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Different Pathways (different + pathway)
Selected AbstractsDifferent pathways leading to cutaneous leukocytoclastic vasculitis in miceEXPERIMENTAL DERMATOLOGY, Issue 6 2001C. Sunderkötter Abstract: To investigate the pathomechanisms of leukocytoclastic vasculitis (LcV) we compared mouse models of LcV with non-vasculitic irritant contact dermatitis (ICD). Criteria for LcV as met by the immune complex-mediated Arthus reaction (Art-r) were also fulfilled by the localized Shwartzman reaction (Shw-r) and by cutaneous Loxoscelism (Lox) (injection of venom from Loxosceles reclusa containing sphingomyelinase D). After depletion of PMN (by ,-irradiation) vessel damage could not be elicited in these models, distinguishing them from models of direct endothelial insult (necrotizing ICD). Depletion of complement could only delay, but not inhibit the Art-r, and did not change ICD, Lox or the Shw-r. The Shw-r exclusively revealed a sustained local expression of vascular adhesion molecules for 24 h in the preparatory phase (LPS s.c.), not observed in the Art-r, in Lox or ICD. Subsequent challenge with LPS i.p. was associated with upregulation of Mac-1 and ICAM-1 on PMN, but not of VLA-4 or LFA-1 (FACS analysis). Cytokines which were able to replace LPS in priming for LcV in the Shw-r (TNF-, and IL-1,) also induced sustained expression of adhesion molecules, whereas IL-12 and IFN-, did neither. Neutralizing IL-12 or IFN-, also inhibited neither LcV nor sustained expression of adhesion molecules, whereas anti-TNF-, inhibited both. Anti-TNF-, had no marked inhibitory effects in the Art-r, in Lox or ICD. Combined (but not separate) neutralization of both E-selectin and VCAM-1 by antibodies suppressed LcV independent from reducing influx of PMN, proving that their sustained expression is decisive for the Shw-r and interferes with normal diapedesis. Since Loxosceles venom is known to dysregulate diapedesis and degranulation of PMN in vitro, since adherent immune complexes activate PMN at the vessel wall, and since adhesion molecules are dysregulated in the Shw-r, we suggest that LcV develops when activation of PMN coincides with vascular alterations which interfere with normal diapedesis. [source] Metastatic pathways and time courses in the orderly progression of cutaneous melanomaBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2002F. Meier SummaryBackground,,It is known that two-thirds of patients who develop clinical metastases following treatment of a primary cutaneous melanoma initially present with locoregional metastases and one-third initially present with distant metastases. However, few reports in the literature give detailed figures on different metastatic pathways in cutaneous melanoma. Objectives,,The aim of the present study was to perform a detailed analysis of the different metastatic pathways, the time course of the development of metastases and the factors influencing them. Methods,,In a series of 3001 patients with primary cutaneous melanoma at first presentation, 466 subsequently developed metastasis and were followed-up over the long term at the University of Tuebingen, Germany between 1976 and 1996. Different pathways of metastatic spread were traced. Associated risk factors for the different pathways were assessed. Differences in survival probabilities were calculated by the Kaplan,Meier method and evaluated by the log-rank test. Results,,In 50·2% of the patients the first metastasis after treatment of the primary tumour developed in the regional lymph nodes. In the remaining half of the patient sample the first metastasis developed in the lymphatic drainage area in front of the regional lymph nodes, as satellite or in-transit metastases (21·7%) or as direct distant metastases (28·1%). Anatomical location, sex and tumour thickness were significant risk factors for the development of metastasis by different pathways. The most important risk factor appeared to be the location of the primary tumour. The median intervals elapsing before the first metastasis differed significantly between the different metastatic pathways. The direct distant metastases became manifest after a median period of 25 months, thus later than the direct regional lymph node metastases (median latency period, 16 months) and the direct satellite and in-transit metastases (median latency period, 17 months). In patients who developed distant metastases the period of development was independent of the metastatic route. The time at which the distant metastases developed was roughly the same (between 24 and 30 months after the detection of the primary tumour), irrespective of whether satellite or in-transit metastases, lymph node metastases or distant metastases were the first to occur. Conclusions,,The time course of the development of distant metastasis was more or less the same irrespective of the metastatic pathway; this suggests that in patients with in-transit or satellite metastasis or regional lymph node metastasis, haematogenic metastatic spread had already taken place. Thus, the diagnostic value of sentinel lymph node biopsy and the therapeutic benefit of elective lymph node dissection may be limited, as satellite and in-transit metastases or direct distant metastases will not be detected and haematogenous spread may already have taken place when the intervention is performed. [source] Expression of GITR ligand abrogates immunosuppressive function of ocular tissue and differentially modulates inflammatory cytokines and chemokinesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2006Sankaranarayana Abstract The glucocorticoid-induced TNF-related receptor ligand (GITRL) was previously shown to be constitutively expressed at low levels in human eye, including retinal pigment epithelial (RPE) cells. By expressing enhanced yellow fluorescent protein-tagged human GITRL in human RPE cells, we investigated the significance of expression of GITRL on human ocular tissue. Confocal immunofluorescence microscopy and flow cytometry confirmed the surface expression of GITRL on RPE cells. However, a soluble form of GITRL was also detected. Remarkably, expression of GITRL on the RPE cells abrogated RPE-mediated immunosuppression of CD3+ T cells, implicated as a possible mechanism for ocular immune privilege. This abrogation of immunosuppression by GITRL-RPE was dependent on GITR-GITRL interaction and could not be mimicked by anti-CD28 antibody. Analysis of cytokine profiles revealed high level of TGF-beta during the immunosuppression by RPE cells while expression of GITRL abrogated the RPE cell-induced TGF-beta secretion. Expression of GITRL also stimulates secretion of an array of proinflammatory cytokines/chemokines from T cells. GITR-GITRL interaction provides a unique proinflammatory costimulation that may signal through a different pathway than that of CD28-B7 costimulation. This study implicated that GITRL could be a potential candidate for regulation of the ocular immune privilege and the balance between immune privilege and inflammation. [source] The Ritter Reaction under Truly Catalytic Brųnsted Acid ConditionsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 28 2007Roberto Sanz Abstract Simple organic acids like 2,4-dinitrobenzenesulfonic acid (DNBSA) catalyze the Ritter reaction of secondary benzylic alcohols giving rise to the corresponding N -benzylacetamides in usually high yields. Reactions can be conducted without exclusion of oxygen and without the need of dry solvents. With tertiary ,,,-dimethylbenzylic alcohols a different pathway involving a formal dimerization reaction takes place under the acid-catalytic conditions used. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] DNA methylation patterns in adenomas from FAP, multiple adenoma and sporadic colorectal carcinoma patientsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Coral V.A. Wynter Abstract Colorectal adenomas have traditionally been regarded as homogeneous. The aim of our study was to identify molecular features that may differentiate sporadic adenomas from familial adenomas such as Familial Adenomatous Polyposis (FAP) and Multiple Adenoma patients. DNA methylation was tested at Methylated IN Tumor (MINT) loci (1,2,12,31) and the CpG promoter region of genes MLH1, HPP1, MGMT, p14ARF and p16INK4a in FAP-associated adenomas (33) from 5 patients with a known APC mutation (Group 1, FAP), adenomas (29) from 4 Multiple Adenoma patients (Group 2 Multiple), adenomas (14) from 3 patients with sporadic colorectal cancers showing high microsatellite instability (Group 3, MSI-H) and adenomas (16) from 7 patients, with sporadic colorectal cancers showing microsatellite stable or low level instability (Group 4, MSS/MSI-L). Aberrant Crypt Foci (ACFs), Hyperplastic Polyps (HPs) and cancers were also examined for methylation status as well as K- ras mutation. Multiple Adenoma patients were examined for germline polymorphisms in the base excision repair gene, MYH. The familial syndrome, FAP -associated adenomas showed a significantly low frequency of MINT methylation (15.5%,) compared to sporadic MSS/MSI-L-associated adenomas (35.5%). Group 3 (MSI-H) adenomas were different in that many showed serration and a high level of methylation (57.1%). Group 2, Multiple Adenoma cases, resembled sporadic MSS/MSI-L-associated adenomas. However the promoter regions of key genes, MGMT, p14ARF and p16INK4a were methylated to a greater extent than MINTs in both sporadic and familial adenomas. Genetic profiling of adenomas supports the concept that adenomas belonging to familial syndromes pursue a different pathway to tumorigenesis than their sporadic counterpar/ts from their earliest formation. © 2005 Wiley-Liss, Inc. [source] Effect of lectins on the transport of food ingredients in Caco-2 cell culturesBIOFACTORS, Issue 1-4 2004Y. Ohno Abstract We investigated the effect of several lectins, such as soy bean lectin (SBA), concanavalin A (Con A), and wheat germ agglutinin (WGA), on the transport of some food ingredients (isoflavones, quercetin glycosides, carnosine/anserine) across Caco-2 cell monolayers. After incubation of food ingredients (0.03,2 mmol/L) in the presence or absence of lectins (1,180 ,/ml) on the apical side, aliquots were taken from the apical and basolateral solution, and were subjected to HPLC analysis. We also examined the effect of lectins on the permeability of the tight junction by measuring the transepithelial electrical resistance (TER) value of the Caco-2 cell monolayer. Isoflavones, which was not transported to the basolateral solution without lectins, could be transported in the presence of lectins, whereas their aglycones were detected at the same levels with or without the lectin treatment. The transport of quercetin glycosides also increased in the presence of lectins, however, that of peptides was not affected by the lectins. Con A and WGA, but SBA, decreased the TER value, indicating that Con A and WGA increased the transport via paracellular pathway, whereas SBA did via a different pathway. [source] Pathways for Communicating about Objects on Guided ToursCURATOR THE MUSEUM JOURNAL, Issue 3 2008Jeff Camhi Most tour guides rely on rather limited, unidirectional (guide-to-visitor) communication. Instead, this paper outlines six different pathways of communication that are possible among guide, visitors, and object. Each pathway offers several specific types of communicative acts. In addition, 35 guided tours in several different kinds of venue were examined to identify the pathways and types of acts that were used. The professional literature describes other types of acts, and more have been developed at the writer's home museum. All in all, the 58 different types of communicative acts described here present a wide range of opportunities for guides to communicate with visitors. [source] Posttranslational regulation of BCL2 levels in cerebellar granule cells: A mechanism of neuronal survivalDEVELOPMENTAL NEUROBIOLOGY, Issue 13 2009Laura Lossi Abstract Apoptosis can be modulated by K+ and Ca2+ inside the cell and/or in the extracellular milieu. In murine organotypic cultures, membrane potential-regulated Ca2+ signaling through calcineurin phosphatase has a pivotal role in development and maturation of cerebellar granule cells (CGCs). P8 cultures were used to analyze the levels of expression of B cell lymphoma 2 (BCL2) protein, and, after particle-mediated gene transfer in CGCs, to study the posttranslational modifications of BCL2 fused to a fluorescent tag in response to a perturbation of K+/Ca2+ homeostasis. There are no changes in Bcl2 mRNA after real time PCR, whereas the levels of the fusion protein (monitored by calculating the density of transfected CGCs under the fluorescence microscope) and of BCL2 (inWestern blotting) are increased. After using a series of agonists/antagonists for ion channels at the cell membrane or the endoplasmic reticulum (ER), and drugs affecting protein synthesis/degradation, accumulation of BCL2 was related to a reduction in posttranslational cleavage by macroautophagy. The ER functionally links the [K+]e and [Ca2+]i to the BCL2 content in CGCs along two different pathways. The first, triggered by elevated [K+]e under conditions of immaturity, is independent of extracellular Ca2+ and operates via IP3 channels. The second leads to influx of extracellular Ca2+ following activation of ryanodine channels in the presence of physiological [K+]e, when CGCs are maintained in mature status. This study identifies novel mechanisms of neuroprotection in immature and mature CGCs involving the posttranslational regulation of BCL2. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009 [source] How is Education Possible?EDUCATIONAL PHILOSOPHY AND THEORY, Issue 1 2001Preliminary investigations for a theory of education The following text is the result of our ongoing discussions about the notion of intersubjectivity and its significance for an understanding of the process of education. Rather than merging our sometimes diverging ideas into one single line of argument, we decided to try if we could make the movement of divergence and convergence of our thoughts visible in the text itself. Although we definitely explore different pathways, these pathways lead to a similar insight. This is, that it is not the educator who educates, but that it is the educational ,situation',a situation constituted though not determined by the interaction between the educator and the student,which educates. This educational situation, which one of us describes as an ,in between space', emerges from the interaction between the educator and the student. In this respect we can say that it results from the difference between the partners in education. The in-between space of education is an emerging reality, which not only comes into existence as a result of the difference between the partners in education but in fact only exists in this difference. It is precisely in this respect that the form of the following article provides an example of what we want to say about the process of education. The point is, to put it briefly, that this article contains or expresses a meaning that results from the difference between the two texts, but this meaning is neither something that can be attributed to the two texts as such (in this sense this emerging meaning is constituted though not determined by the two texts), nor,and this is crucial,is it something that can be articulated in any positive way in a third text. The interaction between our two texts therefore creates a reality that results from the difference between the texts and only exists in this difference. The order of authorship expresses the fact that the first author wrote the left column and the second author the right column. [source] Human parathyroid cell proliferation in response to calcium, NPS R-467, calcitriol and phosphateEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2001M-C. Roussanne It remains uncertain how calcium, phosphate and calcitriol regulate parathyroid cell growth. The present study was aimed at examining possible direct effects of these modulators and of the calcimimetic NPS R-467 on parathyroid cell growth in vitro. Cell proliferation was determined by [3H]thymidine incorporation and cell cycle antigen Ki 67 expression in a parathyroid cell culture model derived from uraemic patients. The effect of NPS R-467 on parathyroid hormone (PTH) secretion and intracellular [Ca2+]i response was also examined. Increasing the [Ca2+] in the medium from 0·5 to 1·7 mM increased DNA synthesis (P < 0·005) and the number of Ki 67-positive cells (P < 0·005). However, NPS R-467 (0·01,1 µM) inhibited 3[H]thymidine incorporation by 35% in the presence of 0·5 mM [Ca2+]e. Exposure of cells to Ca2+ or NPS R-467 led to a rapid increase of intracellular Ca2+, although the pattern of increase differed. Addition of calcitriol (10,10,10,7 M) to the culture medium suppressed [3H]thymidine incorporation dose-dependently. Finally, high levels of phosphate (3·5 mM) in the medium led to a significant (P < 0·05) increase in [3H]thymidine incorporation. The observed stimulatory effect of Ca2+ in the medium in vitro appears to be at variance with the inhibitory effect of calcimimetic NPS R-467 in vitro. In an attempt to solve these apparent discrepancies, and based on the notion of a reduced calcium-sensing receptor (CaR) expression in parathyroid tissues of uraemic patients, we hypothesize that Ca2+ may regulate parathyroid cell proliferation via two different pathways, with predominant growth inhibition in cases of high CaR expression or activation, but prevailing stimulation of proliferation in cases of low CaR expression. [source] Synthesis and Characterization of Radical Cations Derived from Mono- and Biferrocenyl-Substituted 2-Aza-1,3-butadienes: A Study of the Influence of an Asymmetric and Oxidizable Bridge on Intramolecular Electron TransferEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 12 2005Vega Lloveras Abstract The synthesis and study of structural and electronic properties of mono-ferrocenyl ,-conjugated complexes 5a,d, whose electronic characteristics have been systematically varied by introducing an electron-donating or electron-withdrawing substituent either at the 1-position or at the 4-position of the 2-aza-1,3-butadiene moiety linked to the ferrocenyl unit, are presented. The structural and electronic properties of the homobimetallic complex 5f, with two ferrocene units linked through the asymmetric and oxidizable 2-aza-1,3-butadiene bridge, is also reported. The crystal structures of complexes 5b, 5d, and 5f show a large degree of conjugation in this family of compounds. Complexes 5 show a rich electrochemical behavior due both to the oxidation of ferrocenyl units and the 2-aza-1,3-butadiene bridge, as revealed by cyclic voltammetry. Radical cations 5+· were prepared from 5 by coulometric oxidations following their generation by absorption spectroscopy. The electronic properties of all reported neutral and oxidized ,-conjugated complexes have been investigated by means of UV/Vis,near-IR, EPR and 57Fe Mössbauer spectroscopy. The detailed study of mono-oxidized species 5a+·,5f+· has permitted the determination of the influence of an asymmetric bridge with an electroactive character on the intramolecular electron transfer (IET) phenomenon, thus demonstrating that the 2-aza-1,3-butadiene bridge promotes the IET between the two metallic units of 5f+· through two different pathways. The experimental data and conclusions are supported by DFT computations (B3LYP/3-21G*) and time-dependent DFT methods. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Direction of cross-modal information transfer affects human brain activation: a PET studyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2002Ryuta Kawashima Abstract The purpose of this study was to determine the functional organization of the human brain involved in cross-modal discrimination between tactile and visual information. Regional cerebral blood flow was measured by positron emission tomography in nine right-handed volunteers during four discrimination tasks; tactile,tactile (TT), tactile,visual (TV), visual,tactile (VT), and visual,visual (VV). The subjects were asked either to look at digital cylinders of different diameters or to grasp the digital cylinders with the thumb and index finger of the right hand using haptic interfaces. Compared with the motor control task in which the subjects looked at and grasped cylinders of the same diameter, the right lateral prefrontal cortex and the right inferior parietal lobule were activated in all the four discrimination tasks. In addition, the dorsal premotor cortex, the ventral premotor cortex, and the inferior temporal cortex of the right hemisphere were activated during VT but not during TV. Our results suggest that the human brain mechanisms underlying cross-modal discrimination have two different pathways depending on the temporal order in which stimuli are presented. [source] Functional connections and epileptic spread between hippocampus, entorhinal cortex and amygdala in a modified horizontal slice preparation of the rat brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2000Ron Stoop Abstract The hippocampus, the entorhinal cortex and the amygdala are interconnected structures of the limbic system that are implicated in memory and emotional behaviour. They demonstrate synaptic plasticity and are susceptible to development of temporal lobe epilepsy, which may lead to emotional and psychological disturbances. Their relative anatomical disposition has limited the study of neurotransmission and epileptic spread between these three regions in previous in vitro preparations. Here we describe a novel, modified-horizontal slice preparation that includes in the same plane the hippocampus, entorhinal cortex and amygdala. We found that, following application of bicuculline, each region in our preparation could generate spontaneous bursts that resembled epileptic interictal spikes. This spontaneous activity initiated in the hippocampal CA3/2 region, from where it propagated and controlled the activity in the entorhinal cortex and the amygdala. We found that this spontaneous bursting activity could spread via two different pathways. The first pathway comprises the well-known subiculum,entorhinal cortex,perirhinal cortex,amygdala route. The second pathway consists of a direct connection between the CA1 region and perirhinal cortex, through which the hippocampal bursting activity can spread to the amygdala while bypassing the entorhinal cortex. Thus, our experiments provide a new in vitro model of initiation and spread of epileptic-like activity in the ventral part of the limbic system, which includes a novel, fast and functional connection between the CA1 region and perirhinal cortex. [source] METAMODELS AND PHYLOGENETIC REPLICATION: A SYSTEMATIC APPROACH TO THE EVOLUTION OF DEVELOPMENTAL PATHWAYSEVOLUTION, Issue 11 2009Artyom Kopp Molecular genetic analysis of phenotypic variation has revealed many examples of evolutionary change in the developmental pathways that control plant and animal morphology. A major challenge is to integrate the information from diverse organisms and traits to understand the general patterns of developmental evolution. This integration can be facilitated by evolutionary metamodels,traits that have undergone multiple independent changes in different species and whose development is controlled by well-studied regulatory pathways. The metamodel approach provides the comparative equivalent of experimental replication, allowing us to test whether the evolution of each developmental pathway follows a consistent pattern, and whether different pathways are predisposed to different modes of evolution by their intrinsic organization. A review of several metamodels suggests that the structure of developmental pathways may bias the genetic basis of phenotypic evolution, and highlights phylogenetic replication as a value-added approach that produces deeper insights into the mechanisms of evolution than single-species analyses. [source] Large aggregating and small leucine-rich proteoglycans are degraded by different pathways and at different rates in tendonFEBS JOURNAL, Issue 17 2004Tom Samiric This work investigated the kinetics of catabolism and the catabolic fate of the newly synthesized 35S-labelled proteoglycans present in explant cultures of tendon. Tissue from the proximal region of bovine deep flexor tendon was incubated with [35S]sulfate for 6 h and then placed in explant cultures for periods of up to 15 days. The amount of radiolabel associated with proteoglycans and free [35S]sulfate lost to the medium and retained in the matrix was determined for each day in culture. It was shown that the rate of catabolism of radiolabelled small proteoglycans (decorin and biglycan) was significantly slower (T½ > 20 days) compared with the radiolabelled large proteoglycans (aggrecan and versican) that were rapidly lost from the tissue (T½ , 2 days). Both the small and large newly synthesized proteoglycans were lost from the matrix with either intact or proteolytically modified core proteins. When explant cultures of tendon were maintained either at 4 °C or in the presence of the lysosomotrophic agent ammonium chloride, inhibition of the cellular catabolic pathway for small proteoglycans was demonstrated indicating the involvement of cellular activity and lysosomes in the catabolism of small proteoglycans. It was estimated from these studies that approximately 60% of the radiolabelled small proteoglycans that were lost from the tissue were degraded by the intracellular pathway present in tendon cells. This work shows that the pathways of catabolism for large aggregating and small leucine-rich proteoglycans are different in tendon and this may reflect the roles that these two populations of proteoglycans play in the maintenance of the extracellular matrix of tendon. [source] All or none fibrillogenesis of a prion peptideFEBS JOURNAL, Issue 18 2001Wen-Quan Zou Amyloid proteins and peptides comprise a diverse group of molecules that vary both in size and amino-acid sequence, yet assemble into amyloid fibrils that have a common core structure. Kinetic studies of amyloid fibrillogenesis have revealed that certain amyloid proteins form oligomeric intermediates prior to fibril formation. We have investigated fibril formation with a peptide corresponding to residues 195,213 of the human prion protein. Through a combination of kinetic and equilibrium studies, we have found that the fibrillogenesis of this peptide proceeds as an all-or-none reaction where oligomeric intermediates are not stably populated. This variation in whether oligomeric intermediates are stably populated during fibril formation indicates that amyloid proteins assemble into a common fibrillar structure; however, they do so through different pathways. [source] Multiple cell death programs: Charon's lifts to HadesFEMS YEAST RESEARCH, Issue 2 2004Wilfried Bursch Abstract Cells use different pathways for active self-destruction as reflected by different morphology: while in apoptosis (or "type I") nuclear fragmentation associated with cytoplasmic condensation but preservation of organelles is predominant, autophagic degradation of cytoplasmic structures preceding nuclear collapse is a characteristic of a second type of programmed cell death (PCD). The diverse morphologies can be attributed , at least to some extent , to distinct biochemical and molecular events (e.g. caspase-dependent and -independent death programs; DAP-kinase activity, Ras-expression). However, apoptosis and autophagic PCD are not mutually exclusive phenomena. Rather, diverse PCD programs emerged during evolution, the conservation of which apparently allows cells a flexible response to environmental changes, either physiological or pathological. [source] Complement and its implications in cardiac ischemia/reperfusion: strategies to inhibit complementFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2001Tiphaine Monsinjon Although reperfusion of the ischemic myocardium is an absolute necessity to salvage tissue from eventual death, it is also associated with pathologic changes that represent either an acceleration of processes initiated during ischemia or new pathophysiological changes that were initiated after reperfusion. This so-called ,reperfusion injury' is accompanied by a marked inflammatory reaction, which contributes to tissue injury. In addition to the well known role of oxygen free radicals and white blood cells, activation of the complement system probably represents one of the major contributors of the inflammatory reaction upon reperfusion. The complement may be activated through three different pathways: the classical, the alternative, and the lectin pathway. During reperfusion, complement may be activated by exposure to intracellular components such as mitochondrial membranes or intermediate filaments. Two elements of the activated complement contribute directly or indirectly to damages: anaphylatoxins (C3a and C5a) and the membrane attack complex (MAC). C5a, the most potent chemotactic anaphylatoxin, may attract neutrophils to the site of inflammation, leading to superoxide production, while MAC is deposited over endothelial cells and smooth vessel cells, leading to cell injury. Experimental evidence suggests that tissue salvage may be achieved by inhibition of the complement pathway. As the complement is composed of a cascade of proteins, it provides numerous sites for pharmacological interventions during acute myocardial infarction. Although various strategies aimed at modulating the complement system have been tested, the ideal approach probably consists of maintaining the activity of C3 (a central protein of the complement cascade) and inhibiting the later events implicated in ischemia/reperfusion and also in targeting inhibition in a tissue-specific manner. [source] High dosage Rhp51 suppression of the MMS sensitivity of DNA structure checkpoint mutants reveals a relationship between Crb2 and Rhp51GENES TO CELLS, Issue 7 2003Monique F.M.A. Smeets Background: In eukaryotic cells DNA structure checkpoints organize the cellular responses of DNA repair and transient cell cycle arrest and thereby ensure genomic stability. To investigate the exact role of crb2+ in the DNA damage checkpoint response, a genetic screen was carried out in order to identify suppressors of the conditional MMS sensitivity of a crb2-1 mutant. Here we report the isolation of rhp51+ as a multicopy suppressor. Results: We show that suppression is not specific for the checkpoint mutant while it is specific for the MMS treatment. Rescue by rhp51+ over-expression is not a consequence of increased recombination repair or checkpoint compensation and epistasis analysis confirms that crb2+ and rhp51+ function in different pathways. A tight linkage between the two pathways is nevertheless suggested by the complementary expression or modification of Crb2 and Rhp51 proteins. Crb2 protein stability is down-regulated when Rhp51 is over-expressed and up-regulated in the absence of Rhp51. The up-regulation of Crb2 is independent of the activation of DNA structure checkpoints. Conversely Rhp51 is more readily activated and differentially modified in the absence of Crb2 or other checkpoint proteins. Conclusions: We conclude that fission yeast Crb2 and Rhp51 function in two parallel, tightly connected and coordinately regulated pathways. [source] Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuliGLIA, Issue 3 2007Pamela A. Carpentier Abstract Impaired immune surveillance and constitutive immunosuppressive properties make the central nervous system (CNS) a particular challenge to immune defense, and require that CNS-resident cells be capable of rapidly recognizing and responding to infection. We have previously shown that astrocytes respond to treatment with a TLR3 ligand, poly I:C, with the upregulation of innate immune functions. In the current study, we examine the activation of innate immune functions of astrocytes by Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, which establishes a persistent infection in the CNS of susceptible strains of mice and leads to the development of an autoimmune demyelinating disease that resembles human multiple sclerosis. Astrocytes infected with TMEV are activated to produce type I interferons, the cytokine IL-6, and chemokines CCL2 and CXCL10. We further examined the mechanisms that are responsible for the activation of astrocytes in response to direct viral infection and treatment with poly I:C. We found that the cytoplasmic dsRNA-activated kinase PKR is important for innate immune responses to TMEV infection, but has no role in their induction by poly I:C delivered extracellularly. In contrast, we found that TLR3 has only a minor role in responses to TMEV infection, but is important for responses to poly I:C. These results highlight the differences between responses induced by direct, nonlytic virus infection and extracellular poly I:C. The activation of astrocytes through these different pathways has implications for the initiation and progression of viral encephalitis and demyelinating diseases such as multiple sclerosis. © 2006 Wiley-Liss, Inc. [source] Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration,HEPATOLOGY, Issue 2 2007Yongzhi Cui Growth hormone controls many facets of a cell's biology through the transcription factors Stat5a and Stat5b (Stat5). However, whole body deletion of these genes from the mouse does not provide portentous information on cell-specific cytokine signaling. To explore liver-specific functions of Stat5, the entire Stat5 locus was deleted in hepatocytes using Cre-mediated recombination. Notably, Stat5-mutant mice developed fatty livers and displayed impaired proliferation of hepatocytes upon partial hepatectomy (PHx). Loss of Stat5 led to molecular consequences beyond the reduced expression of Stat5 target genes, such as those encoding suppressor of cytokine signaling 2 (SOCS2), Cish, and insulin-like growth factor 1 (IGF-1). In particular, circulating growth hormone levels were increased and correlated with insulin resistance and increased insulin levels. Aberrant growth hormone (GH)-induced activation of the transcription factors Stat1 and Stat3 was observed in mutant livers. To test whether some of the defects observed in liver-specific Stat5 deficient mice were due to aberrant Stat1 expression and activation, we generated Stat1,/, mice with a hepatocyte-specific deletion of Stat5. Concomitant loss of both Stat5 and Stat1 restored cell proliferation upon PHx but did not reverse fatty liver development. Thus the molecular underpinnings of some defects observed in the absence of Stat5 are the consequence of a deregulated activation of other signal transducers and activators of transcription (STAT) family members. Conclusion: Aberrant cytokine-Stat5 signaling in hepatocytes alters their physiology through increased activity of Stat1 and Stat3. Such cross-talk between different pathways could add to the complexity of syndromes observed in disease. (HEPATOLOGY 2007.) [source] Reversal of expression of 15-lipoxygenase-1 to cyclooxygenase-2 is associated with development of colonic cancerHISTOPATHOLOGY, Issue 4 2007M Yuri Aims:, Two different pathways of linoleic acid (LA) metabolism have opposite effects on the development of colonic cancer: a protumoral prostaglandin cascade metabolized by cyclooxygenase (COX)-2, and an antitumoral peroxisome proliferator-activated receptor (PPAR)-, ligands metabolized by 15-lipooxygenase (LOX)-1. The aim was to examine the switching of the two LA metabolic pathways in colonic adenomas and carcinomas. Materials and methods:, The expression of 15LOX-1 mRNA and COX-2 protein was examined in 54 adenomas, 21 pTis carcinoma-in-adenoma lesions and 36 pT3/p Stage II carcinomas of the colon by in-situ hybridization and immunohistochemistry, respectively. Results:, 15LOX-1 expression was found in 89% (48 of 54) of adenomas, 43% (nine of 21) of adenomas and 10% (two of 21) of carcinomas in carcinoma-in-adenoma lesions, but not in pT3 carcinomas (P < 0.0001). In contrast, COX-2 production was found in 11% (six of 54) of adenomas, 52% (11 of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). Concurrence of 15LOX-1 down-regulation and COX-2 up-regulation was found in 6% (three of 54) of adenomas, 33% (seven of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). Conclusions:, These results suggest that switching of LA metabolism by reversal of the expression of 15LOX-1 and COX-2 is associated with acquisition of malignant potential in colonic neoplasia. [source] Neurological complications of psychiatric drugs: clinical features and management,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S1 2008Peter M. Haddad Abstract This paper reviews the main neurological complications of psychiatric drugs, in particular antipsychotics and antidepressants. Extrapyramidal syndromes include acute dystonia, parkinsonism, akathisia, tardive dyskinesia and tardive dystonia. Extrapyramidal symptoms (EPS) are less frequent with atypical than with conventional antipsychotics but remain common in clinical practice partly due to lack of screening by health professionals. Neuroleptic malignant syndrome (NMS) consists of severe muscle rigidity, pyrexia, change in conscious level and autonomic disturbance but partial forms also occur. NMS is particularly associated with the initiation and rapid increase in dose of high-potency antipsychotics but it has been reported with all the atypical antipsychotics and rarely with other drugs including antidepressants. Serotonin toxicity comprises altered mental state (agitation, excitement, confusion), neuromuscular hyperactivity (tremor, clonus, myoclonus, hyper-reflexia) and autonomic hyperactivity and occurs on a spectrum. Severe cases, termed serotonin syndrome, usually follow the co-prescription of drugs that increase serotonergic transmission by different pathways, for example a monoamine oxidase inhibitor (MAOI) and a selective serotonin reuptake inhibitor (SSRI). Most antipsychotics and antidepressants lower the seizure threshold and can cause seizures; the risk is greater with clozapine than with other atypical antipsychotics and greater with tricyclic antidepressants (TCAs) than with SSRIs. In randomised controlled trials in elderly patients with dementia atypical antipsychotics are associated with a higher risk of stroke and death than placebo. Cohort studies suggest that conventional drugs carry at least the same risk. Cessation of treatment with antipsychotics and antidepressants can lead to a wide range of discontinuation symptoms which include movement disorders and other neurological symptoms. Clinicians need to be familiar with strategies to reduce the risk of these adverse events and to manage them when they arise. Their occurrence needs to be balanced against the benefits of psychiatric drugs in terms of efficacy and improved quality of life in a range of disorders. Copyright © 2007 John Wiley & Sons, Ltd. [source] Predictors of representational aggression in preschool children of low-income urban African American adolescent mothers,INFANT MENTAL HEALTH JOURNAL, Issue 1 2010Geoff Goodman Responses to five doll-story stems thematically related to attachment experiences with the mother were videotaped in the home and used to evaluate child, maternal, and environmental predictors of representational aggression in 93 preschool children of African American women receiving public assistance who had become pregnant as teenagers. Significant correlations were found between representational aggression and child's gender (male), birth weight, maternal depressive affect, maternal educational attainment, recent employment, mother's historical residence with her own mother, and felt social support, accounting for 40% of the variance in representational aggression. A significant Felt Social Support × Gender interaction effect suggested that girls of mothers who perceive higher levels of felt social support are more likely to represent less aggression in their stories; felt social support was not associated with boys' representational aggression. A significant Felt Social Support × Employment interaction effect suggested that representational aggression is associated with lower levels of felt social support only among employed mothers. Findings suggest that different pathways exist for representational aggression in children of low-income adolescent mothers, which nevertheless share predictors associated with poverty. [source] Theoretical study of the oxidative polymerization of aniline with peroxydisulfate: Tetramer formationINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 2 2008-Marjanovi, Gordana Abstract Semi-empirical quantum chemical study of the oxidative polymerization of aniline with ammonium peroxydisulfate, in aqueous solutions without added acid, has been based on the MNDO-PM3 computations of thermodynamic, redox, and acid,base properties of reactive species and the intermediates, combined with the MM2 molecular mechanics force-field method and conductor-like screening model of solvation. The main reaction routes of aniline tetramerization are proposed. The regioselectivity of the formation of aniline tetramers by redox and electrophilic aromatic substitution reactions is analyzed. It was proved that the linear NC4 coupled tetra-aniline is formed as a dominant product by three different pathways: comproportionation redox reaction between N -phenyl-1,4-benzoquinonediimine and 4-aminodiphenylamine, the one-electron oxidation of aniline with its half-oxidized NC4 coupled trimer, and the electrophilic aromatic substitution reaction of aniline with fully oxidized NC4 coupled trianiline nitrenium cation. The electrophilic aromatic substitution reaction of the NC4 coupled aniline trimer with aniline nitrenium cation, as well as the oxidation of aniline with half-oxidized branched trimer, lead to the branched aniline tetramers. The competing character of different tetramerization routes is highlighted. The oxidative intramolecular cyclization of branched oligoanilines and polyaniline, leading to the generation of substituted phenazine units, has been predicted to accompany the classical routes of the polymerization of aniline. Various molecular (branched vs. linear) oligomeric structures produced at different level of acidity during the course of polymerization and their impact on the formation of supramolecular structures of conducting polyaniline (nanorods and nanotubes vs. granular morphology), are discussed. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [source] Gold Catalysis: Anellated Heterocycles and Dependency of the Reaction Pathway on the Tether LengthADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 17 2009A. Stephen Abstract A series of furan-yne substrates with an arylalkynylamide substructure were prepared and subjected to catalytic amounts of phosphanegold(I) complexes. With two carbon atoms in the tether between the arylalkynylamide and the furan subunits, the formation of benzoanellated heterocycles was observed, a number of interesting heterocyclic framworks could be accessed in this way. With three carbon atoms in the tether, the outcome was quite different, cyclopentadiene derivatives anellated to tetrahydropyridine rings were isolated. The two different pathways suggested are supported by calculations regarding the selectivity-determining step. [source] Improved Protocols for Molybdenum- und Tungsten-Catalyzed HydrostannationsADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 9 2009Alexander Abstract A series of (isonitrile)tungsten carbonyl complexes of type W(CO)m(CNR)n has been synthesized and evaluated as hydrostannation catalysts. The results are compared with those obtained by the previously reported tri(tert -butylisonitrile)molybdenum tricarbonyl catalyst, Mo(CO)3(CN- t- Bu)3 (=MoBI3). The yields and selectivities strongly depend on the isonitriles used, and with certain substrates better results are obtained compared to the molybdenum catalyst. No side products are observed in hydrostannations under microwave irradiation or when the reactions are carried out under an atmosphere of carbon monoxide. Based on these findings, a mechanistic rational is given, explaining the different pathways responsible for the formation of hydrostannation or distannation products. [source] Phosphorylation by COP9 Signalosome-Associated CK2 Promotes Degradation of p27 during the G1 Cell Cycle PhaseISRAEL JOURNAL OF CHEMISTRY, Issue 2 2006Xiaohua Huang The cell cycle regulator p27Kip1 (p27) is controlled by 26S proteasome-mediated proteolysis by two different pathways. From the S till the G2 phase of the cell cycle, degradation of p27 takes place in the nucleus and is initiated by CDK2-dependent phosphorylation of threonine 187 with subsequent ubiquitination by the SCFSkp2 ubiquitin ligase. During the G1 cell cycle phase (G1), p27 breakdown is cytosolic and is initiated by nuclear export with subsequent ubiquitination by a RING finger ligase called kip1 ubiquitination complex. Here we show that the COP9 signalosome (CSN) is a regulator of p27 proteolysis during G1. The CSN interacts with p27 and the CSN-associated kinase CK2 phosphorylates p27 at two regions. One is central to the protein (amino acids 101,113), and the other was mapped near to the C-terminus (amino acids 170,189). Elimination of the putative C-terminal phosphorylation sites stabilizes ectopic p27 towards proteasomal degradation and abolishes CSN,p27 binding. Inhibition of CSN-associated kinase activity by curcumin attenuates loss of p27 upon cell cycle re-entry. Similar but not additive effects of the phosphoinositol-3-kinase blocker LY 290042 may point to a common pathway of CSN-associated CK2 and protein kinase B/Akt (Akt) in regulating p27 abundance. Akt is found in Flag pulldowns of lysates obtained from cells permanently expressing Flag-tagged CSN2, indicating that Akt is a novel kinase associated with the CSN. Thus, the CSN seems to regulate p27 proteolysis at G1 downstream of Ras-mediated signal pathways. [source] A discourse on cancer cell chemotaxis: Where to from here?IUBMB LIFE, Issue 2 2007Lilian L. Soon Abstract The study of cancer cell chemotaxis on two-dimensional surfaces in vitro has relevance to the diverse migratory behaviours exhibited in vivo that involve a directed path. These may include translocation along collagen fibres, invasion into the basement membrane and across stroma, intravasation and extravasation to arrive at a secondary destination designated for cancer cell colonization. Chemotaxis invariably denotes the ability of cells to sense gradients, polarize, adhere and deadhere to substrate, and translocate in the right direction. Amongst these, the sensing function is perhaps the unifying aspect of different migration styles, permitting the cells to resolve its orientation and path. This review examines the decision-making processes that take place during chemotaxis and illustrates that a universal mechanism is involved. In various cell types from Dictyostelium to neutrophils, there are some unifying principles that dictate sensing and how the putative leading edge and trailing end of cells are determined. Some of these principles have recently been applied in the study of cancer cell chemotaxis albeit different pathways are substituted. In amoeboid-like cancer cells, local excitation of the EGFR/PLC,/cofilin pathway and parallel, global inhibition of cofilin by LIMK occur to promote the asymmetric distribution and amplification of these internal signals in response to an external EGF gradient. IUBMB Life, 59: 60-67, 2007 [source] Efficacy of in-feed probiotics against Aeromonas bestiarum and Ichthyophthirius multifiliis skin infections in rainbow trout (Oncorhynchus mykiss, Walbaum)JOURNAL OF APPLIED MICROBIOLOGY, Issue 3 2008N. Pieters Abstract Aims:, The aim of this study was to assess the efficacy of in-feed probiotics as a preventive measure against skin infections caused by Aeromonas bestiarum and Ichthyophthirius multifiliis (Ich) in rainbow trout. Methods and Results:, Fin rot was induced in fish by intradermal injection with 0·1 ml volumes containing 105 cells per ml A. bestiarum at the base of the dorsal fin. Ich infections resulted from immersion in Ich-contaminated water. Each probiotic was administered orally [108 cells per g feed for GC2 (Aeromonas sobria) and 1010 cells per g feed for BA211 (Brochothrix thermosphacta)] for 14 days. Results showed that, after challenge with A. bestiarum, probiotics GC2 and BA211 led to 76% and 88% survival, respectively, in contrast to 22% survival for controls. Fish fed with probiotic GC2 had 100% survival after challenge with Ich compared with 2% for probiotic BA211 and 0% for controls. Analysis of innate immune responses revealed that probiotic GC2 promoted higher phagocytic activity, whereas probiotic BA211 led to enhanced respiratory burst activity. Conclusion:, Of the two probiotics examined, GC2 was more effective in protecting against both fin rot and Ich. Each probiotic appeared to stimulate different pathways within the innate immune system. Significance and Impact of the Study:, This is the first demonstration that probiotics can protect fish against surface infections. Furthermore, this is the first time a probiotic has been shown to protect against a eucaryotic pathogen, namely I. multifiliis. [source] | ||||||||||||||||||||||||||||||||||||||||