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Main Pathway (main + pathway)
Selected AbstractsNovel Model Sulfur Compounds as Mechanistic Probes for Enzymatic and Biomimetic OxidationsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 1 2005Alicia B. Peñéñory Abstract To test for the intermediacy of sulfide radical cations in biomimetic and enzymatic oxidations, the sulfides PhSCH3 (1a), PhSCH2Ph (1b), PhSCHPh2 (1c), PhSCPh3 (1d), CH3SCHPh2 (2), PhSCH2CH=CH2 (3), PhSCH2CH=CHPh (4) and CH3SCH2CH=CHPh (5) were studied, and their results were compared to those obtained for the corresponding chemical electron transfer (CET) and photoinduced electron transfer (PET) oxidations. The radical cations generated from 3,5 by CET in the presence of cerium(IV) ammonium nitrate (CAN) yielded only fragmentation products from the alkyl cations and the thiyl radicals (RS·), whereas 2·+ afforded both fragmentation and mainly ,-deprotonation products. Photochemical treatment of the sulfides 1a and 1b with C(NO2)4 gave only the corresponding sulfoxides, while fragmentation was the main pathway for the photoreactions of 1c, 2 and 5, and for 1d only this latter process was observed. These results support our selection of the sulfides RSCHPh2, RSCH2CH=CHPh (R = Me, Ph) and PhSCPh3 as models for the biomimetic and enzymatic studies. As evidenced by the sulfoxides and sulfones detected as unique products both in protic and in aprotic solvents, it is proposed that the mechanism of the biomimetic sulfoxidations of sulfides 1c and 2,5 by TPPFeIIICl is direct oxygen transfer. Three enzymes , Coprinus cinereus peroxidase (CiP), horseradish peroxidase (HRP) and chloroperoxidase (CPO) , were studied in the oxidation of sulfides 1a, 2, 4 and 5. The use of a racemic alkyl hydroperoxide in the CiP enzymatic oxidation of sulfides 5 and 2 yielded the corresponding sulfoxides (23 and 29%) and the aldehyde or benzophenone (5%), respectively. These results suggest the involvement of an ET process for the CiP-catalysed oxidation. Fragmentation products were observed in the enzymatic oxidation of sulfide 4 with HRP, which confirms the previously proposed ET mechanism. On the other hand, the CPO-enzymatic oxidation of sulfide 5 yielded only the corresponding sulfoxide, as would be expected for a direct oxygen-transfer or oxene mechanism. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Implication of the glutamine synthetase/glutamate synthase pathway in conditioning the amino acid metabolism in bundle sheath and mesophyll cells of maize leavesFEBS JOURNAL, Issue 12 2008Marie-Hélène Valadier We investigated the role of glutamine synthetases (cytosolic GS1 and chloroplast GS2) and glutamate synthases (ferredoxin-GOGAT and NADH-GOGAT) in the inorganic nitrogen assimilation and reassimilation into amino acids between bundle sheath cells and mesophyll cells for the remobilization of amino acids during the early phase of grain filling in Zea mays L. The plants responded to a light/dark cycle at the level of nitrate, ammonium and amino acids in the second leaf, upward from the primary ear, which acted as the source organ. The assimilation of ammonium issued from distinct pathways and amino acid synthesis were evaluated from the diurnal rhythms of the transcripts and the encoded enzyme activities of nitrate reductase, nitrite reductase, GS1, GS2, ferredoxin-GOGAT, NADH-GOGAT, NADH-glutamate dehydrogenase and asparagine synthetase. We discerned the specific role of the isoproteins of ferredoxin and ferredoxin:NADP+ oxidoreductase in providing ferredoxin-GOGAT with photoreduced or enzymatically reduced ferredoxin as the electron donor. The spatial distribution of ferredoxin-GOGAT supported its role in the nitrogen (re)assimilation and reallocation in bundle sheath cells and mesophyll cells of the source leaf. The diurnal nitrogen recycling within the plants took place via the specific amino acids in the phloem and xylem exudates. Taken together, we conclude that the GS1/ferredoxin-GOGAT cycle is the main pathway of inorganic nitrogen assimilation and recycling into glutamine and glutamate, and preconditions amino acid interconversion and remobilization. [source] A pathway through interferon-, is the main pathway for induction of nitric oxide upon stimulation with bacterial lipopolysaccharide in mouse peritoneal cellsFEBS JOURNAL, Issue 19 2003Motohiro Matsuura Production of nitric oxide (NO) in response to bacterial lipopolysaccharide (LPS) was investigated using cultures of mouse peritoneal exudate cells (PEC) and the macrophage cell line RAW264.7. In the presence of anti-(interferon-,) (IFN-,), NO production was markedly suppressed in the PEC culture but not in the RAW264.7 culture. In the PEC culture, LPS induced both IFN-, production and activation of IFN response factor-1, which leads to the gene expression of inducible NO synthase, but neither was induced in the culture of RAW264.7 cells. In addition to anti-(IFN-,), antibodies against interleukin (IL)-12 and IL-18 showed a suppressive effect on LPS-induced NO production in the PEC culture, and these antibodies in synergy showed strong suppression. Stimulation of the PEC culture with IL-12 or IL-18 induced production of IFN-, and NO, and these cytokines, in combination, exhibited marked synergism. Stimulation of the culture with IFN-, induced production of NO, but not IL-12. The macrophage population in the PEC, prepared as adherent cells, responded well to LPS for IL-12 production, but weakly for production of IFN-, and NO. The macrophages also responded well to IFN-, for NO production. For production of IFN-, by stimulation with LPS or IL-12 + IL-18, nonadherent cells were required in the PEC culture. Considering these results overall, the indirect pathway, through the production of intermediates (such as IFN-,-inducing cytokines and IFN-,) by the cooperation of macrophages with nonadherent cells, was revealed to play the main role in the LPS-induced NO production pathway, as opposed to the direct pathway requiring only a macrophage population. [source] Skin hydration and possible shunt route penetration in controlled estradiol delivery from ultradeformable and standard liposomesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2001Gamal M. M. El Maghraby Human skin delivery of estradiol from ultradeformable and traditional liposomes was explored, comparing occlusive and open application, with the aim of examining the role of skin hydration. Partially hydrated epidermis was used for open hydration, but fully hydrated membranes were used for occluded studies. In addition, we developed a novel technique to investigate the role of shunt route penetration in skin delivery of liposomal estradiol. This compared delivery through epidermis with that through a stratum corneum (SC)/epidermis sandwich from the same skin with the additional SC forming the top layer of the sandwich. This design was based on the fact that orifices of shunts only occupy 0.1% of skin surface area and thus for SC/epidermis sandwiches there will be a negligible chance for shunts to superimpose. The top SC thus blocks most shunts available on the bottom membrane. If shunts play a major role then the delivery through sandwiches should be much reduced compared with that through epidermis, taking into consideration the expected reduction owing to increased membrane thickness. After open application, both ultradeformable and traditional liposomes improved estradiol skin delivery, with the ultradeformable liposomes being superior. Occlusion reduced the delivering efficiency of both vesicle types, supporting the theory that a hydration gradient provides the driving force. Shunt route penetration was found to play only a very minor role in liposomal delivery. In conclusion, full hydration of skin reduces estradiol delivery from liposomes and the shunt route is not the main pathway for this delivery. [source] Manganese ions as intracellular contrast agents: proton relaxation and calcium interactions in rat myocardiumNMR IN BIOMEDICINE, Issue 2 2003Wibeke Nordhøy Abstract Paramagnetic manganese (Mn) ions (Mn2+) are taken up into cardiomyocytes where they are retained for hours. Mn content and relaxation parameters, T1 and T2, were measured in right plus left ventricular myocardium excised from isolated perfused rat hearts. In the experiments 5,min wash-in of MnCl2 were followed by 15,min wash-out to remove extracellular (ec) Mn2+ MnCl2, 25 and 100,µM, elevated tissue Mn content to six and 12 times the level of control (0,µM MnCl2). Variations in perfusate calcium (Ca2+) during wash-in of MnCl2 and experiments including nifedipine showed that myocardial slow Ca2+ channels are the main pathway for Mn2+ uptake and that Mn2+ acts as a pure Ca2+ competitor and a preferred substrate for slow Ca2+ channel entry. Inversion recovery analysis at 20,MHz revealed two components for longitudinal relaxation: a short T1,,,1 and a longer T1,,,2. Approximate values for control and Mn-treated hearts were in the range 600,125,ms for T1,,,1 and 2200,750,ms for T1,,,2. The population fractions were about 59 and 41% for the short and the long component, respectively. The intracellular (ic) R1,,,1 and R2,,,1 correlated best with tissue Mn content. Applying two-site exchange analyses on the obtained T1 data yielded results in parallel to, but also differing from, results reported with an ec contrast agent. The calculated lifetime of ic water (,ic) of about 10,s is compatible with a slow water exchange in the present excised cardiac tissue. The longitudinal relaxivity of Mn ions in ic water [60 (s mM),1] was about one order of magnitude higher than that of MnCl2 in water in vitro [6.9 (s mM),1], indicating that ic Mn-protein binding is an important potentiating factor in relaxation enhancement. Copyright © 2003 John Wiley & Sons, Ltd. [source] THE LOCATION OF THE TREASURY OF ATREUSOXFORD JOURNAL OF ARCHAEOLOGY, Issue 1 2007DAVID J. MASON Summary. The Treasury of Atreus, the largest and most impressive of the nine tholos tombs found at Mycenae, stands by itself at the southern edge of a bowl in the east slope of the Panagia ridge. This paper argues that the tomb was constructed on this particular spot so that it would be seen from the trackways/roads that led to Mycenae from the east, south-east and south-west and from the main pathway to the palace. The view of the acropolis hill and Mt. Profitis Ilias from the space occupied by the earthen mound above the tholos also appears to have influenced the choice of location. It is suggested that the position of the Treasury of Atreus was, like the tomb itself, a political statement, calculated to show that the ruler who built the tomb succeeded in extending the territory of Mycenae across the central Argolid. [source] Rethinking Late Weichselian ice-sheet dynamics in coastal NW SvalbardBOREAS, Issue 1 2005JON Y. LANDVIK New marine geological evidence provides a better understanding of ice-sheet dynamics along the western margin of the last Svalbard/Barents Sea Ice Sheet. A suite of glacial sediments in the Kongsfjordrenna cross-shelf trough can be traced southwards to the shelf west of Prins Karls Forland. A prominent moraine system on the shelf shows minimum Late Weichselian ice extent, indicating that glacial ice also covered the coastal lowlands of northwest Svalbard. Our results suggest that the cross-shelf trough was filled by a fast-flowing ice stream, with sharp boundaries to dynamically less active ice on the adjacent shelves and strandflats. The latter glacial mode favoured the preservation of older geological records adjacent to the main pathway of the Kongsfjorden glacial system. We suggest that the same model may apply to the Late Weichselian glacier drainage along other fjords of northwest Svalbard, as well as the western margin of the Barents Ice Sheet. Such differences in glacier regime may explain the apparent contradictions between the marine and land geological record, and may also serve as a model for glaciation dynamics in other fjord regions. [source] KC 12291: An Atypical Sodium Channel Blocker with Myocardial Antiischemic PropertiesCARDIOVASCULAR THERAPEUTICS, Issue 1 2004Gareth W. John ABSTRACT KC 12291 was designed as a voltage-gated sodium channel (VGSC) blocker with cardioprotective properties. KC 12291 has moderate inhibitory effects on peak (or rapid) Na+ current, and markedly reduces sustained (or slowly or non-inactivating) Na+ current. This distinguishes KC 12291 from conventional VGSC blockers such as local anesthetics or antiarrhythmics, which have little or no cardioprotective properties. Since VGSCs represent the main pathway for ischemic Na+ loading by failing to inactivate fully, KC 12291 exerts pronounced antiischemic activity principally by reducing the amplitude of sustained Na+ current. In isolated atria and Langendorff-perfused hearts, KC 12291 inhibits diastolic contracture, renowned for its resistance to pharmacological inhibition, reduces ischemic Na+ loading and preserves cardiac energy status. KC 12291 exerts oral antiischemic activity in vivo in the absence of major hemodynamic effects. Cardiac VGSC blockers such as KC 12291, which block cardiac VGSCs in atypical fashion by effectively inhibiting the sustained component of Na+ current, represent, therefore, promising potential antiischemic and cardioprotective drugs. [source] Quality of working life and turnover intention in information technology workHUMAN FACTORS AND ERGONOMICS IN MANUFACTURING & SERVICE INDUSTRIES, Issue 4 2008Christian Korunka High turnover has been a major issue in information technology (IT) organizations. A conceptual model to explain turnover was developed and tested in two national samples of IT and IT manufacturing work. The model postulates that quality of working life mediates the relations between job/organizational characteristics and turnover intention. The American sample consisted of 624 IT employees of five IT organizations. The Austrian sample consisted of 677 employees from an international IT production company (IT manufacturing work). A similar questionnaire was used in both studies. The model was tested with path analysis. A core model with main pathways between job demands and supervisory support to emotional exhaustion, and between emotional exhaustion and job satisfaction to turnover intention was confirmed in the national samples and in subsamples of demographics and job types. © 2008 Wiley Periodicals, Inc. [source] Contribution of non-agricultural pesticides to pesticide load in surface water,PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 6 2004Christian Skark Abstract Two small creeks, tributaries of the River Ruhr near Schwerte, Federal Republic of Germany, were investigated to reveal the regional agricultural and non-agricultural sources of pesticide inputs and the main pathways to surface water. In addition, the receiving water was monitored for pesticides. The watersheds are situated at the northern margin of the Rhenian Schiefergebirge, a highland landscape in North-Rhine,Westphalia. Solid carboniferous shale is covered by a shallow layer of quaternary unconsolidated rock (porous aquifer thickness <5 m). Occurrence of herbicides such as chlortoluron, isoproturon and terbuthylazine in surface water could be due to their broad agricultural application in regional dominant crops, such as barley, wheat and maize. Occurrence of diuron and glyphosate results from their use in residential settlements and industrial areas as well as from weed control on railway tracks. Atrazine concentrations up to 0.8 µg litre,1 indicated recent use of this herbicide, which has been banned since 1991, and was also the result of non-agricultural applications. Pathways for pesticide input to the receiving waters were related to both surface run-off and underground passage. Two-thirds of the observed diuron load in the surface water resulted from an input by run-off. This was expected as a result of total herbicide application targets to sealed surfaces infringing current regulations and recommendations. Diuron load varied between 0.6 and 1.2% of the estimated amount applied annually in the investigated catchments. Non-agricultural pesticide use contributed more than two-thirds of the whole observed pesticide load in the tributaries and at least one-third in the River Ruhr. Copyright © 2004 Society of Chemical Industry [source] Differential Role of Naïve and Memory CD4+ T-Cell Subsets in Primary AlloresponsesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010D. Golshayan The T cell response to major histocompatibility complex (MHC) alloantigens occurs via two main pathways. The direct pathway involves the recognition of intact allogeneic MHC:peptide complexes on donor cells and provokes uniquely high frequencies of responsive T cells. The indirect response results from alloantigens being processed like any other protein antigen and presented as peptide by autologous antigen-presenting cells. The frequencies of T cells with indirect allospecificity are orders of magnitude lower and comparable to other peptide-specific responses. In this study, we explored the contributions of naïve and memory CD4+ T cells to these two pathways. Using an adoptive transfer and skin transplantation model we found that naive and memory CD4+ T cells, both naturally occurring and induced by sensitization with multiple third-party alloantigens, contributed equally to graft rejection when only the direct pathway was operative. In contrast, the indirect response was predominantly mediated by the naïve subset. Elimination of regulatory CD4+CD25+ T cells enabled memory cells to reject grafts through the indirect pathway, but at a much slower tempo than for naïve cells. These findings have implications for better targeting of immunosuppression to inhibit immediate and later forms of alloimmunity. [source] Contribution of death receptor and mitochondrial pathways to Fas-mediated apoptosis in the prostatic carcinoma cell line PC3THE PROSTATE, Issue 4 2002Natalya V. Guseva Abstract BACKGROUND Two main pathways of apoptosis in mammalian cells have been described: the death receptor pathway and the mitochondrial pathway. Two different cell types have been identified for Fas-mediated apoptosis, each using almost exclusively one of two different signaling pathways. Human prostatic carcinoma cell line, PC3 is sensitive to Fas-mediated apoptosis, but relation of receptor and mitochondrial pathways is not clear. METHODS Cell viability was estimated by calcein assay. Apoptosis was determined by preparation of DNA ladder. Expression of Fas-associated death domain-dominant negative (FADD-DN) and Bcl-2, activation of caspases, PARP, DFF45, Bid cleavage, and cytochrome c release were assessed using Western blotting techniques. [35S] Methionine-labeled caspase-3 was transcribed in vitro and translated using the TNT kit (Promega). A vector containing caspase-3 was prepared by the ligation of EcoR I/BamHI flanked PCR fragment of full size caspase-3 cDNA into pBlusckript II SK(+/,) (Stratagen). RESULTS Overexpression of both FADD-DN and Bcl-2 genes prevent Fas-mediated apoptosis in PC3. As predicted, overexpression of FADD-DN prevented activation of caspase-8 and Bid cleavage and attenuated the release of cytochrome c and activation of caspases -2, -7, and -9. Bcl-2 overexpression did not affect caspase-8 activation and cleavage of Bid but blocked the release of cytochrome c and activation of mitochondria localized caspases -2, -7, and,9. Overexpression of FADD-DN and Bcl-2 affected the activation of caspase-3 and PARP cleavage differently: FADD-DN attenuated the activation of caspase-3 and PARP cleavage whereas Bcl-2 overexpression prevented caspase-3 activation and completely blocked cleavage of PARP. CONCLUSIONS These data suggest that activation of caspase-8 is necessary but not sufficient to complete Fas-mediated apoptosis in PC3 cells without activation of the mitochondrial pathway. In addition, caspase-3 activation after Fas-receptor ligation involves two steps and is dependent on mitochondrial activation. Prostate 51: 231,240, 2002. © 2002 Wiley-Liss, Inc. [source] Role of mitogen-activated protein kinases, nuclear factor-,B, and interferon regulatory factor 3 in Toll-like receptor 4-mediated activation of HIV long terminal repeatAPMIS, Issue 2 2009RANDI S. BERG Monocytes/macrophages are known to represent a potential reservoir of human immunodeficiency virus type 1 (HIV-1), which ensures continuous replication of the virus in patients on highly active antiretroviral therapy (HAART). Infected macrophages are a highly productive source of HIV-1 during infections with common opportunistic pathogens. Previous studies report that toll like receptors (TLR)s play a role in HIV-1 replication in macrophages. Here, we investigate the three main pathways activated through TLR4 and the interactions with the HIV-1 long terminal repeat (LTR), using human embryonic kidney (HEK) 293 cells expressing TLR4 and transfected with a luciferase reporter under the control of the HIV-1 LTR. Here, we demonstrate, that TLR4-mediated activation of HIV-LTR is largely governed by the nuclear factor-,B pathway. Neither of the mitogen-activated protein kinases ERK1/2, JNK, or p38 nor the transcription factor interferon regulatory factor 3 were involved in the direct transactivation of HIV-LTR through stimulation of TLR4. [source] Induction of type I interferons by bacteriaCELLULAR MICROBIOLOGY, Issue 7 2010Kathryn M. Monroe Summary Type I interferons (IFNs) are secreted cytokines that orchestrate diverse immune responses to infection. Although typically considered to be most important in the response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. Although diverse mechanisms have been described, bacterial induction of type I IFNs occurs upon stimulation of two main pathways: (i) Toll-like receptor (TLR) recognition of bacterial molecules such as lipopolysaccharide (LPS); (ii) TLR-independent recognition of molecules delivered to the host cell cytosol. Cytosolic responses can be activated by two general mechanisms. First, viable bacteria can secrete stimulatory ligands into the cytosol via specialized bacterial secretion systems. Second, ligands can be released from bacteria that lyse or are degraded. The bacterial ligands that induce the cytosolic pathways remain uncertain in many cases, but appear to include various nucleic acids. In this review, we discuss recent advances in our understanding of how bacteria induce type I interferons and the roles type I IFNs play in host immunity. [source] Developmental disorders of glucose metabolism in infantsCHILD: CARE, HEALTH AND DEVELOPMENT, Issue 2002R. Hume Abstract Background Developmental failures to adequately control postnatal blood glucose levels are common in the transition from fetal to infant life and can persist for many months. The standard method of functionally measuring hepatic glucose production and/or disordered glucose production is the response to a glucagon tolerance test. Method We adapted the standard glucagon tolerance test used for children and adults for use in preterm infants. 79 consecutive preterm infants gestational age range 25,36 weeks (mean 32.2 weeks), mean birth weight 1.66 kg admitted to the Neonatal Intensive Care Unit, Ninewells Hospital, Dundee and who survived to discharge home were recruited into the study. At the time of discharge home the characteristics of the group were as follows: adjusted mean gestational age 36.7 weeks, mean discharge weight 2.23 kg. Results In this study of preterm infants the maximal increase in plasma glucose following administration of a glucagon tolerance test is 1.39 ± 07 mmol/L, n = 78 (range 0,3.98 mmol/L). Conclusions An increase in plasma glucose of less than 4 mmol/L is considered abnormal in adults following administration of a fasting glucagon tolerance test. The responses of preterm infants and adults to glucagon are clearly different. The attenuated response to glucagon in the preterm infants is consistent with the low levels of hepatic glucose-6-phosphatase activity in premature infants as glucose-6-phosphatase is the terminal step of the two main pathways of liver glucose production. [source] Deregulation of cell-death pathways as the cornerstone of skin diseasesCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 6 2010N. Zutterman Summary Deregulation of cell-death pathways plays a key role in the pathogenesis of various skin diseases. The different types of cell death are mainly defined by morphological criteria, and include apoptosis, autophagic cell death, and necrosis. The process of apoptosis is well characterized at the molecular level and involves the activation of two main pathways, the intrinsic and extrinsic pathways, converging into the execution of apoptosis by intracellular cysteine proteases, called caspases. The relevance and implication of these apoptotic pathways in the pathophysiology of skin diseases, such as toxic epidermal necrolysis, graft-versus-host disease and skin cancer, has been extensively studied. The role of autophagic cell death in progression of skin tumours and response to cytotoxic drugs is only beginning to be elucidated. [source] | ||||||||||||||||