth, stress adaptation, cell-cycle progression, and morphogenesis, accompanied by widespread aneuploidy and genome instability. In murine infection models, far11Δ strains were avirulent, whereas far9Δ mutants caused delayed but ultimately fatal disease and underwent host-associated genome remodeling, with recovered isolates exhibiting chromosome 11 amplification despite no consistent in vitro fitness advantage. In contrast, deletion of MOB3 produced a hypervirulent phenotype. mob3Δ cells exhibited enhanced transmigration across an in vitro blood-brain barrier model, increased survival in macrophages, and generated small-cell morphotypes, features associated with increased dissemination. Phosphoproteomic profiling revealed extensive and overlapping phosphorylation changes among core STRIPAK mutants, affecting pathways involved in signaling, cytoskeletal and cell-cycle control, chromatin regulation, RNA metabolism, and stress responses. Conversely, mob3Δ mutants displayed a smaller, largely distinct phosphoproteomic signature. Network and functional enrichment analyses highlighted STRIPAK-dependent regulation of TORC2-associated signaling, MAPK/GTPase signaling, autophagy, nuclear transport, RNA processing, DNA replication, and ribosome biogenesis. Together, these findings establish STRIPAK as a coordinator of genome stability, morphological plasticity, stress adaptation, and virulence in C. neoformans, and demonstrate that individual STRIPAK subunits drive shared yet divergent signaling outputs that shape host-pathogen interactions.

Journal Article↗

PubMed1999

Mechanisms of cancer chemoprevention in hepatic carcinogenesis: modulation of focal lesion growth in mice.

Studies in our laboratory have concentrated on further understanding the mechanism by which chemicals induce cancer and the means to prevent or retard this process. Recent investigations have revolved around the role of oxidative stress and oxidative damage in the induction of cancer by nongenotoxic carcinogens. Hepatocarcinogenic compounds including selective chlorinated hydrocarbons appeared to induce oxidative stress in the liver. This oxidative stress and oxidative damage in turn may be responsible for the tumor-promoting activity of these compounds. Reduction of oxidative damage by antioxidants, or dietary-restriction, results in an ablation of the induction of selective cell growth by these agents. The oxidative stress induced by nongenotoxic agents may influence cell proliferation and/or apoptosis in the preneoplastic cells. Our studies with nongenotoxic hepatic carcinogens showed a dose-dependent increase in oxidative stress and an increase in hepatic focal lesion growth. Antioxidant dietary supplementation or caloric restriction prevented the lesion growth. This appeared to be through an increase in apoptosis in the hepatic lesions.

Animals↗

PubMed2002

[Correlation of length of vascular segment in vitro with endothelin-1 metabolism of endothelial cells--study on accumulative effect of tensile stress in the upper endothelial cell membrane. III].

A few of flow experiments were utilized to verify a theoretical hypothesis proposed by Fung and coworker which showed that the tensile stress in the upper cell membrane of the vascular endothelium could accumulate upstream against the direction of blood flow. Endothelial cells from replicate human umbilical vein segment (HUVSEC) in vitro with length of 11 cm and 21 cm were exposed to the same pulsatile laminar shear stress averaged of 0.12 N/m2 for 42 hours. The average production rate of endothelin-1(ET-1), at 11 cm segment is 50% lower than that at 21 cm segment(16.93 +/- 0.89) vs. (26.13 +/- 1.79) pg/cm2.h respectively. The average production rate of ET-1 under pulsatile laminar flow was significantly higher than that under steady laminar flow. It showed that, high correlation of the length of HUVSEC with their ET-1 metabolism exists, suggesting that the tensile stress in the upper endothelial cell membrane could accumulate.

Cell Membrane↗

PubMed1993

Replication of damaged DNA and the molecular mechanism of ultraviolet light mutagenesis.

On UV irradiation of Escherichia coli cells, DNA replication is transiently arrested to allow removal of DNA damage by DNA repair mechanisms. This is followed by a resumption of DNA replication, a major recovery function whose mechanism is poorly understood. During the post-UV irradiation period the SOS stress response is induced, giving rise to a multiplicity of phenomena, including UV mutagenesis. The prevailing model is that UV mutagenesis occurs by the filling in of single-stranded DNA gaps present opposite UV lesions in the irradiated chromosome. These gaps can be formed by the activity of DNA replication or repair on the damaged DNA. The gap filling involves polymerization through UV lesions (also termed bypass synthesis or error-prone repair) by DNA polymerase III. The primary source of mutations is the incorporation of incorrect nucleotides opposite lesions. UV mutagenesis is a genetically regulated process, and it requires the SOS-inducible proteins RecA, UmuD, and UmuC. It may represent a minor repair pathway or a genetic program to accelerate evolution of cells under environmental stress conditions.

DNA Damage↗

PubMed2005

Dimensionality of the posttraumatic stress response among police officers and fire fighters: an evaluation of two self-report scales.

Confirmatory factor analyses were done to assess the dimensionality of the stress response in a sample of police officers and fire fighters (n = 1,168) involved in the 1992 air disaster in Amsterdam. The confirmatory factor analyses were applied to the responses on two psychometrically different instruments, i.e., the Self-Rating Inventory for Posttraumatic Stress Disorder (SRIP) and the Impact of Event Scale (IES). The previously found distinction between (active) avoidance and numbing in samples highly affected by posttraumatic stress disorder appears to be applicable to the stress response of a less affected sample. For the SRIP, a five-factor structure (i.e., intrusion, avoidance, hyperarousal, emotional numbing and sleep disturbance) appeared to fit slightly better than the four-factor structures from previous findings. For the IES, our results replicated findings of a four-dimensional structure (i.e., intrusion, avoidance, numbing and sleep disturbance) underlying the posttraumatic stress response. The factors of the best-fitting structure of both instruments proved reliable. Due to the psychometric properties of the two instruments, the relationship between similar factors in both instruments was only low to moderate. Compared with the IES, factors of the SRIP were, however, less discriminative from other symptoms of psychopathology. Replication in different traumatized or community samples is recommended.

Adult↗

PubMed2004

Metabolic and endocrine consequences of social stress in a visible burrow system.

The visible burrow system (VBS) is an ethologically relevant model of social stress, which has been used to study the aggression of male rats in a social context. Previous studies using the VBS have established physiological, endocrine, and neurochemical characteristics associated with chronic social stress in dominant and subordinate animals. A critical criterion in establishing an animal model for research is the replication of findings and the independent validation of the model. Here, we independently confirm previously reported findings and include novel control groups that are important in dissociating the effects of chronic social stress from those resulting from group-housing the male rats in an "enriched environment". Furthermore, we show that whereas the VBS model is useful for males, it is not effective for studies of females because they do not form dominance hierarchies when housed in groups. We also extend the use of the VBS model to examine the etiology of stress-induced anorexia and obesity, finding that weight loss in subordinate rats is attributable to decreased adipose and lean tissue, whereas in dominant rats, it is associated only with adipose tissue loss. Consistent with this, the adiposity hormones leptin and insulin are decreased in subordinates and, to a lesser extent, in dominants, compared with the controls. In summary, the VBS model of chronic social stress is an ethologically relevant animal model and provides a valuable tool for studies of stress-related conditions and pathologies.

Aggression↗

PubMed2004

Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage.

Ground glass hepatocytes (GGHs) are the historic hallmarks for the hepatocytes in the late and non-replicative stages of hepatitis B virus (HBV) infection. We have identified type I and type II GGHs that contain two mutant types of large HBV surface antigens (HBsAg) with deletions over the pre-S1 and pre-S2 regions, respectively. These pre-S mutant HBVsAg accumulate in endoplasmic reticulum (ER), resulting in strong ER stress. Type II GGHs often appear in hepatic nodules in the late phases of HBV infection and proliferate in clusters, suggesting that these mutant pre-S1/S2 HBsAg may be involved in HBV-related hepatocarcinogenesis, associated with ER stress. In this study, we investigated the potential genomic instability imposed by pre-S mutant HBsAg. Based on the analysis of comet assays, we found that the pre-S1 and pre-S2 mutant HBsAg caused oxidative stress and DNA damage. The DNA repair gene ogg1 was greatly induced by over-expression of pre-S mutant HBsAg. Induction of the DNA repair gene ogg1 was also detected in the pre-S2 HBsAg transgenic mice, as well as the type II GGHs from patients with hepatocellular carcinoma, strongly suggesting that the pre-S mutant HBsAg contributes to the oxidative DNA damage to hepatocytes. In addition, the mutation rates in the X-linked hprt gene were enhanced in mouse hepatoma ML1-4a cells, which constitutively expressed the pre-S1/S2 HBsAg. These results indicate that pre-S1/S2 mutant HBsAg, which make up GGHs, induce oxidative DNA damage and mutations in hepatocytes in the late stages of HBV infection.

Animals↗

PubMed1998

Involvement of topoisomerases in the initiation of simian virus 40 minichromosome replication.

Topoisomerases provide the unlinking activity necessary for replication fork movement during DNA replication. It is uncertain, however, whether topoisomerases are also required for the initiation of replication. To investigate this point, we have performed pulse-chase experiments with SV40 minichromosomes as template to distinguish between the initiation and the elongation of replication. Using an unfractionated cytosolic extract as a source of replication functions, we found that the addition of topoisomerases at the initiation step significantly increased the number of active chromatin templates, whereas addition of topoisomerases at the elongation step had only minor effects. Minichromosomes with an extended chromatin structure as well as protein-free DNA required less topoisomerase for effective replication initiation. We could exclude the possibility that topoisomerases enhance the origin binding of T antigen, the SV40 replication initiator, and propose instead that the arrangement of nucleosomes influences the diffusion of supercoils during initial DNA unwinding. Efficient initiation therefore requires a high local concentration of topoisomerases to relax the torsional stress.

Antigens, Viral, Tumor↗

PubMed1989

Economic stress and suicide: multilevel analyses. Part 1: Aggregate time-series analyses of economic stress and suicide.

Of the research on health and economic stress, the approach that has produced the strongest findings has been the aggregate time-series analysis of unemployment and suicide rates. A review of the literature indicates that this aggregate work has been disputed on both methodological and interpretive grounds. To address these issues, two studies of the relationship between economic stress and suicide were conducted on the same population. The first, reported in this paper (Part 1), replicated the aggregate time-series work with improvements in method, using monthly data for 1975-1982 for Los Angeles. A second study (reported in Part 2) combined aggregate economic indicators with individual-level measures of stressful events, symptoms, and suicidal ideation.

Adult↗

PubMed2005

A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress.

Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.

Animals↗

PubMed1989

Effect of experimental stress on masseter and temporalis muscle activity in human subjects with temporomandibular disorders.

Temporomandibular (TM) disorders have an uncertain aetiology. The purpose of this study was to replicate and extend the work of Yemm (1969) (Archs oral Biol. 14, 873-878, 1437-1439; Br. dent. J. 127, 508-510), who reported a lack of habituation to experimentally induced stress in subjects with TM disorders. In this study, 20 TM disorder patients and 20 controls, matched for age and sex, performed a timed psychomotor task while bilateral masseter and anterior temporalis electromyographic (EMG) activity, finger temperature and skin admittance were monitored. These data were sampled, stored every 4s and averaged by an Apple II Plus/ISAAC interface. A significant trials effect for finger temperature (F[4/152] = 34.99, p less than 0.001) and skin admittance (F[4/152] = 41.90, p less than 0.001) was found, suggesting that the independent variable (stress) had been successfully manipulated. A significant trials by groups effect was found for right temporalis EMG activity (F[3/144] = 3.94, p less than 0.05); the left temporalis showed a similar, but not significant, trend. The masseter muscles did not show differences or trends between groups. No significant differences were found in resting EMG levels or in the initial magnitude of EMG responses during baseline. These results provide support for the hypothesis that TM disorder and control groups respond differently to stress in terms of habituation to stressful stimuli.

Adolescent↗

PubMed1999

Phenotypic modulation by intracellular bacterial pathogens.

Microorganisms have the capacity to sense their environment and to respond to it by alteration in gene expression and protein synthesis. Two-dimensional electrophoresis (2-DE) provides a powerful tool to examine the global response in bacterial protein synthesis upon exposure to different environmental signals. One of the most complex environments encountered by facultative intracellular pathogenic bacteria is the intracellular environment of the host cell. Numerous studies have documented that intracellular bacterial pathogens that replicate within phagosomes are simultaneously exposed to multiple signals and they respond to them by a global alteration in protein synthesis that involves elevated levels of several stress-induced proteins. This stress response is manifested regardless of the nature or the stage of maturation of the phagosome of different intracellular pathogens. In contrast, intracellular bacterial pathogens that replicate within the cytoplasm undergo phenotypic modulation in response to the cytoplasmic environment, but their responses do not include elevated levels of stress-induced proteins. This review describes the use of 2-DE to examine bacterial phenotypic modulation in response to the intracellular environment and contrasts this response between three intracellular pathogens; Legionella pneumophila, Salmonella typhimurium, and Listeria monocytogenes. The Legionella pneumophila phagosome is completely blocked from maturation through the endosomal lysosomal pathway but the S. typhimurium phagosome is a specialized compartment that has partial characteristics of an acidified late endosome, while L. monocytogenes rapidly escapes from an acidified phagosome into the cytoplasm.

Animals↗

PubMed1992

The effect of age on the response of the detrusor to intracellular mechanical stimulus: DNA replication and the cell actin matrix.

Benign prostatic hypertrophy and posterior urethral valves present at both extremes of the age spectrum. Both disease processes can obstruct the urinary stream and ultimately have pathophysiological effects on detrusor structure and function. The mechanisms regulating the structural reorganization of the detrusor to a mechanical outflow obstruction are not known. In an attempt to identify maturational differences in myocyte ultrastructure and consequent effects these might have in modifying the response of the detrusor to mechanical stimulus, we studied differences in dynamic nuclear-cytoskeletal interactions in detrusor tissue in an animal model. Using a drug which specifically severs actin, cytochalasin D (CD), as an intracellular mechanical stimulus, we measured changes in nuclear area and the rate of DNA synthesis in detrusor myocytes from young (2-3 week) and old (8-12 mon) guinea pigs. We found that there were age specific differences to intracellular mechanical stimuli in detrusor muscle. Nuclei of myocytes from young animals showed elastic recoil on severing the cell actin matrix and the tissue from young animals increased replicative DNA synthesis with an intracellular stimulus. In contrast, nuclear shape changes in myocytes from old animals suggested less elasticity, and there was no increase in DNA synthesis with disruption of the cell actin matrix. Anti-alpha-smooth muscle actin antibody and rhodamine phalloidin staining of actin in cytochalasin D treated primary explants of detrusor myocytes showed dose dependent disruption of the actin component of the cytoskeleton. These results suggest that there are fundamental modifications in detrusor myocyte ultrastructure with age. These maturational changes might result in differences in the pathophysiological and structural reorganization of the detrusor in response to outflow obstruction in infancy and adulthood. Furthermore, they suggest that 1) a tensile equilibrium exists between the myocyte nucleus and cytoskeleton; 2) there appears to be a decrease in myocyte nuclear elasticity with ageing; 3) release of nuclear template restrictions increases activity of DNA polymerase alpha in young, but not old, detrusor myocytes; and 4) mechanico-chemical signal transduction in detrusor myocytes may be mediated via the cytoskeleton. In addition, based on previous reports of actin within the nucleus, the results suggest that 1) nuclear actin may have a homeostatic structural role, maintaining the tensile equilibrium between nucleus and cytoskeleton, and 2) integrity of nuclear actin may function to maintain the spatial template restriction on DNA polymerase alpha activity.

Actins↗