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Increased Susceptibility (increased + susceptibility)
Selected AbstractsRAPID GROWTH RESULTS IN INCREASED SUSCEPTIBILITY TO PREDATION IN MENIDIA MENIDIAEVOLUTION, Issue 9 2003Stephan B. Munch Abstract Several recent studies have demonstrated that rapid growth early in life leads to decreased physiological performance. Nearly all involved experiments over short time periods (<1 day) to control for potentially confounding effects of size. This approach, however, neglects the benefits an individual accrues by growing. The net effect of growth can only be evaluated over a longer interval in which rapidly growing individuals are allowed the time required to attain the expected benefits of large size. We used two populations of Menidia menidia with disparate intrinsic growth rates to address this issue. We compared growth and survivorship among populations subject to predation in mesocosms under ambient light and temperature conditions for a period of up to 30 days to address two questions: Do the growth rates of fish in these populations respond differently to the presence of predators? Is the previously demonstrated survival cost of growth counterbalanced by the benefits of increased size? We found that growth was insensitive to predation risk: neither population appeared to modify growth rates in response to predation levels. Moreover, the fast-growing population suffered significantly higher mortality throughout the trials despite being 40% larger than the slow-growing population at the experiment's end. These results confirm that the costs of rapid growth extend over prolonged intervals and are not ameliorated merely by the attainment of large size. [source] Increased Susceptibility of Rice Following Insertion of Amylopullulanase Gene, to Brown Spot Caused by Bipolaris oryzaeJOURNAL OF PHYTOPATHOLOGY, Issue 9 2008M.-Y. Ting Abstract Transgenic rice expressing an amylopullulanase (APU) from the bacterium Thermoanaerobacter ethanolicus 39E produces grains which are less expensive to process for production of sugar syrup and protein-enriched flour. During risk assessment of the transgenic line in a field test, brown spot disease caused by Bipolaris oryzae was found more severe on the transgenic line APU than on its parental line TNG67. When lines APU and TNG67 were inoculated at seedling, tillering or heading stage with B. oryzae isolated from line TNG67, the disease was more severe on line APU than on line TNG67 at heading stage, but not at the seedling or tillering stage. However, when B. oryzae isolated from line APU was used in the inoculation tests, the disease was more severe on line APU than on line TNG67 at seedling stage, but not at the tillering or heading stage. To our knowledge, this is the first report of an unintended change in a transgenic plant to become more susceptible to a disease than the non-transgenic plant. [source] Increased susceptibility to oxidative stress as a proximate cost of reproductionECOLOGY LETTERS, Issue 5 2004Carlos Alonso-Alvarez Abstract In iteroparous species high investment in current reproduction is usually paid in terms of reduced future reproduction and increased mortality. However, the proximal mechanisms of these costs remain poorly understood. Free radicals arising as by-products of normal metabolic activities have deleterious effects on cellular proteins, lipids and DNA, and this phenomenon is known as oxidative stress. Since reproduction is an energetically demanding activity, which increases both basal and field metabolic rates, one could expect that breeding effort generates an oxidative stress whose strength depends on the availability and efficiency of antioxidant defences. In agreement with this prediction, we show here for the first time that reproduction decreases antioxidant defences, illustrating that oxidative stress represents a cost of reproduction. We suggest that increased susceptibility to oxidative stress might be a general proximal connection between reproduction and survival underlying other mechanistic links previously acknowledged. [source] Paternal contribution to fetal alcohol syndromeADDICTION BIOLOGY, Issue 2 2004Ernest Abel Maternal alcohol use during pregnancy is associated with a wide range of adverse outcomes for the child. Many women who drink during pregnancy also have male partners who abuse alcohol. Existing data on paternal effects of alcohol abuse during the preconceptual period and at the time of conception are reviewed. Epidemiological data offer some support for a paternal influence on birth weight, congenital heart defects, and some evidence of mild cognitive impairments. Animal data have demonstrated decreased litter size, increased prevalence of low birth weight fetuses and mixed data on risk of malformations. Increased susceptibility to Pseudomonas bacterial infection has been reported. Cognitive and behavioral findings are the most robust effects. These include learning and memory deficits, hyperactivity, and poor stress tolerance. Multiple causal mechanisms for a paternal effect have been suggested, but none seems satisfactory to explain all findings. Further research is needed on paternal effects in animals and human populations. The results of this research may influence prevention activities. [source] Inhibitory effects of aspirin and indometacin on the growth of Helicobacter pylori in vitroJOURNAL OF DIGESTIVE DISEASES, Issue 4 2002Wei Hong WANG OBJECTIVE: The interactions between non-steroidal anti-inflammatory drugs and Helicobacter pylori have not been sufficiently documented to date. The aim of this study was to investigate the possible effects of aspirin and indometacin on the growth of H. pylori and to determine the effects of aspirin on the susceptibility of H. pylori to some antimicrobials. METHODS: Kinetic studies were performed by inoculating strains of H. pylori in brucella broth with different concentrations of aspirin and indometacin. Growth of bacteria in the broth was assessed spectrophotometrically and by viable colony counts after incubation for 24 and 48 h. Bacterial morphology was determined by Gram stain under light microscopy. The minimal inhibitory concentration (MIC) of aspirin and indometacin was determined by the standard agar dilution method. The MIC of amoxicillin, clarithromycin and metronidazole was measured in the presence and absence of aspirin by the E -test method. RESULTS: Kinetic studies revealed that aspirin and indometacin inhibited the growth of H. pylori in a dose-dependent manner. The bactericidal activity of these agents was expressed by cell lysis. Aspirin at 400 µg/mL produced an almost 2-log decrease in the number of CFU/mL at 48 h. Similar inhibitory effects were obtained when 100 µg/mL indometacin was tested. The MIC at which 90% of H. pylori was inhibited was 512 µg/mL and 128 µg/mL for aspirin and indometacin, respectively. Increased susceptibility of H. pylori to amoxicillin, clarithromycin and metronidazole was found in the presence of aspirin. CONCLUSIONS: Aspirin and indometacin could significantly inhibit the growth of H. pylori when incubated in brucella broth in vitro. A subinhibitory concentration of aspirin enhanced the susceptibility of H. pylori to some antimicrobial agents. [source] fMRI BOLD Response to the Eyes Task in Offspring From Multiplex Alcohol Dependence FamiliesALCOHOLISM, Issue 12 2007Shirley Y. Hill Background:, Increased susceptibility for developing alcohol dependence (AD) may be related to structural and functional differences in brain circuits that influence social cognition and more specifically, theory of mind (ToM). Alcohol dependent individuals have a greater likelihood of having deficits in social skills and greater social alienation. These characteristics may be related to inherited differences in the neuroanatomical network that comprises the social brain. Methods:, Adolescent/young adult participants from multiplex AD families and controls (n = 16) were matched for gender, age, IQ, education, and handedness and administered the Eyes Task of Baron-Cohen during functional magnetic resonance imaging (fMRI). Results:, High-risk (HR) subjects showed significantly diminished blood oxygen level dependent (BOLD) response in comparison with low-risk control young adults in the right middle temporal gyrus (RMTG) and the left inferior frontal gyrus (LIFG), areas that have previously been implicated in ToM tasks. Conclusions:, Offspring from multiplex families for AD may manifest one aspect of their genetic susceptibility by having a diminished BOLD response in brain regions associated with performance of ToM tasks. These results suggest that those at risk for developing AD may have reduced ability to empathize with others' state of mind, possibly resulting in diminished social skill. [source] A cytoskeletal tropomyosin can compromise the structural integrity of skeletal muscleCYTOSKELETON, Issue 9 2009Anthony J. Kee Abstract We have identified a number of extra-sarcomeric actin filaments defined by cytoskeletal tropomyosin (Tm) isoforms. Expression of a cytoskeletal Tm (Tm3) not normally present in skeletal muscle in a transgenic mouse resulted in muscular dystrophy. In the present report we show that muscle pathology in this mouse is late onset (between 2 and 6 months of age) and is predominately in the back and paraspinal muscles. In the Tm3 mice, Evans blue dye uptake in muscle and serum levels of creatine kinase were markedly increased following downhill exercise, and the force drop following a series of lengthening contractions in isolated muscles (extensor digitorum longus) was also significantly increased in these mice. These results demonstrate that expression of an inappropriate Tm in skeletal muscle results in increased susceptibility to contraction-induced damage. The extra-sarcomeric actin cytoskeleton therefore may have an important role in protecting the muscle from contractile stress. Cell Motil. Cytoskeleton 2009. © 2009 Wiley-Liss, Inc. [source] Neuronal plasticity: implications in epilepsy progression and managementDRUG DEVELOPMENT RESEARCH, Issue 8 2007Sherifa A. HamedArticle first published online: 12 FEB 200 Abstract Epilepsy is a common neurological disease. A growing number of research studies provide evidence regarding the progressive neuronal damage induced by prolonged seizures or status epilepticus (SE), as well as recurrent brief seizures. Importantly, seizure is only one aspect of epilepsy. However, cognitive and behavioral deficits induced by progressive seizures or antiepileptic treatment can be detrimental to individual function. The neurobiology of epilepsy is poorly understood involving complex cellular and molecular mechanisms. The brain undergoes changes in its basic structure and function, e.g., neural plasticity with an increased susceptibility in neuronal synchronization and network circuit alterations. Some of these changes are transient, while others are permanent with an involvement of both glutamatergic and ,-aminobutyric acid (GABA)ergic systems. Recent data suggest that impaired neuronal plasticity may underlie the cognitive impairment and behavioral changes associated with epilepsy. Many neurologists recognize that the prevention or suppression of seizures by the use of antiepileptic drugs (AEDs) alone is insufficient without clear predictions of disease outcome. Hence, it is important to understand the molecular mechanisms underlying epileptogenesis because this may allow the development of innovative strategies to prevent or cure this condition. In addition, this realization would have significant impact in reducing the long-term adverse consequences of the disease, including neurocognitive and behavioral adverse effects. Drug Dev Res 68:498,511, 2007. © 2008 Wiley-Liss, Inc. [source] Genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemiaENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2004Renata Canalle Abstract Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. Although exposure to environmental agents appears to predispose individuals to this disease, little attention has been paid to the role of genetic susceptibility to environmental exposures in the etiology of childhood ALL. The enzymes GSTM1, GSTT1, GSTP1, CYP1A1, and CYP2E1 are involved in the bioactivation and detoxification of a variety of xenobiotics present in food, organic solvents, tobacco smoke, drugs, alcoholic drinks, pesticides, and environmental pollutants. Polymorphisms in the genes coding for these enzymes have been associated with increased susceptibility to different cancers, including hematologic malignancies. To investigate whether these polymorphisms represent risk-modifying factors for childhood ALL, a study was conducted involving 113 Brazilian patients of childhood ALL and 221 controls with similar ethnic backgrounds. The data revealed that carriers of the rare GSTP1 Val allele were at higher risk of ALL (odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.1,6.8; P = 0.04). No difference was found in the prevalence of the GSTM1 and GSTT1 null genotypes between ALL patients and the controls, and no association was found between CYP1A1*2 and CYP2E1*3 variants and ALL. However, when the mutant CYP1A1 and CYP2E1 alleles were considered together with the GSTM1 and GSTP1 risk-elevating genotypes, the risk of ALL was increased further (OR = 10.3; 95% CI = 1.0,111.8; P = 0.05), suggesting a combined effect. These results imply that genetic variants of xenobiotic metabolizing genes influence the risk of developing childhood ALL. Environ. Mol. Mutagen. 43:100,109, 2004. © 2004 Wiley-Liss, Inc. [source] Association of prostate cancer with rapid N -acetyltransferase 1 (NAT1*10) in combination with slow N -acetyltransferase 2 acetylator genotypes in a pilot case-control studyENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2002David W. Hein Abstract N -acetyltransferase-1 (NAT1) and N -acetyltransferase-2 (NAT2) are important in the metabolism of aromatic and heterocyclic amine carcinogens that induce prostate tumors in the rat. We investigated the association of genetic polymorphisms in NAT1 and NAT2, alone and in combination, with human prostate cancer. Incident prostate cancer cases and controls in a hospital-based case-control study were frequency-matched for age, race, and referral pattern. The frequency of slow acetylator NAT1 genotypes (NAT1*14, *15, *17) was 5.8% in controls but absent in cases. In contrast, in comparison with all other NAT1 genotypes the putative rapid acetylator NAT1 genotype (NAT1*10) was significantly higher in prostate cancer cases than controls (OR, 2.17; 95% CI, 1.08,4.33; P = 0.03). Combinations of NAT1*10 with NAT2 slow acetylator genotypes (OR, 5.08; 95% CI, 1.56,16.5; P = 0.008) or with NAT2 very slow (homozygous NAT2*5) acetylator genotypes (OR, 7.50; 95% CI, 1.55,15.4; P = 0.016) further increased prostate cancer risk. The results of this small pilot study suggest increased susceptibility to prostate cancer for subjects with combinations of NAT1*10 and slow (particularly very slow) NAT2 acetylator genotypes. This finding should be investigated further in larger cohorts and in other ethnic populations. Environ. Mol. Mutagen. 40:161,167, 2002. © 2002 Wiley-Liss, Inc. [source] Synergistic effects of esfenvalerate and infectious hematopoietic necrosis virus on juvenile chinook salmon mortalityENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2005Mark A. Clifford Abstract Sublethal concentrations of pollutants may compromise fish, resulting in increased susceptibility to endemic pathogens. To test this hypothesis, juvenile chinook salmon (Oncorhynchus tshawytscha) were exposed to sublethal levels of esfenvalerate or chlorpyrifos either alone or concurrently with infectious hematopoietic necrosis virus (IHNV). Three trials were performed with fish exposed to concentrations of IHNV between 0.8 × 102 and 2.7 × 106 plaque-forming units/ml and to 5.0 ,g/L of chlorpyrifos or 0.1 ,g/L of esfenvalerate. The presence and concentration of IHNV in dead fish were assayed by virus isolation and plaque assay techniques, respectively. Among groups exposed to both esfenvalerate and IHNV, 83% experienced highly significant (p < 0.001) mortality, ranging from 20 to 90% at 3 d post-virus exposure, and cumulatively died from 2.4 to 7.7 d sooner than fish exposed to IHNV alone. This trend was not seen in any other treatment group. Virus assays of dead fish indicate a lethal synergism of esfenvalerate and IHNV. Chlorpyrifos had no observed effect on total mortality or IHNV susceptibility. The present results suggest that accepted levels of pollutants may be seemingly nonlethal to fish but, in fact, be acting synergistically with endemic pathogens to compromise survivorship of wild fish populations through immunologic or physiologic disruption. [source] Association between lymphocyte proliferation and polychlorinated biphenyls in free-ranging harbor seal (Phoca vitulina) pups from British Columbia, CanadaENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 5 2005Milton Levin Abstract Recent pinniped die-offs have led to the speculation that persistent organic pollutants (POPs) are immunomodulatory, making individuals more susceptible to viral infections. Eighteen healthy harbor seal (Phoca vitulina) pups (aged 3,4 weeks) were live-captured from southern British Columbia, Canada, and maintained temporarily in captivity for an immunotoxicological assessment. The relationships between mitogen-induced peripheral blood lymphocyte proliferation and blubber concentrations of three major immunotoxic POP classes (the polychlorinated biphenyls [PCBs], polychlorinated dibenzo- p -dioxins [PCDDs], and the polychlorinated dibenzofurans [PCDFs]) were evaluated. A significant body weight-independent positive correlation was observed between both T-cell mitogen (phytohemagglutinin [PHA])- and B-cell mitogen (lipopolysaccharide [LPS])-induced lymphocyte proliferation and the blubber concentrations of total PCB. Best subset regression analysis revealed that total PCBs, and not total PCDD or total PCDF, explained 24 and 29% of the changes in both T-cell mitogen-and B-cell mitogen-induced lymphocyte proliferation, respectively. Further regression analysis performed on the PCB classes measured in this study showed that di - ortho PCBs accounted for 25 and 30% of the changes in both T-cell and B-cell lymphocyte proliferation, respectively. Results suggest that POPs, and PCBs in particular, are associated with changes in lymphocyte proliferation, something that could result in increased susceptibility to infections in harbor seal pups. Further research is needed to evaluate the relative roles of natural and contaminant-related influences on the immune system of marine mammals. [source] Serum paraoxonase activity in patients with type 1 diabetes compared to healthy controlsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2002B. Mackness Abstract Background The oxidation of low-density lipoprotein (LDL) is central to current theories on the initiation and progression of atherosclerosis. Type 1 diabetes is associated with an increase in oxidative stress, which may be responsible for the increased susceptibility to coronary heart disease seen in type 1 diabetes. High-density lipoprotein (HDL) associated paraoxonase (PON1) can retard the oxidation of LDL. Design Paraoxonase activity, concentration and genotype were therefore investigated in 152 people with type 1 diabetes and 282 healthy controls. These parameters were also investigated in the group with type 1 diabetes in relation to the presence of diabetic complications. Results Both PON1 activity and concentration were significantly lower by 16·7% and 19·2% (both P < 0·05) in the type 1 diabetes group. These differences were independent of the PON1 coding region polymorphisms. The distribution of PON1 activity and mass were the same in both populations, i.e. for the PON1-192 polymorphism RR > RQ > QQ and for the PON1-55 polymorphism LL > LM > MM. There were no differences in either the PON1 polymorphisms, PON1 activity and concentration in people with type 1 diabetes in the presence or absence of micro and macro vascular complications of diabetes. Conclusions Low PON1 activity may contribute to the increased atherosclerosis found in type 1 diabetes by reducing the ability of HDL to retard LDL oxidation despite the frequently-found increased HDL in type 1 diabetes when good glycaemic control is established. [source] Immunopathogenesis of cholestatic autoimmune liver diseasesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2001J. Medina Primary biliary cirrhosis and primary sclerosing cholangitis are well recognized chronic cholestatic liver diseases that are considered to have an autoimmune basis. Recent progress in the study of autoimmune liver diseases has improved the recognition and characterization of these conditions. An important component of this progress has been the identification of liver disease-associated autoantibodies and their respective target antigens, and the development of specific assays for these autoantibodies. In addition, some nonhumoral immunological findings imply an involvement of specific immunopathogenic mechanisms in the development of these conditions. Furthermore, immunogenetic factors associated with increased susceptibility to some of these diseases have been identified. This article reviews the most relevant information relating to the postulated autoimmune pathogenesis of these diseases, with special emphasis on their associated humoral and cellular immunological abnormalities and immunopathogenetic factors. Some of the remaining important unresolved issues relating to the pathogenesis of these diseases, that need to be addressed in further research, are highlighted. [source] Generalized multi-organ autoimmunity in CCR7-deficient miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2007Abstract Development of autoimmunity is a multi-factorial process involving genetic predisposition as well as environmental and stochastic factors. Although the mechanisms responsible for the initiation of autoimmunity remain only partially understood, several studies have demonstrated that genetic predisposition plays a major role in this process. In the present study, we analyzed the influence of CCR7 signaling in the development of autoimmunity, because this chemokine receptor is essentially involved in the functional organization of thymus architecture. We demonstrate that CCR7-deficient mice are prone to develop generalized multi-organ autoimmunity. The autoimmune phenotype of CCR7,/, mice encompasses the presence of lymphocyte infiltrates in several peripheral organs, circulating autoantibodies against a multitude of tissue-specific antigens and IgG deposition on renal glomeruli. Additionally, CCR7-deficient mice show increased susceptibility to streptozotocin-induced diabetes and spontaneously display signs of chronic autoimmune renal disease. Thus, this study identifies CCR7 as a genetic factor involved in the regulation of autoimmunity. [source] NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's diseaseEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2004Mihai Abstract Mutations of the NOD2 gene have been associated with an increased susceptibility to Crohn's disease, but the pathogenetic mechanisms mediated by NOD2 remain elusive. In the present study, we demonstrate that the 3020insC frameshift-mutation in the NOD2 gene associated with Crohn's disease results in defective release of IL-10 from blood mononuclear cells after stimulation with the Toll-like receptor (TLR)2 ligands, peptidoglycan and Pam3Cys-KKKK, but not with bacterial LPS, a TLR4 ligand. The potential pathophysiological significance of this finding in patients with Crohn's disease and who are homozygous for this NOD2 mutation was substantiated by the finding of decreased anti-inflammatory cytokine release when cells from these patients were stimulated with different species of Bacteroides, an enteric microorganism implicated in the pathogenesis of Crohn's disease. In conclusion, defective NOD2 function results in a pro-inflammatory cytokine bias after stimulation of mononuclear cells with TLR2 stimuli, and this could contribute to the overwhelming inflammation seen in Crohn's disease. See Mini-review in this issue http://dx.doi.org/10.1002/eji.200425095 [source] Oral status of 35 subjects with eating disorders , A 1-year studyEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 4 2000Rolf Öhrn The aim was to record changes over time in the oral status of subjects with diagnosed eating disorders. The outpatient psychiatrist had referred to the hospital dental clinic 35 women (19,47 yr, median 27 yr) with eating disorders, diagnosed according to DSM III-R criteria. At the baseline examination, dental, medical and dietary histories were taken, and intra-oral clinical and radiographic examinations were supplemented by intra-oral photographs, study casts and salivary analysis. The subjects were re-examined 1 yr later. Together, the investigators assessed progression of tooth wear blindly by comparing coded study casts from the baseline and 12-month examinations. Progression of erosive tooth wear was recorded in almost half of the subjects. Several subjects had low unstimulated salivary flow rates (<0.1 ml/min) and very high counts of mutans streptococci and lactobacilli, both at baseline and 1 yr later. The flow rates for paraffin-stimulated saliva at baseline were significantly lower for subjects with progression of erosive tooth wear than for those without. Because of the increased susceptibility to both caries and erosion, patients with eating disorders should be encouraged to have regular dental check-ups. Test of salivary flow may serve as an indicator of patients' risk of progression of erosive tooth wear. [source] Expression of the human Cathepsin L inhibitor hurpin in mice: skin alterations and increased carcinogenesisEXPERIMENTAL DERMATOLOGY, Issue 9 2007Markus Walz Abstract:, The serine protease inhibitor (serpin) hurpin (serpin B13) is a cross class-specific inhibitor of the cysteine protease Cathepsin (Cat) L. Cat L is involved in lysosomal protein degradation, hair follicle morphogenesis, epidermal differentiation and epitope generation of antigens. Hurpin is a 44 kDa protein which is expressed predominantly in epidermal cells. In psoriatic skin samples, hurpin was strongly overexpressed when compared with normal skin. Keratinocytes overexpressing hurpin showed increased resistance towards UVB-induced apoptosis. To further analyse the functional importance of this inhibitor, we have generated transgenic mice with deregulated Cat L activity by expressing human hurpin in addition to the endogenous mouse inhibitor. The three independent transgenic lines generated were characterized by identical effects excluding insertional phenotypes. Macroscopically, mice expressing human hurpin are characterized by abnormal abdominal fur. The number of apoptotic cells and caspase-3 positive cells was reduced after UV-irradiation in transgenic animals compared with wild-type mice. Interestingly, after chemical carcinogenesis, transgenic mice showed an increased susceptibility to develop skin cancer. Array analysis of gene expression revealed distinct differences between wild-type and hurpin-transgenic mice. Among others, differentially expressed genes are related to antigen presentation and angiogenesis. These results suggest an important role of Cat L regulation by hurpin which might be of clinical relevance in human skin diseases. [source] Molecular basis of perinatal hypophosphatasia with tissue-nonspecific alkaline phosphatase bearing a conservative replacement of valine by alanine at position 406FEBS JOURNAL, Issue 11 2008Structural importance of the crown domain Hypophosphatasia, a congenital metabolic disease related to the tissue-nonspecific alkaline phosphatase gene (TNSALP), is characterized by reduced serum alkaline phosphatase levels and defective mineralization of hard tissues. A replacement of valine with alanine at position 406, located in the crown domain of TNSALP, was reported in a perinatal form of hypophosphatasia. To understand the molecular defect of the TNSALP (V406A) molecule, we examined this missense mutant protein in transiently transfected COS-1 cells and in stable CHO-K1 Tet-On cells. Compared with the wild-type enzyme, the mutant protein showed a markedly reduced alkaline phosphatase activity. This was not the result of defective transport and resultant degradation of TNSALP (V406A) in the endoplasmic reticulum, as the majority of newly synthesized TNSALP (V406A) was conveyed to the Golgi apparatus and incorporated into a cold detergent insoluble fraction (raft) at a rate similar to that of the wild-type TNSALP. TNSALP (V406A) consisted of a dimer, as judged by sucrose gradient centrifugation, suggestive of its proper folding and correct assembly, although this mutant showed increased susceptibility to digestion by trypsin or proteinase K. When purified as a glycosylphosphatidylinositol-anchorless soluble form, the mutant protein exhibited a remarkably lower Kcat/Km value compared with that of the wild-type TNSALP. Interestingly, leucine and isoleucine, but not phenylalanine, were able to substitute for valine, pointing to the indispensable role of residues with a longer aliphatic side chain at position 406 of TNSALP. Taken together, this particular mutation highlights the structural importance of the crown domain with respect to the catalytic function of TNSALP. [source] Microheterogeneity of recombinant human phenylalanine hydroxylase as a result of nonenzymatic deamidations of labile amide containing amino acidsFEBS JOURNAL, Issue 20 2000Effects on catalytic, stability properties The microheterogeneity of recombinant human phenylalanine hydroxylase (hPAH) was investigated by isoelectric focusing and 2D electrophoresis. When expressed in Escherichia coli four main components (denoted hPAH I-IV) of ,,50 kDa were observed on long-term induction at 28,37 °C with isopropyl thio-,- d -galactoside (IPTG), differing in pI by about 0.1 pH unit. A similar type of microheterogeneity was observed when the enzyme was expressed (1 h at 37 °C) in an in vitro transcription-translation system, including both its nonphosphorylated and phosphorylated forms which were separated on the basis of a difference in mobility on SDS/PAGE. Experimental evidence is presented that the microheterogeneity is the result of nonenzymatic deamidations of labile amide containing amino acids. When expressed in E. coli at 28 °C, the percentage of the acidic forms of the enzyme subunit increased as a function of the induction time with IPTG, representing about 50% on 8 h induction. When the enzyme obtained after 2 h induction (containing mainly hPAH I) was incubated in vitro, its conversion to the acidic components (hPAH II,IV) revealed a pH and temperature dependence characteristic of a nonenzymatic deamidation of asparagine residues in proteins, with the release of ammonia. Comparing the microheterogeneity of the wild-type and a truncated form of the enzyme expressed in E. coli, it is concluded that the labile amide groups are located in the catalytic domain as defined by crystal structure analysis [Erlandsen, H., Fusetti, F., Martínez, A., Hough, E., Flatmark, T. & Stevens, R. C. (1997) Nat. Struct. Biol. 4, 995,1000]. It is further demonstrated that the progressive deamidations which occur in E. coli results in a threefold increase in the catalytic efficiency (Vmax/[S]0.5) of the enzyme and an increased susceptibility to limited tryptic proteolysis, characteristic of a partly activated enzyme. The results also suggest that deamidation may play a role in the long term regulation of the catalytic activity and the cellular turnover of this enzyme. [source] In vitro response to Candida albicans in cultures of whole human blood from young and aged donorsFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 2 2007Celia Murciano Abstract Invasive infections with opportunistic fungi, such as Candida albicans, have become an increasing problem in aged adults in recent years. This work investigates the influence of human ageing on C. albicans recognition by toll-like receptors (TLRs), essential components of the innate immune system, using a cohort of 96 young (15,42 years) and aged (>70 years) human volunteers. No significant differences between aged and young donors were observed on (1) cell surface TLR2, TLR6 and TLR4 expression on lymphocytes, monocytes and granulocytes, (2) production of cytokines [IL-8, IL-1,, IL-6, IL-10, tumour necrosis factor (TNF)-, and IL-12p70] and prostaglandin E2 (PGE2) by whole human blood in response to C. albicans and (3) fungicidal activity of whole blood. A statistically significant higher titre of natural anti- C. albicans antibodies was found in plasma of volunteers between 80 and 95 years old when compared with other age groups, probably as a consequence of the increased levels of serum Ig that has been described in elderly subjects. Therefore, the results indicate that the increased susceptibility to C. albicans infections in the elderly is not a consequence of defects in TLRs expression or signalling, nor of an impaired fungicidal activity of blood. [source] Increased mite parasitism as a cost of testosterone in male striped plateau lizards Sceloporus virgatusFUNCTIONAL ECOLOGY, Issue 2 2007ROBERT M. COX Summary 1Testosterone (T) co-ordinates the seasonal and sex-specific expression of numerous physiological, behavioural and morphological traits that contribute to male reproductive success. However, increased susceptibility to parasitism has been proposed as a potential cost of elevated plasma T. 2During the spring breeding season, male striped plateau lizards Sceloporus virgatus harbour significantly more ectoparasitic mite larvae (Acari: Trombiculidae) than females. Plasma T levels are also elevated in males at this time, suggesting that sex differences in mite parasitism may be driven by underlying sex differences in circulating T. 3We tested this hypothesis experimentally by manipulating plasma T levels of yearling males via surgical castration and exogenous T implants. Upon recapture of free-living animals, we found significantly fewer mites on castrated males relative to either intact controls or castrated males that received T implants. 4After removing variance attributable to treatment effects, we observed (1) a positive correlation between residual measures of plasma T and mite load, and (2) a negative correlation between residual measures of mite load and growth rate. These correlations suggest a growth cost associated with mite parasitism. 5Previous studies have shown that exogenous T increases parasitism, but ours is one of the few to show that castration also reduces parasitism. This result, coupled with the fact that our induced plasma T levels remain within physiological limits, makes this one of the clearest demonstrations of a functional relationship between T and parasitism in any free-living vertebrate. [source] C1584 in von Willebrand factor is necessary for enhanced proteolysis by ADAMTS13 in vitroHAEMOPHILIA, Issue 4 2007S. KEENEY Summary., The cysteine variant of the amino acid change tyrosine/cysteine 1584 (Y/C1584) in von Willebrand factor (VWF) has previously been shown to cosegregate with increased susceptibility of VWF to proteolysis by ADAMTS13. It is not known whether C1584 itself confers increased proteolysis or is linked to a causative change elsewhere in VWF. To address whether C1584 underlies enhanced susceptibility of VWF to ADAMTS13-mediated proteolysis, a single family comprising two heterozygous Y/C1584 individuals and four homozygous Y/Y1584 individuals was investigated. The essential regions of the VWF gene were sequenced in all six individuals and ADAMTS13-mediated proteolysis of plasma VWF was assessed for each individual. Comparison of the VWF coding sequences for the Y/C1584 individuals with those for the Y/Y1584 individuals revealed that two amino acid variants were unique to the heterozygotes: R484 and C1584. The plasma VWF of the two heterozygotes showed increased susceptibility to proteolysis in vitro compared with that of the four homozygotes. In the present study we demonstrate that R484, in the absence of C1584, does not influence VWF proteolysis. Enhanced proteolysis occurred only in the presence of Cys1584. Thus, Cys1584 is necessary for increased susceptibility of VWF to proteolysis by ADAMTS13. [source] Association of estrogen receptor , polymorphisms with susceptibility to chronic hepatitis B virus infectionHEPATOLOGY, Issue 2 2004Guohong Deng Several studies have demonstrated that estrogen receptor , (ESR1) participates in the pathogenesis of persistent hepatitis B virus (HBV) infection. To examine whether polymorphisms at the ESR1 gene locus are associated with persistent HBV infection, we resequenced ESR1 genomic region for single nucleotide polymorphisms (SNPs) in 27 unrelated Chinese. Two haplotype-tagged SNPs (htSNP), T29C and A252966G, were selected for genotyping in 1,277 persistent HBV-infected cases, 748 spontaneously recovered controls, and 293 nuclear families using polymerase chain reaction (PCR)-restriction fragment length polymorphism (PCR-RFLP) analysis. We observed that the subjects bearing ESR1 29T/T genotype had an increased susceptibility to persistent HBV infection compared to those bearing at least one 29C allele (odds ratio 1.41; 95% CI, 1.17-1.71, P < .001). Consistent with the results of population-based association study, a significantly greater than expected transmission of the 29T allele (56.4%) from heterozygous parents to offspring with persistent HBV infection was observed (,2 = 4.60, P = .033) using the transmission-disequilibrium test (TDT) in 293 nuclear families. Linkage disequilibrium (LD) mapping analysis indicated that the T29C polymorphism contained within a LD block located from promoter region to intron 3 of ESR1, suggesting that the strong association detected with T29C in ESR1 originated from ESR1 itself. In conclusion, our results suggest that the genetic variation at the ESR1 locus influences susceptibility to persistent HBV infection in a Chinese population. (HEPATOLOGY 2004;40:318,326.) [source] Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liverHEPATOLOGY, Issue 2 2002Ping Zhao Chronic alcohol consumption may potentiate acetaminophen (APAP) hepatotoxicity through enhanced formation of N -acetyl- p -benzoquinone imine (NAPQI) via induction of cytochrome P450 2E1 (CYP2E1). However, CYP2E1 induction appears to be insufficient to explain the claimed magnitude of the interaction. We assessed the role of selective depletion of liver mitochondrial glutathione (GSH) by chronic ethanol. Rats were fed the Lieber-DeCarli diet for 10 days or 6 weeks. APAP toxicity in liver slices (% glutathione- S -transferase , released to the medium, GST release) and NAPQI toxicity in isolated liver mitochondria (succinate dehydrogenase inactivation, SDH) from these rats were compared with pair-fed controls. Ethanol induced CYP2E1 in both the 10-day and 6-week groups by ,2-fold. APAP toxicity in liver slices was higher in the 6-week ethanol group than the 10-day ethanol group. Partial inhibition of NAPQI formation by CYP2E1 inhibitor diethyldithiocarbamate to that of pair-fed controls abolished APAP toxicity in the 10-day ethanol group only. Ethanol selectively depleted liver mitochondrial GSH only in the 6-week group (by 52%) without altering cytosolic GSH. Significantly greater GSH loss and APAP covalent binding were observed in liver slice mitochondria of the 6-week ethanol group. Isolated mitochondria of the 6-week ethanol group were ,50% more susceptible to NAPQI (25-165 ,mol/L) induced SDH inactivation. This increased susceptibility was reproduced in pair-fed control mitochondria pretreated with diethylmaleate. In conclusion, 10-day ethanol feeding enhances APAP toxicity through CYP2E1 induction, whereas 6-week ethanol feeding potentiates APAP hepatotoxicity by inducing CYP2E1 and selectively depleting mitochondrial GSH. [source] Photoprotein aequorin as a novel reporter for SNP genotyping by primer extension,application to the variants of mannose-binding lectin gene,HUMAN MUTATION, Issue 3 2006Panayotis G. Zerefos Abstract Mannose-binding lectin (MBL) is a key component of the innate immune system, and its deficiency is associated with increased susceptibility to various infections and autoimmune disorders. Since several nucleotide variations in the mannose-binding lectin 2 gene (MBL2) have been associated with the functional deficiency of MBL, there is a growing need to screen its allelic variants and develop genotyping methods for MBL2. In this context we propose a rapid, robust, cost-efficient, and automatable method for detecting all known allelic variants of MBL2. This report introduces for the first time the photoprotein aequorin as a reporter in genotyping by primer extension (PEXT) reactions. The method involves a single PCR amplification of a genomic region that spans all six variant nucleotide sites, i.e., three structural mutations in exon 1 (c.154C>T, pArg52Cys; c.161A>G, p.Gly54Asp; and c.170A>G, p.Gly57Glu), two single nucleotide polymorphisms (SNPs) at positions c.,619G>C and c.,290G>C (promoter region), and one SNP at position c.,66C>T of the 5, untranslated region. PCR is followed by PEXT reactions for each site. Biotin-dUTP is incorporated in the extended primer. The genotyping primers contain a poly(dA) segment at their 5, end. The products are captured by hybridization on the surface of microtiter wells that are coated with a poly(dT)-albumin. The extended primers only are detected by reaction with a streptavidin-aequorin conjugate. The bound photoprotein aequorin is measured within 3,sec by simply adding Ca2+. We carried out extensive optimization studies of the PEXT reaction and genotyped the six nucleotide variant sites using blood specimens from 27 normal DNA samples. The results of the proposed method agreed entirely with the sequencing data. Hum Mutat 27(3), 279,285, 2006. © 2006 Wiley-Liss, Inc. [source] Attenuated apoptosis response to Fas-ligand in active ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 12 2008Jakob B. Seidelin MD Abstract Background: From mainly carcinoma cell line studies, apoptosis has been thought to play a major role in the pathogenesis of ulcerative colitis (UC). Apoptosis has been suggested to be due to a Fas ligand / Fas receptor interaction, but has never been studied in cells from patients with active UC. The aim was to investigate both the spontaneous and the cell death receptor ligand-induced apoptosis in UC. Methods: Twenty patients with UC and 16 control subjects who underwent routine colonoscopy either for the control or surveillance of their disease or where the diagnosis of irritable bowel syndrome was subsequently reached were included. Cultures of isolated colonic crypts were obtained from biopsies and cultured for 4 to 16 hours with Fas ligand or Fas ligand and costimulation with interferon-, (IFN-,). Control experiments were performed on HT29 cells. Apoptosis was assessed by independent methods. Results: Isolated colonocytes from healthy subjects or patients with remission in UC had a dose-dependent response to Fas ligand. This response was abolished in patients with active UC (P < 0.002), and costimulation with IFN-, did not alter this response. Patients with active UC had an increased apoptosis rate of 9.5% compared with controls (P < 0.05). Conclusions: The current study indicates that colonocytes do not respond to cytokine exposure and inflammation by an increased vulnerability, as previously thought. Colonocytes seem to activate cytoprotective programs in response to inflammation. Apart from supporting the regeneration process during inflammation, this response could additionally cause an increased susceptibility to neoplastic transformation. (Inflamm Bowel Dis 2008) [source] Absence of acute apoptotic response to genotoxic carcinogens in p53 -deficient mice is associated with increased susceptibility to azoxymethane-induced colon tumoursINTERNATIONAL JOURNAL OF CANCER, Issue 4 2005Ying Hu Abstract Acute apoptotic response to genotoxic carcinogens (AARGC) might be important for controlling the consequences of mutational load in the colon. It has been shown to occur in parallel with activation of DNA repair mechanisms. Inadequate AARGC might allow development of mutated clones with the potential to progress to cancer. In this study, we tested if p53 levels were important for AARGC in the colon and whether defective AARGC was associated with increased risk for colorectal oncogenesis. Apoptosis was measured in colonic epithelium of mice from each p53 genotype (p53,/,, p53+/,, wild-type) without and 8 hr following a single injection of azoxymethane (AOM). To determine risk for carcinogen-induced colorectal cancer (CRC), groups of mice from each p53 genotype received 3 weekly injections of AOM and colons were examined for tumour 20 weeks later. Rates of spontaneous apoptosis in colon were not affected by p53 level. However, AARGC was absent in p53,/, mice and reduced by 50% in p53+/, mice (both p < 0.01) compared to wild-type mice. AOM induced tumours in 30% of wild-type mice (average multiplicity 1.0 tumours/mouse) compared to 72% of p53+/, mice (2.0 tumours/mouse, p < 0.01) and 100% of p53,/, mice (2.8 tumours/mouse, p < 0.01). Without AOM, significantly fewer mice in all groups had tumours. Rates of apoptosis in tumours were independent of p53 status. p53 dysfunction puts intestinal epithelia at increased risk of genotoxin-induced oncogenesis due to impairment of apoptotic response mechanisms. p53 levels do not appear, however, to be important for spontaneous apoptosis in normal epithelium or apoptosis in tumours. Subsequent studies are now warranted to test the converse, namely, that enhanced apoptotic response to carcinogen reduces risk for colorectal oncogenesis. © 2005 Wiley-Liss, Inc. [source] Abortions and breast cancer: Record-based case-control studyINTERNATIONAL JOURNAL OF CANCER, Issue 5 2003Gunnar Erlandsson Abstract It has been suggested that abortions leave the breast epithelium in a proliferative state with an increased susceptibility to carcinogenesis. Results from previous studies of induced or spontaneous abortions and risk of subsequent breast cancer are contradictory, probably due to methodological considerations. We investigated the relationship between abortions and subsequent breast cancer risk in a case-control study using prospectively recorded exposure information. The study population comprised women recorded in the population-based Swedish Medical Birth Register between 1973,91. Cases were defined by linkage of the birth register to the Swedish Cancer Register and controls were randomly selected from the birth register. From the subjects' antenatal care records we abstracted prospectively collected information on induced and spontaneous abortions, as well as a number of potential confounding factors. Relative risk of breast cancer was estimated by odds ratios (OR) with 95% confidence intervals (95% CI). A reduced risk of breast cancer was observed for women with a history of at least 1 compared to no abortions (adjusted OR = 0.84, 95% CI = 0.72,0.99). The adjusted OR decreases step-wise with number of abortions to 0.59 (95% CI = 0.34,1.03) for 3 or more compared to no abortions. The patterns are similar for induced and spontaneous abortions. In conclusion, neither a history of induced nor spontaneous abortions is associated with an increased risk of breast cancer. Our data suggest a protective effect of pregnancies regardless of outcome. © 2002 Wiley-Liss, Inc. [source] Analysis of hair lipids and tensile properties as a function of distance from scalpINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 4 2005L. Duvel Synopsis Cuticle cells form the outer covering surrounding and protecting the cortex. The cuticle cells are thin, flat and overlap, and intercellular lipid lamellae are found in the gaps between the cell boundaries. The lipid lamellae are also found within the cortex in the cell boundaries between the long fribrous corticle cells. In addition, the outer surfaces of the cuticle cells are covered by a monolayer of covalently bound fatty acids, a major component of which is 18-methyleicosanoic acid. The fatty acids are thought to be attached through thio-ester linkages. Together these lipids are thought to be major determinants of the physical properties of the hair. The present study tested the hypothesis that both free and covalently bound lipids are progressively lost during normal environmental exposures. This progressive loss within the cuticle layers may, in part, lead to an increased susceptibility of the protein and lipid lamellae in the cortex to degradation. This degradation, in turn, would contribute to a progressive decrease in the tensile properties of the hair. Research grade hair was cut into five segments from the root to the distal end. Lipids from each segment were extracted and analyzed by thin-layer chromatography in conjunction with photodensitometry. The major free polar lipid classes in the hair included ceramides, glucosylceramides and cholesterol sulfate. The concentrations of all of the free polar lipids as well as the covalently bound fatty acids decreased in going from the root to the distal end of the hair. In addition, there was a significant reduction in tensile properties of the hair from the root to distal end. In conclusion, the progressive loss of endogenous free and covalently bound lipids from hair, which are probably related to normal weathering of the hair and grooming practices, may help contribute to a marked decrease in tensile properties to the hair. Résumé Les cellules de la cuticule forment le revêtement externe qui protège le cortex des cheveux. Les cellules de la cuticule sont minces, plates et se chevauchent. De fines couches de lipides sont présentes dans le matériau assurant la jonction entre les cellules cuticulaires. D'autres fines couches de lipides sont également présentes dans les espaces intercellulaires du cortex, entre les longues cellules corticales fibreuses. De plus, les surfaces externes des cellules de la cuticule sont recouvertes d'une couche monomoléculaire d'acides gras liés par covalence, un des composants majoritaires étant l'acide 18-méthyleicosanoique. On pense que ces acides gras sont fixés par liaisons thioesters. On pense également que l'ensemble de ces lipides joue un rôle important sur les propriétés physiques du cheveu. L'hypothèse testée dans cette étude est que les lipides libres et ceux liés par covalence sont progressivement éliminés lors de l'exposition normale des cheveux à l'environnement extérieur. Cette délipidation progressive de la cuticule pourrait, en partie, entraîner une plus grande sensibilité des constituants lipidiques et protéiniques du cortex aux agressions externes et accroître leur dégradation. Cette dégradation, à son tour, contribuerait à une diminution progressive des propriétés mécaniques en extension des cheveux. Des cheveux de provenance commerciale ont été coupés en cinq segments de leur racine à leur extrémité distale. Les lipides de chaque segment ont été extraits, séparés par chromatographie couche mince et dosés par densitométrie photographique. Les classes majoritaires de lipides polaires libres sont constituées de céramides, de glucosylcéramides et de sulfate de cholestérol. Les teneurs de tous les lipides polaires libres ainsi que des acides gras liés par covalence diminuent de la racine à l'extrémité distale du cheveu. De plus, on constate une réduction considérable des propriétés mécaniques en extension des cheveux de la racine à l'extrémité distale.-.En conclusion, la perte progressive des lipides endogènes libres et liés par covalence, probablement attribuables aux expositions à l'environnement et au stress des traitements capillaires peut aider à contribuer à une baisse marquée des propriétés mécaniques en extension des cheveux. [source] | |||||||||||||||||||||||||||||||||||||||||||