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Search Results: 1 - 10 of 2889 matches for " Steve Peigneur "
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Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels
Marijke Stevens,Steve Peigneur,Jan Tytgat
Frontiers in Pharmacology , 2011, DOI: 10.3389/fphar.2011.00071
Abstract: Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called “channelopathies.” The first insights into the mechanism of action potentials and the involvement of sodium channels originated from Hodgkin and Huxley for which they were awarded the Nobel Prize in 1963. These concepts still form the basis for understanding the function of VGSCs. When VGSCs sense a sufficient change in membrane potential, they are activated and consequently generate a massive influx of sodium ions. Immediately after, channels will start to inactivate and currents decrease. In the inactivated state, channels stay refractory for new stimuli and they must return to the closed state before being susceptible to a new depolarization. On the other hand, studies with neurotoxins like tetrodotoxin (TTX) and saxitoxin (STX) also contributed largely to our today’s understanding of the structure and function of ion channels and of VGSCs specifically. Moreover, neurotoxins acting on ion channels turned out to be valuable lead compounds in the development of new drugs for the enormous range of diseases in which ion channels are involved. A recent example of a synthetic neurotoxin that made it to the market is ziconotide (Prialt?, Elan). The original peptide, ω-MVIIA, is derived from the cone snail Conus magus and now FDA/EMA-approved for the management of severe chronic pain by blocking the N-type voltage-gated calcium channels in pain fibers. This review focuses on the current status of research on neurotoxins acting on VGSC, their contribution to further unravel the structure and function of VGSC and their potential as novel lead compounds in drug development.
Venomous Secretions from Marine Snails of the Terebridae Family Target Acetylcholine Receptors
Yvonne Kendel,Christian Melaun,Alexander Kurz,Annette Nicke,Steve Peigneur,Jan Tytgat,Cora Wunder,Dietrich Mebs,Silke Kauferstein
Toxins , 2013, DOI: 10.3390/toxins5051043
Abstract: Venoms from cone snails (Conidae) have been extensively studied during the last decades, but those from other members of the suborder Toxoglossa, such as of Terebridae and Turridae superfamilies attracted less interest so far. Here, we report the effects of venom and gland extracts from three species of the superfamily Terebridae. By 2-electrode voltage-clamp technique the gland extracts were tested on Xenopus oocytes expressing nicotinic acetylcholine receptors (nAChRs) of rat neuronal (α 3β 2, α 3β 4, α 4β 2, α 4β 4, α 7) and muscle subtypes (α 1β 1γδ), and expressing potassium (Kv1.2 and Kv1.3) and sodium channels (Nav1.2, 1.3, 1.4, 1.6). The extracts were shown to exhibit remarkably high inhibitory activities on almost all nAChRs tested, in particular on the α 7 subtype suggesting the presence of peptides of the A-superfamily from the venom of Conus species. In contrast, no effects on the potassium and sodium channels tested were observed. The venoms of terebrid snails may offer an additional source of novel biologically active peptides.
Atypical Reactive Center Kunitz-Type Inhibitor from the Sea Anemone Heteractis crispa
Irina Gladkikh,Margarita Monastyrnaya,Elena Leychenko,Elena Zelepuga,Victoria Chausova,Marina Isaeva,Stanislav Anastyuk,Yaroslav Andreev,Steve Peigneur,Jan Tytgat,Emma Kozlovkaya
Marine Drugs , 2012, DOI: 10.3390/md10071545
Abstract: The primary structure of a new Kunitz-type protease inhibitor InhVJ from the sea anemone Heteractis crispa ( Radianthus macrodactylus) was determined by protein sequencing and cDNA cloning. InhVJ amino acid sequence was shown to share high sequence identity (up to 98%) with the other known Kunitz-type sea anemones sequences. It was determined that the P1 Thr at the reactive site resulted in a decrease of the K i of InhVJ to trypsin and α-chymotrypsin (7.38 × 10 ?8 M and 9.93 × 10 ?7 M, respectively). By structure modeling the functional importance of amino acids at the reactive site as well as at the weak contact site were determined. The significant role of Glu45 for the orientation and stabilization of the InhVJ-trypsin complex was elucidated. We can suggest that there has been an adaptive evolution of the P1 residue at the inhibitor reactive site providing specialization or functional diversification of the paralogs. The appearance of a key so-called P1 Thr residue instead of Lys might lead to refinement of inhibitor specificity in the direction of subfamilies of serine proteases. The absence of Kv channel and TRPV1-receptor modulation activity was confirmed by electrophysiological screening tests.
Biochemical and Electrophysiological Characterization of Two Sea Anemone Type 1 Potassium Toxins from a Geographically Distant Population of Bunodosoma caissarum
Diego J. B. Orts,Steve Peigneur,Bruno Madio,Juliana S. Cassoli,Gabriela G. Montandon,Adriano M. C. Pimenta,José E. P. W. Bicudo,José C. Freitas,André J. Zaharenko,Jan Tytgat
Marine Drugs , 2013, DOI: 10.3390/md11030655
Abstract: Sea anemone (Cnidaria, Anthozoa) venom is an important source of bioactive compounds used as tools to study the pharmacology and structure-function of voltage-gated K + channels (K V). These neurotoxins can be divided into four different types, according to their structure and mode of action. In this work, for the first time, two toxins were purified from the venom of Bunodosoma caissarum population from Saint Peter and Saint Paul Archipelago, Brazil. Sequence alignment and phylogenetic analysis reveals that BcsTx1 and BcsTx2 are the newest members of the sea anemone type 1 potassium channel toxins. Their functional characterization was performed by means of a wide electrophysiological screening on 12 different subtypes of K V channels (K V1.1–K V1.6; K V2.1; K V3.1; K V4.2; K V4.3; hERG and Shaker IR). BcsTx1 shows a high affinity for rKv1.2 over rKv1.6, hKv1.3, Shaker IR and rKv1.1, while Bcstx2 potently blocked rKv1.6 over hKv1.3, rKv1.1, Shaker IR and rKv1.2. Furthermore, we also report for the first time a venom composition and biological activity comparison between two geographically distant populations of sea anemones.
Why Can’t Canada Spend More on Mental Health?  [PDF]
Steve Lurie
Health (Health) , 2014, DOI: 10.4236/health.2014.68089
Abstract: The World Health Organization (WHO) notes that mental illness accounts for 13% of the world’s disease burden, yet most countries under invest despite the social and economic costs of mental illness. It has been suggested that this lack of investment may be a result of stigma. A number of high income countries invest 10% or more in their mental health services. Although Canada is a high income country, its mental health spending is 7.2% according to the WHO Mental Health Atlas. This article will review the factors influencing Canada and its provinces’ under investment in mental health, compare its performance with other countries and make the case on why and how this could change.
Understanding the Relationships between Environmental and Social Risk Factors and Financial Performance of Global Infrastructure Projects  [PDF]
Daniil Kiose, Steve Keen
iBusiness (IB) , 2017, DOI: 10.4236/ib.2017.94007
Abstract: This study analyses the link between environmental and social risk (ESR) factors and the risk-return profile of infrastructure bonds. We provide support for the hypothesis that credit standing of infrastructure bonds is associated with ESR factors. Considering these factors along with bond and issuer specific information we discovered that several environmental and social risk covariates are strongly related to 1) expected risk-return profile of infrastructure bonds; and 2) the balance of risk around the expectation. Thus along with traditional drivers of bond risks (e.g. time to maturity, base interest rate, etc.) we find that also CO2 emission and percentage of independent directors emerge as important predictors. This study benefits from thoroughly developed, justified and validated non-parametric regression model used to derive key insights into the research question. This work makes a methodological contribution by applying non-parametric modelling techniques to study the financial risk of infrastructure projects. Moreover, it provides bond investors as well as policy makers with the guidance on where to focus their attention.
Evidence Based Medicine, in Precision Oncology  [PDF]
M. Nezami, Steve Hager
Journal of Cancer Therapy (JCT) , 2018, DOI: 10.4236/jct.2018.99057
Abstract: The disagreements in clinical data and therapy recommendations extracted from different sources/studies are a common finding in oncology research. Knowingly “biology is less reproducible than physics and mechanic engineering”, in order to overcome the disagreements and to find common grounds, we still rely on meta-analysis and systemic reviews for the highest level of evidence. To gather systemic review data base, a bibliographic search usually is conducted in the PubMed and in Cochrane Central Register of Controlled Trials databases to address a common clinical challenge. That said, frequently due to common conflicts between articles outcomes, an opinion of a third investigator is sought. Here in this article, we propose a rationale that could explain the differences in outcomes as a result of imperfect understanding of the current research database secondary to the unique biology of the tumor, rather than statistical interpretation on findings. We believe that the differences in findings merely are based on blinded inclusion criteria, and lack of accurate companion diagnostics to correlate the magnitude of response to each therapy. The objective of this article is to discuss a strategy to overcome such discordance by providing quantitative biological measures for genomic classification and correlation of tumor response to the selected targeted therapy. We further review such analysis in a case series of Her 2 positive breast cancer and conclude that
Dual Epidermal Growth Factor Inhibition and Multi Targeted Epigenetic Therapy (MTET)  [PDF]
Mohammad Nezami, Steve Hager
Journal of Cancer Therapy (JCT) , 2018, DOI: 10.4236/jct.2018.911072
Abstract: Since the discovery of tyrosine kinase inhibitors in treatment of lung cancer harboring such actionable targets, many lives have been prolonged. To the same extent, same group of patients have failed to benefit from this category of drugs, in long run, either initially or during the course of treatments, simply due to either known or unknown mechanism of resistance which occurs very often in the first few months after initiation of therapy. The resistance is 100 percent expected, and no patient is reported to be a waiver of such pattern. With best practices of oncology, the average duration of response is expected to be below 12 months [1]. About half of the resistance is caused by mutation at T790M in EGFR target, which can be revealed by liquid biopsy [1] [2]. The most recent studies have revealed the significant role of epigenome in controlling this complicated resistance pattern. We have learned that Histone deacetylation, as opposed to promoter methylation, may contribute to the epigenetic silencing and to EGFR TKI resistance in NSCLC [3] [4]. Here we present a case study with a model of combinational therapy that targets the EGFR molecule, (by small molecule inhibitor, Afatanib) with simultaneous epigenetic modification of the target, (by application of multitargeted epigenetic therapy (MTET) with significantly improved clinical results. We propose further trials are needed to support such hypothesis, which if proved, could significantly shift the current practices in management of this set of cases in lung adenocarcinomas.
Beliefs, Anxiety, and Avoiding Failure in Mathematics
Steve Chinn
Child Development Research , 2012, DOI: 10.1155/2012/396071
Abstract: Mathematics anxiety has been the subject of several books and numerous research papers, suggesting that it is a significant issue for many people. Children and adults develop strategies to cope with this anxiety, one of which is avoidance. This paper presents data taken from over 2500 mathematics test papers in order to compare the levels of accuracy and the frequency of the use of the “no attempt” strategy, that is, avoidance, for arithmetic problems given to children aged from 10 years to adults aged up to 49 years from across the UK. 1. Introduction The difficulties in learning mathematics are a fascinating and complex area for study. The interactions between factors that can be attributed to the cognitive domain and those that can be attributed to the affective domain are many and varied. For example, anxiety has a negative influence on working memory [1]. Skemp ([2], page 127) suggested that the reflective activity of intelligence is most easily inhibited by anxiety. Lundberg and Sterner [3] claim that “over and above common cognitive demands and neurological representations and functions, performance in reading and arithmetic is influenced by a number of motivational and emotional factors such as need for achievement, task orientation, helplessness, depression, anxiety, self-esteem, self-concept….” Hattie [4] selects a pithy quote from O’Connor and Paunonen [5], “Whereas cognitive ability reflects what an individual can do, personality traits reflect what an individual will do.” The implications on learning of anxiety, motivation, self-worth, self-efficacy and attributional style are significant (e.g., [6–8]) particularly in mathematics where a curriculum may make inappropriate assumptions about how some children learn. Those assumptions may be rooted in beliefs about mathematics and how it can be taught and learnt. There are a number of beliefs about mathematics that are long established and embedded in its culture. This does not necessarily make them helpful in creating a positive student attitude to mathematics, especially for those who have difficulties with learning mathematics or, indeed, mathematics learning difficulties. For example, Mtetwa and Garofalo [9] discuss five beliefs, which include “mathematics problems have only one correct answer” and “computation problems must be solved by using a step-by-step algorithm.” The first belief leads children to perceive of mathematics as highly judgmental, that answers are right or they are wrong. The second belief leads children and their teachers to perceive of mathematics as a series of
Perinatal Programming of Childhood Asthma: Early Fetal Size, Growth Trajectory during Infancy, and Childhood Asthma Outcomes
Steve Turner
Clinical and Developmental Immunology , 2012, DOI: 10.1155/2012/962923
Abstract: The “fetal origins hypothesis” or concept of “developmental programming” suggests that faltering fetal growth and subsequent catch-up growth are implicated in the aetiology of cardiovascular disease. Associations between reduced birth weight, rapid postnatal weight gain, and asthma suggest that there are fetal origins to respiratory disease. The present paper first summarises the literature relating birth weight and post natal growth trajectories to asthma outcomes. Second, issues regarding the interpretation of antenatal fetal ultrasound measurements are discussed. Finally, recent reports linking antenatal measurement and growth trajectory to early childhood asthma outcomes are discussed. Understanding the nature and timing of factors which influence antenatal growth may give important insight into the antecedents of early-onset asthma with implications for interventions.
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