Home About us Contact
|
Home About us Contact | ||
|
|
||
Insensitivity
Kinds of Insensitivity Terms modified by Insensitivity Selected AbstractsPHOTOSYNTHETIC INSENSITIVITY OF THE TERRESTRIAL CYANOBACTERIUM NOSTOC FLAGELLIFORME TO SOLAR UV RADIATION WHILE REHYDRATED OR DESICCATED,JOURNAL OF PHYCOLOGY, Issue 4 2007Kunshan Gao Photosynthetic performance of the terrestrial cyanobacterium Nostoc flagelliforme (M. J. Berkeley et M. A. Curtis) Bornet et Flahault during rehydration and desiccation has been previously characterized, but little is known about the effects of solar UV radiation (280,400 nm) on this species. We investigated the photochemical activity during rehydration and subsequent desiccation while exposing the filamentous colonies to different solar radiation treatments. Photochemical activity could be reactivated by rehydration under full-spectrum solar radiation, the species being insensitive to both ultraviolet-A radiation (UVAR; 315,400 nm) and ultraviolet-B radiation (UVBR). When the rehydrated colonies were exposed for desiccation, the effective PSII photochemical yield was inhibited by visible radiation (PAR) at the initial stage of water loss, then increased with further decrease in water content, and reached its highest value at the water content of 10%,30%. However, no significant difference was observed among the radiation treatments except for the moment when they were desiccated to critical water content of about 2%,3%. At such a critical water content, significant reduction by UVBR of the effective quantum yield was observed in the colonies that were previously rehydrated under indoor light [without ultraviolet radiation (UVR)], but not in those reactivated under scattered or direct solar radiation (with UVR), indicating that preexposure to UVR during rehydration led to higher resistance to UVR during desiccation. The photosynthetic CO2 uptake by the desiccated colonies was enhanced by elevation of CO2 but was not affected by both UVAR and UVBR. It increased with enhanced desiccation to reach the maximal values at water content of 40%,50%. The UV-absorbing compounds and the colony sheath were suggested to play an important role in screening harmful UVR. [source] EPR Insensitivity of the Metal-Nitrosyl Spin-Bearing Moiety in Complexes [LnRuII -NO·]kEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 14 2004Stéphanie Frantz Abstract A survey of 18 paramagnetic species [LnRu(NO)]k, including seven new examples studied by in situ electrolysis, reveals a surprisingly narrow range of EPR parameters despite a wide variety of ligands such as pyridine, polypyridines, imines, amines, nitriles, phosphanes, carbonyl, cyclopentadienides, halides, hydride, hydroxide, thiocyanate or cyanide: g1 = 2.015 ± 0.02, g2 = 1.990 ± 0.015, g3 = 1.892 ± 0.03, gav = 1.968 ± 0.02, ,g = g1 , g3 = 0.122 ± 0.037, A2(14N) = 3.3 ± 0.5 mT. This rather small variability, smaller still if the organometallic compounds are excluded, differs from the wider range of EPR data reported for nitrosyliron species with S = 1/2; apparently, the {RuNO}7 configuration involves a rather invariant and relatively covalent metal,NO interaction. DFT calculations were employed for [(NC)5Ru(NO)]3, to reproduce the EPR data, to evaluate the spin distribution (58% spin density on NO), and to reveal structural changes on reduction such as the Ru,N,O bending and Ru,NO bond lengthening. In addition, the possibility of staggered and eclipsed conformations is discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations,HUMAN MUTATION, Issue 9 2010James J. Cox Abstract SCN9Aencodes the voltage-gated sodium channel Nav1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-,R1370-L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley-Liss, Inc. [source] Insensitivity to glutamate neurotoxicity mediated by NMDA receptors in association with delayed mitochondrial membrane potential disruption in cultured rat cortical neuronsJOURNAL OF NEUROCHEMISTRY, Issue 5 2008Yuki Kambe Abstract We have attempted to elucidate mechanisms underlying differential vulnerability to glutamate (Glu) using cultured neurons prepared from discrete structures of embryonic rat brains. Brief exposure to Glu led to a significant decrease in the mitochondrial activity in hippocampal neurons cultured for 9 or 12 days at 10 ,M to 1 mM with an apoptosis-like profile, without markedly affecting that in cortical neurons. Brief exposure to Glu also increased lactate dehydrogenase release along with a marked decrease in the number of cells immunoreactive for a neuronal marker protein in hippocampal, but not cortical, neurons. Similar insensitivity was seen to the cytotoxicity by NMDA, but not to that by tunicamycin, 2,4-dinitrophenol, hydrogen peroxide or A23187, in cortical neurons. However, NMDA was more efficient in increasing intracellular free Ca2+ levels in cortical neurons than in hippocampal neurons. Antagonists for neuroprotective metabotropic Glu receptors failed to significantly affect the insensitivity to Glu, while NMDA was more effective in disrupting mitochondrial membrane potentials in hippocampal than cortical neurons. These results suggest that cortical neurons would be insensitive to the apoptotic neurotoxicity mediated by NMDA receptors through a mechanism related to mitochondrial membrane potentials, rather than intracellular free Ca2+ levels, in the rat brain. [source] Imperfection Sensitivity or Insensitivity of Zero-stiffness Postbuckling , that is the QuestionPROCEEDINGS IN APPLIED MATHEMATICS & MECHANICS, Issue 1 2009Xin Jia Zero-stiffness postbuckling of a structure is characterized by a secondary load-displacement path along which the load remains constant. In sensitivity analysis of the (initial) postbuckling path it is usually considered as a borderline case between imperfection sensitivity and imperfection insensitivity. However, it is unclear whether zero-stiffness postbuckling as such is imperfection sensitive or insensitive. In this paper, Koiter's initial postbuckling analysis is used as a tool for sensitivity analysis. Distinction between two kinds of imperfections is made on the basis of the behavior of the equilibrium path of the imperfect structure. New definitions of imperfection insensitivity of the postbuckling behavior are provided according to the classification of imperfections. A structure with two degrees of freedom with a zero-stiffness postbuckling path is studied, considering four different imperfections. The results from this example show that zero-stiffness postbuckling is a case of transition from imperfection sensitivity to imperfection insensitivity for imperfections of the first kind and that it is imperfection insensitive for imperfections of the second kind. (© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Sectoral Effects of Monetary Policy: Evidence from MalaysiaASIAN ECONOMIC JOURNAL, Issue 1 2005Mansor H. Ibrahim E40; E52 The present paper analyzes the effects of monetary policy shocks on aggregate and eight sectoral outputs for Malaysia using vector autoregressive models. In line with many existing studies on Malaysia, the results are supportive of the real effects of monetary policy shocks. More importantly, we find evidence suggesting sector-specific responses to innovations in monetary policy. In response to positive interest rate shocks, we note that the manufacturing, construction, finance, insurance, real estate and business services sectors seem to decline more than aggregate production. By contrast, we observe the relative insensitivities of agriculture, forestry and fishing, mining and quarrying, electricity, gas and water to interest rate changes. The results, therefore, seem to confirm potential disparities in the effect of monetary policy on real sectoral activities. [source] Role of orexin in the regulation of glucose homeostasisACTA PHYSIOLOGICA, Issue 3 2010H. Tsuneki Abstract Orexin-A (hypocretin-1) and orexin-B (hypocretin-2) are hypothalamic neuropeptides that play key roles in the regulation of wakefulness, feeding, reward, autonomic functions and energy homeostasis. To control these functions indispensable for survival, orexin-expressing neurones integrate peripheral metabolic signals, interact with many types of neurones in the brain and modulate their activities via the activation of orexin-1 receptor or orexin-2 receptor. In addition, a new functional role of orexin is emerging in the regulation of insulin and leptin sensitivities responsible for whole-body glucose metabolism. Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. In fact, the expression of orexin gene is known to be down-regulated by hyperglycaemia in the rodent model of diabetes, such as ob/ob and db/db mice. Moreover, the levels of orexin receptor-2 mRNA have been shown to decline in the brain of mice along with ageing. These suggest that hyperglycaemia due to insulin insensitivity during ageing or by habitual consumption of a high-fat diet leads to the reduction in orexin expression in the hypothalamus, thereby further exacerbating peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for possible future treatment of hyperglycaemia in patients with type 2 diabetes. [source] Impaired selection of relevant positive information in depressionDEPRESSION AND ANXIETY, Issue 5 2009Sara M. Levens Ph.D. Abstract Background: A hallmark characteristic of depression is the inability to regulate the effect of emotional material on cognition. Previous research has demonstrated that depressed individuals are less able than are nondepressed persons to expel irrelevant negative information from working memory (WM), thereby exacerbating the effects of negative content on cognition. The primary goal of this study was to examine whether depressed individuals are also impaired at selecting relevant positive content in the context of representations competing for resources in WM; such an impairment would limit depressed persons' ability to use positive material to ameliorate the cognitive effects of negative information. Methods: We administered a Recency-probes task with neutral, positive, and negative words to 20 currently depressed and 22 never-depressed participants. This task assesses the selection of relevant content in WM by inducing interference between current and prior representations of a stimulus in WM. Reaction times to interference and noninterference trials were compared across valence and group to assess how effectively depressed individuals select task-relevant emotional content to resolve interference. Results: Compared to never-depressed controls, depressed individuals were impaired in selecting task-relevant positive stimuli; the performance of the two groups was comparable for selecting task-relevant neutral and negative stimuli. Conclusions: Findings indicate that a valence-specific deficit in WM may contribute to the inability of depressed individuals to regulate emotion, and provide empirical support for formulations that implicate positive insensitivity in the maintenance of depression. Depression and Anxiety, 2009. Published 2009 Wiley-Liss, Inc. [source] Hepatic dysfunction and insulin insensitivity in type 2 diabetes mellitus: a critical target for insulin-sensitizing agentsDIABETES OBESITY & METABOLISM, Issue 9 2008P. D. Home The liver plays an essential role in maintaining glucose homeostasis, which includes insulin-mediated processes such as hepatic glucose output (HGO) and uptake, as well as in clearance of insulin itself. In type 2 diabetes, the onset of hyperglycaemia [itself a potent inhibitor of hepatic glucose output (HGO)], alongside hyperinsulinaemia, indicates the presence of hepatic insulin insensitivity. Increased HGO is central to the onset of hyperglycaemia and highlights the need to target hepatic insulin insensitivity as a central component of glucose-lowering therapy. The mechanisms underlying the development of hepatic insulin insensitivity are not well understood, but may be influenced by factors such as fatty acid oversupply and altered adipocytokine release from dysfunctional adipose tissue and increased liver fat content. Furthermore, although the impact of insulin insensitivity as a marker of cardiovascular disease is well known, the specific role of hepatic insulin insensitivity is less clear. The pharmacological tools available to improve insulin sensitivity include the biguanides (metformin) and thiazolidinediones (rosiglitazone and pioglitazone). Data from a number of sources indicate that thiazolidinediones, in particular, can improve multiple aspects of hepatic dysfunction, including reducing HGO, insulin insensitivity and liver fat content, as well as improving other markers of liver function and the levels of mediators with potential involvement in hepatic function, including fatty acids and adipocytokines. The current review addresses this topic from the perspective of the role of the liver in maintaining glucose homeostasis, its key involvement in the pathogenesis of type 2 diabetes and the tools currently available to reduce hepatic insulin insensitivity. [source] Behavioral economic analysis of cue-elicited craving for alcoholADDICTION, Issue 9 2010James MacKillop ABSTRACT Aims Craving as a motivational determinant of drug use remains controversial because of ambiguous empirical findings. A behavioral economic approach may clarify the nature of craving, theorizing that subjective craving functionally reflects an acute increase in a drug's value. The current study tested this hypothesis via a multidimensional assessment of alcohol demand over the course of an alcohol cue reactivity procedure. Design One-way within-subjects design. Setting Human laboratory environment. Participants Heavy drinkers (n = 92) underwent exposures to neutral (water) cues followed by personalized alcohol cues. Assessments Participants were assessed for craving, alcohol demand, affect, and salivation following each exposure. Findings Alcohol versus neutral cues significantly increased craving and multiple behavioral economic measures of the relative value of alcohol, including alcohol consumption under conditions of zero cost (intensity), maximum expenditure on alcohol (Omax), persistence in drinking to higher prices (breakpoint) and proportionate price insensitivity (normalized Pmax). Craving was significantly correlated with demand measures at levels ranging from 0.21,0.43. Conclusions These findings support the potential utility of a behavioral economic approach to understanding the role of environmental stimuli in alcohol-related decision making. Specifically, they suggest that the behavioral economic indices of demand may provide complementary motivational information that is related to though not entirely redundant with measures of subjective craving. [source] Influence of isolation on the recovery of pond mesocosms from the application of an insecticide.ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2007Abstract The immediate response and recovery of the macrobenthic communities of nonisolated and isolated freshwater outdoor 9 m3 mesocosms following an acute stress caused by the addition of deltamethrin were studied over a 14-month period. To discriminate between internal and external recovery mechanisms, half of the treated ponds were covered by 1-mm mesh lids that restricted aerial recolonization. Both structural (abundance of the different taxonomic groups) and functional (litter breakdown) parameters were monitored. Insects were broadly reduced in numbers by deltamethrin addition. In general, noninsect groups were not affected or increased in abundance in deltamethrin-treated ponds, probably because of relative insensitivity to deltamethrin, reduced predation, and lower competition for food. No major change in litter breakdown rates were seen, probably because of functional redundancy among the macrobenthic community. Chironominae larvae recovered in open, treated mesocosms 62 d after deltamethrin addition and most insect groups recovered 84 d after the treatment date. However, the presence of lids significantly reduced insect recovery rate, suggesting that it largely depends on the immigration of winged forms (i.e., external recovery) from surrounding non- or less affected systems. These results indicate that the recovery time of macrobenthic communities in an affected natural pond would depend on spatial characteristics of the landscape and also the season that exposure occurs. Isolated ecosystems would display posttreatment insect recovery dynamics very different from highly connected ones, evolving toward alternate pseudoequilibrium states, possibly with lower biodiversity but with preserved functionality. Consequences for higher tier risk assessment of pesticides are discussed. [source] Is CEO Pay Really Inefficient?EUROPEAN FINANCIAL MANAGEMENT, Issue 3 2009A Survey of New Optimal Contracting Theories D2; D3; G34; J3 Abstract Bebchuk and Fried (2004) argue that executive compensation is set by CEOs themselves rather than boards on behalf of shareholders, since many features of observed pay packages may appear inconsistent with standard optimal contracting theories. However, it may be that simple models do not capture several complexities of real-life settings. This article surveys recent theories that extend traditional frameworks to incorporate these dimensions, and show that the above features can be fully consistent with efficiency. For example, optimal contracting theories can explain the recent rapid increase in pay, the low level of incentives and their negative scaling with firm size, pay-for-luck, the widespread use of options (as opposed to stock), severance pay and debt compensation, and the insensitivity of incentives to risk. [source] When is a minority a minority?EUROPEAN JOURNAL OF SOCIAL PSYCHOLOGY, Issue 4 2002Active versus passive minority advocacy, social influence Some conceptions of minority influence have stressed the impact of the mere existence of an unpopular, deviant position. Others (e.g. Moscovici, 1980) have emphasized the active opposition of a committed minority to a powerful majority. An active advocate is defined as one that is aware of the level of support for his/her position, expresses his/her position openly, and whose outcomes may depend on others' agreement/disagreement. In the present study, the potential moderating role of an advocates' active/passive status on opinion change was examined. When the issue was highly relevant to the target of influence, all that mattered was the quality of the source's arguments (i.e. majority, minority, active source,=,passive source). When the issue was not highly relevant to the target, though, active and passive sources had different impact: (1) active sources prompted attention to argument quality (for minorities) and heuristic compliance (for majorities); (2) passive sources prompted insensitivity to both the popularity of the position and to the quality of the source's arguments. Copyright © 2002 John Wiley & Sons, Ltd. [source] Reduced FAS transcription in clones of U937 cells that have acquired resistance to Fas-induced apoptosisFEBS JOURNAL, Issue 2 2009Jeanette Blomberg Susceptibility to cell death is a prerequisite for the elimination of tumour cells by cytotoxic immune cells, chemotherapy or irradiation. Activation of the death receptor Fas is critical for the regulation of immune cell homeostasis and efficient killing of tumour cells by apoptosis. To define the molecular changes that occur during selection for insensitivity to Fas-induced apoptosis, a resistant variant of the U937 cell line was established. Individual resistant clones were isolated and characterized. The most frequently observed defect in the resistant cells was reduced Fas expression, which correlated with decreased FAS transcription. Clones with such reduced Fas expression also displayed partial cross-resistance to tumour necrosis factor-, stimulation, but the mRNA expression of tumour necrosis factor receptors was not decreased. Reintroduction of Fas conferred susceptibility to Fas but not to tumour necrosis factor-, stimulation, suggesting that several alterations could be present in the clones. The reduced Fas expression could not be explained by mutations in the FAS coding sequence or promoter region, or by silencing through methylations. Protein kinase B and extracellular signal-regulated kinase, components of signalling pathways downstream of Ras, were shown to be activated in some of the resistant clones, but none of the three RAS genes was mutated, and experiments using chemical inhibitors could not establish that the activation of these proteins was the cause of Fas resistance as described in other systems. Taken together, the data illustrate that Fas resistance can be caused by reduced Fas expression, which is a result of an unidentified mode of regulation. [source] Modeling the Qo site of crop pathogens in Saccharomyces cerevisiae cytochrome bFEBS JOURNAL, Issue 11 2004Nicholas Fisher Saccharomyces cerevisiae has been used as a model system to characterize the effect of cytochrome b mutations found in fungal and oomycete plant pathogens resistant to Qo inhibitors (QoIs), including the strobilurins, now widely employed in agriculture to control such diseases. Specific residues in the Qo site of yeast cytochrome b were modified to obtain four new forms mimicking the Qo binding site of Erysiphe graminis, Venturia inaequalis, Sphaerotheca fuliginea and Phytophthora megasperma. These modified versions of cytochrome b were then used to study the impact of the introduction of the G143A mutation on bc1 complex activity. In addition, the effects of two other mutations F129L and L275F, which also confer levels of QoI insensitivity, were also studied. The G143A mutation caused a high level of resistance to QoI compounds such as myxothiazol, axoxystrobin and pyraclostrobin, but not to stigmatellin. The pattern of resistance conferred by F129L and L275F was different. Interestingly G143A had a slightly deleterious effect on the bc1 function in V. inaequalis, S. fuliginea and P. megasperma Qo site mimics but not in that for E. graminis. Thus small variations in the Qo site seem to affect the impact of the G143A mutation on bc1 activity. Based on this observation in the yeast model, it might be anticipated that the G143A mutation might affect the fitness of pathogens differentially. If so, this could contribute to observed differences in the rates of evolution of QoI resistance in fungal and oomycete pathogens. [source] Lead and cadmium uptake in the marine fungi Corollospora lacera and Monodictys pelagicaFEMS MICROBIOLOGY ECOLOGY, Issue 3 2005Michael A.S. Taboski Abstract This study provides observations on the effects of lead and cadmium ions on the growth of two species of marine fungi, Corollospora lacera and Monodictys pelagica. On solid media lead appeared to have no effect on the radial rate of growth of fungi. Exposure to increasing cadmium concentrations on solid media resulted in significant reduction (P < 0.05) in the radial mycelial growth rates of both fungi, especially in M. pelagica. These results reveal significant difference in species sensitivity toward cadmium and, essentially, insensitivity toward lead exposure. In liquid cultures, the metal content of mycelia (metal mass found in mycelium, in mg), and the concentration of metal in dry mycelium (metal mass in 1 g of mycelium, in mg g,1) were both found to increase (P < 0.05) with the increase in the metal cation concentration, while mycelium dry mass decreased. As it was observed on solid media, cadmium cation affected more severely (P < 0.05) the growth of M. pelagica in liquid cultures. Ergosterol content of mycelia of C. lacera exposed to increasing cadmium cation concentration decreased, similarly to the trend observed for dry mycelial mass. It was found that ca. 93% of all lead sequestered by C. lacera is located extracellularly. M. pelagica was found to bioaccumulate over 60 mg of cadmium and over 6 mg of lead per 1 g of mycelium, while C. lacera bioaccumulated over 7 mg of cadmium and up to 250 mg of lead per 1 g of mycelium. Overall, the results indicate that both metal ions affect the growth of marine fungi with lead being accumulated extracellularly in the mycelia. Both metals accumulated by fungi may then enter the marine ecosystem food web, of which marine fungi are integral members. [source] A new metric for evaluating the correspondence of spatial patterns in vegetation modelsGLOBAL ECOLOGY, Issue 4 2008Guoping Tang ABSTRACT Aim, To present a new metric, the ,opposite and identity' (OI) index, for evaluating the correspondence between two sets of simulated time-series dynamics of an ecological variable. Innovation, The OI index is introduced and its mathematical expression is defined using vectors to denote simulated variations of an ecological variable on the basis of the vector addition rule. The value of the OI index varies from 0 to 1 with a value 0 (or 1) indicating that compared simulations are opposite (or identical). An OI index with a value near 0.5 suggests that the difference in the amplitudes of variations between compared simulations is large. The OI index can be calculated in a grid cell, for a given biome and for time-series simulations. The OI indices calculated in each grid cell can be used to map the spatial agreement between compared simulations, allowing researchers to pinpoint the extent of agreement or disagreement between two simulations. The OI indices calculated for time-series simulations allow researchers to identify the time at which one simulation differs from another. A case study demonstrates the application and reliability of the OI index for comparing two simulated time-series dynamics of terrestrial net primary productivity in Asia from 1982 to 2000. In the case study, the OI index performs better than the correlation coefficient at accurately quantifying the agreement between two simulated time-series dynamics of terrestrial net primary productivity in Asia. Main conclusions, The OI index provides researchers with a useful tool and multiple flexible ways to compare two simulation results or to evaluate simulation results against observed spatiotemporal data. The OI index can, in some cases, quantify the agreement between compared spatiotemporal data more accurately than the correlation coefficient because of its insensitivity to influential data and outliers and the autocorrelation of simulated spatiotemporal data. [source] Mild haemophilia: a disease with many faces and many unexpected pitfallsHAEMOPHILIA, Issue 2010K. PEERLINCK Summary., Despite major advances in diagnosis and treatment, the management of patients with mild haemophilia (MH) remains a major challenge. Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU mL,1. The bleeding associated with mild haemophilia is most frequently episodic, occurring during surgery or following trauma. Spontaneous bleeding is rare. Diagnosis is sometimes delayed because of insensitivity of screening clotting assays or discrepancies in factor VIII activity as measured by different assays. The treatment of choice in mild haemophilia A is desmopressin, which typically induces a 2,6-fold increase of factor VIII over baseline. However, desmopressin has its limitations in this setting such as the occurrence of tachyphylaxis and failure to respond in an undetermined proportion of patients. Factors underlying poor biological response or magnitude of response to desmopressin are incompletely understood. Inhibitor development in mild haemophilia is particularly distressing. This complication arises at an older age in this patient group because of infrequent need for factor VIII replacement. Inhibitors in mild haemophilia patients often cross-react with endogenous factor VIII resulting in severe spontaneous bleeding frequently in a postoperative setting. Intensive perioperative use of factor VIII and some specific mutations induce a particularly high risk for inhibitor development, but risk factors are incompletely understood. For reasons of the older age of the patients, treatment of bleeding with bypassing agents may cause major thrombotic complications. Data on therapeutic options for inhibitor eradication in patients with mild haemophilia are particularly scarce. With increased life-expectancy for all haemophilia patients, the group of elderly patients with mild haemophilia requiring major surgery will further increase. Prevention of inhibitors, particularly in this patient group, should be a major topic of interest in both clinic and research. [source] Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations,HUMAN MUTATION, Issue 9 2010James J. Cox Abstract SCN9Aencodes the voltage-gated sodium channel Nav1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-,R1370-L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley-Liss, Inc. [source] Selectivity of lynx proteins on insect nicotinic acetylcholine receptors in the brown planthopper, Nilaparvata lugensINSECT MOLECULAR BIOLOGY, Issue 3 2010B. Yang Abstract Neuronal nicotinic acetylcholine receptors (nAChRs) are major excitatory neurotransmitter receptors in both vertebrates and invertebrates. Two lynx proteins (Nl-lynx1 and Nl-lynx2) have been identified in the brown planthopper, Nilaparvata lugens, which act as modulators on insect nAChRs. In the present study, two lynx proteins were found to act on the triplet receptor Nl,1/Nl,2/,2 expressed in Xenopus oocytes, increasing agonist-evoked macroscopic currents, but not changing agonist sensitivity and desensitization properties. Nl-lynx1 and Nl-lynx2 increased Imax (maximum responses) of acetylcholine to 4.85-fold and 2.40-fold of that of Nl,1/Nl,2/,2 alone, and they also increased Imax of imidacloprid to 2.57-fold and 1.25-fold. Although, on another triplet nAChRs Nl,3/Nl,8/,2, Nl-lynx2 increased Imax of acetylcholine and imidacloprid to 3.63-fold and 2.16-fold, Nl-lynx1 had no effects on Imax of either acetylcholine or imidacloprid. The results demonstrate the selectivity of lynx proteins for different insect nAChR subtypes. This selectivity was also identified in native N. Lugens. Co-immunoprecipitation was found between Nl,1/Nl,2-containing receptors and both Nl-lynx1 and Nl-lynx2, but was only found between Nl,3/Nl,8-containing receptors and Nl-lynx2. When the previously identified Nl,1Y151S and Nl,3Y151S mutations were included (Nl,1Y151S/Nl,2/,2 and Nl,3Y151S/Nl,8/,2), the increase in Imax of imidacloprid, but not acetylcholine, caused by co-expression of Nl-lynx1 and Nl-lynx2 was more noticeable than that of their wildtype counterparts. Taken together, these data suggest that two modulators, Nl-lynx1 and Nl-lynx2, might serve as an influencing factor in target site insensitivity in N. lugens, such as Y151S mutation. [source] Corticosteroid insensitivity in severe asthma: significance, mechanisms and aetiologyINTERNAL MEDICINE JOURNAL, Issue 5 2010M. Hew Abstract Chronic severe asthma remains a challenging clinical problem despite the availability of modern treatments. Relative corticosteroid insensitivity is present in severe asthma and may contribute to continuing disease severity. Advances in the understanding of molecular mechanisms underlying corticosteroid insensitivity may yield new therapeutic targets. Furthermore, aetiological factors for corticosteroid insensitivity have been identified and these may be amenable to modification. [source] Kennedy's disease: pathogenesis and clinical approachesINTERNAL MEDICINE JOURNAL, Issue 5 2004K. J. Greenland Abstract Kennedy's disease, also known as spinal and bulbar muscular atrophy, is a progressive degenerative condition affecting lower motor neurons. It is one of nine neurodegenerative disorders caused by a polyglutamine repeat expansion. Affecting only men, Kennedy's disease is the only one of these conditions that follows an X-linked mode of inheritance. The causative protein in Kennedy's disease, with a polyglutamine expansion residing in the first N-terminal domain, is the androgen receptor. Research in this field has made significant advances in recent years, and with the increased understanding of pathogenic mechanisms, feasible approaches to treatments are being investigated. In Kennedy's disease research, the most significant issue to emerge recently is the role of androgens in exacerbating the disease process. On the basis of animal experiments, a viable hypothesis is that higher circulating levels of androgens in men could trigger the degeneration of motor neurons causing this disease, and that lower levels in heterozygous and homozygous women are protective. This is a major issue, as treatment of individuals affected by Kennedy's disease with testosterone has been considered a reasonable therapy by some neurologists. The rationale behind this approach relates to the fact that Kennedy's disease is accompanied by mild androgen insensitivity. It was therefore believed that treatment with high doses of testosterone might compensate for this loss of androgen action, with the added benefit of preventing muscle wasting. The current review provides an overview of recent advances in the field of Kennedy's disease research, including approaches to treatment. (Intern Med J 2004; 34: 279,286) [source] A fractional adaptation law for sliding mode controlINTERNATIONAL JOURNAL OF ADAPTIVE CONTROL AND SIGNAL PROCESSING, Issue 10 2008Mehmet Önder Efe Abstract This paper presents a novel parameter tuning law that forces the emergence of a sliding motion in the behavior of a multi-input multi-output nonlinear dynamic system. Adaptive linear elements are used as controllers. Standard approach to parameter adjustment employs integer order derivative or integration operators. In this paper, the use of fractional differentiation or integration operators for the performance improvement of adaptive sliding mode control systems is presented. Hitting in finite time is proved and the associated conditions with numerical justifications are given. The proposed technique has been assessed through a set of simulations considering the dynamic model of a two degrees of freedom direct drive robot. It is seen that the control system with the proposed adaptation scheme provides (i) better tracking performance, (ii) suppression of undesired drifts in parameter evolution, (iii) a very high degree of robustness and improved insensitivity to disturbances and (iv) removal of the controller initialization problem. Copyright © 2008 John Wiley & Sons, Ltd. [source] The CAG repeat polymorphism within the androgen receptor gene and maleness,INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2003Michael Zitzmann Summary The androgen testosterone and its metabolite dihydrotestosterone exert their effects on gene expression and thus effect maleness via the androgen receptor (AR). A diverse range of clinical conditions starting with complete androgen insensitivity has been correlated with mutations in the AR. Subtle modulations of the transcriptional activity induced by the AR have also been observed and frequently assigned to a polyglutamine stretch of variable length within the N-terminal domain of the receptor. This stretch is encoded by a variable number of CAG triplets in exon 1 of the AR gene located on the X chromosome. First observations of pathologically elongated AR CAG repeats in patients with X-linked spino-bulbar muscular atrophy showing marked hypoandrogenic traits were supplemented by partially conflicting findings of statistical significance also within the normal range of CAG repeat length: an involvement of prostate tissue, spermatogenesis, bone density, hair growth, cardiovascular risk factors and psychological factors has been demonstrated. The highly polymorphic nature of glutamine residues within the AR protein implies a subtle gradation of androgenicity among individuals within an environment of normal testosterone levels providing relevant ligand binding to ARs. This modulation of androgen effects may be small but continuously present during a man's lifetime and, hence, exerts effects that are measurable in many tissues as various degrees of androgenicity and represents a relevant effector of maleness. It remains to be elucidated whether these insights are important enough to become part of individually useful laboratory assessments. [source] Androgen insensitivity and male infertility,INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2003O. Hiort Summary Abnormal human spermatogenesis can be caused by defects in androgen action because of androgen insensitivity. A variety of mutations have been described in the human androgen receptor gene associated with male infertility. These can be attributed to two molecular mechanisms. First, point mutations in the androgen receptor gene cause alterations in the amino acid sequence and, hence, lead to apparently slight changes in the androgen receptor effector mechanisms and mild androgen insensitivity. Secondly, variations in the polymorphic poly glutamine segment within the N-terminal end of the androgen receptor have been ascribed to correlate with fertility aspects possibly because of modifications of transcriptional regulatory mechanisms. It has been postulated that longer poly glutamine segments are associated with decreased sperm counts. However, the molecular mechanisms that lead to inhibition of spermatogenesis because of a mutated androgen receptor are poorly understood and will need more focus in the future. [source] Monitoring Delamination Progression in Thermal Barrier Coatings by Mid-Infrared Reflectance ImagingINTERNATIONAL JOURNAL OF APPLIED CERAMIC TECHNOLOGY, Issue 2 2006Jeffrey I. Eldridge Mid-infrared (MIR) reflectance imaging is shown to be a reliable diagnostic tool for monitoring delamination progression in thermal barrier coatings (TBCs). MIR reflectance imaging utilizes the maximum transparency of TBCs in the 3,6 ,m wavelength region to probe below-surface delamination crack propagation that is typically hidden from visible wavelength inspection. The image contrast that identifies delamination progression arises from the increased reflectance produced by a large component of total internal reflection at the TBC/buried-crack interface. Imaging was performed at a wavelength of 4 ,m to take advantage of the relatively high transmittance of plasma-sprayed 8 wt% yttria-stabilized zirconia (8YSZ) TBCs along with a desirable relative insensitivity to potentially interfering absorptions by atmospheric constituents at that wavelength. A key advantage of MIR reflectance imaging over competing techniques is that it is sensitive to delamination progression even at very early stages before delamination cracks start linking together; therefore, TBC health assessment can be achieved throughout the life of the TBC well before TBC failure is imminent. Examples are presented to demonstrate monitoring delamination progression by MIR reflectance imaging in 8YSZ TBC-coated specimens subjected to furnace cycling to 1163°C. The experimental results were in good agreement with reflectance values predicted by a four-flux Kulbelka,Munk approximation applied to the extreme cases of a completely adherent and a completely detached TBC. Practical considerations, including potential interfering effects from surface contamination, sintering, and erosion are discussed. [source] Efficacy of skin self-examination for the early detection of melanomaINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 2 2010Reyhaneh Hamidi BA The National Cancer Institute's "Melanoma Action Plan" calls for reduction of melanoma mortality through early detection. Routine skin self-examination (SSE) has the potential to increase chances of early detection and treatment and may be the key to melanoma survival. We provide a focused review of the accuracy of SSE for detecting premalignant lesions and cutaneous risk factors for melanoma, with suggestions for future directions for enhancing measurement of SSE accuracy and ways in which to improve the public's perceptions of melanoma efficacy. We examined published data on the efficacy of skin self-examination for the early detection of melanoma. We searched the MEDLINE database for publications between January 1, 1987 and June 1, 2007 using search terms for "melanoma" and "self-examination." We found that sensitivity of skin self-examination is low, ranging from 25% to 93%, while specificity is generally higher (83% to 97%). Attempts to increase improve the lay public's perceptions of the early signs of melanoma have proved effective, while those aimed at increasing accuracy of SSE with targeted interventions have been moderately successful. SSE's insensitivity for detection of pigmented lesions should prompt further investigation of educational interventions to enhance its accuracy and lead to its adoption as a cheap, simple screening tool. Assessment of the accuracy and efficacy of SSE should proceed using standardized definitions and measurements such that it is easier to pool data on the overall value of SSE as a screening modality. [source] Sliding mode control of boost and buck-boost power converters using the dynamic sliding manifoldINTERNATIONAL JOURNAL OF ROBUST AND NONLINEAR CONTROL, Issue 14 2003Yuri B. Shtessel Abstract Non-minimum phase tracking control is studied for boost and buck-boost power converters. A sliding mode control algorithm is developed to track directly a causal voltage tracking profile given by an exogenous system. The approximate causal output non-minimum phase asymptotic tracking in non-linear boost and buck-boost power converters is addressed via sliding mode control using a dynamic sliding manifold (DSM). Use of DSM allows the stabilization of the internal dynamics when the output tracking error tends asymptotically to zero in the sliding mode. The sliding mode controller with DSM links features of conventional sliding mode control (insensitivity to matched non-linearities and disturbances) and a conventional dynamic compensator (accommodation to unmatched disturbances). Numerical examples demonstrate the effectiveness of the sliding mode controller even for a known time-varying load. Copyright © 2003 John Wiley & Sons, Ltd. [source] Pay Without Performance: Overview of the IssuesJOURNAL OF APPLIED CORPORATE FINANCE, Issue 4 2005Lucian A. Bebchuk In their recent book, Pay Without Performance: The Unfulfilled Promise of Executive Compensation, the authors of this article provided a comprehensive critique of U.S. executive pay practices and the corporate governance processes that produce them, and then offered a number of proposals for improving both pay and governance. This article presents an overview of their analysis and proposals. The authors' analysis suggests that the pay-setting process in U.S. public companies has strayed far from the economist's model of "arm's-length contracting" between executives and boards in a competitive labor market. In place of this conventional model, which is standard in corporate law as well as economics, the authors argue that managerial power and influence play a major role in shaping executive pay, and in ways that end up imposing significant costs on investors and the economy. The main concern is not the levels of executive pay, but rather the distortion of incentives caused by compensation practices that fail to tie pay to performance and to limit executives' ability to sell their shares. Also troubling are "the correlation between power and pay, the systematic use of compensation practices that obscure the amount and performance insensitivity of pay, and the showering of gratuitous benefits on departing executives." To address these problems, the authors propose three kinds of changes: 1)increases in transparency, accomplished in part by new SEC rules requiring annual corporate disclosure that provides "the dollar value of all forms of compensation" (including "stealth compensation" in the form of pensions and other post-retirement benefits) and an analysis of the relationship between the past year's pay and performance, as well as more timely and informative disclosure of insider stock purchases and sales; 2)improvements in pay practices, including greater use of "indexed" stock and options to limit "windfalls," tougher limits on executives' freedom to sell shares, and greater use of "clawback" provisions in bonus plans that would force executives to return pay for performance that proves to be temporary; and 3)improvements in board accountability to shareholders, including limits on the use of staggered boards and granting shareholders the right to nominate directors and propose changes to governance arrangements in the corporate charter. [source] Correlation between the high expression of C/EBP, protein in F442A cells and their relative resistance to antiadipogenic action of TCDD in comparison to 3T3-L1 cellsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2002Phillip C. C. Liu Abstract We compared the ability of two clonally derived murine preadipocyte cell lines, 3T3-L1(L1) and 3T3-F442A (F442A), to differentiate after treatment by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), and found that the former cell line was clearly suppressed by TCDD but the latter was not. It was initially postulated that the easiest way to explain the lack of response to TCDD in F442A cells could be an alteration in aryl hydrocarbon receptor (AhR) functionality. This hypothesis was tested first, but no differences were found in the levels or functions of AhR. To find an alternate explanation for such a differential effect of TCDD, we tested the action of several diagnostic agents on the process of adipocyte differentiation of these two cells. No differences were found between these two lines of cells in the susceptibility to the antiadipogenic action of 12-0-tetradecanoylphorbol-13-acetate (TPA), or to TNF,, indicating that the basic biochemical components engaged in the antiadipogenic actions of these agents in these two cell lines are similar. In contrast, F442A cells were found to be more resistant to the antiadipogenic action of EGF or TGF, than L1 cells which were tested side by side. Based on the knowledge that TNF, preferentially affects C/EBP, and that TGF, specifically controls C/EBP, and , in their antiadipogenic action, we hypothesized that the major cause for the differential response of these two similar cell lines could be the insensitivity of C/EBP, and/or , of F442A cells to the action of TCDD. We could obtain supporting data for this hypothesis, showing that in F442A cells, the level of C/EBP, is already high even before the addition of adipocyte differentiation factors and that TCDD did not cause any significant changes in the titer of C/EBP,. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:70,83, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/jbt.10020 [source] | ||||||||||||||||||||||||||||||||||||||||||||||||||||