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Specific Pathways (specific + pathway)
Selected AbstractsThe chemotaxis defect of Shwachman-Diamond Syndrome leukocytesCYTOSKELETON, Issue 3 2004Vesna Stepanovic Abstract Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive, multisystem disorder presenting in childhood with intermittent neutropenia and pancreatic insufficiency. It is characterized by recurrent infections independent of neutropenia, suggesting a functional neutrophil defect. While mutations at a single gene locus (SBDS) appear to be responsible for SDS in a majority of patients, the function of that gene and a specific defect in SDS neutrophil behavior have not been elucidated. Therefore, employing 2D and 3D computer-assisted motion analysis systems, we have analyzed the basic motile behavior and chemotactic responsiveness of individual polymorphonuclear leukocytes (PMNs) of 14 clinically diagnosed SDS patients. It is demonstrated that the basic motile behavior of SDS PMNs is normal in the absence of chemoattractant, that SDS PMNs respond normally to increasing and decreasing temporal gradients of the chemoattractant fMLP, and that SDS PMNs exhibit a normal chemokinetic response to a spatial gradient of fMLP. fMLP receptors were also distributed uniformly through the plasma membrane of SDS PMNs as in control PMNs. SDS PMNs, however, were incapable of orienting in and chemotaxing up a spatial gradient of fMLP. This unique defect in orientation was manifested by the PMNs of every SDS patient tested. The PMNs of an SDS patient who had received an allogenic hematopoietic stem cell transplant, as well as PMNs from a cystic fibrosis patient, oriented normally. These results suggest that the defect in SDS PMNs is in a specific pathway emanating from the fMLP receptor that is involved exclusively in regulating orientation in response to a spatial gradient of fMLP. This pathway must function in parallel with additional pathways, intact in SDS patients, that emanate from the fMLP receptor and regulate responses to temporal rather than spatial changes in receptor occupancy. Cell Motil. Cytoskeleton 57:158,174, 2004. © 2004 Wiley-Liss, Inc. [source] Immune-related mechanisms participating in resistance and susceptibility to glutamate toxicityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2002Hadas Schori Abstract Glutamate is an essential neurotransmitter in the CNS. However, at abnormally high concentrations it becomes cytotoxic. Recent studies in our laboratory showed that glutamate evokes T cell-mediated protective mechanisms. The aim of the present study was to examine the nature of the glutamate receptors and signalling pathways that participate in immune protection against glutamate toxicity. We show, using the mouse visual system, that glutamate-induced toxicity is strain dependent, not only with respect to the amount of neuronal loss it causes, but also in the pathways it activates. In strains that are genetically endowed with the ability to manifest a T cell-dependent neuroprotective response to glutamate insult, neuronal losses due to glutamate toxicity were relatively small, and treatment with NMDA-receptor antagonist worsened the outcome of exposure to glutamate. In contrast, in mice devoid of T cell-dependent endogenous protection, NMDA receptor antagonist reduced the glutamate-induced neuronal loss. In all strains, blockage of the AMPA/KA receptor was beneficial. Pharmacological (with ,2 -adrenoceptor agonist) or molecular intervention (using either mice overexpressing Bcl-2, or DAP-kinase knockout mice) protected retinal ganglion cells from glutamate toxicity but not from the toxicity of NMDA. The results suggest that glutamate-induced neuronal toxicity involves multiple glutamate receptors, the types and relative contributions of which, vary among strains. We suggest that a multifactorial protection, based on an immune mechanism independent of the specific pathway through which glutamate exerts its toxicity, is likely to be a safer, more comprehensive, and hence more effective strategy for neuroprotection. It might suggest that, because of individual differences, the pharmacological use of NMDA-antagonist for neuroprotective purposes might have an adverse effect, even if the affinity is low. [source] Weak and non-independent association between plasma TAFI antigen levels and the insulin resistance syndromeJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2003H. Aubert Summary., Increased plasma thrombin-activatable fibrinolysis inhibitor (TAFI) levels were recently shown to be a part of the insulin resistance syndrome. We investigated the relationship between plasma TAFI antigen levels and insulin resistance markers and compared these results with those obtained for PAI-1 and fibrinogen which are known to be closely related to insulin resistance syndrome and fat mass, respectively. Eighty-nine obese females had 1.3-, 1.2-, and 3-fold higher circulating TAFI, fibrinogen and PAI-1, respectively, compared with 64 lean females. Univariate analysis showed that the significance level for association between TAFI or fibrinogen concentrations and insulin resistance markers was lower than the significance level for association between PAI-1 and insulin resistance markers. Nevertheless, TAFI, fibrinogen, and PAI-1 plasma levels were significantly associated to each other. In linear stepwise ascendant analysis, insulin resistance markers accounted for 50% of the interindividual variability of plasma PAI-1 and only for 10% of plasma TAFI and 13% of fibrinogen variability. The contribution of insulin resistance markers to plasma TAFI antigen levels variability disappeared when PAI-1 or fibrinogen was entered in the statistical model. TAFI mRNA was detected in the liver but not in adipose tissue and endothelial cells. No TAFI mRNA was detected in normal or atherosclerotic vessels either. These results suggest that elevated TAFI antigen levels found in obese subjects are not independently associated with the metabolic markers of the insulin resistance syndrome. Increased plasma TAFI antigen levels in obesity might reflect a specific pathway of regulation at the liver level. [source] Ooplasmic segregation in the zebrafish zygote and early embryo: Pattern of ooplasmic movements and transport pathwaysDEVELOPMENTAL DYNAMICS, Issue 8 2010Ricardo Fuentes Abstract Patterns of cytoplasmic movements and organization of transport pathways were examined in live or fixed zygotes and early zebrafish embryos using a variety of techniques. The zygote blastodisc grows by accumulation of ooplasm, transported to the animal pole from distinct sectors of ecto- and endoplasm at different speeds and developmental periods, using specific pathways or streamers. Slow transport (5 ,m/min) occurs during the first interphase along short streamers, whereas fast transport (9.6,40 ,m/min) takes place during the first cleavage division along axial and meridional streamers. Interconnections between streamers allow cargoes to change their speed and final destination. A similar sequence of events occurs during the following divisions. A complex network of microtubules and actin filaments in the endo- and ectoplasm appears to be involved in the transport of inclusions and mRNAs. Actin-dependent intermittent pulsations provoked high-speed back-and-forth movements of cytoplasm that may contribute to redistribution of organelles and maternal determinants. Developmental Dynamics 239:2172,2189, 2010. © 2010 Wiley-Liss, Inc. [source] The dynamics of development and evolution: Insights from behavioral embryologyDEVELOPMENTAL PSYCHOBIOLOGY, Issue 8 2007Robert Lickliter Abstract The perspective that features of species-typical behavior could be traced to experience that occurred prenatally was raised by Zing-Yang Kuo [1921 Journal of Philosophy 18: 645,664] early in the last century and Gilbert Gottlieb subsequently elaborated on and provided empirical support for this idea over the course of more than four decades of innovative psychobiological research. Although we are still a long way from fully understanding the specific pathways and processes by which prenatal experience can influence postnatal development, Gottlieb's research with precocial birds provided significant insights into the conditions and experiences of prenatal development involved in the achievement of species-typical perception and behavior. In particular, his elegant series of studies on the development of species identification in ducklings documented how the features and patterns of recurring prenatal sensory experience (including self-stimulation) guide and constrain the young individual's selective attention, perception, learning, and memory during both prenatal and postnatal periods. I review how this body of research supports the view that the structure and functions of the developing organism and its developmental ecology together form a relationship of mutual influence on the emergence, maintenance, and transformation of species-typical behavior. I also explore how Gottlieb's empirical demonstrations of the prenatal roots of so-called "instinctive" behavior provided a foundation for his conceptual efforts to define the links between developmental and evolutionary change. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 749,757, 2007. [source] GENETIC STUDY: The dopamine D4 Receptor (DRD4) gene exon III polymorphism, problematic alcohol use and novelty seeking: direct and mediated genetic effectsADDICTION BIOLOGY, Issue 2 2009Lara A. Ray ABSTRACT The present study sought to integrate convergent lines of research on the associations among the dopamine D4 receptor (DRD4) gene, novelty seeking and drinking behaviors with the overall goal of elucidating genetic influences on problematic drinking in young adulthood. Specifically, this study tested a model in which novelty seeking mediated the relationship between DRD4 variable number of tandem repeats (VNTR) genotype and problematic alcohol use. Participants (n = 90, 40 females) were heavy-drinking college students. Analyses using a structural equation modeling framework suggested that the significant direct path between DRD4 VNTR genotype and problematic alcohol use was reduced to a trend level in the context of a model that included novelty seeking as a mediator, thereby suggesting that the effects of DRD4 VNTR genotype on problematic alcohol use among heavy-drinking young adults were partially mediated by novelty seeking. Cross-group comparisons indicated that the relationships among the model variables were not significantly different in models for men versus women. These results extend recent findings of the association between this polymorphism of the DRD4 receptor gene, problematic alcohol use and novelty seeking. These findings may also help elucidate the specific pathways of risk associated with genetic influences on alcohol use and abuse phenotypes. [source] APC/CTNNB1 (,-catenin) pathway alterations in human prostate cancersGENES, CHROMOSOMES AND CANCER, Issue 1 2002Amy V. Gerstein Genetic alterations serve as beacons for the involvement of specific pathways in tumorigenesis. It was previously shown that 5% of prostate tumors harbor CTNNB1 mutations, suggesting that this tumor type may involve a deregulated APC/CTNNB1 pathway. To explore this possibility further, we searched for mutations in genes implicated in this pathway in 22 samples that included cell lines, xenografts, and primary tumors. We identified seven alterations: two in CTNNB1, three in APC, and two in hTRCP1 (also known as BTRC) which controls the degradation of CTNNB1. Alterations in the CTNNB1 regulatory domain, APC, and hTRCP1 were mutually exclusive, consistent with their equivalent effects on CTNNB1 stability. These results suggest that CTNNB1 signaling plays a critical role in the development of a significant fraction of prostate cancers. Moreover, they provide the first evidence that hTRCP1 plays a role in human neoplasia. © 2002 Wiley-Liss, Inc. [source] Genome-wide association analyses of expression phenotypesGENETIC EPIDEMIOLOGY, Issue S1 2007Gary K. Chen Abstract A number of issues arise when analyzing the large amount of data from high-throughput genotype and expression microarray experiments, including design and interpretation of genome-wide association studies of expression phenotypes. These issues were considered by contributions submitted to Group 1 of the Genetic Analysis Workshop 15 (GAW15), which focused on the association of quantitative expression data. These contributions evaluated diverse hypotheses, including those relevant to cancer and obesity research, and used various analytic techniques, many of which were derived from information theory. Several observations from these reports stand out. First, one needs to consider the genetic model of the trait of interest and carefully select which single nucleotide polymorphisms and individuals are included early in the design stage of a study. Second, by targeting specific pathways when analyzing genome-wide data, one can generate more interpretable results than agnostic approaches. Finally, for datasets with small sample sizes but a large number of features like the Genetic Analysis Workshop 15 dataset, machine learning approaches may be more practical than traditional parametric approaches. Genet Epidemiol 31 (Suppl. 1): S7,S11, 2007. © 2007 Wiley-Liss, Inc. [source] Psychosocial Functioning of Carcinoid Cancer Patients: Test of a Stress and Coping Mediated Model,JOURNAL OF APPLIED BIOBEHAVIORAL RESEARCH, Issue 3 2004Elizabeth Soliday This study examined a mediated-effects stress and coping model among cancer patients with carcinoid tumors to identify specific pathways with a view toward determining (a) which coping strategies predict more positive adjustment, (b) which strategies predict less positive adjustment, and (c) whether coping would mediate the effect of optimism on psychosocial outcomes. Coping strategies partially mediated the effects of optimism on the psychological adjustment in cancer patients with carcinoid tumors. Specifically, self-blame and active coping significantly predicted outcomes of distress. Thirty-seven percent of the respondents met criteria for elevated depressive symptoms warranting intervention. Generalizability of the mediated-effects stress and coping model and findings unique to the carcinoid population are discussed. [source] Genetic and epigenetic heterogeneity in cancer: A genome-centric perspectiveJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2009Henry H.Q. Heng Genetic and epigenetic heterogeneity (the main form of non-genetic heterogeneity) are key elements in cancer progression and drug resistance, as they provide needed population diversity, complexity, and robustness. Despite drastically increased evidence of multiple levels of heterogeneity in cancer, the general approach has been to eliminate the "noise" of heterogeneity to establish genetic and epigenetic patterns. In particular, the appreciation of new types of epigenetic regulation like non-coding RNA, have led to the hope of solving the mystery of cancer that the current genetic theories seem to be unable to achieve. In this mini-review, we have briefly analyzed a number of mis-conceptions regarding cancer heterogeneity, followed by the re-evaluation of cancer heterogeneity within a framework of the genome-centric concept of evolution. The analysis of the relationship between gene, epigenetic and genome level heterogeneity, and the challenges of measuring heterogeneity among multiple levels have been discussed. Further, we propose that measuring genome level heterogeneity represents an effective strategy in the study of cancer and other types of complex diseases, as emphasis on the pattern of system evolution rather than specific pathways provides a global and synthetic approach. Compared to the degree of heterogeneity, individual molecular pathways will have limited predictability during stochastic cancer evolution where genome dynamics (reflected by karyotypic heterogeneity) will dominate. J. Cell. Physiol. 220: 538,547, 2009. © 2009 Wiley-Liss, Inc. [source] Molecular basis of therapeutic approaches to gastric cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 1 2009Kaichun Wu Abstract Gastric cancer is the top lethal cancer in Asia. As the majority of cases present with advanced disease, conventional therapies (surgery, chemotherapy, and radiotherapy) have limited efficacy to reduce mortality. Emerging modalities provide promise to combat this malignancy. Target-protein-based cancer therapy has become available in clinical practice. Numerous molecules have been shown potential to target specific pathways for tumor cell growth. Cyclooxygenase-2 (COX-2) is overexpressed in and correlated with gastric cancer, and knockdown of COX-2 or administration of COX-2 inhibitors suppresses tumor formation in models of gastric cancer. Induction of apoptosis, reduction of angiogenesis, and blocking of potassium ion channels may present new mechanisms of COX-2 inhibition. Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene whose deficiency is causally related to gastric cancer. RUNX3 is downregulated in metastatic gastric cancer. RUNX3 activation inhibits angiogenesis in xenograft tumors in nude mice. Tumor microenvironment modulation also provides a powerful tool to inhibit cancer development and progress; details of the potential roles of angiopoietins are discussed in this review. Osteopontin is a secreted protein involved in stress response, inflammation, wound healing, and immune response. Inhibition of osteopontin by RNA interfering technique suppressed tumorigenesis as well as angiogenesis in gastric cancer. Immunotherapy remains another important choice of adjuvant therapy for cancer. A tumor-specific antigen MG7-Ag has been identified with great potential for inducing immune response in gastric cancer. Using HLA-A-matched allogeneic gastric cancer cells to induce tumor-specific cytotoxic T lymphocytes appeared to be an alternative option of immunotherapy for gastric cancer. [source] Trophic factors attenuate nitric oxide mediated neuronal and axonal injury in vitro: roles and interactions of mitogen-activated protein kinase signalling pathwaysJOURNAL OF NEUROCHEMISTRY, Issue 6 2005Alastair Wilkins Abstract Inflammation in the central nervous system occurs in diseases such as multiple sclerosis and leads to axon dysfunction and destruction. Both in vitro and in vivo observations have suggested an important role for nitric oxide (NO) in mediating inflammatory axonopathy. The purposes of this study were to model inflammatory axonopathy in vitro and identify modulators of the process. Rat cortical neurones were cultured and exposed to an NO-donor plus potential protective factors. Cultures were then assessed for neuronal survival, axon survival and markers of intracellular signalling pathways. The NO-donor produced dose-dependent neuronal loss and a large degree of axon destruction. Oligodendrocyte conditioned medium (OCM) and insulin-like growth factor type-1 (IGF-1), but not glial cell line-derived neurotrophic factor (GDNF), improved survival of neurones exposed to NO donors. In addition p38 MAP kinase was activated by NO exposure and inhibition of p38 signalling led to neuronal and axonal survival effects. OCM and IGF-1 (but not GDNF) reduced p38 activation in NO-exposed cortical neurones. OCM, IGF-1 and GDNF improved axon survival in cultures exposed to NO, a process dependent on mitogen-activated protein kinase/extracellular signal-related kinase signalling. This study emphasizes that different mechanisms may underlie neuronal/axonal destructive processes, and suggests that trophic factors may modulate NO-mediated neurone/axon destruction via specific pathways. [source] Racial differences in the associations of neighborhood disadvantage, exposure to violence, and criminal recidivism among female juvenile offenders,BEHAVIORAL SCIENCES & THE LAW, Issue 4 2009Preeti Chauhan M.A. The current study examined the impact of exposure to violence and neighborhood disadvantage on criminal recidivism among Black (n,=,69) and White (n,=,53) female juvenile offenders. Participants were girls between the ages of 13 and 19 (M,=,16.8; SD,=,1.2) who were sentenced to secure custody. Using a multi-method research design, the study assessed neighborhood disadvantage through census level data, exposure to violence through self-report, and criminal recidivism through official records. Results indicated that Black girls were significantly more likely than White girls to live in disadvantaged neighborhoods, but both reported similar levels of parental physical abuse and witnessing neighborhood violence. In structural equation models, neighborhood disadvantage and witnessing neighborhood violence were indicative of future recidivism for the group as a whole. However, multiple group analyses indicated the existence of race specific pathways to recidivism. Witnessing neighborhood violence was associated with recidivism for Black girls while parental physical abuse was associated with recidivism for White girls. Results suggest that characteristics within the neighborhood play a considerable role in recidivism among female juvenile offenders generally and Black female juvenile offenders, specifically. Race specific risk models warrant further investigation, and may help lawmakers and clinicians in addressing racial disparities in the justice system. Copyright © 2009 John Wiley & Sons, Ltd. [source] Revealing metabolic phenotypes in plants: inputs from NMR analysisBIOLOGICAL REVIEWS, Issue 1 2005R. G. Ratcliffe ABSTRACT Assessing the performance of the plant metabolic network, with its varied biosynthetic capacity and its characteristic subcellular compartmentation, remains a considerable challenge. The complexity of the network is such that it is not yet possible to build large-scale predictive models of the fluxes it supports, whether on the basis of genomic and gene expression analysis or on the basis of more traditional measurements of metabolites and their interconversions. This limits the agronomic and biotechnological exploitation of plant metabolism, and it undermines the important objective of establishing a rational metabolic engineering strategy. Metabolic analysis is central to removing this obstacle and currently there is particular interest in harnessing high-throughput and/or large-scale analyses to the task of defining metabolic phenotypes. Nuclear magnetic resonance (NMR) spectroscopy contributes to this objective by providing a versatile suite of analytical techniques for the detection of metabolites and the fluxes between them. The principles that underpin the analysis of plant metabolism by NMR are described, including a discussion of the measurement options for the detection of metabolites in vivo and in vitro, and a description of the stable isotope labelling experiments that provide the basis for metabolic flux analysis. Despite a relatively low sensitivity, NMR is suitable for high-throughput system-wide analyses of the metabolome, providing methods for both metabolite fingerprinting and metabolite profiling, and in these areas NMR can contribute to the definition of plant metabolic phenotypes that are based on metabolic composition. NMR can also be used to investigate the operation of plant metabolic networks. Labelling experiments provide information on the operation of specific pathways within the network, and the quantitative analysis of steady-state labelling experiments leads to the definition of large-scale flux maps for heterotrophic carbon metabolism. These maps define multiple unidirectional fluxes between branch-points in the metabolic network, highlighting the existence of substrate cycles and discriminating in favourable cases between fluxes in the cytosol and plastid. Flux maps can be used to define a functionally relevant metabolic phenotype and the extensive application of such maps in microbial systems suggests that they could have important applications in characterising the genotypes produced by plant genetic engineering. [source] Oxalate ions and calcium oxalate crystal-induced up-regulation of osteopontin and monocyte chemoattractant protein-1 in renal fibroblastsBJU INTERNATIONAL, Issue 3 2006TOHRU UMEKAWA OBJECTIVE To examine the responses of renal fibroblasts to high oxalate (Ox) and calcium Ox (CaOx) crystals, as the latter are found in the renal interstitium of patients with primary or enteric hyperoxaluria, and in animals with experimental CaOx nephrolithiasis, and are associated with tubulointerstitial inflammation (TI). TI might begin with the production of chemoattractants by the renal epithelial cells exposed to high Ox and/or CaOx crystals; as Ox levels are also high in the renal interstitium and crystal deposition in nephrolithiasis might start in the interstitium, we hypothesized that renal fibroblasts might also be involved in the development of TI. MATERIALS AND METHODS We exposed renal fibroblast cells of line NRK 49F in vitro to Ox ions (500 µmol/L) or CaOx monohydrate crystals (67 µg/cm2). We assessed the production of osteopontin and monocyte chemoattractant protein-1 (MCP-1), and expression of their mRNA, in the cells. We also determined the cellular malondialdehyde content as a marker of reactive oxygen species (ROS)-induced lipid peroxidation, and Trypan blue staining and the release of lactate dehydrogenase as markers of injury. RESULTS Similar to renal epithelial cells, renal fibroblasts were stimulated by exposure to Ox and CaOx crystals. They showed signs of injury and ROS-induced lipid peroxidation. The mRNA expression and production of osteopontin and MCP-1 increased significantly. CONCLUSIONS These results indicate that fibroblasts respond to high Ox and CaOx crystals by up-regulating specific pathways producing pro-inflammatory conditions. Migration of monocytes/macrophages to sites of interstitial crystal deposits can lead to localized interstitial inflammation and fibrosis. [source] Haemostatic screening and identification of zebrafish mutants with coagulation pathway defects: an approach to identifying novel haemostatic genes in manBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2000Pudur Jagadeeswaran Zebrafish were used as a model to study haemostasis, a vertebrate function of paramount importance. A limitation of the zebrafish model is the difficulty in assaying small amounts of blood to detect coagulation mutants. We report the use of a rapid total coagulation activity (TCA) assay to screen for coagulation defects in individual adult zebrafish. We screened the TCA in 1000 gynogenetic half-tetrad diploids derived from 86 clutches. Each clutch was from a single F1 female offspring of males mutagenized with ethylnitrosourea (ENU). We found 30,50% defective zebrafish among six clutches, consistent with a heritable defect. The assay developed here provided a rapid screen to detect overall coagulation defects. However, because of the limited amounts of plasma, we could not detect defects in specific pathways. Therefore, a novel, ultra-sensitive kinetic method was developed to identify specific pathway defects. To test whether the kinetic assay could be used as a screening tool, 1500 Florida wild-type zebrafish pairs were analysed for naturally occurring coagulation defects. We detected 30 fish with extrinsic pathway defects, but with intact common and intrinsic pathways. We conclude that it is now possible to identify specific coagulation pathway defects in zebrafish. [source] Are MAP Kinases Drug Targets?CHEMMEDCHEM, Issue 8 2007but Difficult Ones Abstract Pharmaceutical companies are facing an increasing interest in new target identification and validation. In particular, extensive efforts are being made in the field of protein kinase inhibitors research and development, and the past ten years of effort in this field have altered our perception of the potential of kinases as drug targets. Therefore, in the drug discovery process, the selection of relevant, susceptible protein kinase targets combined with searches for leads and candidates have become a crucial approach. The success of recent launches of protein kinase inhibitors (Gleevec, Imatinib, Sutent, Iressa, Nexavar, Sprycel) gave another push to this field. Numerous other kinase inhibitors are currently undergoing clinical trials or clinical development. Some questions are nevertheless unanswered, mostly related to the great number of known kinases in the human genome, to their similarity with each other, to the existence of functionally redundant kinases for specific pathways, and also because the connection between particular pathways and diseases is not always clear. The review is leading the reader through a panoramic view of protein kinase inhibition with a major focus on MAPK, successful examples and clinical candidates. [source] | ||||||||||||||||