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At least 955 records · Page 53Linked to original sources
PubMed2006

Thioredoxins in bacteria: functions in oxidative stress response and regulation of thioredoxin genes.

Thioredoxins fulfill a number of different important cellular functions in all living organisms. In bacteria, thioredoxin genes are often regulated by external factors. In turn, thioredoxins influence the expression of many other genes. The multiple and important functions of thioredoxins in cells necessitate to appropriately adjust their level. This review outlines different strategies that have evolved for the regulation of bacterial thioredoxin genes. It also summarizes effects of thioredoxins on gene regulation and presents a recent model for a redox-dependent gene regulation that is mediated by thioredoxins.

Bacteria↗
PubMed2006

Viruses, endoplasmic reticulum stress, and interferon responses.

Viral infection induces endoplasmic reticulum (ER) stress and interferon responses. While viral double-stranded RNA intermediates trigger interferon responses, viral polypeptides synthesized during infection stimulate ER stress. Among the interferon-regulated gene products, the double-stranded RNA-dependent protein kinase (PKR) plays a key role in limiting viral replication. Thus, to establish productive infection, viruses have evolved mechanisms to overcome the deleterious effects of PKR. It has become clear that ER stress causes translational attenuation and transcriptional upregulation of genes encoding proteins that facilitate folding or degradation of proteins. Notably, prolonged ER stress triggers apoptosis. Therefore, viruses are confronted with the consequences of ER stress. Emerging evidence suggests that viruses not only interfere with the interferon system involving PKR but also manipulate the programs emanating from the ER in a complex way, which may facilitate viral replication or pathogenesis. This review highlights recent progress in these areas.

Activating Transcription Factor 6↗
PubMed2006

Role of Claspin in regulation of nucleotide excision repair factor DDB2.

The replication checkpoint protein Claspin is important for maintenance of genomic stability and is required for cells to overcome genotoxic stress. Upon UV-induced DNA damage, Claspin is required for activation of the ATR-mediated DNA damage checkpoint response, leading to arrest of DNA replication and inhibition of cell cycle progression. Located at the DNA replication fork, Claspin is also suggested to monitor replication and sense damage. Our present studies in HeLa cells demonstrate associations between the Claspin/ATR-related DNA damage checkpoint response and the global genomic nucleotide excision repair pathway. siRNA-mediated knockdown of Claspin abolishes the UV-induced degradation of DDB2 and impairs the co-localization of DDB2 to DNA damage sites. Thus, the presence of Claspin is required for the total turnover of DNA damage binding protein DDB2, as well as for its functionality in DNA damage recognition. Claspin, however, seems not to be required for maintaining the cellular level of the NER factor XPC and its UV-induced post-translational modifications. Co-localization of XPC with DNA lesions is also intact in the absence of Claspin as is the repair of the UV-induced lesions CPD and 6-4PP. Claspin itself may be directly responsible for physical interaction between the two pathways since Claspin is able to associate with DDB1, DDB2 and XPC. Taken together, these findings reveal physical and functional interplay between Claspin and NER-related proteins and demonstrate crosstalk between the DNA damage checkpoint control and DNA damage repair pathways.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Loss of CD28 expression on T lymphocytes: a marker of replicative senescence.

The CD28 molecule, a disulfide-linked homodimer expressed on peripheral T cells and thymocytes, mediates an essential costimulatory signal following engagement of the T cell receptor (TCR). Increased proportions of CD28- T cells have been observed during aging and in situations of chronic immune stimulation, but the origin and functional characteristics of these cells have been unclear. T cells which reach replicative senescence in culture after multiple rounds of cell division have shortened telomeres, respond poorly to stress stimuli, and no longer express CD28, suggesting that CD28- T cells observed in vivo may be the progeny of memory cells which have been repeatedly stimulated. This review describes the features of T cell replicative senescence, presents several possible mechanisms for the generation of senescent T cells in vivo, and proposes that replicative senescence may explain immune exhaustion.

Biomarkers↗
PubMed2006

Challenges identifying genetic determinants of pediatric cancers--the childhood leukemia experience.

Pediatric cancers affect approximately 1 in every 500 children before the age of 15. Little is known about the etiology of this heterogeneous group of diseases despite the fact they constitute the major cause of death by disease among this population. Because of its relatively high prevalence, most of the work done in pediatric oncogenetics has been focused on leukemias, particularly acute lymphoblastic leukemia (ALL). Although it is now well accepted that genetic variation plays a significant role in determining individual's cancer susceptibility, few studies have explored genetic susceptibility to childhood leukemia with respect to common polymorphisms. The biochemical and genetic mechanisms contributing to cancer susceptibility are numerous and can be grouped into broad categories: (1) cellular growth and differentiation, (2) DNA replication and repair, (3) metabolism of carcinogens (4) apoptosis, (5) oxidative stress response and (6) cell cycle. To evaluate whether candidate genes in these pathways are involved in childhood leukemogenesis, we conducted case-control studies. We showed that leukemogenesis in children may be associated with DNA variants in some of these genes and that the combination of genotypes seems to be more predictive of risk than either of them independently. We also observed that, at least at some loci, the parental genetics might be important in predicting the risk of cancer in this pediatric model of a complex disease. Taken together, these results indicate that the investigation of a single enzyme and/or a single genotype might not be sufficient to explain the etiology of childhood leukemia because of the complexity of the environment and that of the inter-individual variability in cancer susceptibility.

Child↗
PubMed2006

Cell mechanics: filaminA leads the way.

Actin filaments are thought to be the major structural components of most eukaryotic cells, but reconstituted actin networks have yet to account for the remarkable strength exhibited by cellular networks. A new study has found that reconstituted networks that include the cross-linker filaminA can replicate many of the mechanical properties of cells if they are stressed prior to mechanical measurement.

Actin Cytoskeleton↗
PubMed2003

beta-Lactam induction of colanic acid gene expression in Escherichia coli.

An unexpected observation led us to examine the relationship between beta-lactam exposure and synthesis of colonic acid capsular polysaccharide in Escherichia coli. Strains containing a cps-lacZ transcriptional fusion were challenged with antibiotics having various modes of action, and gene expression was detected by a disk-diffusion assay and in broth cultures. The cps genes were induced by a subset of beta-lactams but not by agents inhibiting protein synthesis or DNA replication, indicating that cps expression was specific and not due to stresses accompanying cell death or by a general inhibition of peptidoglycan synthesis. A narrow concentration just below the MIC triggered cps expression in liquid culture, suggesting the response may be triggered by near-lethal levels of antibiotic. Because colanic acid is important for maturation of biofilm architecture, antibiotics that increase its synthesis might exacerbate the formation or persistence of biofilms.

Artificial Gene Fusion↗
PubMed2002

UVB-induced premature senescence of human diploid skin fibroblasts.

In this work, we show that repeated stresses with UVB (290-320 nm) induce stress-induced premature senescence (SIPS) of skin human diploid fibroblasts (HDFs). HDFs at early cumulative population doublings were exposed three or five times to increasing subcytotoxic doses of UVB with one stress per day. After 2 days of recovery, several biomarkers of replicative senescence were established. First, there was an increase in the proportion of cells positive for senescence-associated beta-galactosidase activity. Second, there was a loss of replicative potential as assessed by a very low level of [3H]-thymidine incorporation. Third, the steady-state level of the mRNA of three senescence-associated genes, i.e. fibronectin, osteonectin and SM22, was increased in HDFs at 72 h after three and five exposures to UVB. In conclusion, these results suggest that it is possible to induce SIPS in HDFs after repeated exposures to subcytotoxic doses of UVB. This model could be used to test whether HDFs in UVB-induced premature senescence are able to promote epithelial cell growth and tumorigenesis in skin, as shown recently with HDFs in H(2)O(2)-induced premature senescence.

Cell Line↗
PubMed2004

Hallmarks of senescence in carcinogenesis and cancer therapy.

Cellular senescence is a signal transduction program leading to irreversible cell cycle arrest. This growth arrest can be triggered by many different mechanisms including recognition by cellular sensors of DNA double-strand breaks leading to the activation of cell cycle checkpoint responses and recruitment of DNA repair foci. Senescence is initiated by the shortening of telomeres (replicative senescence) or by other endogenous and exogenous acute and chronic stress signals (STASIS: stress or aberrant signaling-induced senescence). The process of carcinogenesis involves a series of changes that allow tumor cells to bypass the senescence program. Nevertheless, tumor cells retain the capacity to undergo senescence. Treatment of tumor cells with many conventional anticancer therapies activates DNA damage signaling pathways, which induce apoptosis in some cells and senescence in others. Overexpression of tumor suppressors or inhibition of oncogenes can also induce rapid senescence in tumor cells. Senescent cells, while not dividing, remain metabolically active and produce many secreted factors, some of which stimulate and others inhibit the growth of tumors. The emerging knowledge about the pathways that lead to senescence and determine the pattern of gene expression in senescent cells may lead to more effective treatments for cancer.

Animals↗
PubMedDate not supplied

Mechanisms of cell-cycle checkpoints: at the crossroads of carcinogenesis and drug discovery.

Human tumors arise from multiple genetic changes that gradually transform growth-limited cells into highly invasive cells that are unresponsive to growth controls. The genetic evolution of normal cells into cancer cells is largely determined by the fidelity of DNA replication, repair, and division. Cell-cycle arrest in response to stress is integral to the maintenance of genomic integrity. The control mechanisms that restrain cell-cycle transition or induce apoptotic signaling pathways after cell stress are known as cell-cycle checkpoints. This review will focus on the mechanisms of cell-cycle checkpoint pathways and how different components of these pathways are frequently altered in the genesis of human tumors. As our knowledge of cell-cycle regulation and checkpoints increases, so will our understanding of how xenobiotic agents can affect these processes to either initiate or inhibit tumorigenesis.

Antineoplastic Agents↗
PubMed2005

Prevention of accelerated cell aging in Werner syndrome using a p38 mitogen-activated protein kinase inhibitor.

We investigated the role of p38 mitogen-activated protein kinase (MAPK) signalling in the accelerated aging of Werner Syndrome (WS) fibroblasts by use of SB203580, a cytokine-suppressive anti-inflammatory drug that targets p38 activity. SB203580 treatment reverts the aged morphology of young WS fibroblasts to that seen in young normal fibroblasts. In addition, SB203580 increases the life span and growth rate of WS fibroblasts to within the normal range. In young WS cells, p38 is activated coincident with an up-regulation of p21(WAF1), and a reduction in the levels of both activated p38 and p21(WAF1) are seen following treatment with SB203580. As these effects are not seen in young normal cells, our data suggest that the abbreviated replicative life span of WS cells is due to a stress-induced, p38-mediated growth arrest that is independent of telomere erosion. With some p38 inhibitors already in clinical trials, our data suggest a potential route to drug intervention in a premature aging syndrome.

Actins↗
PubMed1992

Qualitative analysis of the Program of All-inclusive Care for the Elderly (PACE).

The innovative model of capitated acute and chronic care for nursing-home-eligible elderly persons, which was developed at On Lok in San Francisco's Chinatown and stresses using community care in lieu of institutional care, has been replicated at eight sites around the country. The early experience in developing these sites tests the extent to which the principles of this approach, based on day health care, can be reproduced in a variety of other settings. Four of the eight sites have begun formal capitated care; enrollment has been less active than anticipated, apparently due to reluctance to change physicians and resistance to day care.

Acute Disease↗
PubMed2001

Water deficit inhibits cell division and expression of transcripts involved in cell proliferation and endoreduplication in maize endosperm.

Water deficit at the early post-pollination stage in cereal grains decreases endosperm cell division and, in turn, decreases the capacity for storage material accumulation. Post-mitotic replication of nuclear DNA (endoreduplication) may also play a role in stress effects. To gain a better understanding of the extent to which cell proliferation and endoreduplication are affected by water deficit, nuclear numbers and size were examined in endosperms of maize (Zea mays L.) by flow cytometry and the transcript levels of genes which have recognized roles in the cell cycle were quantified. Water deficit from 5-13 d after pollination (DAP) decreased the rate of endosperm cell division by 90% and inhibited [3H]-thymidine incorporation into DNA from 9-13 DAP. The proportion of nuclei engaging in endoreduplication and nuclear DNA content increased steadily from 9-13 DAP in controls, but water deficit initially increased the proportion of endoreduplicating nuclei at 9 DAP, then halted further entry into endoreduplication and S-phase cycling from 9-13 DAP. Transcript levels of alpha-tubulin, and the S-phase gene products histone H3 and PCNA were not affected by water deficit until 13 DAP, whereas those of ZmCdc2, a cyclin dependent kinase (CDK) with regulatory roles in mitosis, were inhibited substantially from 9-13 DAP. Cell proliferation and associated processes were inhibited at initial stages of the stress episode, whereas endoreduplication and associated S-phase processes were not inhibited until the stress was more advanced. It was concluded that endosperm mitosis has greater sensitivity than endoreduplication to water deficit.

Adaptation, Physiological↗
PubMed2004

Incongruity versus instability in the etiology of posttraumatic arthritis.

The etiology of posttraumatic arthritis is understood poorly but it clearly has a pathomechanical component. Posttraumatic arthritis likely results from irreversible cartilage damage sustained at the time of injury and chronic cartilage overloading resulting from articular incongruity and instability. However, the relative importance of instability and incongruity is unknown. Clinical studies show that the hip, knee, and ankle tolerate incongruity differently. However, all three joints poorly tolerate instability. Basic mechanical studies have shown that static loading of articular surface incongruities have caused relatively modest increases in contact pressure. However, static testing poorly replicates normal viscoelastic properties of cartilage, which may mask important transient stress elevations that occur during motion. Static tests also ignore potential abnormal loads that may accumulate throughout a motion cycle. We review the clinical and basic scientific evidence linking incongruity and instability to posttraumatic arthritis. Preliminary data from a newly developed dynamic ankle testing device are presented. Dynamic testing allows measurement of transient contact loads and loading rates that occur through the entire motion cycle and it opens the door to measure mechanical abnormalities associated with instability.

Ankle Injuries↗
PubMed2002

Sexual selection fails to promote adaptation to a new environment.

Selection can be divided into sexual and nonsexual components. Some work finds that a component of sexual selection, adaptive female selection for good genes, can promote nonsexual fitness. Less studied is the benefit from sexual selection in toto, that is, when intra- and intersexual selection are both present and able to affect females directly and indirectly. Here an upper bound for the net benefit of sexual selection is estimated for Drosophila melanogaster. Replicate populations were allowed to adapt to low-grade thermal stress, with or with out the operation of sexual selection. Because proteins and lipids are highly sensitive to temperature, low-grade thermal stress will select broadly across the genome for alternative alleles. Such broad, directional selection for thermal tolerance should increase the measurable benefits of sexual selection far beyond that available under stabilizing selection. Sexual selection was removed by enforced monogamy without mate choice and retained by enforced polyandry (four males per female). After 36 generations of thermal stress exposure, there was substantial adaptation to the new environment (the net reproductive rate increased six standard deviations relative to thermal controls). However, sexual selection did not affect the rate of adaptation. Therefore, adaptive female selection for thermal tolerance either was insignificant or negated by other aspects of sexual selection, for example, male-induced female harm, which has been shown to diminish under monogamy. This experiment employed two parameters that reduced the opportunity for divergence in such harm: a truncated intersexual interaction period and strong directional selection for thermal tolerance. No divergence in male-induced harm was observed.

Adaptation, Physiological↗
PubMed2006

Systems biology of AGC kinases in fungi.

Sch9 appears to be the Saccharomyces cerevisiae homolog of protein kinase B and is involved in the control of numerous nutrient-sensitive processes, including regulation of cell size, cell cycle progression, and stress resistance. Sch9 has also been implicated in the regulation of replicative and chronological life span. Systematic comparison of the phenotypes of sch9 and other AGC kinase mutants in fungal species with their counterparts in model eukaryotic organisms provides insight into the functions of AGC kinases. The availability of data from global studies of protein-protein interactions now makes it possible to predict and validate functional connections between Sch9, its putative substrates, and other proteins. This review highlights several emerging paradigms of AGC kinase signaling that are relevant for growth, development, and aging.

Aging↗
PubMed2003

Yielding of the clamped-wire system in the Ilizarov external fixator.

This study demonstrates that the clamped-wire system used to suspend bones within an Ilizarov external fixator yields when the perpendicular load exceeds 50 N per wire. Cyclic loading was applied to tensioned wires clamped within an Ilizarov ring component, with steadily increasing load amplitude. Wires were tested at four initial tension settings. The amount of energy lost within the clamped-wire system per load cycle was calculated for every test. The results showed that there was a consistent trend to increasing non-recoverable energy loss per load cycle when peak loads exceed 50 N for all initial tension settings. A finite element (FE) model replicating the experimental conditions was performed to investigate the levels of stress within the loaded wires. The FE model analyses showed that high stresses were generated in the wires close to the clamping sites, and that the stress levels could reasonably be expected to exceed the material yield stress when loaded to about 55 N, for all initial tension settings. The results show that material yield, accompanied by some wire slippage through the clamps, is responsible for system yield, in agreement with previous studies. Although the initial wire tension has an appreciable effect on the wire stiffness, it did not affect the elastic load range of the clamped-wire system. To prevent yield of the clamped-wire system in practice, the fixator should be assembled with sufficient wires to ensure that the load transmitted to each wire by the patient does not exceed 50 N.

Bone Wires↗
PubMed2003

Evaluation of risks related to the use of adeno-associated virus-based vectors.

Recombinant AAV efficacy has been demonstrated in numerous gene therapy preclinical studies. As this vector is increasingly applied to human clinical trials, it is a priority to evaluate the risks of its use for workers involved in research and clinical trials as well as for the patients and their descendants. At high multiplicity of infection, wild-type AAV integrates into human chromosome 19 in approximately 60% of latently infected cell lines. However, it has been recently demonstrated that only approximately 1 out of 1000 infectious units can integrate. The mechanism of this site-specific integration involves AAV Rep proteins which are absent in vectors. Accordingly, recombinant AAV (rAAV) do not integrate site-specifically. Random integration of vector sequences has been demonstrated in established cell lines but only in some cases and at low frequency in primary cultures and in vivo. In contrast, episomal concatemers predominate.Therefore, the risks of insertional mutagenesis and activation of oncogenes are considered low. Biodistribution studies in non-human primates after intramuscular, intrabronchial, hepatic artery and subretinal administration showed low and transient levels of vector DNA in body fluids and distal organs. Analysis of patients body fluids revealed rAAV sequences in urine, saliva and serum at short-term. Transient shedding into the semen has been observed after delivery to the hepatic artery. However, motile germ cells seemed refractory to rAAV infection even when directly exposed to the viral particles, suggesting that the risk of insertion of new genetic material into the germ line is absent or extremely low. Risks related to viral capsid-induced inflammation also seem to be absent since immune response is restricted to generation of antibodies. In contrast, transgene products can elicit both cellular and humoral immune responses, depending on the nature of the expressed protein and of the route of vector administration. Finally, a correlation between early abortion as well as male infertility and the presence of wt AAV DNA in the genital tract has been suggested. Although no causal relationship has been established, this issue stresses the importance of using rAAV stocks devoid of contaminating replication-competent AAV. This review comprehensively examines virus integration, biodistribution, immune interactions, and other safety concerns regarding the wild-type AAV and recombinant AAV vectors.

Animals↗