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Selected AbstractsChanges within maturing neurons limit axonal regeneration in the developing spinal cordDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2006Murray Blackmore Abstract Embryonic birds and mammals display a remarkable ability to regenerate axons after spinal injury, but then lose this ability during a discrete developmental transition. To explain this transition, previous research has emphasized the emergence of myelin and other inhibitory factors in the environment of the spinal cord. However, research in other CNS tracts suggests an important role for neuron-intrinsic limitations to axon regeneration. Here we re-examine this issue quantitatively in the hindbrain-spinal projection of the embryonic chick. Using heterochronic cocultures we show that maturation of the spinal cord environment causes a 55% reduction in axon regeneration, while maturation of hindbrain neurons causes a 90% reduction. We further show that young neurons transplanted in vivo into older spinal cord can regenerate axons into myelinated white matter, while older axons regenerate poorly and have reduced growth cone motility on a variety of growth-permissive ligands in vitro, including laminin, L1, and N-cadherin. Finally, we use video analysis of living growth cones to directly document an age-dependent decline in the motility of brainstem axons. These data show that developmental changes in both the spinal cord environment and in brainstem neurons can reduce regeneration, but that the effect of the environment is only partial, while changes in neurons by themselves cause a nearly complete reduction in regeneration. We conclude that maturational events within neurons are a primary cause for the failure of axon regeneration in the spinal cord. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Re-evaluation of intramolecular long-range electron transfer between tyrosine and tryptophan in lysozymesFEBS JOURNAL, Issue 17 2003Evidence for the participation of other residues One-electron oxidation of six different c-type lysozymes from hen egg white, turkey egg white, human milk, horse milk, camel stomach and tortoise was studied by gamma- and pulse-radiolysis. In the first step, one tryptophan side chain is oxidized to indolyl free radical, which is produced quantitatively. As shown already, the indolyl radical subsequently oxidizes a tyrosine side chain to the phenoxy radical in an intramolecular reaction. However this reaction is not total and its stoichiometry depends on the protein. Rate constants also vary between proteins, from 120·s,1 to 1000·s,1 at pH 7.0 and room temperature [extremes are hen and turkey egg white (120·s,1) and human milk (1000·s,1)]. In hen and turkey egg white lysozymes we show that another reactive site is the Asn103,Gly104 peptidic bond, which gets broken radiolytically. Tryptic digestion followed by HPLC separation and identification of the peptides was performed for nonirradiated and irradiated hen lysozyme. Fluorescence spectra of the peptides indicate that Trp108 and/or 111 remain oxidized and that Tyr20 and 53 give bityrosine. Tyr23 appears not to be involved in the process. Thus new features of long-range intramolecular electron transfer in proteins appear: it is only partial and other groups are involved which are silent in pulse radiolysis. [source] Soft Decision with Soft Target for Car-like Mobile Vehicle in Dynamic EnvironmentIEEJ TRANSACTIONS ON ELECTRICAL AND ELECTRONIC ENGINEERING, Issue 4 2009Yougen Chen Non-member Abstract Online flexible operation of a car-like mobile vehicle with non-holonomic constraints in dynamic environment is still a very challenging problem because the surrounding situations are not qualified in static, knowledge is only partial and the execution is often associated with uncertainty. The difficulty lies in the setting of appropriate moving sub-targets in real-time to obtain a collision-free and low-cost path. In this paper, we present a new approach for the autonomous motion control of mobile vehicle in a narrow area with static and dynamic obstacles. It is based on the selection of sub-target points of vehicle's movement called ,soft target' which is a target set defined as all possible and reachable via-points in a navigation space. The soft target is acquired by online learning based on the final target and environment information. Each element of it has its membership value in [0, 1] denoting its evaluation degree. With the acquired soft target, soft decision is made like human's decision process by predictive fuzzy control (PFC) to achieve final target safely and economically. The simulation results show the effectiveness and flexibility of the proposed vehicle motion control method. © 2009 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc. [source] Partial and transient modulation of the CD3,T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic miceIMMUNOLOGY, Issue 1 2010Devangi S. Mehta Summary It has been established that a total of 250 ,g of monoclonal anti-mouse CD3 F(ab,)2 fragments, administered daily (50 ,g per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing , cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab,)2 in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3,T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4+, CD8+ and CD4+ FoxP3+ T cells. Four doses of 2 ,g (total dose 8 ,g) induced 53% remission of diabetes, similarly to the 250 ,g dose regimen, whereas four doses of 1 ,g induced only 16% remission. While the 250 ,g dose regimen produced nearly complete and sustained modulation of the CD3 ,TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4+ and CD8+ T cells decreased, whereas the proportions of CD4+ FoxP3+ T cells increased; these effects were transient. Mice with greater residual ,-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3,TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment. [source] Strategic Decision Mking, Discourse, And Strategy As Social PracticeJOURNAL OF MANAGEMENT STUDIES, Issue 7 2000John Hendry In this paper we argue that the existing conceptualizations of strategic decision making, while each affording valuable insights, offer only partial and disconnected perspectives of the strategy process that leave important questions un-addressed. To overcome this problem we develop an empirically grounded conceptualization of strategic decisions as elements of a strategic discourse, operating at both the structural level of social reproduction and the instrumental level of intentional communication, and constituting the medium through which choices are discussed and recorded, interpretations developed and expressed, and strategic actions initiated, authorized and acknowledged. This conceptualization opens up a number of research questions concerning the role of strategic decision making in the overall strategy process and leads to a fruitful conceptualization of strategy itself as a technological and appropriative social practice. [source] Retrograde processes in migmatites and granulites revisitedJOURNAL OF METAMORPHIC GEOLOGY, Issue 1 2002Michael Brown Abstract Many migmatites and granulites preserve evidence of a clockwise P,T evolution involving decompression (decrease in P) while close to the thermal peak. The extent of post-thermal peak reaction is influenced by several factors, including: (1) the P,T path in relation to invariants in the system and the Clapeyron slopes of the equilibria; (2) the rate of cooling; and (3) the availability of fluid (H2O-rich volatile phase or melt) for fluid-consuming reactions. Reaction may occur between products of a prograde (increasing T) fluid-generating reaction as the same equilibrium is re-crossed in the retrograde (decreasing T) sense. In general, reaction reversal or ,back reaction' requires the P,T path to approximate isobaric heating and cooling, without significant decompression, and evolved fluid to remain within the equilibration volume. The larger the decompression segment in the P,T evolution, the more chance there is of crossing different reactions along the retrograde segment from those crossed along the prograde segment. For common pelite compositions, we may generalize by considering three pressure regimes separated by the [Spl, Ms, H2O] invariant in KFMASH (approximately 9 kbar) and the intersection of muscovite breakdown with the H2O-rich volatile phase-saturated solidus (approximately 4 kbar). Reaction reversal cannot occur along P,T paths that traverse around one of these points, but may occur along P,T paths confined to one of the three regimes in between. Additionally, above the solidus, melt segregation and loss potentially change the composition of the equilibration volume; and, the size of the equilibration volume shrinks with decreasing T. Since the proportion of melt to residue in the equilibration volume may change with decreasing size, the composition of the equilibration volume may change throughout the supra-solidus part of the retrograde segment of the P,T evolution. If melt has been lost from the equilibration volume, reaction reversal may not be possible or may be only partial; indeed, the common preservation of close-to-peak mineral assemblages in migmatite and granulite demonstrates that extensive reaction with melt is uncommon, which implies melt isolation or loss prior to crossing potential melt-consuming reactions. Water dissolved in melt is transported through the crust to be exsolved on crystallization at the solidus appropriate to the intrinsic a(H2O). This recycled water causes retrogression at subsolidus conditions. Consideration of the evidence for supra-solidus decompression-dehydration reactions, and review of microstructures that have proven controversial, such as corona and related microstructures, selvage microstructures and ,late' muscovite, leads to the conclusion that there is more than one way for these microstructures to form and reminds us that we should always consider multiple working hypotheses! [source] Structure and Phase Transitions of Poly(heptamethylene p,p,-bibenzoate): Time-Resolved Synchrotron WAXS and DSC StudiesMACROMOLECULAR CHEMISTRY AND PHYSICS, Issue 14 2003Ernesto Pérez Abstract Time-resolved wide-angle X-ray scattering (WAXS), as well as differential scanning calorimetry (DSC) and polarisation microscopy studies, were applied to investigate the structure and phase transitions of poly(heptamethylene p,p,-bibenzoate). Temperature dependencies of several structural parameters were determined. Complete transformation from an isotropic melt to a smectic phase was suggested whereas the transition from a smectic to crystalline phase is only partial (around 30%), although it takes place from the ordered SCA phase. Crystals are formed within the SCA domains with nearly the same coherent length. On the basis of the analysis of the position and the profile of the diffuse wide-angle X-ray scattering and mesogenic layer spacing, it was assumed that either crystallisation modifies the smectic structure, or mesophase losses its positional order because of the lack of mobility of the spacers at low temperatures. WAXS scattering profiles corresponding to P7MB: a) cooling from the isotropic melt at 2,°C,·,min,1; b) subsequent melting at 12,°C,·,min,1. [source] Voltage-Gated Sodium Channels: Therapeutic Targets for PainPAIN MEDICINE, Issue 7 2009Sulayman D. Dib-Hajj PhD ABSTRACT Objective., To provide an overview of the role of voltage-gated sodium channels in pathophysiology of acquired and inherited pain states, and of recent developments that validate these channels as therapeutic targets for treating chronic pain. Background., Neuropathic and inflammatory pain conditions are major medical needs worldwide with only partial or low efficacy treatment options currently available. An important role of voltage-gated sodium channels in many different pain states has been established in animal models and, empirically, in humans, where sodium channel blockers partially ameliorate pain. Animal studies have causally linked changes in sodium channel expression and modulation that alter channel gating properties or current density in nociceptor neurons to different pain states. Biophysical and pharmacological studies have identified the sodium channel isoforms Nav1.3, Nav1.7, Nav1.8, and Nav1.9 as particularly important in the pathophysiology of different pain syndromes. Recently, gain-of-function mutations in SCN9A, the gene which encodes Nav1.7, have been linked to two human-inherited pain syndromes, inherited erythromelalgia and paroxysmal extreme pain disorder, while loss-of-function mutations in SCN9A have been linked to complete insensitivity to pain. Studies on firing properties of sensory neurons of dorsal root ganglia demonstrate that the effects of gain-of-function mutations in Nav1.7 on the excitability of these neurons depend on the presence of Nav1.8, which suggests a similar physiological interaction of these two channels in humans carrying the Nav1.7 pain mutation. Conclusions., These studies suggest that isoform-specific blockers of these channels or targeting of their modulators may provide novel approaches to treatment of pain. [source] Gene Induction by Phenobarbital: An Update on an Old Question that Receives Key Novel Answers,BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2001Laurent Corcos The drug is the representative of a myriad of lipophilic molecules able to evoke a pleiotropic response in the liver and also in prokaryotes and flies. A great deal of novel information has been obtained in recent years regarding the mechanism of cytochrome P450 (CYP) gene induction by phenobarbital. Most importantly, a nuclear orphan receptor, the constitutive androstane receptor has been identified as a primary determinant of the transcriptional activation of CYP genes in response to phenobarbital-like inducers in mammals. Another nuclear receptor, the pregnane X receptor can also mediate some of the phenobarbital response, but the functional overlap of the two inductive pathways is only partial. The response of mammalian CYP2B genes to phenobarbital was abolished in the liver of mice carrying a null allele of the constitutive androstane receptor gene, whereas that of CYP3A genes was lost in pregnane X receptor knock-out mice. [source] Massive postpartum haemorrhage after uterus-conserving surgery in placenta percreta: the danger of the partial placenta percretaBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 6 2008SBL Teo Placenta percreta is a rare but potentially life-threatening condition associated with high maternal mortality and morbidity rates, usually arising from severe obstetric haemorrhage. Due to rising caesarean section rates, an increase in the incidence of morbidly adherent placentas (accreta, increta and percreta) has been observed. Various treatment strategies have been employed in different centres, ranging from performing a caesarean hysterectomy at the time of delivery to leaving the placenta in situ, with or without adjuvant internal iliac and uterine arterial embolisation and/or methotrexate therapy. In the case of placenta percreta, irrespective of the treatment method employed, women are still at high risk of life-threatening haemorrhage and morbidity secondary to placental invasion beyond the confines of the uterine serosa into surrounding organs, most commonly the bladder. We describe an unusual case of a partially adherent placenta percreta in which partial separation of the normally implanted placenta led to torrential haemorrhage on the third postoperative day after the placenta was left in situ at the time of delivery. We therefore advise caution in following a conservative approach in the treatment of cases of placenta percreta in which the percreta feature is only partial and will discuss the merits and disadvantages of alternative options. [source] Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib ("Iressa")-sensitive and resistant xenograft modelsCANCER SCIENCE, Issue 12 2004Fumiko Taguchi ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor (VEGF) receptor-2 (KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 has been shown to inhibit angiogenesis and tumor growth in a range of tumor models. Gefitinib ("Iressa") is an selective EGFR tyrosine kinase inhibitor (TKI) that blocks signal transduction pathways. We examined the antitumor activity of ZD6474 in the gefitinib-sensitive lung adenocarcinoma cell line, PC-9, and a gefitinib-resistant variant (PC-9/ZD). PC-9/ZD cells showed cross-resistance to ZD6474 in an in vitro dye formation assay. In addition, ZD6474 showed dose-dependent inhibition of EGFR phosphorylation in PC-9 cells, but inhibition was only partial in PC-9/ZD cells. ZD6474-mediated inhibition of tyrosine residue phosphorylation (Tyr992 and Tyr1045) on EGFR was greater in PC-9 cells than in PC-9/ZD cells. These findings suggest that the inhibition of EGFR phosphorylation by ZD6474 can contribute a significant, direct growth-inhibitory effect in tumor cell lines dependent on EGFR signaling for growth and/or survival. The effect of ZD6474 (12.5,50 mg/kg/day p.o. for 21 days) on the growth of PC-9 and PC-9/ZD tumor xenografts in athymic mice was also investigated. The greatest effect was seen in gefitinib-sensitive PC-9 tumors, where ZD6474 treatment (>12.5 mg/kg/day) resulted in tumor regression. Dose-dependent growth inhibition, but not tumor regression, was seen in ZD6474-treated PC-9/ZD tumors. These studies demonstrate that the additional EGFR TKI activity may contribute significantly to the anti-tumor efficacy of ZD6474, in particular in those tumors that are dependent on continued EGFR-signaling for proliferation or survival. In addition, these results provide a preclinical rationale for further investigation of ZD6474 as a potential treatment option for both EGFR-TKI-sensitive and EGFR-TKI-resistant tumors. [source] Normal physical working capacity in prepubertal children with type 1 diabetes compared with healthy controlsACTA PAEDIATRICA, Issue 10 2005Elsa Heyman Abstract Background: Exercise testing has become a valuable help for the physician to examine the influence of recommended exercise training on physical fitness. However, the question as to how diabetic prepubertal children differ from their non-diabetic peers in their performance capacity has only partial and sometimes conflicting answers in the literature. Aim and methods: The aim of the current study was thus to evaluate aerobic fitness during an incremental submaximal test (measure of the Physical Working Capacity 170 (PWC170)) in 17 well-controlled prepubertal insulin-dependent diabetic boys aged 8.5,13 y. Eighteen healthy prepubertal boys matched for age, body size and physical activity served as controls. Part of the method was to check capillary blood glucose level in the diabetic patients and in nine of the healthy subjects throughout the exercise. Results: From this experiment it appeared that the level of physical fitness was similar in diabetic and healthy boys (PWC170 2.28±0.09 vs 2.37±0.13 W·kg,1). While glucose homeostasis was well maintained in the healthy group, diabetic children showed a marked fall in blood glucose during the exercise. In addition, the PWC170 level correlated significantly with the estimate of energy expenditure attributed to vigorous activities in the diabetic boys. Conclusion: By studying the responses to incremental exercise there is growing evidence that normal physical fitness is preserved in diabetic prepubertal boys given appropriate involvement in physical activity. [source] | ||||||||||