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PubMed2005

Protein synthesis in eukaryotes: the growing biological relevance of cap-independent translation initiation.

Ribosome recruitment to eukaryotic mRNAs is generally thought to occur by a scanning mechanism, whereby the 40S ribosomal subunit binds in the vicinity of the 5'cap structure of the mRNA and scans until an AUG codon is encountered in an appropriate sequence context. Study of the picornaviruses allowed the characterization of an alternative mechanism of translation initiation. Picornaviruses can initiate translation via an internal ribosome entry segment (IRES), an RNA structure that directly recruits the 40S ribosomal subunits in a cap and 5' end independent fashion. Since its discovery, the notion of IRESs has extended to a number of different virus families and cellular RNAs. This review summarizes features of both cap-dependent and IRES-dependent mechanisms of translation initiation and discusses the role of cis-acting elements, which include the 5' cap, the 5'-untranslated region (UTR) and the poly(A) tail as well as the possible roles of IRESs as part of a cellular stress response mechanism and in the virus replication cycle.

5' Untranslated Regions↗
PubMed1985

Culture media for propagation of mammalian cells, viruses, and other biologicals.

In this brief review, we have illustrated the historical development of the growth media commonly employed for the propagation of cultured mammalian cells. While substantial progress has been achieved, the field may best be described as conservative and pragmatic. To date, the function of many components of the growth medium essential for cellular proliferation and biological production has not been precisely defined at the molecular level. Thus, for most large-scale biological production requirements, as well as for routine cell culture and bench-scale pilot development, the traditional enriched culture medium supplemented with fetal bovine serum represents the most convenient culture system. Many cell types may be more economically grown without reduction in biological yield by substituting alternative mammalian sera. Where reduction of total protein or greater definition of growth medium components outweighs the use of more universally applicable culture media, substitution of serum-free, customized formulations of highly enriched growth medium plus defined growth factors may be of significant utility. Optimization of mammalian cell culture media for large-scale biological production should include the following: An initial time investment to optimize the cell culture medium by enriching intermediary metabolite composition (rather than expecting serum or additional growth factors to perform nutritional functions) may result in higher productivity and reduced cost. When screening potential growth media for biological production applications, proliferative rate should not be the sole criterion for performance. Although rapid, logarithmic growth is advantageous to establish large-scale cultures, the maximal cell density and duration of the viable, productive period must also be weighed. Many cell types generate the highest titers of biological product either at stationary phase or under mildly stressful ("controlled death") conditions suboptimal for cellular replication. Thus, the ultimate determinant of growth medium efficacy is neither the degree of definition of medium composition nor the cellular proliferative rate, but the ability to support synthesis of substantial titers of the desired product at reasonably high purity.

Animals↗
PubMed1980

Mortality from heat stress in broiler chickens influenced by anticoccidial drugs.

The relationship of anticoccidial drug to heat stress mortality in broilers was studied in a replicated floor-pen experiment during a period of hot weather in Georgia. Overall mortality during the 8-week study averaged 6% in unmedicated and monensin-medicated birds or lasalocid-medicated birds, 10% in arprinocid-medicated birds, and 36% in nicarbazin-medicated birds. Most of the death losses were attributed to heat stress. Maximum death losses coincided with three periods of hot weather, when the birds were 22, 33, or 49 days old. Of 114 dead birds in the nicarbazin treatment, 68 were male and 46 were female.

Animals↗
PubMed1996

Thermoelectric technique to precisely control hyperthermic exposures of human whole blood.

The need in military research to avoid exposing humans to harsh environments and reduce animal use requires the development of in vitro models for the study of hyperthermic injury. A thermoelectric module (TEM) system was employed to heat human whole blood (HWB) in a manner similar to that experienced by heat-stroked rats. This system precisely and accurately replicated mild, moderate, and extreme heat-stress exposures. Temperature changes could be monitored without the introduction of a test sample thermistor, which reduced contamination problems. HWB with hematocrits of 45 or 50% had similar heating curves, indicating that the system compensated for differences in sample character. The unit's size permitted its containment within a standard carbon dioxide incubator to further control sample environment. These results indicate that the TEM system can precisely control temperature change in this heat stress in vitro model employing HWB. Information obtained from such a model could contribute to military preparedness.

Blood↗
PubMed2003

Pain differs from non-painful attention-demanding or stressful tasks in its effect on postural control patterns of trunk muscles.

Pain changes postural activation of the trunk muscles. The cause of these changes is not known but one possibility relates to the information processing requirements and the stressful nature of pain. This study investigated this possibility by evaluating electromyographic activity (EMG) of the deep and superficial trunk muscles associated with voluntary rapid arm movement. Data were collected from control trials, trials during low back pain (LBP) elicited by injection of hypertonic saline into the back muscles, trials during a non-painful attention-demanding task, and during the same task that was also stressful. Pain did not change the reaction time (RT) of the movement, had variable effects on RT of the superficial trunk muscles, but consistently increased RT of the deepest abdominal muscle. The effect of the attention-demanding task was opposite: increased RT of the movement and the superficial trunk muscles but no effect on RT of the deep trunk muscles. Thus, activation of the deep trunk muscles occurred earlier relative to the movement. When the attention-demanding task was made stressful, the RT of the movement and superficial trunk muscles was unchanged but the RT of the deep trunk muscles was increased. Thus, the temporal relationship between deep trunk muscle activation and arm movement was restored. This means that although postural activation of the deep trunk muscles is not affected when central nervous system resources are limited, it is delayed when the individual is also under stress. However, a non-painful attention-demanding task does not replicate the effect of pain on postural control of the trunk muscles even when the task is stressful.

Abdominal Muscles↗
PubMedDate not supplied

Testing the relationship between job stress and satisfaction in correctional nurses.

BACKGROUND: Correctional nurses function in a high stress environment due to the nature of their clients and the primacy of environmental security. Job stress and satisfaction are theorized relational concepts that influence intent to stay and turnover as described in the anticipated turnover model. An increased understanding of the nature and sources of stress and satisfaction provides necessary information about correctional nursing. OBJECTIVE: To (a) replicate an earlier study of correctional nurses to determine whether similar findings could be duplicated in a study of prison nurses from another state and (b) test the concepts of stress and satisfaction as represented in the anticipated turnover model. METHODS: Using the Index of Work Satisfaction and the Nurse Stress Index, a correlational mail survey was designed to assess job stress and satisfaction among 454 nurses in a northeastern state prison system. RESULTS: Overall stress scores were not significantly different from the original study despite differences in demographic characteristics. Highest to lowest mean scores on actual sources of satisfaction include physician-nurse interaction, autonomy, professional status, task requirements, organizational policies, and pay. Satisfaction scores were significantly higher in the original study. An inverse relationship exists between job stress and satisfaction among correctional nurses. Job stress was a significant predictor of job satisfaction, supporting the theorized conceptual relationship between job stress and job satisfaction as described in the anticipated turnover model. DISCUSSION: Stress levels and the top two sources of stress were essentially the same for both groups of correctional nurses. Sources of satisfaction are ranked similarly but subscale and overall scores indicate that the nurses in the replication study were more dissatisfied. Findings validate the theoretical proposition in the anticipated turnover model that job stress is a major predictor variable in explaining job satisfaction.

Female↗
PubMed1985

Systemic lymphoid atrophy in coxsackievirus B3-infected mice: effects of virus and immunopotentiating agents.

Adult mice infected with coxsackievirus B3 (CB3) showed a generalized lymphoid involution. This effect was produced by most of the isolates and clones of CB3 and, to a lesser extent, by coxsackievirus B1 but not by other highly pathogenic picornaviruses. While moderate involution of the thymus also occurred in mild CB3 infections, peripheral changes strictly correlated with the severity of disease. The major alteration of the thymus was a massive cortical depletion, whereas the reduction of spleen and lymph node cellularity appeared devoid of selectivity. No histological and ultrastructural signs of CB3 replication in such organs could be detected. Attempts to demonstrate CB3 replication in thymus, spleen, and lymph node cells were unsuccessful. CB3-induced lymphoid atrophy was not prevented by adrenalectomy and was exacerbated by three different immunopotentiating agents. Thus, certain picornaviruses may cause severe stress-independent lymphoid damage in the absence of viral replication in situ. A role for autoreactive mechanisms is suggested.

Adjuvants, Immunologic↗
PubMed2005

Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function.

Oxidative stress leads to increased risk for osteoarthritis (OA) but the precise mechanism remains unclear. We undertook this study to clarify the impact of oxidative stress on the progression of OA from the viewpoint of oxygen free radical induced genomic instability, including telomere instability and resulting replicative senescence and dysfunction in human chondrocytes. Human chondrocytes and articular cartilage explants were isolated from knee joints of patients undergoing arthroplastic knee surgery for OA. Oxidative damage and antioxidative capacity in OA cartilage were investigated in donor-matched pairs of intact and degenerated regions of tissue isolated from the same cartilage explants. The results were histologically confirmed by immunohistochemistry for nitrotyrosine, which is considered to be a maker of oxidative damage. Under treatment with reactive oxygen species (ROS; 0.1 micromol/l H2O2) or an antioxidative agent (ascorbic acid: 100.0 micromol/l), cellular replicative potential, telomere instability and production of glycosaminoglycan (GAG) were assessed in cultured chondrocytes. In tissue cultures of articular cartilage explants, the presence of oxidative damage, chondrocyte telomere length and loss of GAG to the medium were analyzed in the presence or absence of ROS or ascorbic acid. Lower antioxidative capacity and stronger staining of nitrotyrosine were observed in the degenerating regions of OA cartilages as compared with the intact regions from same explants. Immunostaining for nitrotyrosine correlated with the severity of histological changes to OA cartilage, suggesting a correlation between oxidative damage and articular cartilage degeneration. During continuous culture of chondrocytes, telomere length, replicative capacity and GAG production were decreased by treatment with ROS. In contrast, treatment with an antioxidative agent resulted in a tendency to elongate telomere length and replicative lifespan in cultured chondrocytes. In tissue cultures of cartilage explants, nitrotyrosine staining, chondrocyte telomere length and GAG remaining in the cartilage tissue were lower in ROS-treated cartilages than in control groups, whereas the antioxidative agent treated group exhibited a tendency to maintain the chondrocyte telomere length and proteoglycan remaining in the cartilage explants, suggesting that oxidative stress induces chondrocyte telomere instability and catabolic changes in cartilage matrix structure and composition. Our findings clearly show that the presence of oxidative stress induces telomere genomic instability, replicative senescence and dysfunction of chondrocytes in OA cartilage, suggesting that oxidative stress, leading to chondrocyte senescence and cartilage ageing, might be responsible for the development of OA. New efforts to prevent the development and progression of OA may include strategies and interventions aimed at reducing oxidative damage in articular cartilage.

Aged↗
PubMedDate not supplied

Cigarette smoking: effects upon self-rated stress and arousal over the day.

Feelings of stress and arousal were assessed over a day of cigarette smoking. Smokers reported heightened stress prior to smoking, and reduced stress immediately after smoking (p < .002). Feelings of arousal were also significantly affected by cigarette use, with lower arousal prior to smoking, and increased arousal postsmoking (p < .011). This pattern was found with both "sedative" and "stimulant" smokers, as defined by the Smoking Motive Questionnaire (SMQ). These findings demonstrate that smoking can simultaneously produce both increased arousal and decreased stress. They lend doubt to the arousal modulation theory, which states that smoking leads either to reduced stress, or to increased arousal, but not both together. The present data broadly replicated some earlier findings (O'Neill & Parrott, 1992), and confirmed that smokers experience vacilating feelings of stress and arousal over the day. Thus, while feeling-state improvements often accompany cigarette smoking, they are followed by negative feelings (during nicotine withdrawal), which are alleviated by the next cigarette. These feeling-state changes also provide a clear psychological rationale for the repetitive/addictive nature of tobacco use.

Adult↗
PubMed2001

HtrA homologue of Legionella pneumophila: an indispensable element for intracellular infection of mammalian but not protozoan cells.

Legionella pneumophila replicates within alveolar macrophages, and possibly, alveolar epithelial cells and also within protozoa in the aquatic environment. Here we characterize an L. pneumophila mutant defective in the HtrA/DegP stress-induced protease/chaperone homologue and show that HtrA is indispensable for intracellular replication within mammalian macrophages and alveolar epithelial cells and for intrapulmonary replication in A/J mice. Importantly, amino acid substitutions of two conserved residues in the catalytic domain of (H103mapstoR and S212mapstoA) and in-frame deletions of either or both of the two conserved PDZ domains of HtrA abolish its function. Interestingly, the htrA mutant exhibits a parental-type phenotype in intracellular replication within the protozoan host Acanthamoeba polyphaga. We used a promoterless lacZ fusion to the htrA promoter to probe the phagosomal microenvironment harboring L. pneumophila within macrophages and within A. polyphaga for the exposure to stress stimuli. The data show that expression through the htrA promoter is induced by 12,000- to 20,000-fold throughout the intracellular infection of macrophages but its induction is by 120- to 500-fold within protozoa compared to in vitro expression. Data derived from confocal laser scanning microscopy reveal that in contrast to the parental strain, phagosomes harboring the htrA mutant within U937 macrophages colocalize with the late endosomal-lysosomal marker LAMP-2, similar to killed L. pneumophila. Coinfection experiments examined by confocal laser scanning microscopy show that in communal phagosomes harboring both the parental strain and the htrA mutant, replication of the mutant is not rescued, while replication of a dotA mutant control, which is normally trafficked into a phagolysosome, is rescued by the parental strain. Our data show, for the first time, that the stress response by L. pneumophila (mediated, at least in part, by HtrA) is indispensable for intracellular replication within mammalian but not protozoan cells.

Animals↗
PubMed2004

Do post-traumatic stress symptoms predict reactions of adaptation to disability after a sudden-onset spinal cord injury?

Based on the perspective that post-traumatic stress disorder (PTSD) reflects a reaction of adaptation to trauma, the goal of this research was to examine the ability of PTSD symptom clusters (re-experiencing, avoidance, and hyperarousal) to predict eight reactions of adaptation to disability (shock, anxiety, denial, depression, internalized anger, externalized hostility, acknowledgment, and adjustment) among individuals with non-congenital spinal cord injuries. Individuals (all of whom attended either a specialized civilian or a veteran spinal cord injury clinic in Texas) completed two self-report questionnaires--the Reactions to Impairment and Disability Inventory (RIDI) and the Purdue Posttraumatic Stress Disorder Scale Revised (PPTSD-R). According to the statistical fit indices, five of the fit indices suggested that the revised model was a good fit to the data, whereas one fit index and the chi/df ratio indicated that the revised model fit the data poorly. The model provided information on the ability of PTSD clusters to predict reactions of adaptation, which suggested a specific pattern of vacillation of post-traumatic responses during the process of adaptation. These findings need replication before proposing interventions for post-traumatic stress responses after the onset of a spinal cord injury.

Adaptation, Psychological↗
PubMed2002

Glucosylceramide synthesis and synthase expression protect against ceramide-induced stress.

Ceramides (Cers), critical for epidermal barrier function, also can inhibit keratinocyte proliferation, while glucosylceramides (GlcCers) exert pro-mitogenic effects. Since alterations in Cer-to-GlcCer ratios appear to modulate cellular growth versus apoptosis, we assessed whether keratinocytes up-regulate GlcCer synthesis as a protective mechanism against Cer-induced stress. Exogenous sphingomyelinase (SMase) treatment of cultured human keratinocytes (CHK) initially decreased proliferation and cellular sphingomyelin (50-60% decrease; P < 0.001), and increased Cer levels (6.1- to 6.8-fold; P < 0.001). Proliferation recovered to normal rates by 24 h, in parallel with increased cellular GlcCer. Both GlcCer synthesis and GlcCer synthase activity increased significantly by 8 h following SMase (8.2- and 2.4-fold, respectively; P < 0.01 each vs. control), attributed to antecedent increases in GlcCer synthase mRNA and protein expression. Further evidence that GlcCer production is responsible for normalized CHK proliferation includes: a) attenuation of SMase-induced inhibition of proliferation by exogenous GlcCer; and b) enhancement of the SMase effect in cells cotreated with the GlcCer synthase inhibitor, PDMP (D-threo-1-phenyl-2(decanoylamino)-3-morpholino-1-propanol). Finally, although proliferation in immortalized, nontransformed keratinocytes (HaCaT) also was inhibited by SMase, HaCaT cells that overexpress GlcCer synthase were resistant to this effect. Thus, SMase-induced stress initiates a response in keratinocytes that includes upregulation of GlcCer synthesis which may protect against the deleterious effects of excess Cer.

Base Sequence↗
PubMed2006

Herpes simplex virus type I disrupts the ATR-dependent DNA-damage response during lytic infection.

Like other DNA viruses, herpes simplex virus type 1 (HSV-1) interacts with components of the cellular response to DNA damage. For example, HSV-1 sequesters endogenous, uninduced, hyperphosphorylated RPA (replication protein A) away from viral replication compartments. RPA is a ssDNA-binding protein that signals genotoxic stress through the ATR (ataxia telangiectasia-mutated and Rad3-related) pathway. The sequestration of endogenous hyperphosphorylated RPA away from replicating viral DNA suggests that HSV-1 prevents the normal ATR-signaling response. In this study we examine the spatial distribution of endogenous hyperphosphorylated RPA with respect to ATR, its recruitment factor, ATRIP, and the cellular dsDNA break marker, gammaH2AX, during HSV-1 infection. The accumulation of these repair factors at DNA lesions has previously been identified as an early event in signaling genotoxic stress. We show that HSV-1 infection disrupts the ATR pathway by a mechanism that prevents the recruitment of repair factors, spatially uncouples ATRIP from ATR and sequesters ATRIP and endogenous hyperphosphorylated RPA within virus-induced nuclear domains containing molecular chaperones and components of the ubiquitin proteasome. The HSV-1 immediate early protein ICP0 is sufficient to induce the redistribution of ATRIP. This is the first report that a virus can disrupt the usually tight colocalization of ATR and ATRIP.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Cellular UV damage responses--functions of tumor suppressor p53.

DNA damage, provoked by ultraviolet (UV) radiation, evokes a cellular damage response composed of activation of stress signaling and DNA checkpoint functions. These are translated to responses of replicative arrest, damage repair, and apoptosis aimed at cellular recovery from the damage. p53 tumor suppressor is a central stress response protein, activated by multiple endogenous and environmental insults, including UV radiation. The significance of p53 in the DNA damage responses has frequently been reviewed in the context of ionizing radiation or other double strand break (DSB)-inducing agents. Despite partly similar patterns, the molecular events following UV radiation are, however, distinct from the responses induced by DSBs and are profoundly coupled with transcriptional stress. These are illustrated, e.g., by the UV damage-specific translocations of Mdm2, promyelocytic leukemia protein, and nucleophosmin and their interactions with p53. In this review, we discuss UV damage-provoked cellular responses and the functions of p53 in damage recovery and cell death.

Animals↗
PubMed2005

An experimental and theoretical composite model of the human mandible.

The purpose is to design and manufacture a composite mandible replicate suitable for testing the influence of prosthetic materials on the stress distribution of bone. Composite mandibles made of a poly(methylmethacrylate) core and a glass reinforced outer shell are manufactured and characterised through mechanical tests assisted by the finite element analysis. The mandible replicate has been conveniently equipped with strain gauges, moreover a video extensometer has also been used in order to measure the arch width change during loading. A close agreement is found between the experimental data and the theoretical predictions. By laterally loading the mandibles the maximum values of stress and strain take place in the premolar-incisal region. By varying technological parameters such as the fiber volume fraction and orientation, it is easy to replicate the behaviour of mandibles having different stiffnesses. The results obtained by laterally loading the composite mandibles through the condyles or through the gonion regions are consistent with literature data relative to the arch width decrease of natural jaws during opening and closing. This novel synthetic system coupled with the Finite Element model constitutes an experimental-theoretical model suitable to investigate the biomechanical effects of oral rehabilitations on mandibular bone.

Humans↗
PubMed2006

Thioredoxin 1 promotes intracellular replication and virulence of Salmonella enterica serovar Typhimurium.

The effect of the cytoplasmic reductase and protein chaperone thioredoxin 1 on the virulence of Salmonella enterica serovar Typhimurium was evaluated by deleting the trxA, trxB, or trxC gene of the cellular thioredoxin system, the grxA or gshA gene of the glutathione/glutaredoxin system, or the dsbC gene coding for a thioredoxin-dependent periplasmic disulfide bond isomerase. Mutants were tested for tolerance to oxidative and nitric oxide donor substances in vitro, for invasion and intracellular replication in cultured epithelial and macrophage-like cells, and for virulence in BALB/c mice. In these experiments only the gshA mutant, which was defective in glutathione synthesis, exhibited sensitization to oxidative stress in vitro and a small decrease in virulence. In contrast, the trxA mutant did not exhibit any growth defects or decreased tolerance to oxidative or nitric oxide stress in vitro, yet there were pronounced decreases in intracellular replication and mouse virulence. Complementation analyses using defined catalytic variants of thioredoxin 1 showed that there is a direct correlation between the redox potential of thioredoxin 1 and restoration of intracellular replication of the trxA mutant. Attenuation of mouse virulence that was caused by a deficiency in thioredoxin 1 was restored by expression of wild-type thioredoxin 1 in trans but not by expression of a catalytically inactive variant. These results clearly imply that in S. enterica serovar Typhimurium, the redox-active protein thioredoxin 1 promotes virulence, whereas in vitro tolerance to oxidative stress depends on production of glutathione.

Animals↗
PubMed2004

Low posttrauma GABA plasma levels as a predictive factor in the development of acute posttraumatic stress disorder.

BACKGROUND: Gamma amino-butyric acid (GABA) regulates the intensity and the duration of the central hyperadrenergic response in times of high stress and has been negatively associated with anxiety, depression, and sleep problems. We hypothesized that individuals with low plasma GABA levels may be more prone to develop posttraumatic stress disorder (PTSD) in the aftermath of trauma exposure. METHODS: To test this hypothesis, we measured plasma GABA levels in a population of 108 road traffic accident victims on arrival at a traumatology department and assessed them for PTSD 6 weeks later. RESULTS: The mean GABA level (nmol/mL) in the PTSD group (n = 55; M =.20; SD =.08) was significantly lower compared with members of the trauma-exposed group who did not develop PTSD [n = 17; M =.30; SD =.09), t(70) = 3.94, p =.0002]. CONCLUSIONS: Provided that GABA levels in the brain are genetically predetermined, our results would suggest that individuals with low plasma GABA levels are premorbidly more vulnerable to stress-related disorders such as acute PTSD. If replicated, plasma GABA levels measured in the aftermath of trauma exposure might help to identify individuals at high risk for developing PTSD.

Acute Disease↗