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Daniel, Jollee Jaye. "Adolescent Methylone Exposure and its Effects on Behavioural Development in Adulthood." Thesis, University of Canterbury. Psychology, 2011. http://hdl.handle.net/10092/5460.
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Originally developed as an anti-depressant and later available as a ‘party-pill’ in New Zealand, methylone is currently classed as an illegal drug. This is due to findings of its similarity in chemical structure to that of Ecstasy (MDMA). Methylone is a relatively new drug into which little research has been conducted. Consequently, no known study has investigated the long-term effects on behavioural development arising from exposure during adolescence. The present thesis therefore aimed to identify long-term effects of chronic adolescent exposure to methylone on adult anxiety-like behaviours. This was achieved by the use of 80 rats (40 males: 40 females) and exposing them to either a methylone or saline treatment for ten consecutive days. Two different treatment age groups (early versus late adolescence) were examined and to ensure adequate comparisons could be made, two control groups were utilised. All rats were tested during adulthood in four specifically selected anxiety-measure tests; the open-field, preference for the light side of a light-dark box, acoustic startle and responsiveness to the novel arm of a Y-maze. The results suggested methylone-exposed rats displayed more anxiolytic behaviours than saline-treated rats. In the open field methylone exposed rats exhibited less ambulation than controls and those treated in early adolescence defecated more while rats treated in late adolescence occupied the corners of the apparatus more exhibiting higher anxiety-like behaviours. Exploratory behaviours in the Y-maze were decreased in methylone-treated rats, and those exposed in early adolescence entered the novel arm less often. However, acoustic startle results suggested methylone-exposed rats were less anxious as evidenced by a lower startle amplitude than controls. Overall, the results suggested differences in anxiety-like behaviours between methylone-exposed rats and controls. It did not appear that being exposed to methylone in early adolescence resulted in vast differences in anxiety-like behaviours than if exposure began in late adolescence.
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Allen, Serena. "The Combined Neuropharmacology and Toxicology of Major 'Bath Salts' Constituents MDPV, Mephedrone, and Methylone." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etd/3431.
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The synthetic cathinones, 3,4- methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4- methylenedioxymethcathinone (methylone), gained worldwide notoriety as the psychoactive components of ‘bath salts;’ a marketing term used to circumvent federal drug laws and permit their legal sale. Previous studies have shown that these drugs share pharmacological characteristics with cocaine and the amphetamines, however, descriptions of their neurotoxic properties are limited. Moreover, while forensic analysis has revealed that the most frequently abused bath salts ‘brands’ contain binary and ternary mixtures of MDPV, mephedrone, and methylone, the majority of preclinical research has focused on explicating the individual effects of these drugs. Therefore, the present dissertation aimed to address this limitation and characterize the acute and chronic effects of combined synthetic cathinone exposure on dopaminergic tone in mesolimbic and nigrostriatal brain regions. To accomplish this, male Swiss-Webster mice were administered MDPV, mephedrone, and methylone, individually or concomitantly, 1 time or 7 times over the course of two weeks and the corresponding effects of each treatment on mesolimbic and nigrostriatal brain tissue levels of dopamine (DA) and DA metabolites were analyzed using a high performance liquid chromatography – electrochemical detection (HPLC-ECD) assay. Additionally, motor-stimulant activity was evaluated after both dosing regimens using locomotor activity assays, while immunoblot and immunostaining techniques were used to evaluate the chronic effects of co-synthetic cathinone exposure on tissue levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), and glial fibrillary acidic protein (GFAP). Results from these studies provide evidence of a significant pharmacological interaction among major bath salt constituents, MDPV, mephedrone, and methylone. This was observed acutely as enhanced DA responses and chronically as functional toxicity at the DA synapse. Furthermore, such interactions may contribute to the deleterious effects reported by bath salt users. Together, these findings have shown that the composition of bath salts preparations can significantly influence their psychostimulant and toxic effects, substantiating the importance of modeling bath salts as drug mixtures.
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Troglin, Courtney G., J. Brooke Bouldin, Shannon Schreiner, Emily Perez, Stacy D. Ph D. Brown, and Brooks B. Ph D. Pond. "Pharmacokinetics of individual versus combined exposure to "bath salts" compounds MDPV, Mephedrone, and Methylone." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/182.
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Earlier this decade, “bath salts” were popularized as legal alternatives to the pyschostimulants cocaine and the amphetamines. These products contained synthetic cathinones including 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). Studies indicate that the cathinones have similar pharmacology to controlled psychostimulants, increasing levels of dopamine (DA) in the synaptic cleft. Most preclinical investigations have only assessed the effect of these synthetic cathinones independently; however, case reports and DEA studies indicate that “bath salts” often contain mixtures of these substances. Therefore, in a recent study by our laboratory, we examined effects of individual versus combined exposure to MDPV, mephedrone, and methylone. Interestingly, an enhanced effect on the levels of DA was observed, as well as significant alterations in locomotor activity following co-exposure to the cathinones. In this study, we examine whether the enhanced effects of the drug combination were due to pharmacokinetic (PK) interactions. It is known that many of the same cytochrome P450 (CYP) isoenzymes metabolize each of these three drugs. Therefore, it is probable that the drugs’ PK would differ when administered individually as compared to in combination. We hypothesize that combined exposure to MDPV, mephedrone, and methylone will result in increased drug concentrations and enhanced total drug concentrations when compared to individual administration. The pharmacokinetics of MDPV, mephedrone, and methylone in the brain and plasma were examined following intraperitoneal injection in mice. Briefly, adolescent male Swiss-Webster mice were injected intraperitoneally with either 10 mg/kg MDPV, 10 mg/kg mephedrone, 10 mg/kg methylone, or 10 mg/kg combined MDPV, mephedrone, and methylone. Following injection, brains and plasma were collected at the following time points: 1, 10, 15, 30, 60, and 120 minutes. Samples were then flash-frozen and stored at -70°C until analysis. Drugs were extracted via solid-phase extraction and concentrations were determined using a previously validated and published high pressure-liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Following intraperitoneal administration, all drugs quickly crossed the blood-brain barrier and entered the brain. Peak drug concentrations, time to peak concentration, drug half-lives, and total drug exposure (as measured by area under the curve) are compared when drugs were given individually versus in combination. These data provide insight into the consequences of co-exposure to popular “bath salt” products.
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Tran, Lily H., Serena A. Allen, Hannah V. Oakes, Russell W. Brown, and Brooks B. Pond. "Dopaminergic Effects of major Bath Salt Constituents 3, 4-methylenedioxypyrovalerone (MDPV), Mephedrone, and Methylone are Enhanced Following Co-exposure." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/139.
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An unprecedented rise in the availability of new synthetic drugs of abuse has been observed in the recent years. One of the most noted cases is that of a popularized designer drug mixture known as ‘bath salts’. Commonly obtained from various shops and on the internet, “bath salts” often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in diverse combinations. Individually, the synthetic cathinones are known to have similar pharmacology to controlled psychostimulants such as cocaine and the amphetamines, increasing the levels of dopamine (DA) in the synaptic cleft. DA is an important neurotransmitter that regulates a variety of behaviors and functions; neurons within the mesolimbic DA pathway (ventral tegmental area to nucleus accumbens) are involved in reward and motivation and are activated by these drugs of abuse. Additionally, psychostimulant-induced increases in DA in the nigrostriatal pathway (substantia nigra to corpus striatum) lead to increases in locomotor behavior. However, the majority of preclinical investigations have only assessed the effects of individual bath salt constituents and have provided little information regarding the possibility of significant drug interactions with the co-exposure of MDPV, mephedrone, and methylone. This study sought to evaluate and compare the effects of individual versus combined MDPV, mephedrone, and methylone on dopamine (DA) levels in discrete brain regions as well as motor stimulant responses in mice. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline, MDPV, mephedrone, methylone (1.0 or 10.0 mg/kg), or the cathinone cocktail (MDPV + mephedrone + methylone at 1.0, 3.3, or 10 mg/kg). The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure utilizing high pressure liquid chromatography with electrochemical detection (HPLC-ECD). Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. The results demonstrate that MDPV, mephedrone, and methylone produce dose-related increases in the mesolimbic and nigrostriatal DA levels that are significantly enhanced following their co-administration. Additionally, a decrease in locomotor activity on day 1 that was exacerbated by day 7 was noted in mice treated with the cathinone cocktail and was not observed with any of the single agents. The decrease in locomotor activity was accompanied by an increase in stereotypic-like behavior including excessive grooming and even self-mutilation. Our findings demonstrate a significantly enhanced effect of MDPV, mephedrone, and methylone on both DA and its metabolites resulting in significant alterations in locomotor activity. This work provides insight into the potential enhanced risk of the use of these combination synthetic cathinone products.
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Pachhain, Sudhan. "Analysis of gene expression associated with drug-induced hyperthermia in rat." Bowling Green State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1562330027757666.
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Schreiner, Shannon CA, J. Brooke Bouldin, Emily Perez, Stacy D. Brown, and Brooks B. Pond. "PHARMACOKINETICS OF SYNTHETIC CATHINONES FOUND IN "BATH SALTS" IN MOUSE BRAIN AND PLASMA USING LIQUID CHROMATOGRAPHY - MASS SPECTROMETRY." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/196.
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“Bath salts” and “plant food”, which were legally marketed synthetic cathinones, have a high potential for abuse. Several recent studies indicate that 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxymethcathinone (methylone), two common drugs of this type, have similar pharmacology to controlled psychostimulants such as cocaine, methamphetamine, and methylphenidate. MDPV acts as a norepinephrine (NE) and dopamine (DA) reuptake inhibitor via blockade of their transporters (DAT and NET), whereas methylone is a substrate for the NE, DA, and serotonin (5-HT) transporters, increasing the non-vesicular release of these monoamines. Both drugs cause significant increases in the levels of these neurotransmitters in the cleft. Increases in DA are associated with euphoric effects and thus promote drug abuse and addiction, hence the high addiction potential of MDPV and methylone. Indeed, MDPV is 50 times more potent at the DAT and 10 times more potent at the NET than cocaine. Here, we examined the pharmacokinetics of MDPV and methylone in the brain and plasma, following intraperitoneal injection in mice. These types of injections have similar pharmacokinetics to insufflation (snorting), which is the manner in which MDPV and methylone are commonly abused. Briefly, adolescent male Swiss-Webster mice were injected intraperitoneally with either 10 mg/kg MDPV or 10 mg/kg methylone, and brains and plasma were collected at the following time points: 1, 10, 15, 30, 60, and 120 minutes. Samples were then flash-frozen and stored at -70°C until analysis. Samples were spiked with deuterium-labeled MDPV or methylone (internal standards), and the drugs were extracted from tissue using a previously published solid phase extraction method. Chromatographic separation of the compounds was achieved using a HILIC column with a gradient elution of acetonitrile and 5 mM ammonium formate at a flow rate of 0.2 mL/min. Mass spectrometric detection utilized a Shimadzu IT-TOF system with the electrospray source running in positive mode. Data acquisition utilized a direct MS-MS method using a precursor ion of 276.3 m/z for MDPV and methylone. The calibration curve ranged from 100 ng/ml to 0.1 ng/ml. These conditions allowed for a lower limit of detection (LLOD) of less than or equal to 1 ng/mL and a lower limit of quantification (LLOQ) of less than or equal to 5 ng/mL for MDPV and methylone. MDPV and methylone peak concentrations in plasma were seen immediately at 1 min, while brain concentrations peaked at 15 min; however, MDPV reached higher concentrations in the brain the methylone. This is consistent with MDPV’s higher lipophilicity (logP value). In conclusion, the pharmacokinetic profile of these drugs reflects a quick uptake and distribution of the drugs to the brain, followed by the quick distribution out of the brain, which likely contributes to the binge use of these drugs.
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López, Arnau Raúl. "Nuevas drogas psicoestimulantes. Estudio farmacológico y neurotoxicológico de la metilona." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/284625.
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La metilona (3,4-metilendioximetcatinona), también conocida como M1, MDMC, bk-MDMA o “Ease” es un psicoestimulante y entactógeno de la familia de las catinonas, también incluida dentro del grupo de las fenetilaminas o de las β-ceto anfetaminas. Cabe destacar que la metilona posee una gran similitud estructural con la MDMA o “éxtasis” (Figura 20), de la cual sólo difiere por la presencia de un grupo cetona en la posición β del anillo de fenetilamina. La mayoría de estas catinonas poseen una similitud estructural con otros derivados anfetamínicos, como la MDMA o la metanfetamina por lo que sus efectos psicoestimulantes y empatógenicos podrían ser similares a los producidos por éstos (Schifano et al., 2011). Concretamente, la metilona, objeto de la presente Tesis Doctoral, es una sustancia relativamente nueva, y por ello, la información disponible es muy limitada. El rápido aumento del consumo/abuso de esta sustancia, juntamente con los serios efectos sobre la salud, exige un mejor conocimiento tanto de su perfil farmacocinético como farmacodinámico. No podemos subestimar tampoco el potencial de la metilona para producir efectos a largo plazo de índole neurotóxica.
En nuestro modelo in vitro, utilizando sinaptosomas de rata, tanto la butilona como la mefedrona y la metilona produjeron una reducción concentración-dependiente de la captación de [3H]5-HT, [3H]DA y [3H]NA, además tanto el componente de membrana como el componente vesicular están involucrados en el efecto inhibitorio final de estas catinonas. Cuando a los animales se les administró, 30 minutos antes de la catinona, ketanserina (antagonista 5- HT2A) o haloperidol (antagonista no-selectivo dopaminérgico), se inhibió el aumento de la actividad locomotora inducido por las catinonas, sugiriendo la implicación tanto del sistema serotoninérgico como del dopaminérgico. La afinidad de estos compuestos por los receptores 5-HT2A respalda tal hipótesis. Sin embargo, su relativa baja afinidad por los receptores D2 nos permite descartar un efecto directo sobre este tipo de receptores, lo cual nos lleva a creer que este tipo de sustancias al producir un aumento de la concentración de DA extracelular, será ésta la que finalmente interactúe con este tipo de receptores.
El tiempo de semivida de la metilona tras la administración oral fue significativamente más elevado que tras la administración intravenosa, lo que nos lleva a pensar que su farmacocinética se ajusta a un modelo flipflop. La ruta metabólica propuesta consta de, en primer lugar, una reacción de desmetilación, dando lugar a la correspondiente amina primaria, la metilendioxicatinona (MDC), estructuralmente relacionada con uno de los metabolitos activos de la MDMA, la MDA. Además creemos que la metilona puede ser sustrato de una hidroxilación alifática, dando lugar a la 3’-hidroxi-metilendioximetcatinona (3’-OH-MDMC). También se identificaron dos metabolitos hidroxilados, la 4-hidroxi-3- metoximetcatinona (4-OH-3-MeO-MC) y la 3-hidroxi-4- metoximetcatinona (3-OH-4-MeO-MC).
Los cambios neuroquímicos inducidos por metilona son más aparentes cuando ésta es administrada 4 veces al día cada 3 horas, mostrando una disminución de los marcadores de los terminales neuronales serotoninérgicos en corteza frontal e hipocampo, juntamente con una activación astroglial en la región del giro dentado y la CA1 del hipocampo una semana después del tratamiento. A diferencia de la neurotoxicidad especie-dependiente de la MDMA, la metilona induce alteraciones en el cerebro de rata que no difieren cualitativamente de las observadas en ratón utilizando un régimen de administración similar. La metilona produce, en ratón, efectos depresivos tras un régimen de administración neurotóxico. Tras un tratamiento similar en rata, la metilona provoca una disfunción en la memoria referencial.A decrease in the illegal availability of chemical compounds used for the synthesis of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) or Ecstasy, coupled with a more than 50% decrease in the purity of ecstasy or cocaine (Measham et al., 2010; Winstock et al., 2011), has resulted in the appearance on the black market of a new generation of designer drugs known as ‘cathinones’ or ‘beta-keto amphetamines’ (the latter name deriving from the characteristic presence of a ketone in the side chain). These derivatives include a wide range of substances such as butylone, ethylone, methylone and mephedrone (4-methylmethcathinone). Butylone, mephedrone and methylone caused hyperlocomotion, which was prevented with ketanserin or haloperidol. Methylone was the most potent compound inhibiting both [3H]5-HT and [3H]dopamine uptake. Mephedrone was found to be the cathinone derivative with highest affinity for vesicular monoamine transporter-2 causing the inhibition of dopamine uptake. The affinity of cathinones for 5-HT2A receptors was similar to that of MDMA. Oral administration of methylone induced a dose-dependent increase in locomotor activity in rats. The plasma concentrations after i.v. administration were described by a two-compartment model. For oral administration, peak methylone concentrations were achieved between 0.5 and 1 h and fitted to a flip-flop model. Absolute bioavailability was about 80%. We have identified four Phase I metabolites after oral administration. The major metabolic routes are N-demethylation, aliphatic hydroxylation and O-methylation of a demethylenate intermediate. Repeated methylone administration induced hyperthermia and a significant loss in rodent body weight. Methylone induced transient dopaminergic (frontal cortex) and serotoninergic (hippocampus) impairment in mice. We found evidence of astrogliosis in the CA1 and the dentate gyrus of the hippocampus. The animals also showed an increase in immobility time in the forced swim test, pointing to a depressive-like behavior. We also determined a serotonergic impairment in methylone-treated rats, especially in the frontal cortex, where it was accompanied by astrogliosis. Some serotonergic alterations were also present in the hippocampus and striatum. No significant neurotoxic effect on the dopaminergic system was identified. Methylone-treated rats only displayed impairments in the probe trial of the Morris water maze, which concerns reference memory, while the spatial learning process seemed to be preserved.
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DEMBELE, YENIMEGUE-ALBERT. "Synthese asymetrique d'alpha-methylene gamma-butyrolactames." Nantes, 1991. http://www.theses.fr/1991NANT2045.
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L'utilisation d'(alpha-bromomethyl) acrylates d'alkyles et d'imines en presence de zinc dans des conditions appropriees demeure la meilleure voie d'acces aux alpha-methylene gamma-butyrolactames. Au cours de cette etude, nous avons realise la premiere synthese totalement selective d'alpha-methylene gamma-butyrolactames secondaires chiraux, avec de bons rendements chimiques par transfert de chiralite lors du couplage d'organozinciques derives d'alpha-bromomethyl) acrylates, et d'une imine portant une copule chirale issue d'un alpha-aminoester ou d'un beta-aminoalcool
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GRUIEC, ANNE. "Halogenation, arylation, alkylation et lactonisation des 3-hydroxy 2-methylene propanoates de methyle et de leurs nitriles en presence de sels metalliques deposes sur un support solide." Rennes 1, 1991. http://www.theses.fr/1991REN10055.
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On montre, en utilisant comme substrat les 3-hydroxy 2-methylene propanoates de methyle et les nitriles correspondants que la reactivite des halogenures de cu#+#2, co#+#2, fe#+#3, zn#+#2 et mn#+#2, depose sur un support solide inorganique est plus grande que la reactivite des sels purs. Une etude electrochimique du bromure cuivrique depose sur silica gel montre que le sel est dans un etat hautement divise. Le melange se comporte comme une source d'ions bromure vis-a-vis du substrat organique. Ces halogenures metalliques deposes sur silica gel ont permis de realiser avec les esters et nitriles utilises comme substrat, des substitutions nucleophiles avec transposition allylique, des reactions de friedel et crafts (phenylation avec transposition allylique, reaction de ritter, synthese de lactones en particulier avec fecl#3 et fecl#3/sio#2). L'acetate de cobalt depose sur silica gel catalyse la condensation de l'acetylacetate de methyle avec les 3-hydroxy 2-methylenes propanoates de methyle pour conduire aux dihydrofurannes. On montre que le chauffage avec un four a micro-ondes en presence d'une petite quantite de solvant peu volatil permet de reduire de facon significative la duree de la reaction et d'ameliorer les rendements
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Provencal, Nadine. "The methylome of early adversity and aggression." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114317.
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Acts of violence account for 1.43 million deaths worldwide annually and individual acts of aggression account for the majority of these lives lost. Longitudinal studies on the development of physical aggression have found that while children start using physical aggression very early in life, the majority of them learn to use alternative behaviors during childhood and adolescence. The challenge is that a minority of children (3-7%) maintain chronic levels of physical aggression. While we know that genetic factors and early social experiences are involved in the development of aggression, the main question is "What is the mechanism that registers the response to early life adversity as well as stores life-long and system-wide programs of aggressive phenotypes?" Evidence in animals and in humans has emerged suggesting that epigenetic mechanisms, such as DNA methylation, are responsive to adverse environments and are maintained until adulthood. Epigenetic mechanisms are known to serve as long-lasting regulators of gene expression programs. This doctoral thesis delineates the effects of early adversity in a rhesus macaque model of maternal deprivation on DNA methylation patterns in the prefrontal cortex (PFC) and in T cells to compare the central and the peripheral epigenetic marks of social experience. Moreover, it determines the associations between DNA methylation patterns in T cells and childhood physical aggression in men. Whole genome methylation analyses using methylated DNA immunoprecipitation followed by hybridization to genome-wide promoter microarrays were used to assess the DNA methylation profiles in adult monkeys who were randomized into differential rearing groups (maternal versus surrogate-peer rearing) in their first year of life. We show that differential rearing leads to differential DNA methylation profiles in both the PFC and T cells. These differentially methylated promoters tend to cluster by chromosomal region and by gene function in both tissues, suggesting that the response to early adversity is genome- and system-wide. These results support the use of peripheral tissues in human studies examining epigenetic and phenotypic consequences of social adversity. We then used peripheral blood samples from adult men who were on a chronic physical aggression trajectory from childhood to adolescence (CPA) and compared them to a control group from the same background. ELISA analysis of plasma levels of 10 inflammatory cytokines identified that men from the CPA group had lower plasma levels of five cytokines (IL-1α, IL-4, IL-6, IL-8 and IL-10). Moreover, interrogation of the state of DNA methylation across the entire genomic loci containing these five cytokines and cytokine regulator genes (NFkB1, NFAT5 and STAT6) revealed significant associations between differential DNA methylation and CPA. Using whole genome methylation analysis in these men from either CPA or control groups, we revealed associations between physical aggression and DNA methylation in specific gene promoters that tended to cluster into distinct chromosomal regions as well as in relevant gene function categories known to be involved in aggression. In summary, my study demonstrates that adverse social experiences and adverse social phenotypes are associated with altered DNA methylation patterns across the genome. My findings are consistent with the hypothesis that DNA methylation is a mechanism that registers the response to early life adversity in the genome and has a long-lasting association with aggressive phenotypes in humans. Moreover, the finding of DNA methylation alterations in relevant immune genes and immune signaling pathways further supports the hypothesis that the epigenetic programs associated with aggression are not limited to the brain and occur in the immune system as well. This is consistent with several studies that indicate peripheral immune components playing a role in regulating behavioral states.Les actes de violence représentent 1,43 millions de morts par an dans le monde. Des études longitudinales sur le développement de l'agressivité physique (AP) ont montré que bien que les enfants commencent à se servir de l'AP très tôt dans leur vie, la majorité d'entre eux apprennent à utiliser des comportements alternatifs au cours de l'enfance. Le problème est qu'une minorité d'enfants (3-7%) maintiennent des niveaux d'AP élevés. Bien que nous sachions que les facteurs génétiques ainsi que les premiers contacts sociaux sont impliqués dans le développement de l'AP, la question principale demeure:«Quel sont les mécanismes qui sont capable d'enregistrer la réponse à l'adversité social à l'enfance, de la conserver durant la vie et de programmer les phénotypes agressifs?» Des évidences chez les animaux et l'homme ont émergé suggérant que des mécanismes épigénétiques, tels que la méthylation de l'ADN, réagissent aux environnements adverses et se maintiennent jusqu'à l'âge adulte. Les mécanismes épigénétiques sont aussi connus pour réguler les programmes d'expression génique. Cette thèse de doctorat détermine les effets de l'adversité au début de la vie sur les profils de méthylation de l'ADN du cortex préfrontal (CPF) et des cellules T afin de comparer les marques épigénétiques centrales et périphériques des contacts sociaux chez le macaque rhesus. De plus, elle détermine les associations entre les profils de méthylation de l'ADN dans les cellules T et l'AP à l'enfance chez l'homme. Des analyses de la méthylation du génome entier utilisant l'immunoprécipitation de l'ADN méthylé suivie par l'hybridation sur micropuces de promoteurs, ont servie à mesurer les profils de méthylation de singes adultes qui ont été randomisés dans des groupes d'élevage différents (élevé par leur mère versus par des pairs). Nous montrons que les différentes conditions d'élevage conduisent à des profils de méthylation différents à la fois dans le CPF et dans les cellules T. Ces promoteurs différentiellement méthylés tendent à être regroupés par région chromosomique et par fonction génique dans les deux tissus, suggérant que la réponse à l'adversité se produit à une échelle génomique et systémique. Nous avons ensuite utilisé des échantillons de sang provenant d'hommes adultes qui étaient sur une trajectoire d'AP chronique de l'enfance à l'adolescence (APC) et nous les avons comparés à un groupe control ayant les mêmes origines. L'analyse du niveau plasmatique de 10 cytokines par une méthode immuno-enzymatique indique que les hommes du groupe APC ont des niveaux plasmatiques plus faibles pour cinq cytokines (IL-1α, IL-4, IL-6, IL-8 et IL-10). L'interrogation du niveau de méthylation de l'ADN des loci génomiques de ces cinq cytokines et de leurs régulateurs révèle des associations significatives entre la méthylation et l'APC. En utilisant des analyses génomiques de la méthylation de l'ADN chez ces hommes, nous avons révélé des associations entre l'AP et la méthylation dans plusieurs promoteurs. Ces promoteurs tendent à se regrouper dans des régions chromosomiques distinctes ainsi que dans des catégories fonctionnelles déjà connues pour être impliquées dans l'AP. En résumé, mon étude doctorale démontre que les expériences sociales et les phénotypes adverses sont associés à des profils de méthylation de l'ADN altérés au travers du génome. Mes données soutiennent l'hypothèse que la méthylation de l'ADN est un mécanisme qui enregistre la réponse à l'adversité au début de la vie et qu'il s'associe de façon continue avec les phénotypes d'agressivité chez l'homme. De plus, la découverte que ces altérations surviennent à l'intérieur de gènes et de fonctions du système immunitaire supporte l'hypothèse que les programmes épigénétiques associés avec l'AP ne sont pas limités au cerveau mais se produisent également dans le système immunitaire. Ceci est cohérent avec plusieurs études qui indiquent que le système immunitaire joue un rôle dans la régulation des comportements.
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Yates, M. I. "Reactivity of methylene at a diruthenium centre." Thesis, University of Bristol, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384457.
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Mhike, Morgen. "Characterization of Methylene Diphenyl Diisocyanate Protein Conjugates." PDXScholar, 2014. https://pdxscholar.library.pdx.edu/open_access_etds/1844.
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Diisocyanates (dNCO) such as methylene diphenyl diisocyanate (MDI) are used primarily as cross-linking agents in the production of polyurethane products such as paints, elastomers, coatings and adhesives, and are the most frequently reported cause of chemically induced immunologic sensitization and occupational asthma (OA). Immune mediated hypersensitivity reactions to dNCOs include allergic rhinitis, asthma, hypersensitivity pneumonitis and allergic contact dermatitis.
There is currently no simple diagnosis for the identification of dNCO asthma due to the variability of symptoms and uncertainty regarding the underlying mechanisms. Immunological sensitization due to dNCO exposure is traditionally thought to require initial conjugation of the dNCO to endogenous proteins to generate neoantigens, which trigger production of dNCO specific T lymphocytes and ultimately dNCO specific IgE. Testing for dNCO-specific IgE, for diagnosis of dNCO asthma is however, only specific (96-98%) but not sensitive (18-27%). The low prevalence of detectable dNCO specific IgE has been attributed to both assay limitations and a potential IgE-independent dNCO asthma mechanism(s). The identity of the conjugated proteins responsible for the sensitization also remains unknown. It is also not clear whether dNCOs bind to extracellular, cell membrane, or intracellular proteins as a way of triggering non-IgE asthma. Standardization and optimization of immunoassays used to screen for dNCO specific antibodies in sera is important if its utility as a dNCO asthma diagnostic tool is to be achieved. This will potentially improve sensitivity and allow comparison of results across studies. Current studies on assays of dNCO-specific IgE and IgG lack or have limited characterization of the conjugates used.
Diisocyanates bound to hemoglobin (Hb), human serum albumin (HSA), and THP-1 proteins were quantified by HPLC with fluorescence detection. Proteomic tandem mass spectrometry (MS) was used to delineate TDI and MDI specific amino acid binding sites on Hb as well as identification of proteins from MDI exposed THP-1 cells. The trinitrobenzene sulfonic acid assay (TNBS) and SDS gel electrophoresis were used to evaluate extent of intra and intermolecular cross-linking in dNCO-HSA conjugates. Binding of monoclonal antibodies (mAbs) to dNCO bound proteins in enzyme-linked immunosorbent assay (ELISA) was used to evaluate antigenicity of dNCO-protein conjugates.
The amount of dNCO binding to HSA and Hb increased with the concentration of the dNCO used for conjugation. All the dNCOs reacted with HSA more than with Hb. Eight binding sites were observed with both MDI and TDI on Hb. The N-terminal valines of both the alpha and beta subunits on Hb, lysine 40 of the alpha subunit and lysine 61 of the beta subunit were common binding sites for both TDI and MDI. Lysine 7 of the alpha subunit and lysines 8, 65 and 66 of the beta subunit were unique to MDI. On the other hand, lysines 11, and 16 of the alpha subunit and lysines 17 and 144 of the beta subunit were unique to TDI. Protein bound MDI was detected in a dose-dependent manner in membrane and cytoplasm fractions of MDI exposed THP-1 cells. MDI was also detected in 11 of the 13 cytoplasmic protein bands. The extent of MDI intracellular protein binding was not affected by cytochalasin D, a chemical that binds actin filaments and inhibits active uptake into cells. The extent of cross-linking shown using the TNBS assay was found to increase with amount of dNCO used. Clear bands from both intra and intermolecular cross-linking were observed on all dNCO-Hb/HSA SDS gels. Using ELISA, both TDI-Hb and TDI-HSA conjugates were reactive to monoclonal antibodies produced against TDI conjugated HSA indicating that dNCO-Hb is also antigenic.
The best characterization of dNCO-protein conjugates is achieved by the quantitative determination of conjugated dNCO per mole of protein as well as determining the extent of dNCO cross-linking. Although HSA is more reactive to dNCOs than other serum proteins such as Hb, contribution from other serum proteins to development of OA should not be overlooked as dNCO-Hb was found to be reactive to dNCO specific mAbs. dNCO-conjugated proteins identified in the soluble fraction of MDI exposed THP-1 cells were all of intracellular origin suggesting that MDI can cross the cell membrane and react with intracellular proteins. The entry of MDI into live cells is a passive process, as the extent of intracellular binding was not affected by cytochalasin D. The present study support the potential involvement of dNCO-haptenated membrane and intracellular proteins in development of non-IgE dNCO asthma.
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Costanzo, Jerry Lee. "In vitro comparison of methylene diphosphonate radiopharmaceuticals." Scholarly Commons, 1985. https://scholarlycommons.pacific.edu/uop_etds/484.
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The radiopharmaceutical methylene diphosphonate (MDP) is a relatively new diagnostic tool and currently in widespread use as a gone imaging agent to delineate areas of altered osteogenesis. MDP is chelated with radioactive technetium-99m (Tc99m) and injected into the venous system of the body. It quickly clears from the bloodstream and is deposited into areas of bone transformation. Osteoporosis, primary carcinoma, bony metastases, osteomyelitis, and stress fractures are diagnosed with the use of Tc99m-MDP (1). In the presence of disease, the biodistribution of Tc99m-MDP is altered and this change is reflected in the images or scans. Ideally, the product would show a high ration of radioactivity in the target organ tot that of the surrounding tissue, with a minimization of radiation exposure to the patient. The purpose of this study will be to investigate Methylene Diphosphonate radiopharmaceuticals for their binding efficiencies, stability, and subsequent changes due to varying technetium levels.
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Kaiser, Delene Anne. "Stereoselective reactions of 16-Methylene 19-Norsteroids." Master's thesis, University of Cape Town, 1991. http://hdl.handle.net/11427/22136.
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The influence of the 17-substituent upon epoxidation of 3-methoxy-16-methylene-estra- 1,3,5(10)-trien-17-one and the derived 17β-hydroxy and 17β-acetoxy compounds was investigated. Alkaline hydrogen peroxide epoxidation of 3-methoxy-16-methyleneestra- 1,3,5(10)-trien-17-one occurred in good yields, but poor stereoselectivity was obtained due to mechanistic considerations. Poor stereoselectivity was also obtained for the peracid epoxidation of 3-methoxy-16-methylene-estra-1,3,5(10)-trien-17β-ol, due to the pseudo-equatorial position of the 17β-hydroxyl group. However, excellent stereoselectivity was obtained using Sharpless conditions (vanadium catalyst), which gave only the epoxide syn to the hydroxyl group, in good yields. Surprisingly, peracid epoxidation of 3-methoxy-16-methylene-estra-1,3,5(10)-trien-17β-yl acetate favoured equatorial attack resulting in a 2:1 ratio of the (16R)- and (16S)-epoxide isomers, instead of the expected axial approach by the peracid.
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Jones, Helen. "Studies on EcoRV methylase." Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295684.
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Wang, Man-Ping. "Effects of Methylene Chloride on Immune Function in Mice and the In Vitro Effect of Methylene Chloride in Immunologic Assays." DigitalCommons@USU, 1989. https://digitalcommons.usu.edu/etd/4649.
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A number of toxicities associated with methylene chloride have been found in both human subjects and mice. However, relatively few studies have probed immunotoxicities of methylene chloride. In order to examine possible immunotoxicities or immunomodulating effects of methylene chloride, several tests of cellular immune function were performed using both human in In Vitro studies and a mouse model.
Body weights and specific organ weights of thymus, spleen, liver, and kidney were normal in CD-1 mice given various concentrations of methylenechloride. However, a significantly reduced mitogenic response to phytohemagglutinin (PHA} and reduced interleukin-2 (IL-2} production was found in these methylene-chloride-treated mice. The findings in the mouse model provide additional evidence that immune suppression may be associated with exposure to methylene chloride.
Splenic mononuclear cells isolated from CD-1 mice were incubated with various concentrations of methylene chloride in vitro and investigated for blastogenic response to mitogen PHA and IL-2 production. The results show no significant difference between methylene-chloride-treated cells and the cells treated with growth media.
Peripheral blood mononuclear cells isolated from healthy donors were incubated with various concentrations of methylene chloride and tested for blastogenic activity, natural killer (NK) cell activity, and IL-2 production. The findings showed that the NK cell activity, the T-cell blastogenesis in response to PHA mitogen, and IL-2 production activity were not affected.
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Palomeras, Sònia. "DNA methylome in HER2-positive resistant breast cancer." Doctoral thesis, Universitat de Girona, 2019. http://hdl.handle.net/10803/667582.
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The major clinical problem for HER2+ breast cancer target therapies is the acquisition of resistance. The DNA methylation status of the promoter gene region has been described as a common epigenetic alteration for transcriptional repression in human malignancies as breast cancer. The purpose of this thesis was to evaluate how the DNA methylation was involved in trastuzumab and lapatinib resistance in HER2+ breast cancer. We identify the epigenetic silencing of the TGFBI gene in trastuzumab resistance HER2+ breast cancer cell model and in post-treatment samples of patients treated with neoadjuvant anthracycline-taxane-based chemotherapy plus trastuzumab. Furthermore, the in vitro analysis revealed that the TGFBI reexpression induced greater sensitivity to trastuzumab in our resistant model, probably through its integrin-binding domains (EPDIM, NKDIL, YH and RGD). These results provide a basis for further studies to validate the hypermethylation status of TGFBI gene as monitoring biomarkers of trastuzumab resistance in HER2 breast cancer patients.L'adquisició de resistència a les teràpies actuals és el principal problema del càncer de mama HER2+. L’estat de metilació de l’ADN a la regió promotora s’ha descrit com una alteració epigenètica associada a la repressió transcripcional de gens involucrats en diferents càncers, com el càncer de mama. L’objectiu d’aquesta tesi doctoral ha estat avaluar la implicació de la metilació en càncer de mama HER2+ resistent a trastuzumab i lapatinib. S’ha identificat el silenciament epigenètic de TGFBI en el model cel·lular resistent a trastuzumab així com en mostres humanes posttractament, tractades amb quimioteràpia neoadjuvant més trastuzumab. L’anàlisi funcional in vitro va revelar com la re-expressió de TGFBI induïa a una major sensibilitat al tractament en el model resistent, probablement a través dels seus dominis d’interacció amb integrines. Aquests resultats són la base per futurs estudis de validació de TGFBI com a possible biomarcador de resistència en càncer de mama HER2+.
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Muritu, John Waititu. "Oxidative addition reactions and methylene-bridged diiridium complexes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape3/PQDD_0013/MQ59855.pdf.
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Hazafy, David. "Development of colorimetric indicators based on Methylene Blue." Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18932.
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Leeming, Peter. "2-methylene-1,3-dioxolanes : mechanistic and synthetic studies." Thesis, University of Salford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261838.
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Patient, Lee. "Lewis acid mediated cyclisations of methylene and alkylidenecyclopropanes." Thesis, University of Southampton, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400490.
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Moeng, Mmushi Moses. "Terthienyl carbene complexes." Diss., Pretoria : [s.n.], 2001. http://upetd.up.ac.za/thesis/available/etd-02092006-153600/.
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Karambelkar, Vineet V. "Proposed Route to Cyclopenta[c]thiophenes via Activated Methylene." TopSCHOLAR®, 2008. http://digitalcommons.wku.edu/theses/25.
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The synthesis of cyclopenta[c]thiophenes has been sparsely reported in the literature owing to several difficulties involved in their synthesis. The present work involves the proposed synthesis of cyclopenta[c]thiophenes and their precursors using activated methylene. Cyclopenta[c]thiophene compounds show promise in the field of polymer and catalysis chemistry. These substituted polythiophenes are potential organic semiconductors and anti-tumor agents. The research presented shows the successful and novel conversion of 3,4-bis(chloromethyl)-2,5-dimethylthiophene and 3,4-bis(bromomethyl)-2,5-dimethylthiophene to a fused 5,5'-fused membered ring which is the precursor to cyclopenta[c]thiophene the sulfone ester, 5-carbomethoxy-5- phenylsulfonyl-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene, in just two steps as compared to four steps previously reported in the literature. This valuable precursor intermediate currently made and proven by characterization is one synthetic step away from a substituted cyclopenta[c]thiophene. A paper has been submitted to Letters in Organic Chemistry to report our work.
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Granström, Andreas. "Adsorption of methylene blue on iron-doped lignin hydrochar." Thesis, Umeå universitet, Kemiska institutionen, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-150540.
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Mitchell, Ellen Margaret. "Photochemical Studies of Dinuclear Methylene-Bridged Transition- Metal Complexes /." The Ohio State University, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487930304688889.
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Joonwichien, Supawan. "Magnetic Field Effects on Heterogeneous Photocatalytic Degradation of Methylene Blue." Kyoto University, 2011. http://hdl.handle.net/2433/151897.
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Lu, Xiaosong. "Generation and reactions of aryloxy and diaryloxycarbenes /." *McMaster only, 2001.
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Sukhapan, Jariya. "Surfactants in atmospheric aerosols." Thesis, University of East Anglia, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251504.
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Welagedara, Asanka. "Phosphorus Removal and Methylene Blue Adsorption by Porous Calcium Silicate Hydrate." Thesis, KTH, Mark- och vattenteknik (flyttat 20130630), 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-171836.
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Nutrients (nitrogen and phosphorus) should be removed and recycled from wastewater in order to reduce the nutrient load to recipient waters, avoiding contamination of groundwater and conserve resources. There is a need to pay more attention to phosphorus (P) removal and recycling from wastewater due to limited availability of phosphorus recourses. For such purpose reactive filter media can be used to remove nutrient from wastewater as a sustainable technology. The present study was aimed to evaluate calcium silicate hydrate crystallization in Absol as a reactive filter media for removal and recycle of phosphorus from household wastewater and assess physical and chemical characteristics of Absol. A study of the color removing capacity of Absol was also performed. Several batch experiments were done for comparing absorption mechanism. Collected data were applied to Langmuir and Freundlich isotherm models to study type of adsorption isotherms and pseudofirst- order and second order models were run for study of adsorption kinetics. The experiment demonstrated a very high P and Methylene Blue (MB) sorption capacity. The amount of adsorbed P and MB vary with initial solution concentrations, contact time, and adsorbent dosage. Both equilibrium data (P, MB) were fitted very well in the Langmuir isotherm equation, confirming the monolayer physical sorption and adsorption kinetic followed by the pseudo-second order kinetic model. It is concluded that Absol can have potential to be use for the removal of P, textile dye contaminants and probably also pharmaceuticals present in wastewater.
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Baror, Roey. "Exploring the methylome and transcriptome of young adult and aged OPCs." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/273343.
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Remyelination is the restoration of myelin sheaths to denuded axons following demyelinating events, which occurs spontaneously in adult mammals, including humans. The principal cells which participate in remyelination are the Oligodendrocyte Progenitor Cells (OPCs). Similar to other regenerative processes, remyelination efficiency declines with ageing. It is still unknown how much of this decline can be attributed to intrinsic changes in the OPCs themselves rather than environmental changes arising from changes in the cellular niche. Thus, we currently have a fundamental gap in our knowledge regarding the basic biology of adult OPCs, and therefore the changes that occur to them with ageing. In order to address these questions, I have developed a method to reliably isolate all cell types of the oligodendrocyte (OL) lineage from adult rats. This allowed me to identify the specific transcriptome state unique to adult OPCs, which is different to the transcriptome of neonatal OPCs, upon which previous studies have focused. This included genes which support the notion that following the initial phases of developmental myelination, adult OPCs enter a quiescent mode, in a manner similar to other tissue resident stem cells. Moreover, using a recently established isolation method, I was able to isolate aged OPCs, and develop a transcriptional database that can allow researchers to explore the changes in aged OPCs and identify new targets for enhancing their function. Lastly, I present in this thesis novel ideas regarding the influence of microglia cell surface molecules on OPC differentiation. I show that changes in the cell surface of aged microglia are inhibitory for OPC differentiation into OLs, and that these changes in microglia are a result of the increase in TGFb levels with ageing. In summary, this dissertation introduces new tools and methods that will allow x further in-depth study of adult OPCs, and specifically will help to shed light on the role of adult OPCs in the CNS in homeostasis. Furthermore, I explore the changes that occur within OPCs as they age, and show how such changes reduce aged OPCs ability to efficiently facilitate the process of remyelination.
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Shukla, Pooja. "Effect of DNMT3B expression on the human pluripotent stem cell methylome." Thesis, University of Nottingham, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738337.
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Reprogramming of somatic cells into induced pluripotent stem cells is accompanied by extensive changes in gene expression and epigenetic marks. The single genotype human pluripotent stem cell (hPSC) model system developed in this study overcomes the experimental variability resulting from cell line derivation and culture, and genetic variations which may contribute to the methylation differences observed between human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). On comparing the expression levels of DNA methylation regulating enzymes -DNMTs between HUES7 and HUES7-iPSC cells of the model system, DNMT1 and DNMT3B showed significantly reduced expression in the iPSCs. DNMT3B in particular displayed —50% reduced expression, when compared to HUES7. From methylated DNA precipitation sequencing (MeDIP-Seq) the methylation profiles of HUES7-iPSCs and HUES7 were found to be globally very similar, with the exception of few subtle differences observed in the iPSC methylome which were predominantly hypermethylated. Knockdown of DNMT3B in HUES7 and HUES7-iPSCs resulted in a hypomethylated state of their genome. The hypermethylated differentially methylated regions (DMRs) in HUES7-iPSCs and the hypomethylated DMRs in knockdown HUES7 and HUES7-iPSCs, were unevenly distributed across the chromosomes and found to be largely enriched in gene bodies and intergenic regions, suggesting DNMT3B's affinity to methylate these regions. A more dramatic effect of DNMT3B knockdown was seen in HUES7-iPSCs compared to HUES7, which might largely be due to the normally reduced expression of DNMT3B seen in these cells. Genes affected by DMRs in DNMT3B knockdown HUES7 and HUES7-iPSCs were found unique to them. Three genes FAM19A5, FZD10 and SLITRK2 affected by hypermethylated DMRs in HUES7-iPSCs had their methylation levels restored to those seen in HUES7, on loss of DNMT3B expression, suggesting a role of DNMT3B in maintaining the methylation levels of these regions. Very little correlation was seen between the methylation and transcriptional profiles for both untreated and knockdown hPSCs. In knockdown cells, a large number of differentially expressed genes were identified with respect to their corresponding untreated samples, this indicates a methylation-independent regulatory role of DNMT3B and demands further investigation. Lastly, the functional analysis of the affected genes in knockdown hPSCs highlights their involvement in cardiac, nervous system, and cellular development. Thus, even though the methylation and transcriptional data for knockdown hPSCs show little correlation, the differentially methylated regions might be primed for later de novo methylation event during differentiation.
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Parisel, Olivier. "Du methylene au coronene : methodologies de chimie quantique et applications astrophysiques." Paris 11, 1995. http://www.theses.fr/1995PA112364.
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Cette these d'astrochimie presente essentiellement des calculs de signatures spectrales de molecules d'interet astrophysique. Ce travail est cependant un travail de chimie theorique: diverses methodologies permettant d'acceder a des resultats quantitatifs et predictifs sont utilisees ou developpees parmi lesquelles la methodologie mc/p qui couple traitement variationnel (interaction de configurations) et traitement de perturbation, offrant ainsi un outil de choix pour le calcul des spectres electroniques ou des electroaffinites. Dans le premier chapitre sont presentees les specificites du milieu interstellaire (mis) et dans le second une description du formalisme de la chimie quantique variationnelle (scf, mcscf, casscf, ic). Une approche detaillee de la correlation electronique est faite au chapitre iii qui s'acheve sur la description des approches multireferences cipsi, castp2, gmpn et mc/p. L'approche mc/p est ensuite appliquee aux especes ch#2, nh#2, sih#2, o#2, c#2h#4, h#2co et h#2c#2. Le chapitre suivant predit les signatures spectrales des composes sin, sinh#2+, h#2sin+ et hsinh+ en s'appuyant sur une calibration prealable obtenue par l'etude de hnsi, hsin, hsinh#2 et h#2sinh. Le chapitre v reformule la methode mc/p dans un cadre semi-empirique utilisant des hamiltoniens effectifs (ppp, cs/indo) et l'applique aux diphenylmethylene (dpm) et 2-naphtylphenylcarbene (npc) dont le spectre de fluorescence et les constantes zfs sont determines pour differentes conformations. Enfin, la methode mc/p est appliquee au probleme des bandes diffuses interstellaires (dib) via la determination des spectres d'absorption des neutres, anions et cations de pah (hydrocarbures aromatiques polycycliques), de leurs derives methyles ou des produits issus de leur fragmentation
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Karunaratne, Kalani Udara. "Probing the methylene and hydride transfers in flavin- dependent thymidylate synthase." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6443.
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All organisms must maintain an adequate level of thymidylate, which gets phosphorylated twice and then utilized by DNA polymerases for DNA replication that must precede cell division. Most organisms rely on classical thymidylate synthase (TSase) for this function. However, a subset of microorganisms – including a number of notable, widespread human pathogens – relies on an enzyme with a distinct structure and catalytic strategy. This enzyme is termed flavin-dependent thymidylate synthase (FDTS), as the flavin is required for thymidylate production. Because of this considerable orthogonality between FDTS and classical TSase, FDTS serves as a promising target for new therapeutics – one that could have only mild adverse effects on the host organism. FDTS catalyzes the reductive methylation of uridylate (2′-deoxyuridine-5′-monophosphate; dUMP) to yield thymidylate (2′-deoxythymidine-5′-monophosphate; dTMP). The methylene originally resides on CH2H4folate and is eventually transferred to the nucleotide. This methylene’s route to dUMP is unique in enzymology, and our experiments described herein strive to gain an understanding of the molecular details of its transfer. Compounds that mimic intermediates and transition states along this path are likely to bind FDTS tightly and could be leads for drugs, and our new insights could facilitate this. After methylene transfer is complete, a hydride transfer from flavin to the nucleotide occurs. We utilized rapid quench flow techniques in heavy water to follow the hydrogen transfers in FDTS; solvent isotope effects were measured and analyzed, furnishing evidence that the hydride transfer contributes to rate limitation. Reconstitution of the enzyme with unnatural flavins both reinforced these conclusions and suggested new hypotheses and experiments.
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Upadhyaya, Ashraya. "Nitrogen Doped Titanium Dioxide in the Photocatalytic Degradation of Methylene Blue." ScholarWorks@UNO, 2018. https://scholarworks.uno.edu/honors_theses/120.
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Titanium dioxide(TiO2) is a stable, effective and well-known photocatalyst for degradation of pollutants. However, its practical applications are limited due to the need for energy higher than 3.2 eV, or a wavelength lower than 390 nm (high frequency waves, ultraviolet and above) hindering its ability to effectively work in the visible light region (about 400 nm to 700 nm). Nitrogen-doped TiO2 (N-TiO2) has garnered some attention as a photocatalyst as it appears to work even in the visible light region. This could allow the utilization of a larger part of the solar spectrum. This thesis presents the results of photocatalytic degradation of methylene blue (MB) carried out under simulated visible light by using TiO2 and N-TiO2(doped in the lab) to evaluate and compare their efficiencies under similar conditions.
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Hazeland, E. Louise. "Optically active methylene-diphos ligands via a P/Si exchange reaction." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.702868.
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The synthesis of optically-active diphos ligands is normally multi-step and/or requires an optical resolution step. This thesis reports a mild, one-step route to optically active, C1-backbone diphos ligands via a P/Si exchange reaction between a chlorophosphite and a (phosphinomethyl)silane. The route is remarkably efficient, where the only by-product of the reaction is CISiMe3 which is volatile and readily removed from the reaction mixture. The route is shown to be modular,and has been used to make R2P(CH2)P(OR')2, R2P(CH2)PR'2, R2P(CHR" )P(OR')2 and R2P(NH)P(OR)2 type ligands, where P(OR)2 and PR'2 are optically active phosphacycles. Rh(I) complexes of the C1-backbone diphos ligands were applied to the asymmetric hydrogenation of three benchmark substrates DMI, MAA and MAC with up to 99% ee obtained; the catalyst loading was reduced to 0.2 mol% for one example. Furthermore, analysis of the quadrant blocking diagrams for the complexes confirmed that the absolute configurations of the products of asymmetric hydrogenation conform to the quadrant rule. The potential of this synthetic route for high throughput experimentation methods was demonstrated through a one-pot procedure to generate the Rh(I) complex in situ. The 97% ee obtained compared favourably with the 98% ee obtained with the isolated complex. A mechanistic investigation was carried out in order to understand the scope and limitations of the P/Si exchange route. The order of reaction with respect to both P reagents was found to be (pseudo) zero order. An initial rate dependence was found on the initial concentration of the chlorophosphite, suggesting an impurity was catalysing the reaction; this was identified as HCI (H+); the reaction was completely inhibited by addition of NEt3. The mechanism has been proposed to proceed via a secondary phosphine ylide intermediate R2P(H)CHSiMe3. Evidence for this intermediate was provided by: (i) the observation of exchange of the optically active phosphacycle during a cross-over experiment; (ii) a Peterson-like reaction upon addition of an aldehyde to a phosphinosilane; (iii) deuterium incorporation into the CH2 backbone of the diphos product upon addition of DCI to the reaction of the chlorophosphite with the (phosphinomethyl)silane. Kinetic simulations of the proposed model gave excellent fits with a wide range of experimental data, including varying concentrations of both of the reagents and addition of HCI. The P/Si exchange route was extended to the synthesis of optically active, unsymmetrical diphos ligands with a NH-backbone. The free ligands were found to form almost exclusively as the P-P=N tautomer in solution, and then tautomerised to the PNP isomer upon heating or coordination to Pd(II) or Rh(I). Furthermore, the proton of the PNP was found to reside on the P of the PiPr2 group in solution, evident from a large J PH value in both the 1 Hand 31 P NMR spectra. A Rh(I) complex of one P rp ligand was applied to the asymmetric hydrogenation of DMI, MAA and MAC, but the PNP complex gave only 57-80% ee. To probe electronic effects in asymmetric hydrogenation, two isosteric C1-backbone ligands were prepared, one with a binol group and one where the 0 atoms are replaced by CH2 groups. The asymmetric hydrogenation results from their Rh(I) complexes compared. The Rh(I) complex of the ligand with two strongly σ-donating P-.atoms gave lower enantioselectivities than the phosphine-phosphonite derivative. The crystal structures of the [PtCh(L)] (L = (binol)PCH2PtBu2 or (R2HC)PCH2PtBu2) complexes showed differences in the P-Pt bond lengths which may point to the source of the difference in the selectivity of the ligands in catalysts. Finally, ligands of the type R2P(CHR" )P(OR')2 ligands have been synthesised via the P/Si exchange reaction. The presence of a chiral centre on the backbone lead to two diastereomers of the ligand. The Rh(I) complexes of these ligands were screened for the asymmetric hydrogenation of MAA and MAC and in most cases were observed to give slightly higher enantioselectivities than the CH2 analogues.
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Tsuji, Hayato. "Syntheses and Photophysical Properties of Oligosilanes Conformationally Constrained by Methylene Tethers." 京都大学 (Kyoto University), 2001. http://hdl.handle.net/2433/150690.
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Merkley, Nadine. "Carbenes and radicals from benzyloxy [delta]3-1,3,4-oxadiazolines /." *McMaster only, 2001.
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Thesis (Ph.D.) -- McMaster University, 2001.[Delta] in title is a Greek letter. The number 3 in title is superscript. Includes bibliographical references (leaves 147-162). Also available via World Wide Web.
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El-Saidi, Manal M. T. "Synthesis and thermolysis of 2,2-dioxy-5,5-dimethyl-[delta three]-1,3,4-oxadiazolines : dioxycarbenes and their reactions /." *McMaster only, 1996.
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Couture, Philippe. "Syntheses and reactions of aminooxycarbenes from thermolysis of [Delta3]-1,3,4-oxadiazolines /." *McMaster only, 1997.
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Asay, Matt J. "Ylides stabilization of novel, low valent carbon-based ligands with applications in catalysis /." Diss., [Riverside, Calif.] : University of California, Riverside, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3350076.
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Thesis (Ph. D.)--University of California, Riverside, 2009.Includes abstract. Title from first page of PDF file (viewed Mar. 8, 2010). Includes bibliographical references. Issued in print and online. Available via ProQuest Digital Dissertations.
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Lian, Yiqian. "Chromium and iron organometallics in organic synthesis synthetic studies toward total synthesis of taxol and chromium to iron transfer processes /." Diss., Connect to online resource - MSU authorized users, 2006.
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Edlin, Shaun Michael. "Methylene blue, spatial memory and anterior thalamic lesions relevant to amnesic disorders." Thesis, University of Canterbury. Psychology, 2011. http://hdl.handle.net/10092/6521.
Full textAbstract:
While recent studies have focused on methylene blue’s interaction with amyloid plaques and
neurofibrillary tangles in Alzheimer’s disease,!no studies have investigated the efficacy of
methylene blue in animal-lesion models of regional pathology relevant to AD. The goal of
this dissertation was to examine the effects of methylene blue on spatial memory in aged
Wistar rats with lesions to the anterior thalamic nuclei (ATN), part of an extended episodic
memory system that shows early pathology in AD and diencephalic amnesia. First, 12 ATN
rats were compared to 14 aged shams (18 to 22 months old) to assess spatial memory
acquisition in a standard water maze task (10 days). Rats in each group then received
intraperitoneal injections of methylene blue (1 mg/kg) or placebo 1 hour after each daily trial
for 10 days in which acquisition of a new platform position was examined, followed by a
probe trial 5 days later. Anterior thalamic lesions impaired initial acquisition of the reference
memory task. In the subsequent acquisition and probe trial, methylene blue treatment vs.
placebo improved spatial learning in ATN rats, but there was no effect in sham rats. These
results provide the first evidence that methylene blue may prevent the learning impairments
observed in rats with lesions to the anterior thalamus and supports methylene blue as a
potential therapeutic intervention for older humans with memory disorders associated with
injury to the ATN and the extended episodic memory system.
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Smith, Kristen Colleen. "Surface processes ruthenium film growth, silicon nanocrystal synthesis, and methylene partial oxidation /." Access restricted to users with UT Austin EID Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3035980.
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Taylor, Joshua D. "Hydrothermal chemistry of methylene chloride and MTBE : experimental kinetics and reaction pathways." Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/16753.
Full textAbstract:
Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2001.Includes bibliographical references.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
With the growing desire for sustainable technologies, reactions in benign solvents, such as hydrothermal water and supercritical fluids, have become the focus of many investigations. Hydrothermal water has been used as a medium for chemical reactions, where the enhanced dissociation constant of water led to both acid- and base-catalysis without added reagents. Supercritical water oxidation (SCWO) has been proposed as an alternative technology for the treatment of aqueous-organic waste streams. At typical SCWO conditions (T = 550-650°C and P = 250-300 bar), mixed organic waste streams can be completely mineralized (>99.99%) in residence times of less than one minute. In an SCWO process, the waste stream is preheated to temperatures of >400°C in the absence of oxygen prior to the reactor. In the preheater, hydrolysis reactions may occur, significantly changing the composition of the reactor feed. To properly model these processes, a fundamental understanding of the reaction pathways and associated rates is essential. The rates of methylene chloride and methyl tert-butyl ether (MTBE) hydrolysis in sub- and supercritical water have been measured experimentally at 250 bar over a range of temperatures from 100 to 600°C. The rate constants for both compounds showed a local maximum below the critical temperature of water (374°C) followed by a local minimum just above the critical temperature. This behavior was qualitatively attributed to the changes in the solvent properties of water, shifting from a polar solvent in the subcritical region to a nonpolar solvent in the supercritical region. One of the primary objectives of this thesis was to develop a better understanding of the molecular-level effects of the solvent on the reaction rates and mechanistic pathways. The effects of water as a solvent on the hydrolysis reaction of CH2Cl2 were modeled as a dielectric continuum using Kirkwood theory. A correction factor, obtained from ab initio calculations, was applied to adjust the activation energy in order to account for differences in the free energy of solvation of the reactant and the transition state. Application of the Kirkwood correction to the empirical rate expression fit to data from 100-250°C yielded a model that quantitatively agreed with the experimentally measured reaction rate over the entire temperature range (from 100 to 500°C). To explain the extrema in the rate constant measured for MTBE hydrolysis, an acid-catalyzed mechanism was proposed. A new empirical rate expression was determined with a first-order dependence on the concentrations of H+ and MTBE. For the entire temperature range studied from 150 to 600°C, the empirical rate expression quantitatively modeled the experimentally measured decomposition rate within the uncertainty of the experiments. Further experiments were conducted with added HCl or NaOH that validated the acid-catalyzed hydrolysis pathway. The experimentally observed dependence on the concentration of H+ was slightly smaller than predicted by the proposed mechanism. Ab intio tools were employed to determine the relative contribution of a unimolecular decomposition pathway, which concluded that the pathway was not significant below 550°C. The unimolecular decomposition pathway set a lower limit on the overall reaction rate, which was observed experimentally under basic conditions where the acidcatalyzed pathway was effectively shut off. In addition to the kinetic measurements, two new experimental tools were developed to improve the capabilities of the supercritical fluids laboratory. Firstly, a new, large-bore tubular reactor system was built to address limitations in the current flow reactors in the supercritical fluids laboratory. The reactor was designed with the following advantages: 1) large diameter to minimize wall effects; 2) direct organic feed to eliminate hydrolysis during preheaters; 3) movable sampling probe; 4) sapphire windows to allow optical accessibility. The reactor was tested in preliminary runs up to 600°C and 250 bar. Secondly, a new reactor system was built to allow optical accessibility for in situ Raman spectroscopic measurement in supercritical fluids. The system was used in a study to probe local solvent effects in supercritical carbon dioxide. The effect of temperature, pressure, and density of CO2 on the vibrations of benzene and methylene chloride were investigated. As the density of CO2 increased, the vibrations shifted to lower frequency initially, and then leveled off at moderate densities. This leveling off may be due to local clustering of solvent molecules around solutes in these systems.
by Joshua David Taylor.
Ph.D.
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KUO, FANG-WEI, and 郭芳韋. "Chiral Separation of Methylone and Ethylone Enantiomers Using Liquid Chromatography Tandem Mass Spectrometry." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/zkej25.
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碩士慈濟大學
醫學生物技術碩士班
106
近年來合成卡西酮類新興影響精神物質的大幅度氾濫，全世界也開始對此拉起警報，但隨著合成卡西酮的走私受到強制性規範以及國際情勢的影響，導致前驅物與合成方法產生變化。而3,4-亞甲基雙氧甲基卡西酮 (methylone) 和3,4-亞甲基雙氧-N-乙基卡西酮 (ethylone)是合成卡西酮中相當常見的兩個種類，其鏡像異構物比值和純度可提供與合成來源相關的資訊，因此開發一套能夠同時分析這二種合成卡西酮鏡像異構物的方法對於法醫實驗室是必要的。在此方法中，我們藉由多糖衍生物手性管柱以及串聯質譜的偵測來達到鏡像異構物的分離和確認，透過一系列的方法評估，此方法呈現相當良好的再現性，在同日間與異日間的準確度和精密度皆有低於8%的誤差。據我們所知，這是首篇針對3,4-亞甲基雙氧甲基卡西酮 (methylone) 和3,4-亞甲基雙氧-N-乙基卡西酮 (ethylone)之晶體樣品的鏡像異構物的分析研究，我們總共分析了74個於2015至2016期間在台灣查獲的毒品樣品，發現其鏡像異構物比值約為1.0，而純度方面則依查獲地點及包裝型態有所差異。
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Tsai, I.-Lin, and 蔡易霖. "Identify the metabolites of methylone and ethylone using human liver microsomes and human urine." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/8b6k2p.
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碩士國立臺灣大學
法醫學研究所
107
Synthetic cathinone is the most frequently abused new psychoactive substances (NPS) in Taiwan. Methylone and ethylone, which were categorized as scheduled III drug in 2012 and 2016 in Taiwan, are two derivatives of synthetic cathinone. It is important to investigate the metabolism of methylone and ethylone in order to find specific markers in human specimen. However, the metabolic profile of these two compounds are still limited especially for phase II metabolites. In previous study, methylone and ethylone each formed 7 metabolites through 5 metabolic pathways. In this study, we in vitro synthesized phase I and phase II metabolites by human liver microsomes and cytosols, and observed metabolites by fragment pattern and accurate mass using liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-high resolution mass spectrometry (LC-HRMS). Total eight phase I metabolites and three phase II metabolites were detected. Three in vitro phase II metabolites, sulfate conjugate of dihydroxymethcathinone (DHMC-S) from methylone, sulfate conjugate of dihydroxyethcathinone (DHEC-S) from ethylone and glucuronide conjugate of dihydroxymethcathinone (DHEC-G) from ethylone have never reported before. The method was established to identify the metabolites in human specimens. Urine samples from methylone and ethylone abusers were analyzed to evaluate the composition of metabolites. Dihydromethylone and glucuronide conjugate of 3-hydroxy-4-methoxymeth-cathinone (3-OH-4-MeO-MC-G) or its isomer 4-OH-3-MeO-MC-G were major metabolites of methylone, and Dihydroethylone and DHEC-S were major metabolites of ethylone in abusers urine samples. But more urine sample should be analyzed to make the metabolic trend more obvious.
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Teixeira, Catarina Tavares. "In vivo hepatotoxicity of the new drugs of abuse 3,4-dimethylmethcathinone (3,4-DMMC) and methylone." Dissertação, 2019. https://hdl.handle.net/10216/123333.
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Silva, Bárbara Sofia Poléri da. "Enantioselectivity of pentedrone and methylone: enantioresolution by liquid chromatography and in vitro toxicokinetic/toxicodynamic studies." Tese, 2021. https://hdl.handle.net/10216/136398.
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Teixeira, Catarina Tavares. "In vivo hepatotoxicity of the new drugs of abuse 3,4-dimethylmethcathinone (3,4-DMMC) and methylone." Master's thesis, 2019. https://hdl.handle.net/10216/123333.
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Silva, Bárbara Sofia Poléri da. "Enantioselectivity of pentedrone and methylone: enantioresolution by liquid chromatography and in vitro toxicokinetic/toxicodynamic studies." Doctoral thesis, 2021. https://hdl.handle.net/10216/136398.
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