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Mechanism Leading (mechanism + leading)
Kinds of Mechanism Leading Selected AbstractsThe effect of prenatal hypoxia on brain development: short- and long-term consequences demonstrated in rodent modelsDEVELOPMENTAL SCIENCE, Issue 4 2006Hava Golan Hypoxia (H) and hypoxia-ischemia (HI) are major causes of foetal brain damage with long-lasting behavioral implications. The effect of hypoxia has been widely studied in human and a variety of animal models. In the present review, we summarize the latest studies testing the behavioral outcomes following prenatal hypoxia/hypoxia-ischemia in rodent models. Delayed development of sensory and motor reflexes during the first postnatal month of rodent life was observed by various groups. Impairment of motor function, learning and memory was evident in the adult animals. Activation of the signaling leading to cell death was detected as early as three hours following H/HI. An increase in the counts of apoptotic cells appeared approximately three days after the insult and peaked about seven days later. Around 14,20 days following the H/HI, the amount of cell death observed in the tissue returned to its basal levels and cell loss was apparent in the brain tissue. The study of the molecular mechanism leading to brain damage in animal models following prenatal hypoxia adds valuable insight to our knowledge of the central events that account for the morphological and functional outcomes. This understanding provides the starting point for the development and improvement of efficient treatment and intervention strategies. [source] Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2006Alessio Nencioni Dr. Abstract Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen-presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte-derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up-regulation and intracellular redistribution of Bcl-2-associated X,protein (Bax), a pro-apoptotic Bcl-2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen-presenting cell level. [source] Reversible protein kinase C activation in PC12 cells: effect of NGF treatmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2000Jean-Luc Dupont Abstract Although protein kinase C (PKC) is a key enzyme in the signal transduction process, there is little information on the mechanism leading to PKC activation in living cells. Using a new fluorescence imaging method, we studied this mechanism and correlated PKC conformational changes with intracellular Ca2+ concentration. PC12 cells were simultaneously loaded with Fura-2-AM and Fim-1, two fluorescent probes, which recognize Ca2+ and PKC, respectively. KCl and carbachol (an agonist to muscarinic receptors) applications induced dose-dependent increases of fluorescence for both probes. Both Ca2+ and PKC responses were observed within seconds following KCl or carbachol application, and were reversible upon stimulus withdrawal. PKC activation kinetics was slightly more rapid than the Ca2+ response after KCl application. After nerve growth factor (NGF) treatment of the cells, the amplitude of the KCl-induced PKC responses was larger indicating an increase in the activated PKC-pool in these cells. This difference between control and NGF-treated cells was not observed following carbachol application, suggesting the involvement of different PKC pools. While the Ca2+ response uniformly occurred in the cytosol, the PKC response displayed a patch pattern with higher intensities in the peripheral zone near the plasma membrane. This heterogeneous distribution of PKC activation sites was similar to the immunocytological localization of Ca2+ -dependent and independent PKC isoforms, which suggested that at least several PKC isoforms interacted with intracellular elements. Upon repeated stimulation, the PKC response rapidly desensitized. [source] Neutrophil influx during non-typhoidal salmonellosis: who is in the driver's seat?FEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 3 2006Çagla Tükel Abstract A massive neutrophil influx in the intestine is the histopathological hallmark of Salmonella enterica serovar Typhimurium-induced enterocolitis in humans. Two major hypotheses on the mechanism leading to neutrophil infiltration in the intestinal mucosa have emerged. One hypothesis suggests that S. enterica serovar Typhimurium takes an active role in triggering this host response by injecting proteins, termed effectors, into the host cell cytosol which induce a proinflammatory gene expression profile in the intestinal epithelium. The second hypothesis suggests a more passive role for the pathogen by proposing that bacterial invasion stimulates the innate pathways of inflammation because the pathogen-associated molecular patterns of S. enterica serovar Typhimurium are recognized by pathogen recognition receptors on cells in the lamina propria. A review of the current literature reveals that, while pathogen recognition receptors are clearly involved in eliciting neutrophil influx during S. enterica serovar Typhimurium infection, a direct contribution of effectors in triggering proinflammatory host cell responses cannot currently be ruled out. [source] Definitive molecular cytogenetic characterization of 15 colorectal cancer cell lines,GENES, CHROMOSOMES AND CANCER, Issue 3 2010Turid Knutsen In defining the genetic profiles in cancer, cytogenetically aberrant cell lines derived from primary tumors are important tools for the study of carcinogenesis. Here, we present the results of a comprehensive investigation of 15 established colorectal cancer cell lines using spectral karyotyping (SKY), fluorescence in situ hybridization, and comparative genomic hybridization (CGH). Detailed karyotypic analysis by SKY on five of the lines (P53HCT116, T84, NCI-H508, NCI-H716, and SK-CO-1) is described here for the first time. The five lines with karyotypes in the diploid range and that are characterized by defects in DNA mismatch repair had a mean of 4.8 chromosomal abnormalities per line, whereas the 10 aneuploid lines exhibited complex karyotypes and a mean of 30 chromosomal abnormalities. Of the 150 clonal translocations, only eight were balanced and none were recurrent among the lines. We also reviewed the karyotypes of 345 cases of adenocarcinoma of the large intestine listed in the Mitelman Database of Chromosome Aberrations in Cancer. The types of abnormalities observed in the cell lines reflected those seen in primary tumors: there were no recurrent translocations in either tumors or cell lines; isochromosomes were the most common recurrent abnormalities; and breakpoints occurred most frequently at the centromeric/pericentromeric and telomere regions. Of the genomic imbalances detected by array CGH, 87% correlated with chromosome aberrations observed in the SKY studies. The fact that chromosome abnormalities predominantly result in copy number changes rather than specific chromosome or gene fusions suggests that this may be the major mechanism leading to carcinogenesis in colorectal cancer. Published 2009 Wiley-Liss, Inc. [source] Translocation,excision,deletion,amplification mechanism leading to nonsyntenic coamplification of MYC and ATBF1,GENES, CHROMOSOMES AND CANCER, Issue 2 2006Nadine Van Roy Despite oncogene amplification being a characteristic of many tumor types, the mechanisms leading to amplicon formation have remained largely unresolved. In this study, we used a combinatorial approach of fluorescence in situ hybridization and single-nucleotide polymorphism chip gene copy number analyses to unravel the mechanism leading to nonsyntenic coamplification of MYC and ATBF1 in SJNB-12 cells. To explain our findings, we propose a complex series of events consisting of multiple double-strand breaks, accompanied (or triggered) by the formation of a reciprocal translocation t(8;16), as well as excisions and deletions near the translocation breakpoints. This study provides evidence for a translocation,excision,deletion,amplification sequence of events rather than a breakage,fusion,bridge model, which has been more frequently proposed to explain proto-oncogene amplification. Furthermore, it illustrates the power of presently available tools for detailed analysis of the complex rearrangements that accompany amplicon formation. © 2005 Wiley-Liss, Inc. [source] Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cellsHEMATOLOGICAL ONCOLOGY, Issue 4 2007A Allegra Abstract Osteonecrosis of the jaws (ONJ) associated with the use of bisphosphonates is a newly described entity. To elucidate the mechanism leading to ONJ and to test the hypothesis that in patients with ONJ the bisphosphonates may interfere with endothelial cell proliferation, using flow cytometric analysis we evaluated the number of circulating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in eight patients with bisphosphonate treatment and osteonecrosis, eight multiple myeloma (MM) patients with bisphosphonates treatment without ONJ and five normal subjects. MM patients showed an increase of CD34+ cells with respect the control subjects and ONJ subjects. EPCs and CECs were higher in MM patients compared to controls and ONJ patients. ONJ patients showed a decrease of EPCs compared to control subjects while CECs were similar to the controls group. Our results seem to show the possibility that bisphosphonates could have a antiangiogenic effect and a suppressive effect on CECs of patients with ONJ. Copyright © 2007 John Wiley & Sons, Ltd. [source] Recruitment of host progenitor cells in rat liver transplants,HEPATOLOGY, Issue 2 2009Zhaoli Sun Despite major histocompatibility complex incompatibility, liver transplants from Lewis rats to dark agouti (DA) rats survive indefinitely without immunosuppression, and the studies we report sought the mechanism(s) responsible for this. At 1 year, most of the liver reacted positively to host anti-DA antibody. When small (50%) grafts were transplanted, recruitment was more rapid because most of the organ assumed the host phenotype at 3 months. After transplantation, the Y chromosome was detected in the hepatocytes of XX to XY grafts by both in situ hybridization and polymerase chain reaction. Further, livers from transgenic Lewis rats carrying strong green fluorescent protein (GFP) markers lost the marker with time after transplantation to DA, GFP-negative hosts. Few liver cells contained the Y chromosome in syngeneic XX to XY liver grafts or when the hosts of Lewis XX to DA XY allografts were treated with cyclosporine A at 10 mg/kg/day. This dosage also impeded enlargement of the liver at 10 days. Using GFP-positive XX Lewis donors transplanted to GFP-negative XY DA hosts, we found little Y DNA in GFP-positive cells at 10 days. Host-derived OV-6,positive and c-kit,positive, albumin-positive cells were present at 3-10 days, but cells with the CD34 marker were less common and some clearly still had the donor phenotype at 10 days. Cells positive for chemokine cysteine-X-cysteine receptor-4 increased with time and were abundant 1 month after transplantation. We conclude: (1) extrahepatic cells can differentiate into liver tissues; (2) regenerative stimuli accelerate stem cell recruitment; (3) both regeneration and recruitment are impeded by cyclosporine A immunosuppression, and (4) donor GFP-positive cells contained little host Y chromosome after transplantation, suggesting that cell fusion was uncommon and, therefore, unlikely to be the mechanism leading to the changes in genotype and phenotype we observed. (HEPATOLOGY 2008.) [source] Charge transfer in single- and double-strand DNAs: Theoretical analysis based on molecular orbital methodINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 15 2006Kenichi Dedachi Abstract Electrochemical DNA chips determine the sequence of DNA bases by detecting the change in charge conductivity through single- or double-strand DNA. Experimentally, double-strand DNAs were found to conduct much greater electric current than single-strand DNAs. To gain insight into the underlying mechanism leading to such a disparity in charge conductivity, the hole/electron conductivities in single- and double-strand DNAs were examined theoretically by molecular dynamics and molecular orbital (MO) calculations. The hole/electron transfer integrals between the neighboring DNA bases were estimated from the frontier MO energy levels. The current-voltage characteristics of single- and double-strand DNAs, derived from the transfer integrals and the site energy of each DNA base, are qualitatively in agreement with experiment. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006 [source] Cyclobutenes as Isolable Intermediates in the Gold(I)-Catalysed Cycloisomerisation of 1,8-EnynesADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 3 2009Yann Odabachian Abstract The gold(I)-catalysed isomerisation of 1,8-enynes allows the efficient synthesis of functionalised bicyclo[5.2.0]nonenes. Notably, these cyclobutenes derivatives can be isolated as reactive intermediates that could undergo subsequent gold(I)-catalysed transformations such as isomerisation, fragmentation or ene reaction to furnish more structurally complex products. This study also provides useful information related to the mechanism leading to metathesis-type derivatives, examples of which were shown to be produced, in the present case, by a gold(I)-catalysed ring fragmentation of the cyclobutene moiety. [source] Gradients in vegetation cover, structure and species richness of Nama-Karoo shrublands in relation to distance from livestock watering pointsJOURNAL OF APPLIED ECOLOGY, Issue 2 2006SIMON W. TODD Summary 1Gradients of animal impact known as piospheres tend to develop around artificial watering points, particularly in arid zones. Such grazing gradients represent a potential opportunity for differentiating the long-term effects of livestock activity from other environmental patterns. In this study, the impact of watering point provision on the plant cover, species richness and community structure of Karoo shrublands, South Africa, was investigated in the context of the evolutionary history and current grazing management practices of the region. 2The impacts of watering point provision were investigated by sampling plant cover and composition along transects placed at set distances, ranging from 10 m to 2200 m, from 11 watering points. 3Karoo vegetation cover and structure are relatively resilient to livestock grazing. Karoo plant diversity, as measured by species richness, evenness and dominance, was not as resilient. Twice as many species decreased as increased near watering points. The majority of species that decreased were regarded as being highly palatable to livestock. Heavy grazing, leading to death or repeated reproductive failure, is the most likely mechanism leading to the decline of such species. 4The highly disturbed area immediately adjacent to watering points was dominated by forbs and contained a large proportion of alien species. Adjacent to this was a zone dominated by widespread shrub species of medium to low palatability. Areas most distant from watering points contained a greater proportion of species known to be highly palatable to livestock. The ability of dominant Karoo shrubs to tolerate heavy grazing may have allowed rangeland managers to maintain stocking rates above that which can be tolerated by the majority of species but which are supported by a minority of grazing-tolerant species. 5Synthesis and applications. Highly palatable species are more abundant in areas distant from water points. Larger paddocks therefore provide a refuge for sensitive species that might otherwise be lost from the rangeland as a whole. Species that tend to occur away from watering points represent potentially useful indicators of grazing pressure. The use of these species as indicators of rangeland condition among landowners should be promoted. [source] Radiation-induced bystander effects in malignant trophoblast cells are independent from gap junctional communicationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2008Ferya Banaz-Ya Abstract It is controversially discussed that irradiation induces bystander effects via gap junction channels and/or diffusible cellular factors such as nitric oxide or cytokines excreted from the cells into the environment. But up to now the molecular mechanism leading to a bystander response is not well understood. To discriminate between both mechanisms of bystander response, (i) mediated by gap junctional communication and/or (ii) mediated by diffusible molecules, we used non-communicating Jeg3 malignant trophoblast cells transfected with inducible gap junction proteins, connexin43 and connexin26, respectively, based on the Tet-On system. We co-cultivated X-ray irradiated and non-irradiated bystander Jeg3 cells for 4 h, separated both cell populations by flow cytometry and evaluated the expression of activated p53 by Western blot analysis. The experimental design was proven with communicating versus non-communicating Jeg3 cells. Interestingly, our results revealed a bystander effect which was independent from gap junctional communication properties and the connexin isoform expressed. Therefore, it seems more likely that the bystander effect is not mediated via gap junction channels but rather by paracrine mechanisms via excreted molecules in Jeg3 cells. J. Cell. Biochem. 103: 149,161, 2008. © 2007 Wiley-Liss, Inc. [source] Homocysteine induces metalloproteinase and shedding of ,-1 integrin in microvessel endothelial cells,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Suresh Shastry Abstract Although studies have suggested microvessel endothelial cells (MVEC) activation and induction of matrix metalloproteinases (MMPs) by homocysteine (Hcy), the transduction mechanism leading to endothelial activation was unclear. We hypothesized that Hcy induced metalloproteinase and altered the levels of integrin in MVEC. MVEC from mouse brain were isolated and characterized by CD-31 (PECAM-1) FITC labeling. The MVEC were activated with different doses (6,40 ,M) of Hcy. The cultured-conditioned-medium was analyzed for MMP activity by gelatin gel-zymography. TIMP-1, -4, ,-1 integrin, and a disintegrin and metalloproteinase-12 (ADAM-12) were quantified by Western blot analysis. We used MVEC in cell culture to study the effect of increasing concentrations of Hcy upon the secretion of various proteins into the culture medium. MMP-9, ,-1 integrin, ADAM-12, and TIMP-1 were found in increased concentrations in the culture medium of Hcy-treated cells whereas TIMP-4 was decreased. We have shown that purified TIMP-4 blocked the increase of ,-1 integrin shedding in Hcy-treated cells. Interestingly, our results suggest that TIMP-1 and TIMP-4 function antagonistically in Hcy-induced signaling pathways. © 2004 Wiley-Liss, Inc. [source] Regulation of protein phosphatase 1, activity in hypoxia through increased interaction with NIPP1: Implications for cellular metabolismJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2006Kathrina M. Comerford Eukaryotic cells sense decreased oxygen levels and respond by altering their metabolic strategy to sustain non-respiratory ATP production through glycolysis, and thus promote cell survival in a hypoxic environment. Protein phosphatase 1 (PP1) has been recently implicated in the governance of the rational use of energy when metabolic substrates are abundant and contributes to cellular recovery following metabolic stress. Under conditions of hypoxia, the expression of the gamma isoform of PP1 (PP1,), is diminished, an event we have hypothesized to be involved in the adaptive cellular response to hypoxia. Decreased PP1, activity in hypoxia has a profound impact on the activity of the cAMP response element binding protein (CREB), a major transcriptional regulator of metabolic genes and processes. Here, we demonstrate a further mechanism leading to inhibition of PP1 activity in hypoxia which occurs at least in part through increased association with the nuclear inhibitor of PP1 (NIPP1), an event dependent upon decreased basal cAMP/PKA-dependent signaling. Using a dominant negative NIPP1 construct, we provide evidence that NIPP1 plays a major role in the regulation of both CREB protein expression and CREB-dependent transcription in hypoxia. Furthermore, we demonstrate functional sequellae of such events including altered gene expression and recovery of cellular ATP levels. In summary, we demonstrate that interaction with NIPP1 mediates decreased PP1, activity in hypoxia, an event which may constitute an inherent part of the cellular oxygen-sensing machinery and may play a role in physiologic adaptation to hypoxia. J. Cell. Physiol. 209: 211,218, 2006. © 2006 Wiley-Liss, Inc. [source] Aortic Dissection and Third-Degree Atrioventricular Block in a Patient With a Hypertensive CrisisJOURNAL OF CLINICAL HYPERTENSION, Issue 1 2008Nikolaos Lionakis MD A 55-year-old man with a history of uncontrolled hypertension was admitted because of an episode of severely elevated blood pressure. An electrocardiogram revealed complete atrioventricular block while imaging showed a dissecting aneurysm of the descending thoracic and abdominal aorta, type B according to the Stanford classification. Laboratory tests revealed significant increases in serum C-reactive protein. Coronary arteriography was performed and was negative for coronary artery disease. A VDD pacemaker was placed, and a combination of 4 antihypertensive agents was used as treatment. Type B aortic dissection may present with a wide range of manifestations. The authors suggest that measurement of C-reactive protein may be used in hypertensive patients to help reflect vascular injury and its degree, progression, and prognosis. Disorders of intraventricular conductivity are rarely seen in both types of dissection of the aorta (type A, B). Atrioventricular conductivity disorders that result in complete atrioventricular block have been reported only in patients with type A dissection (before the bifurcation of the subclavian artery). In this particular case, however, the authors diagnosed an atrioventricular conductivity disorder causing atrioventricular block in a patient with type B dissection. Consequently, the authors speculate that myocardial fibrosis, as a result of long-standing hypertension, could be the main pathogenetic mechanism leading to the development of such phenomena, resulting from a potential expanding of the fibrotic process to the atrioventricular conduction system. [source] The impacts of changes in vegetation cover on dry season flow in the Kikuletwa River, northern TanzaniaAFRICAN JOURNAL OF ECOLOGY, Issue 2009P. K. T. Munishi Abstract While the decrease in flow is obvious in the Kikuletwa River, the mechanism leading to the decrease is unclear. We assessed the influence of vegetation cover change on dry season flow in the Kikuletwa River. The combined cover of closed and open forests decreased by 68% while closed and open forests decreased by 56% and 64% respectively. Land under agroforestry decreased by 25%, while that under annual crops increased by 41%. Grasslands increased by 116% and riverine vegetation decreased by 53%. Daily dry season flow showed a slightly decreasing trend in one of the stations despite all of them receiving water from the Rundugai natural springs. On the other hand, low flow indices indicated no statistically significant changes in the long-term average flow and there was no identifiable change in the rainfall amount. The majority (93%) of the local people perceived a changing rainfall pattern and decline in dry season flow in the Kikuletwa River. Changes in the dry season flow then can be associated with the identified land cover changes. Further research to substantiate the local people perceptions is important as indigenous knowledge may be good evidence for ascertaining changes in the natural environment. [source] Crosslinking polymerization leading to interpenetrating polymer network formation.JOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 21 2003Abstract As part of our continuing studies concerned with the elucidation of the crosslinking polymerization mechanism leading to interpenetrating polymer network (IPN) formation, in which IPNs consist of both polymethacrylates and polyurethane (PU) networks, this article explores the polyaddition crosslinking reactions of multifunctional poly(methyl methacrylate- co -2-methacryloyloxyethyl isocyanate) [poly(MMA- co -MOI)] [MMA/MOI = 90/10] with various diols leading to PU network formation. Thus, the equimolar polyaddition crosslinking reactions of poly(MMA- co -MOI) with ethylene glycol (EG), 1,6-hexane diol, and 1,10-decane diol (DD) were carried out in N -methyl pyrrolidone at a 0.25 mol/L isocyanate group concentration at 80 °C. The second-order rate constants decreased from EG to DD. The deviation of the actual gel point from the theoretical one was smaller from EG to DD. The intrinsic viscosity of resulting prepolymer demonstrated almost no variation with progressing polymerization for the EG system, whereas it gradually increased with conversion for the DD system. Close to the gel point conversion it increased rather drastically for both systems. The swelling ratio of resulting gel was higher from EG to DD. These are discussed mechanistically in terms of the significant occurrence of intramolecular cyclization and intramolecular crosslinking reactions leading to shrinkage of the molecular size. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3243,3248, 2003 [source] Crosslinking polymerization leading to interpenetrating polymer network formation.JOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 4 2003Abstract At the start of our research program concerned with the elucidation of the crosslinking polymerization mechanism leading to interpenetrating polymer network (IPN) formation, in which IPNs consist of both polymethacrylates and polyurethane (PU) networks, this article deals with the polyaddition crosslinking reaction leading to PU network formation. Therefore, 2-methacryloyloxyethyl isocyanate (MOI) was radically copolymerized with methyl methacrylate (MMA) in the presence of CBr4 as a chain-transfer agent. The resulting poly(MMA- co -MOI)s, having pendant isocyanate (NCO) groups as novel multifunctional polyisocyanates, were used for polyaddition crosslinking reactions with ethylene glycol as a typical diol. The second-order rate constants depended on both the functionality of poly(MMA- co -MOI) and the NCO group concentration. The actual gel points were compared with the theoretical ones calculated according to Macosko's equation; the deviation of the actual gel point from the theoretical value became more remarkable for a greater functionality of poly(MMA- co -MOI) and at a lower NCO group concentration or at a lower poly(MMA- co -MOI) concentration. These are discussed mechanistically, with consideration given to the significance of intramolecular cyclization and intramolecular crosslinking reactions leading to the shrinkage of the molecular size of the prepolymer, along with the data of the intrinsic viscosities of resulting prepolymers and the swelling ratios of resulting gels. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 606,615, 2003 [source] Liver carcinogen aflatoxin B1 as an inducer of mitotic recombination in a human cell lineMOLECULAR CARCINOGENESIS, Issue 3 2001Peter Markus Stettler Abstract The mycotoxin aflatoxin B1 (AFB1) is one of the most potent rodent and human liver carcinogens. Upon cytochrome P450,specific metabolism, it induces mutations as well as mitotic recombination events in in vitro systems. We have found that in the lower eukaryote yeast, the recombinagenic activity of AFB1 surpasses its mutagenic activity, and we speculated on possible consequences in terms of the mechanism of liver carcinogenesis. In this study we investigated whether the recombinagenic activity of AFB1 also would be identified in human cells. To address this question, we followed the fate of a heterozygous thymidine kinase (tk) allele in the human lymphoblastoid cell line TK6 upon exposure to AFB1. Individual mutants that had lost tk activity were subjected to loss of heterozygosity analysis of the tk locus and its flanking markers. Fluorescence in situ hybridization analysis on chromosome 17 also was performed. In parallel, a similar analysis was performed on TK6 cells exposed to the alkylating agent N -nitrosomethylurea, a well-known classic point mutagen. Our analysis showed a difference in the molecular mechanism leading to inactivation of the tk allele upon exposure to these two mutagens. In AFB1 -exposed cells the fraction of recombination-derived mutants predominated, whereas in N -nitrosomethylurea,exposed cells the fraction of point mutants was higher. Thus, the recombinagenic activity of AFB1 previously identified in a lower eukaryote also was found in the human cell line TK6. Our data support the hypothesis that mitotic recombination represents a central mechanism of action in AFB1 -induced liver carcinogenesis. © 2001 Wiley-Liss, Inc. [source] Programmed responses to virus replication in plantsMOLECULAR PLANT PATHOLOGY, Issue 1 2000A. J. Maule Despite their economic importance, we understand very little about the mechanism leading to symptom formation in compatible virus infections. By applying a spatial analysis to advancing infection fronts, we have been able to relate molecular events in small groups of cells to a sequence of virus-induced changes. This sequence starts ahead of the main front of virus replication and virus protein accumulation and lasts beyond the time at which virus replication has ceased. The host changes include alterations in gene expression, physiology and cellular ultrastructure. The relationship between these effects has been analysed in comparative studies between different virus infections in different hosts and abiotic stress. The research points to there being common features for different viruses leading to common effects. Also, although many of the consequences of virus infection are similar to the effects of heat shock, there are sufficient differences to suggest that the two inducers use distinct control pathways. The immediate challenge for the future is to establish synchronous infections of tissues so that the complex relationship between the virus and the host can be investigated using temporal rather than spatial analyses. [source] High incidence of distal vaginal atresia in mice lacking Tyro3 RTK subfamilyMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 12 2008Hui Wu Abstract Vaginal atresia is a congenital abnormality of the female genitourinary system, and the specific molecular mechanism leading to failure of vaginal development remains to be elucidated. Here, we report that the female mice lacking Tyro3 RTK subfamily (Tyro3, Axl, and Mer) exhibit a high incidence of distal vaginal atresia. The ratios of the vaginal atresia in Tyro3 RTKs mutant female mice are as follows: 2.5% for Mer,/, mice, 4.0% for Axl,/,Mer,/,, 3.7% for Mer,/,Tyro3,/,, 16.06% for Tyro,/,Axl,/,Mer,/, mice. We did not find the vaginal atresia in Axl,/,, Tyro3,/,, Axl,/, Tyro,/,, and wild-type mice. These observations suggest that Tyro3 RTKs play roles collaboratively in vaginal development, and Mer is more critical, Axl and Tyro3 support the function of Mer. The phenotype of mice with the vaginal atresia was characterized in this study. Tyro3 RTKs mutant mouse could be a useful model to study the mechanism of vaginal atresia formation. Mol. Reprod. Dev. 75: 1775,1782, 2008. © 2008 Wiley-Liss, Inc. [source] XY chromosomal bivalent: Nucleolar attractionMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 1 2005Laura L. Tres Abstract Nucleolar organization by autosomal bivalents occurs during male meiotic prophase in mammalian species. During late leptotene,early zygotene stages, several autosomal bivalents are engaged in ribosomal RNA synthesis. At pachytene stage, nucleolar masses detach from the sites of primary autosomal origin, relocate close to the XY chromosomal pair, and nucleolar components become segregated. In early pachytene, an extensive synaptonemal complex at the pseudoautosomal region, links X and Y chromosomes in close juxtaposition along most of the length of the Y chromosome, except for a terminal region of the Y that diverges from the pairing region. As meiotic prophase advances, X and Y chromosomes progressively desynapse and, at diplotene, the XY pair is associated end-to-end. Xmr (Xlr-related, meiosis regulated) is a protein component of the nucleolus associated to the XY pair and of the asynapsed portions of the X and Y axial cores. Xmr, like SCP3, is a component of the lateral element of the synaptonemal complex. Both share structural homology in their C-terminal region. This region contains several putative coiled-coil domains known to mediate heterodimeric protein,protein interactions and to provide binding sites to regulatory proteins. Like Xmr, the tumor repressor protein BRCA1 is present along the unsynapsed cores of the XY bivalent. Both Xmr and BRCA1 have been implicated in a mechanism leading to chromatin condensation and transcription inactivation of the XY bivalent. The BRCA1-ATR kinase complex, as recent research suggests, triggers the phosphorylation of histone H2AX, which predominates in the condensed chromatin of the XY chromosomal pair. Xmr is not present in the XY bivalent when the expression of histone H2AX is deficient. The role of Xmr in chromatin condensation of the XY bivalent has not been determined. The partial structural homology of SCP3 and Xmr, their distribution along the unsynapsed axial cores of the X and Y chromosomes, and the presence of Xmr in the XY pair-associated nucleolus raises the possibility that Xmr, and other proteins including protein kinases, may be recruited to the nucleolus to perform functions related to chromosomal synapsis, chromatin condensation and recombination processes, as well as cell cycle progression. Mol. Reprod. Dev. © 2005 Wiley-Liss, Inc. [source] The pathogenesis of cell death in Parkinson's disease , 2007MOVEMENT DISORDERS, Issue S17 2007C. Warren Olanow MD Abstract A number of factors have been implicated in the pathogenesis of cell death in Parkinson's disease (PD). These include oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, and apoptosis. While the precise pathogenic mechanism leading to neurodegeneration in PD is not known, there is considerable evidence suggesting that cell death occurs by way of a signal-mediated apoptotic process. PD is also characterized by intracellular proteinaceous inclusions or Lewy bodies. Proteolytic stress arises as a consequence of the excessive production of misfolded proteins, which exceed the capacity of the ubiquitin-proteasome system to degrade them. Recent genetic and laboratory studies support the possible relevance of proteolytic stress to both familial and sporadic forms of PD. Postmortem studies have shown that in the SNc of sporadic PD patients there are reduced levels of the alpha subunit of the 20S proteasome and reduced proteolytic enzyme activities. A determination as to the precise cause of cell death in PD, and the identification of specific targets for the development of drugs that might modify disease progression is one of the most critical goals in PD research. It is anticipated that over the next few years there will be a flurry of scientific activity examining the mechanism of cell death and putative neuroprotective interventions. © 2007 Movement Disorder Society [source] Early phase of reperfusion of human kidney allograft does not affect an erythrocyte anti-oxidative systemNEPHROLOGY, Issue 5 2006LESZEK DOMA SUMMARY: Background: Generation of reactive oxygen specimens is the basic mechanism leading to ischaemia/reperfusion injury of the kidney graft. Oxygen burst is a trigger for sophisticated biochemical changes leading to generation of oxygenated lipids and changes in microcirculation, which recruit recipient's neutrophils and contribute to delayed graft function. It has been shown that the free radicals generation correlates with the activity of anti-oxidative system. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) are involved in protection against free radicals. Aim: To examine the activity of erythrocyte anti-oxidative system during reperfusion of the transplanted kidney allograft. Methods: The study included 40 renal transplant recipients. Blood was taken from the iliac vein before transplantation and from the graft's renal vein immediately, as well as 2 and 4 min after total reperfusion. The authors assessed the process of reperfusion using ThermaCAM SC500 termovision camera. Spectrophotometric methods were used to measure superoxide dismutase, glutathione peroxidase and catalase activity as well as glutathione concentrations in erythrocytes. Results: There were no statistically significant differences in the activities of superoxide dismutase, catalase and glutathione peroxidase as well as glutathione concentrations during the first 4 min after total graft reperfusion. Nevertheless, there was a positive correlation between the activity of superoxide dismutase and glutathione peroxidase. Conclusion: The results suggest that the erythrocyte anti-oxidative system is stable during the early phase after reperfusion. An association between some anti-oxidative enzymes was noted. [source] The interaction between bird predation and plant cover in determining habitat occupancy of darkling beetlesOIKOS, Issue 1 2001Elli Groner Tenebrionid beetles in the Negev Desert exhibit size-related habitat segregation, with larger species found in denser cover. Size-dependent predation by birds has been suggested as the mechanism behind this habitat segregation. Two predictions of this hypothesis were tested: (1) plant cover reduces the predation efficiency of birds upon large tenebrionids, and (2) birds prefer larger species. Both predictions were supported: plant cover reduced predation rate by the most common spring and summer predatory birds: white storks (Ciconia ciconia) and stone curlews (Burhinus oedicnemus), in cage experiments. Results from preference experiments suggest that tenebrionid species can be divided according to their profitability as prey. Large species are the most profitable, medium-sized species are less profitable but still acceptable and small species are unprofitable and therefore ignored. Field observations demonstrated that the well-vegetated wadi habitats are dominated by large and small species whereas acceptable, medium-sized species are under-represented in this habitat. The results of the cage experiments indicate possible apparent competition between the large profitable and the medium acceptable tenebrionid species in the wadis. Aggregative response of predators in the profitable habitat is suggested as the mechanism leading to truncated distribution of prey species. Large profitable species are refuge-dependent, medium-sized acceptable species use enemy free space and small species are predator independent. [source] Instability of finite-amplitude lower-neutral Eady wavesTHE QUARTERLY JOURNAL OF THE ROYAL METEOROLOGICAL SOCIETY, Issue 620 2006M. Fantini Abstract The problem of the stability of the two-dimensional neutral Eady wave, studied numerically by Fantini and Davolio (2001) as a possible mechanism leading to strong orographic cyclogenesis, is re-examined. An approximate analytic solution is found, and a simple condition for the appearance of meridionally structured unstable secondary modes is proposed, based on the relative vorticity of the primary wave. The approximate analytic solution compares well with the numerical simulations and extends previous results. Copyright © 2006 Royal Meteorological Society [source] Identifying Specific Causes of Kidney Allograft LossAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009Z. M. El-Zoghby The causes of kidney allograft loss remain unclear. Herein we investigated these causes in 1317 conventional kidney recipients. The cause of graft loss was determined by reviewing clinical and histologic information the latter available in 98% of cases. During 50.3 ± 32.6 months of follow-up, 330 grafts were lost (25.0%), 138 (10.4%) due to death with function, 39 (2.9%) due to primary nonfunction and 153 (11.6%) due to graft failure censored for death. The latter group was subdivided by cause into: glomerular diseases (n = 56, 36.6%); fibrosis/atrophy (n = 47, 30.7%); medical/surgical conditions (n = 25, 16.3%); acute rejection (n = 18, 11.8%); and unclassifiable (n = 7, 4.6%). Glomerular pathologies leading to failure included recurrent disease (n = 23), transplant glomerulopathy (n = 23) and presumed nonrecurrent disease (n = 10). In cases with fibrosis/atrophy a specific cause(s) was identified in 81% and it was rarely attributable to calcineurin inhibitor (CNI) toxicity alone (n = 1, 0.7%). Contrary to current concepts, most cases of kidney graft loss have an identifiable cause that is not idiopathic fibrosis/atrophy or CNI toxicity. Glomerular pathologies cause the largest proportion of graft loss and alloinmunity remains the most common mechanism leading to failure. This study identifies targets for investigation and intervention that may result in improved kidney transplantation outcomes. [source] ,2 -adrenoceptors are critical for antidepressant treatment of neuropathic pain,ANNALS OF NEUROLOGY, Issue 2 2009Ipek Yalcin PharmD Objective Tricyclic antidepressants (TCAs) are one of the first-line pharmacological treatments against neuropathic pain. TCAs increase the extracellular concentrations of noradrenaline and serotonin by blocking the reuptake transporters of these amines. However, the precise downstream mechanism leading to the therapeutic action remains identified. In this work, we evaluated the role of adrenergic receptors (ARs) in the action of TCAs. Methods We used pharmacological and genetic approaches in mice to study the role of ARs in the antiallodynic action of the TCA nortriptyline. Peripheral neuropathy was induced by the insertion of a polyethylene cuff around the main branch of the sciatic nerve. The specific role of ,2 -AR was evaluated by studying ,2 -AR,/, mice. We used von Frey filaments to assess mechanical allodynia. Results The antiallodynic action of nortriptyline was not affected by cotreatment with the ,2 -AR antagonist yohimbine, the ,1 -AR antagonists atenolol or metoprolol, or the ,3 -AR antagonist SR 59230A. On the contrary, the ,-AR antagonists propranolol or sotalol, the ,1/,2 -AR antagonists alprenolol or pindolol, or the specific ,2 -AR antagonist ICI 118,551 blocked the action of nortriptyline. The effect of nortriptyline was also totally absent in ,2 -AR,deficient mice. Interpretation Stimulation of ,2 -AR is necessary for nortriptyline to exert its antiallodynic action against neuropathic pain. These findings provide new insight into the mechanism by which antidepressants alleviate neuropathic pain. Our results also raise the question of a potential incompatibility between ,-blockers that affect ,2 -AR and antidepressant drugs in patients treated for neuropathic pain. Ann Neurol 2009;65:218,225 [source] Model study of time-dependent muscle response to pulsed electrical stimulationBIOELECTROMAGNETICS, Issue 5 2010Ravindra P. Joshi Abstract A systems-level model analysis of neuromuscular response to external electrical stimulation is presented. Action potential (AP) generation, dynamics of voltage-based calcium release at the motor endplates controlled by the arrival of APs, and muscle force production are all comprehensively included. Numerical predictions exhibit trends that are qualitatively similar to measurements of muscle response in rats from a burst of cortical stimulation and a nanosecond impulse. Modulation of neural membrane conductances (including possible electroporation) that alters the neural impulse generation frequency is hypothesized as a possible mechanism leading to observed changes in muscle force production. Other possibilities such as calcium release at nerve end endings also exist. It is also proposed that multipulsing strategies and changing the electric field direction by using multielectrode systems would be useful. Bioelectromagnetics 31:361,370, 2010. © 2010 Wiley-Liss, Inc. [source] ESE-3, an Ets family transcription factor, is up-regulated in cellular senescenceCANCER SCIENCE, Issue 9 2007Makoto Fujikawa Normal cells irreversibly stop dividing after being exposed to a variety of stresses. This state, called cellular senescence, has recently been demonstrated to act as a tumor-suppressing mechanism in vivo. A common set of features are exhibited by senescent cells, but the molecular mechanism leading to the state is poorly understood. It has been shown that p38, a stress-induced mitogen-activated protein kinase (MAPK), plays a pivotal role in inducing cellular senescence in diverse settings. To better understand the senescence-inducing pathway, microarray analyses of normal human fibroblasts that ectopically activated p38 were performed. It was found that five genes encoding ESE-3, inhibin ,A, RGS5, SSAT and DIO2 were up-regulated in senescent cells induced by RasV12, H2O2 and telomere shortening, but not in quiescent or actively growing cells, suggesting that these genes serve as molecular markers for various types of cellular senescence. The ectopic expression of ESE-3 resulted in retarded growth, up-regulation of p16INK4a but not of p21, and increased levels of SA-,-gal activity. In contrast, RGS5, SSAT and the constitutive active form of the inhibin ,A receptor gene did not induce such senescence phenotypes when ectopically expressed. ESE-3 expression increased the activity of the p16INK4a promoter in a reporter assay, and recombinant ESE-3 protein bound to the Ets-binding sequences present in the promoter. These results suggest that ESE-3 plays a role in the induction of cellular senescence as a downstream molecule of p38. (Cancer Sci 2007; 98: 1468,1475) [source] | |||||||||||||||||||||||||||||||