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Multiple Mechanisms (multiple + mechanism)

Distribution by Scientific Domains

Medical Sciences	44%
Life Sciences	42%
Chemistry	5%
Earth and Environmental Science	2%
2 Other Domains	7%

Distribution within Medical Sciences

Pharmacology & Pharmaceutical Medicine	18%
Cardiovascular Disease	11%
Immunology	4%
12 Other Subdomains	56%

Selected Abstracts

Toughening by Multiple Mechanisms in Ceramic-Matrix Composites with Discontinuous Elongated Reinforcements

JOURNAL OF THE AMERICAN CERAMIC SOCIETY, Issue 8 2000
Hongxiang Zhai
The dependence of toughening mechanisms on reinforcement orientation and the toughening effect governed by multiple toughening mechanisms were characterized for ceramic-matrix composites (CMCs) with discontinuous elongated reinforcements. Two kinds of Si3N4 -based composites, with directionally oriented and randomly oriented SiC whiskers, respectively, were tested by the three-point bending of chevron-notched bars. Based on microscopic observations and micromechanical analyses, three mechanisms were confirmed to dominate the crack-bridging behavior: (1) bridging and breaking of long reinforcements, (2) frictional pullout and breaking of short reinforcements, and (3) local matrix spalling. Both the occurrence of the multiple mechanisms and their toughening effects were proved dependent on the reinforcement orientation. The combined effect of the multiple mechanisms correlated with random orientation thus was characterized by a statistical approach to solve for the crack-bridging stress function. The theoretical model was in good agreement with the experimental results. [source]

Green Tea Polyphenols and Cancer Chemoprevention: Multiple Mechanisms and Endpoints for Phase II Trials

NUTRITION REVIEWS, Issue 5 2004
M.P.H., Susan B. Moyers Ph.D.
Among the numerous polyphenols isolated from green tea, the catechin EGCG predominates and is the target of anticancer research. But studies suggest that EGCG and other catechins are poorly absorbed and undergo substantial biotransformation to species that include glucuronides, sulfates, and methylated compounds. Numerous studies relate the antioxidant properties of the catechins with anticancer effects, but recent research proposes other mechanisms of action, including those involving methyl transfers that are subject to allelic variability in the enzyme catechol O-methyl transferase. However, preclinical research is promising and EGCG appears to be ready for further study in phase II and III trials. [source]

Multiple Mechanisms Of Early Hyperglycaemic Injury Of The Rat Intestinal Microcirculation

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002
H Glenn Bohlen
SUMMARY 1. Hyperglycaemia in the vast majority of humans with diabetes mellitus is the end result of profound insulin resistance secondary to obesity. For patients in treatment, hyperglycaemia is usually not sustained but, rather, occurs intermittently. In in vivo studies of the rat intestinal microcirculation, endothelial impairment occurs within 30 min at D -glucose concentrations , 300 mg/dL. Endothelial-dependent dilation to acetylcholine and constriction to noradrenaline is impaired. Vasodilation to exogenous nitric oxide (NO) remains normal. 2. When initiated before hyperglycaemia, suppression of oxygen radicals by both scavenging and pretreatment with cyclo-oxygenase blockade to prevent oxygen radical formation minimized endothelial impairments during hyperglycaemia. Neither treatment was effective in restoring endothelial function once it was damaged by hyperglycaemia. 3. A mechanism that may initiate the arachidonic acid, oxygen radical process is activation of specific isoforms of protein kinase C (PKC). De novo formation of diacylglycerol during hyperglycaemia activates PKC. Blockade of the ,II PKC isoform with LY-333531 prior to hyperglycaemia protected NO formation within the arteriolar wall, as judged with NO-sensitive microelectrodes. Furthermore, once suppression of endothelial dilation was present in untreated animals, PKC blockade could substantially restore endothelial-dependent dilation. 4. These results indicate that acute hyperglycaemia is far from benign and, in the rat, causes rapid endothelial impairment. Both oxygen radical scavenging and cyclo-oxygenase blockade prior to bouts of hyperglycaemia minimize endothelial impairment with limited side effects. Blockade of specific PKC isozymes protects endothelial function both as a pre- or post-treatment during moderately severe hyperglycaemia. [source]

Multiple Mechanisms of Thrombosis Complicating Atherosclerotic Plaques

CLINICAL CARDIOLOGY, Issue S6 2000
Peter Libby M.D.
Abstract Atherosclerosis is a highly prevalent disorder and remains a leading cause of morbidity and mortality in the United States. Recent advances in vascular biology have led to a better understanding of the mechanisms underlying atherogenesis. The central role played by plaque disruption, and by adhesion, activation, and aggregation of platelets that trigger activation of the coagulation cascade in the pathogenesis of acute thrombotic events is also better understood. Combination antithrombotic therapy targeting various platelet activation mechanisms and the coagulation cascade may help optimize the management of atherosclerosis. [source]

Multiple mechanisms mediate motor neuron migration in the zebrafish hindbrain

DEVELOPMENTAL NEUROBIOLOGY, Issue 2 2010
Stephanie M. Bingham
Abstract The transmembrane protein Van gogh-like 2 (Vangl2) is a component of the noncanonical Wnt/Planar Cell Polarity (PCP) signaling pathway, and is required for tangential migration of facial branchiomotor neurons (FBMNs) from rhombomere 4 (r4) to r5-r7 in the vertebrate hindbrain. Since vangl2 is expressed throughout the zebrafish hindbrain, it might also regulate motor neuron migration in other rhombomeres. We tested this hypothesis by examining whether migration of motor neurons out of r2 following ectopic hoxb1b expression was affected in vangl2, (trilobite) mutants. Hoxb1b specifies r4 identity, and when ectopically expressed transforms r2 to an "r4-like" compartment. Using time-lapse imaging, we show that GFP-expressing motor neurons in the r2/r3 region of a hoxb1b -overexpressing wild-type embryo migrate along the anterior-posterior (AP) axis. Furthermore, these cells express prickle1b (pk1b), a Wnt/PCP gene that is specifically expressed in FBMNs and is essential for their migration. Importantly, GFP-expressing motor neurons in the r2/r3 region of hoxb1b -overexpressing trilobite mutants and pk1b morphants often migrate, even though FBMNs in r4 of the same embryos fail to migrate longitudinally (tangentially) into r6 and r7. These observations suggest that tangentially migrating motor neurons in the anterior hindbrain (r1-r3) can use mechanisms that are independent of vangl2 and pk1b functions. Interestingly, analysis of tri; val double mutants also suggests a role for vangl2 -independent factors in neuronal migration, since the valentino mutation partially suppresses the trilobite mutant migration defect. Together, the hoxb1b and val experiments suggest that multiple mechanisms regulate motor neuron migration along the AP axis of the zebrafish hindbrain. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2010 [source]

Multiple mechanisms that prevent excessive brain inflammation

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2007
Myung-Soon Yang
Abstract Inflammation of the injured brain has a double-edged effect. Inflammation protects the brain from infection, but it aggravates injury. Furthermore, brain inflammation is considered a risk factor for neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Emerging evidence supports the activation of negative regulatory mechanisms during this process to prevent prolonged and extensive inflammation. The inflammatory stimulators themselves or products of inflammatory cells may induce the expression of negative feedback regulators, such as suppressor of cytokine signaling (SOCS)-family proteins, antioxidant enzymes, and antiinflammatory cytokines. Furthermore, death of activated microglia (major inflammatory cells in the brain) may regulate brain inflammation. Astrocytes, the most abundant cells in the brain, may also act in preventing microglial overactivation. Therefore, we propose that the extent and duration of brain inflammation is tightly regulated through the cooperation of multiple mechanisms to maximize antipathogenic effects and minimize tissue damage. © 2007 Wiley-Liss, Inc. [source]

Impairment of death-inducing signalling complex formation in CD95-resistant human primary lymphoma B cells

BRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2004
Alicia Lajmanovich
Summary Multiple mechanisms exist by which tumour cells can escape CD95-mediated apoptosis. Previous studies by our laboratory have shown that primary B cells from non-Hodgkin's Lymphoma (B-NHL) were resistant to CD95-induced cell death. In the current study, we have analysed the mechanisms underlying CD95 resistance in primary human lymphoma B cells. We report that FADD (FAS-associated death domain protein) and caspase-8 were constitutively expressed in lymphoma B cells and that the CD95 pathway was blocked upstream to caspase-8 activation. However, caspase-8 was processed and functional after treatment with staurosporine (STS). We found that the expression levels of FLICE (FADD-like interleukin-1 beta-converting enzyme)-Inhibitory Protein (c-FLIP) and Bcl-2-related proteins were heterogeneous in B-NHL cells and were not related to CD95 resistance. Finally, we report the absence of a CD95-induced signalling complex [death-inducing signalling complex (DISC)] in lymphoma B cells, with no FADD and caspase-8 recruitment to CD95 receptor. In contrast, DISC formation was observed in CD95-resistant non-tumoural (NT) B cells. Therefore, we propose that the absence of DISC formation in primary lymphoma B cells may contribute to protect these cells from CD95-induced apoptosis. [source]

NEURAL CONTROL OF RENAL MEDULLARY PERFUSION

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2004
Gabriela A Eppel
Summary 1.,There is strong evidence that the renal medullary circulation plays a key role in long-term blood pressure control. This, and evidence implicating sympathetic overactivity in development of hypertension, provides the need for understanding how sympathetic nerves affect medullary blood flow (MBF). 2.,The precise vascular elements that regulate MBF under physiological conditions are unknown, but likely include the outer medullary portions of descending vasa recta and afferent and efferent arterioles of juxtamedullary glomeruli, all of which receive dense sympathetic innervation. 3.,Many early studies of the impact of sympathetic drive on MBF were flawed, both because of the methods used for measuring MBF and because single and often intense neural stimuli were tested. 4.,Recent studies have established that MBF is less sensitive than cortical blood flow (CBF) to electrical renal nerve stimulation, particularly at low stimulus intensities. Indeed, MBF appears to be refractory to increases in endogenous renal sympathetic nerve activity within the physiological range in all but the most extreme cases. 5.,Multiple mechanisms appear to operate in concert to blunt the impact of sympathetic drive on MBF, including counter-regulatory roles of nitric oxide and perhaps even paradoxical angiotensin II-induced vasodilatation. Regional differences in the geometry of glomerular arterioles are also likely to predispose MBF to be less sensitive than CBF to any given vasoconstrictor stimulus. 6.,Failure of these mechanisms would promote reductions in MBF in response to physiological activation of the renal nerves, which could, in turn, lead to salt and water retention and hypertension. [source]

Multiple mechanisms mediate motor neuron migration in the zebrafish hindbrain

The clinical pharmacology of therapeutic monoclonal antibodies

DRUG DEVELOPMENT RESEARCH, Issue 3 2004
Lorin K. Roskos
Abstract Seventeen monoclonal antibodies are currently approved in the United States for therapeutic use in organ transplantation, percutaneous coronary intervention, prophylaxis of respiratory syncytial virus disease, rheumatoid arthritis, Crohn's disease, asthma, chronic lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, breast cancer, and colorectal cancer. All approved antibodies are of the IgG class. Thirteen are unconjugated intact antibodies, three are intact immunoconjugates, and one is a Fab fragment. Three of the antibodies are murine, five are chimeric, eight are humanized, and one is a fully human antibody generated by phage display technology. The antigen target and the structural and binding characteristics of the antibody determine the antibody's mechanism of action, pharmacokinetics, safety, and immunogenicity. Antibodies act through multiple mechanisms that include functional modulation of the antigen, recruitment of ADCC and CDC, and delivery of radionuclide or toxin payloads to target cells. Antibody half-life is usually governed by interaction with the FcRn receptor. In some cases, the antigen may act as a sink for antibody elimination. Safety profiles are determined by the pharmacology and tissue distribution of the target antigen, antibody isotype, the antibody payload, cytokine release, hypersensitivity reactions to xenogeneic protein, and immunogenicity. Fully human antibody technology may allow development of antibodies that have reduced risks of hypersensitivity reactions and immunogenicity, thereby enhancing safety and efficacy. The exquisite target specificity of antibodies, improvements in antibody engineering technology, and the wide availability of novel and validated therapeutic targets provide many current and future opportunities for the clinical development of therapeutic antibodies. Drug Dev. Res. 61:108,120, 2004. © 2004 Wiley-Liss, Inc. [source]

Long-term effects of ungulates on phytophagous insects

ECOLOGICAL ENTOMOLOGY, Issue 2 2007
JOSÉ M. GÓMEZ
Abstract 1.,Most plants interact with a diverse suite of herbivores, allowing the opportunity for the existence of positive and negative interactions between highly dissimilar organisms. However, most studies on herbivorous interactions have been performed under the assumption that they occur mainly between similar species. Consequently, ecologists are still far from a full understanding of the ecological factors that determine insect population dynamics. 2.,In this study, a 7-year field experiment was conducted that manipulated the presence of ungulates to evaluate their effects on the abundance, attack rate, and survival of four guilds of co-occurring herbivorous insects living on the same host plant: seed predators, stem borers, gall makers and sap suckers. These four guilds differed in habits and behaviour, the first three being sessile and endophytic and the last being free-living. 3.,This study shows that the abundance of all four guilds was negatively affected by ungulates. However, the effect on attack rate differed among guilds, as mammals do not affect the seed predator attack rate. Ungulates also differentially affected insect survival, ingesting only seed predators and gall makers. 4.,In summary, this study suggests that diverse mechanisms may affect different insect guilds in different ways. Therefore, competition between disparate herbivores appears to be complex and can be provoked by multiple mechanisms. [source]

Behavioural observations of Pieris brassicae larvae indicate multiple mechanisms of action of analogous drimane antifeedants

ENTOMOLOGIA EXPERIMENTALIS ET APPLICATA, Issue 3 2000
L. Messchendorp
Abstract We tested 11 analogous synthetic drimane antifeedant compounds for their feeding inhibiting effects on larvae of the large white butterfly Pieris brassicae L. (Lepidoptera: Pieridae) in no-choice tests on the host plant Brassica oleracea L. Furthermore, we observed larval feeding behaviour in no-choice tests to analyze temporal effects of five drimanes. The results show that the five analogous antifeedants differentially influence feeding behaviour and locomotion activity. Warburganal and polygodial are most likely sensory mediated antifeedants. Habituation to these compounds occurs soon after the onset of the tests (i.e., within 0.5,1.5 h). Compound 5 and confertifolin are probably not direct, sensory mediated antifeedants. After 0.5,1.5 h of exposure, these compounds inhibit not only feeding, but also locomotion behaviour, indicating postingestive, toxic effects. Isodrimenin inhibits feeding from the onset of the test and is probably a sensory mediated antifeedant. No habituation occurs to this compound, indicating that isodrimenin is either a very strong antifeedant or that it additionally has postingestive, toxic effects. Topical application of the drimanes on the larval cuticle revealed feeding inhibiting effects, but these could not be related to the occurrence of postingestive feeding inhibiting effects, indicating that this method is inappropriate to show possible postingestive effects of drimanes in P. brassicae. In conclusion, the behavioural observations performed in this research indicate that analogous drimanes inhibit feeding by P. brassicae larvae through multiple mechanisms of action. The results show that, when developing a structure activity relationship (SAR) for a series of antifeedants, it is important to distinguish the mode of action which underlies inhibition of feeding. [source]

Use of mechanistic data in IARC evaluations

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2008
Vincent James Cogliano
Abstract Consideration of mechanistic data has the potential to improve the analysis of both epidemiologic studies and cancer bioassays. IARC has a classification system in which mechanistic data can play a pivotal role. Since 1991, IARC has allowed an agent to be classified as carcinogenic to humans (Group 1) when there is less than sufficient evidence in humans but there is sufficient evidence in experimental animals and "strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity." Mechanistic evidence can also substitute for conventional cancer bioassays when there is less than sufficient evidence in experimental animals, just as mechanistic evidence can substitute for conventional epidemiologic studies when there is less than sufficient evidence in humans. The IARC Monographs have used mechanistic data to raise or lower a classification that would be otherwise based on epidemiologic studies and cancer bioassays only. Recently, the IARC Monographs have evaluated several agents where mechanistic data were pivotal to the overall evaluation: benzo[a]pyrene, carbon black and other poorly soluble particles, ingested nitrates and nitrites, and microcystin-LR. In evaluating mechanistic data, it is important to consider alternative mechanistic hypotheses, because an agent may induce tumors through multiple mechanisms. Environ. Mol. Mutagen., 2008. © 2008 Wiley-Liss, Inc. [source]

Adenosine A1 Antagonism Attenuates Atropine-resistant Hypoxic Bradycardia in Rats

ACADEMIC EMERGENCY MEDICINE, Issue 9 2003
Justin L. Kaplan MD
Abstract Objectives: To test the following hypotheses: Hypoxia induces bradycardia and hemodynamic compromise that are resistant to atropine but responsive to selective antagonism of the adenosine A1 receptor (A1AdoR). The mechanism for such attenuation is independent of the vagus nerve. Methods: Ten minutes after sham or actual bilateral cervical vagotomy, paralyzed ventilated rats were made hypoxic (5% fractional inspired oxygen, continued until death). Five minutes after beginning hypoxia, intravenous treatment with BG-9719, a selective A1AdoR antagonist (0.1 mg/kg); atropine (0.1 mg/kg); BG-9719 vehicle; or saline was initiated. These drug doses were based on pilot studies. Of the eight treatment groups (eight possible combinations of vagotomy status and drug/vehicle treatment), n= 8 in all except nonvagotomized, vehicle-treated rats (where n= 7). Results: Heart rate and left ventricular contractility decreased rapidly with hypoxia. Atropine had minimal effects in prolonging survival (from mean ± SEM of 15.5 ± 2.1 minutes to 20.2 ± 2.5 minutes, p = 0.94) and attenuating posthypoxic decreases in heart rate (p = 0.89) and contractility (p = 0.83) compared with saline. BG-9719 prolonged survival, however, from 14.4 ± 1.9 minutes (with vehicle treatment) to 37.2 ± 6.8 minutes (p < 0.001). Survival, heart rate, and contractility were preserved with BG-9719 compared with atropine and vehicle (p < 0.05, all comparisons). Vagotomy prevented the effects of BG-9719 on survival prolongation (p = 0.003), heart rate (p = 0.01), and contractility (p < 0.001) but did not affect those outcomes in saline-treated rats. Conclusions: Survival, heart rate, and contractility were better preserved with BG-9719 than atropine. A1AdoR selective antagonism, possibly because of its multiple mechanisms for attenuating hypoxic cardiac insufficiency, resulted in better hemodynamic and clinical outcomes. That attenuation seems to have a component of vagal mediation. [source]

Reductive transformation of hexahydro-1,3,5-trinitro-1,3,5-triazine, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine, and methylenedinitramine with elemental iron

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2005
Seok-Young Oh
Abstract Reductive (pre)treatment with elemental iron is a potentiallyuseful method for degrading nitramine explosives in water and soil. In the present study, we examined the kinetics, products, and mechanisms of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) degradation with elemental iron. Both RDX and HMX were transformed with iron to formaldehyde, NH, N2O, and soluble products. The yields of formaldehyde were relatively constant (71% ± 5%), whereas the yields of NH and N2O varied, depending on the nitramine and the mechanism. The reactions most likely were controlled by a surface process rather than by external mass transfer. Methylenedinitramine (MDNA) was an intermediate of both RDX and HMX and was transformed quantitatively to formaldehyde with iron. However, product distributions and kinetic modeling results suggest that MDNA represented a minor reaction path and accounted for only 30% of the RDX reacted and 14% of the formaldehyde produced. Additional experiments showed that RDX reduction with elemental iron could be mediated by graphite and Fe2+ sorbed to magnetite, as demonstrated previously for nitroaromatics and nitrate esters. Methylenedinitramine was degraded primarily through reduction in the presence of elemental iron, because its hydrolysis was slow compared to its reactions with elemental iron and surface-bound Fe2+. Our results show that in a cast iron-water system, RDX may be transformed via multiple mechanisms involving different reaction paths and reaction sites. [source]

Selective 5-HT1B receptor inhibition of glutamatergic and GABAergic synaptic activity in the rat dorsal and median raphe

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2006
Julia C. Lemos
Abstract The dorsal (DR) and median (MR) raphe nuclei contain 5-hydroxytryptamine (5-HT) cell bodies that give rise to the majority of the ascending 5-HT projections to the forebrain. The DR and MR have differential roles in mediating stress, anxiety and depression. Glutamate and GABA activity sculpt putative 5-HT neuronal firing and 5-HT release in a seemingly differential manner in the MR and DR, yet isolated glutamate and GABA activity within the DR and MR has not been systematically characterized. Visualized whole-cell voltage-clamp techniques were used to record excitatory and inhibitory postsynaptic currents (EPSC and IPSC) in 5-HT-containing neurons. There was a regional variation in action potential-dependent (spontaneous) and basal [miniature (m)] glutamate and GABAergic activity. mEPSC activity was greater than mIPSC activity in the DR, whereas in the MR the mIPSC activity was greater. These differences in EPSC and IPSC frequency indicate that glutamatergic and GABAergic input have distinct cytoarchitectures in the DR and MR. 5-HT1B receptor activation decreased mEPSC frequency in the DR and the MR, but selectively inhibited mIPSC activity only in the MR. This finding, in concert with its previously described function as an autoreceptor, suggests that 5-HT1B receptors influence the ascending 5-HT system through multiple mechanisms. The disparity in organization and integration of glutamatergic and GABAergic input to DR and MR neurons and their regulation by 5-HT1B receptors may contribute to the distinction in MR and DR regulation of forebrain regions and their differential function in the aetiology and pharmacological treatment of psychiatric disease states. [source]

Erythropoietin reduces Schwann cell TNF-,, Wallerian degeneration and pain-related behaviors after peripheral nerve injury

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006
W. Marie Campana
Abstract Chronic sciatic nerve constriction injury (CCI) induces Wallerian degeneration and exaggerated pain-like behaviors. These effects are mediated in large part by pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-,). In this study, we demonstrate that systemically administered recombinant human erythropoietin (rhEpo) facilitates recovery from chronic neuropathic pain associated with CCI in rats. Because TNF-, has been implicated in the development of pain-related behaviors, we measured TNF-, mRNA at the nerve injury site. Systemically or locally administered rhEpo decreased TNF-, mRNA, compared with that observed in untreated animals. RhEpo also significantly (P < 0.05) decreased axonal degeneration. Immunohistochemistry of CCI nerve showed abundant TNF-, in Schwann cells, axoplasm and macrophages. In rhEpo-treated animals, TNF-, immunopositivity was decreased selectively in Schwann cells. These results suggest a model in which rhEpo counteracts the effects of TNF-, in CCI by blocking expression of TNF-, in Schwann cells. To further test this model, we studied primary Schwann cell cultures. RhEpo inhibited TNF-, expression in response to lipopolysaccharide, supporting the conclusions of our in vivo CCI experiments. In addition, rhEpo directly counteracted Schwann cell death induced by exogenously added TNF-,in vitro. These results indicated that rhEpo regulates TNF-, by multiple mechanisms; rhEpo regulates TNF-, mRNA expression by Schwann cells but also may directly counteract TNF-, signaling pathways that lead to injury, chronic pain and/or death. [source]

Therapeutic angiogenesis and vasculogenesis for tissue regeneration

EXPERIMENTAL PHYSIOLOGY, Issue 3 2005
Paolo Madeddu
Therapeutic angiogenesis/vasculogenesis holds promise for the cure of ischaemic disease. The approach postulates the manipulation of spontaneous healing response by supplementation of growth factors or transplantation of vascular progenitor cells. These supplements are intended to foster the formation of arterial collaterals and promote the regeneration of damaged tissues. Angiogenic factors are generally delivered in the form of recombinant proteins or by gene transfer using viral vectors. In addition, new non-viral methods are gaining importance for their safer profile. The association of growth factors with different biological activity might offer distinct advantages in terms of efficacy, yet combined approaches require further optimization. Alternatively, substances with pleiotropic activity might be considered, by virtue of their ability to target multiple mechanisms. For instance, some angiogenic factors not only stimulate the growth of arterioles and capillaries, but also inhibit vascular destabilization triggered by metabolic and oxidative stress. Transplantation of endothelial progenitor cells was recently proposed for the treatment of peripheral and myocardial ischaemia. Progenitor cells can be transplanted either without any preliminary conditioning or after ex vivo genetic manipulation. Delivery of genetically modified progenitor cells eliminates the drawback of immune response against viral vectors and makes feasible repeating the therapeutic procedure in case of injury recurrence. It is envisioned that these new approaches of regenerative medicine will open unprecedented opportunities for the care of life-threatening diseases. [source]

RpoS involvement and requirement for exogenous nutrient for osmotically induced cross protection in Vibrio vulnificus

FEMS MICROBIOLOGY ECOLOGY, Issue 3 2005
Thomas M. Rosche
Abstract Vibrio vulnificus is an opportunistic human pathogen which is the causative agent of food-borne disease and wound infections. V. vulnificus is able to adapt to a variety of potentially stressful environmental changes, such as osmotic, nutrient, and temperature variations in estuarine environments, as well as oxidative, osmotic, and acidity differences following infection of a human host. After exposure to sub-lethal levels of a particular environmental stress, many bacteria become resistant to unrelated stresses, a phenomenon termed cross protection. In this study, we examined the ability of osmotic shock to cross protect V. vulnificus to high temperature as well as oxidative stress. Log phase cells of V. vulnificus strain C7184o were cross protected by prior osmotic shock to both heat and oxidative challenge, but only when exogenous nutrient was present during the osmotic upshift. Further, and unlike other bacteria, nutrient starvation alone did not result in cross protection against either stress. When small amounts of nutrient were present during osmotic shock, cross protection to an otherwise lethal heat challenge developed extremely rapidly, with significant protection seen within 10 min. Cross protection to oxidative stress was slower to develop, requiring several hours. Although stationary phase alone conferred some cross protection to heat and oxidative stress, the alternate sigma factor RpoS was required for complete cross protection of log phase cells to oxidative stress but not for resistance to heat challenge. Together these findings suggest that the cross protective response in V. vulnificus is complex and appears to involve multiple mechanisms. [source]

Decadal-scale variations of ecosystem productivity and control mechanisms in the Bohai Sea

FISHERIES OCEANOGRAPHY, Issue 4-5 2003
Qisheng Tang
Abstract Decadal-scale variations of ecosystem productivity in the Bohai Sea are described by using the survey data of 1959,60, 1982,83, 1992,93 and 1998,99. Indices including chlorophyll a concentration, primary production, phytoplankton abundance, zooplankton biomass and fishery biomass were used to describe the ecosystem productivity at different trophic levels. During the past four decades, the productivity and community structure of the Bohai Sea ecosystem has been highly variable. Primary productivity and fish productivity decreased from 1959 to 1998, such that phytoplankton abundance in 1992 and 1998 was about 38% of that in 1959 and 1982, fishery biomass in 1998 was particularly low, which was only about 5% of that in 1959. Zooplankton secondary productivity also showed a decreasing trend from 1959 to 1992, but reached high levels in 1998, about three times as much as 1959 and 1982, and four times as much as 1992. These results indicate that a large variation in ecosystem productivity is one of the important characteristics of coastal ecosystem dynamics. Therefore, it is impossible to apply a single theory to explain the causes of variations in the Bohai Sea ecosystem as the changes in productivity are likely to be forced and/or modulated by multiple mechanisms. [source]

Sister chromatid cohesion: the cohesin cleavage model does not ring true

GENES TO CELLS, Issue 6 2007
Vincent Guacci
Sister chromatid cohesion is important for high fidelity chromosome segregation during anaphase. Gene products that provide structural components (cohesin complex or cohesin) and regulatory components responsible for cohesion are conserved through eukaryotes. A simple model where cohesion establishment occurs by replication through static cohesin rings and cohesion dissolution occurs by Esp1p/separase mediated cleavage of the cohesin rings (Mcd1p/Rad21p/Scc1p sub-unit cleavage) has become widespread. A growing body of evidence is inconsistent with this ring cleavage model. This review will summarize the evidence showing that cohesin complex is not static but is regulated at multiple cell cycle stages before anaphase in a separase independent manner. Separase is indeed required at anaphase for complete chromosome segregation. However, multiple mechanisms for cohesion dissolution appear to act concurrently during anaphase. Separase is only one such mechanism and its importance varies from organism to organism. The idea that cohesin is a dynamic complex subjected to regulation at various cell cycle stages by multiple mechanisms makes sense in light of the myriad functions in which it has been implicated, such as DNA damage repair, gene silencing and chromosome condensation. [source]

A unified continuum representation of post-seismic relaxation mechanisms: semi-analytic models of afterslip, poroelastic rebound and viscoelastic flow

GEOPHYSICAL JOURNAL INTERNATIONAL, Issue 3 2010
Sylvain Barbot
SUMMARY We present a unified continuum mechanics representation of the mechanisms believed to be commonly involved in post-seismic transients such as viscoelasticity, fault creep and poroelasticity. The time-dependent relaxation that follows an earthquake, or any other static stress perturbation, is considered in a framework of a generalized viscoelastoplastic rheology whereby some inelastic strain relaxes a physical quantity in the material. The relaxed quantity is the deviatoric stress in case of viscoelastic relaxation, the shear stress in case of creep on a fault plane and the trace of the stress tensor in case of poroelastic rebound. In this framework, the instantaneous velocity field satisfies the linear inhomogeneous Navier's equation with sources parametrized as equivalent body forces and surface tractions. We evaluate the velocity field using the Fourier-domain Green's function for an elastic half-space with surface buoyancy boundary condition. The accuracy of the proposed method is demonstrated by comparisons with finite-element simulations of viscoelastic relaxation following strike-slip and dip-slip ruptures for linear and power-law rheologies. We also present comparisons with analytic solutions for afterslip driven by coseismic stress changes. Finally, we demonstrate that the proposed method can be used to model time-dependent poroelastic rebound by adopting a viscoelastic rheology with bulk viscosity and work hardening. The proposed method allows one to model post-seismic transients that involve multiple mechanisms (afterslip, poroelastic rebound, ductile flow) with an account for the effects of gravity, non-linear rheologies and arbitrary spatial variations in inelastic properties of rocks (e.g. the effective viscosity, rate-and-state frictional parameters and poroelastic properties). [source]

S -adenosylmethionine regulates dual-specificity mitogen-activated protein kinase phosphatase expression in mouse and human hepatocytes,

HEPATOLOGY, Issue 6 2010
Maria Lauda Tomasi
Increased mitogen-activated protein kinase (MAPK) activity correlates with a more malignant hepatocellular carcinoma (HCC) phenotype. There is a reciprocal regulation between p44/42 MAPK (extracellular signal-regulated kinase [ERK]1/2) and the dual-specificity MAPK phosphatase MKP-1/DUSP1. ERK phosphorylates DUSP1, facilitating its proteasomal degradation, whereas DUSP1 inhibits ERK activity. Methionine adenosyltransferase 1a (Mat1a) knockout (KO) mice express hepatic S -adenosylmethionine (SAM) deficiency and increased ERK activity and develop HCC. The aim of this study was to examine whether DUSP1 expression is regulated by SAM and if so, elucidate the molecular mechanisms. Studies were conducted using Mat1a KO mice livers, cultured mouse and human hepatocytes, and 20S and 26S proteasomes. DUSP1 messenger RNA (mRNA) and protein levels were reduced markedly in livers of Mat1a KO mice and in cultured mouse and human hepatocytes with protein falling to lower levels than mRNA. SAM treatment protected against the fall in DUSP1 mRNA and protein levels in mouse and human hepatocytes. SAM increased DUSP1 transcription, p53 binding to DUSP1 promoter, and stability of its mRNA and protein. Proteasomal chymotrypsin-like and caspase-like activities were increased in Mat1a KO livers and cultured hepatocytes, which was blocked by SAM treatment. SAM inhibited chymotrypsin-like and caspase-like activities by 40% and 70%, respectively, in 20S proteasomes and caused rapid degradation of some of the 26S proteasomal subunits, which was blocked by the proteasome inhibitor MG132. SAM treatment in Mat1a KO mice for 7 days raised SAM, DUSP1, mRNA and protein levels and lowered proteosomal and ERK activities. Conclusion: DUSP1 mRNA and protein levels are lower in Mat1a KO livers and fall rapidly in cultured hepatocytes. SAM treatment increases DUSP1 expression through multiple mechanisms, and this may suppress ERK activity and malignant degeneration. HEPATOLOGY 2010 [source]

Approaches to identify genes for complex human diseases: Lessons from Mendelian disorders,,

HUMAN MUTATION, Issue 4 2003
Michael Dean
Abstract The focus of most molecular genetics research is the identification of genes involved in human disease. In the 20th century, genetics progressed from the rediscovery of Mendel's Laws to the identification of nearly every Mendelian genetic disease. At this pace, the genetic component of all complex human diseases could be identified by the end of the 21st century, and rational therapies could be developed. However, it is clear that no one approach will identify the genes for all diseases with a genetic component, because multiple mechanisms are involved in altering human phenotypes, including common alleles with small to moderate effects, rare alleles with moderate to large effects, complex gene,gene and gene,environment interactions, genomic alterations, and noninherited genetic effects. The knowledge gained from the study of Mendelian diseases may be applied to future research that combines linkage-based, association-based, and sequence-based approaches to detect most disease alleles. The technology to complete these studies is at hand and requires that modest improvements be applied on a wide scale. Improved analytical tools, phenotypic characterizations, and functional analyses will enable complete understanding of the genetic basis of complex diseases. Hum Mutat 22:261,274, 2003. Published © 2003 Wiley-Liss, Inc. [source]

How to keep V(D)J recombination under control

IMMUNOLOGICAL REVIEWS, Issue 1 2004
Marjorie A. Oettinger
Summary:, Breaking apart chromosomes is not a matter to be taken lightly. The possible negative outcomes are obvious: loss of information, unstable chromosomes, chromosomal translocations, tumorigenesis, or cell death. Utilizing DNA rearrangement to generate the desired diversity in the antigen receptor loci is a risky business, and it must be carefully controlled. In general, the regulation is so precise that the negative consequences are minimal or not apparent. They are visible only when the process of V(D)J recombination goes awry, as for example in some chromosomal translocations associated with lymphoid tumors. Regulation is imposed not only to prevent the generation of random breaks in the DNA, but also to direct rearrangement to the appropriate locus or subregion of a locus in the appropriate cell at the appropriate time. Antigen receptor rearrangement is regulated essentially at four different levels: expression of the RAG1/2 recombinase, intrinsic biochemical properties of the recombinase and the cleavage reaction, the post-cleavage /DNA repair stage of the process, and accessibility of the substrate to the recombinase. Within each of these broad categories, multiple mechanisms are used to achieve the desired aims. The major focus of this review is on accessibility control and the role of chromatin and nuclear architecture in achieving this regulation, although other issues are touched upon. [source]

MF59® -adjuvanted vaccines for seasonal and pandemic influenza prophylaxis

INFLUENZA AND OTHER RESPIRATORY VIRUSES, Issue 6 2008
Angelika Banzhoff
Abstract, Influenza is a major cause of worldwide morbidity and mortality through frequent seasonal epidemics and infrequent pandemics. Morbidity and mortality rates from seasonal influenza are highest in the most frail, such as the elderly, those with underlying chronic conditions and very young children. Antigenic mismatch between strains recommended for vaccine formulation and circulating viruses can further reduce vaccine efficacy in these populations. Seasonal influenza vaccines with enhanced, cross-reactive immunogenicity are needed to address these problems and can confer a better immune protection, particularly in seasons were antigenic mismatch occurs. A related issue for vaccine development is the growing threat of pandemic influenza caused by H5N1 avian strains. Vaccines against strains with pandemic potential offer the best approach for reducing the potential impact of a pandemic. However, current non-adjuvanted pre-pandemic vaccines offer suboptimal immunogenicity against H5N1. For both seasonal and pre-pandemic vaccines, the addition of adjuvants may be the best approach for providing enhanced cross-reactive immunogenicity. MF59®, the first oil-in-water emulsion licensed as an adjuvant for human use, can enhance vaccine immune responses through multiple mechanisms. A trivalent MF59-adjuvanted seasonal influenza vaccine (Fluad®) has shown to induce significantly higher immune responses to influenza vaccination in the elderly, compared with non-adjuvanted vaccines, and to provide cross-reactive immunity against divergent influenza strains. Similar results have been generated with a MF59-adjuvanted H5N1 pre-pandemic vaccine, which showed higher and broader immunogenicity compared with non-adjuvanted pre-pandemic vaccines. [source]

Ionizing radiation as a response-enhancing agent for CD95-mediated apoptosis

INTERNATIONAL JOURNAL OF CANCER, Issue 4 2001
Michael A. Sheard Ph.D.
Abstract CD95 (Fas/APO-1) is a death receptor on the surface of a wide variety of cell types. In most cells examined, ionizing radiation acts as a response-enhancing agent for CD95-mediated cell death. Although DNA-damaging radiation appears to modulate CD95-mediated signals through multiple mechanisms, the only well-characterized mechanism is activation of the tumor-suppressor protein p53, which transcriptionally regulates the expression of CD95 on various cell types. The ligand for CD95 is expressed by activated lymphocytes and natural-killer cells, which produce factors that sensitize cells resistant to CD95-mediated cell death. Ligation of CD95 on irradiated tumor cells might be achievable using emerging modalities that reactivate the stalled anti-tumor immune response. © 2001 Wiley-Liss, Inc. [source]

Stress and elastic-constant analysis by X-ray diffraction in thin films

JOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 3-2 2003
F. Badawi
Residual stresses influence most physical properties of thin films and are closely related to their microstructure. Among the most widely used methods, X-ray diffraction is the only one allowing the determination of both the mechanical and microstructural state of each diffracting phase. Diffracting planes are used as a strain gauge to measure elastic strains in one or several directions of the diffraction vector. Important information on the thin-film microstructure may also be extracted from the width of the diffraction peaks: in particular, the deconvolution of these peaks allows values of coherently diffracting domain size and microdistortions to be obtained. The genesis of residual stresses in thin films results from multiple mechanisms. Stresses may be divided into three major types: epitaxic stresses, thermal stresses and intrinsic stresses. Diffraction methods require the knowledge of the thin-film elastic constants, which may differ from the bulk-material values as a result of the particular microstructure. Combining an X-ray diffractometer with a tensile tester, it is possible to determine X-ray elastic constants of each diffracting phase in a thin-film/substrate system, in particular the Poisson ratio and the Young modulus. It is important to notice that numerous difficulties relative to the application of diffraction methods may arise in the case of thin films. [source]

When effortful thinking influences judgmental anchoring: differential effects of forewarning and incentives on self-generated and externally provided anchors

JOURNAL OF BEHAVIORAL DECISION MAKING, Issue 3 2005
Nicholas Epley
Abstract Two experiments examined the impact of financial incentives and forewarnings on judgmental anchoring effects, or the tendency for judgments of uncertain qualities to be biased in the direction of salient anchor values. Previous research has found no effect of either manipulation on the magnitude of anchoring effects. We argue, however, that anchoring effects are produced by multiple mechanisms,one involving an effortful process of adjustment from "self-generated" anchors, and another involving the biased recruitment of anchor-consistent information from "externally provided" anchors,and that only the former should be influenced by incentives and forewarning. Two studies confirmed these predictions, showing that responses to "self-generated" anchors are influenced by both incentives and forewarnings whereas responses to "externally provided" anchors are not. Discussion focuses on the implications of these effects for debiasing efforts. Copyright © 2005 John Wiley & Sons, Ltd. [source]

Interactions Between Extracellular Stimuli and Excitation Waves in an Atrial Reentrant Loop

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2003
CHAD R. JOHNSON B.S.E.
Introduction: The interactions between extracellular stimuli and excitation waves propagating in a reentrant loop are a complex function of stimulus parameters, structural properties, membrane state, and timing. Here the goal was a comprehensive understanding of the mechanisms and frequencies of the major interactions between the advancing excitation wave and a single extracellular stimulus, separated from issues of anatomic or geometric complexity. Methods and Results: A modernized computer model of a thin ring of uniform tissue that included a pair of extracellular stimulus electrodes (anode/cathode) was used to model one-dimensional cardiac reentry. Questions and results included the following: (1) What are the major interactions between a stimulus and the reentrant propagation wave, and are they induced near the cathode or near the anode; and, for each interaction, what are the initiating amplitude range and timing interval? At the cathode, the well-known mechanism of retrograde excitation terminated reentry; changes in timing or amplitude produced double-wave reentry or phase reset. At the anode, termination occurred at different cells depending on stimulus amplitude. (2) Relatively how often did termination occur at the anode? For most stimulus amplitudes, termination occurred more often at the anode than at the cathode, although not always at the same cell. (3) With random timing, what is the probability of terminating reentry? Stimulation for 5 msec terminated reentry with a probability from 0% to approximately 10%, as a function of increasing stimulus amplitude. Conclusion: A single extracellular stimulus can initiate major changes in reentrant excitation via multiple mechanisms, even in a simple geometry. Termination of reentry, phase shifts, or double-wave reentry each occurs over well-defined ranges of stimulus amplitude and timing. (J Cardiovasc Electrophysiol, Vol. 14, pp. ***-***, October 2003) [source]