Cyclic, f-Cyclic, and Bicyclic Decompositions of the Complete Graph into the 4-Cycle with a Pendant Edge.

In this paper, we consider decompositions of the complete graph on v vertices into 4-cycles with a pendant edge. In part, we will consider decompositions which admit automorphisms consisting of: (1) a single cycle of length v, (2) f fixed points and a cycle of length v − f, or (3) two disjoint cycles. The purpose of this thesis is to give necessary and sufficient conditions for the existence of cyclic, f-cyclic, and bicyclic Q-decompositions of Kv

Characterization of the membrane transporter OATP1A2 activity towards different classes of drugs

Les transporteurs membranaires sont des éléments importants dans le devenir, l’efficacité, et la toxicité du médicament. Ils influencent la pharmacocinétique et la pharmacodynamie de ces derniers. Plusieurs interactions médicamenteuses observées cliniquement sont attribuables à la fois aux enzymes responsables du métabolisme des médicaments et aux transporteurs membranaires. Il est connu qu’une variabilité existe entre différents individus dans la réponse à un médicament et les polymorphismes génétiques retrouvés dans les gènes codant pour les transporteurs membranaires peuvent partiellement expliquer cette variabilité. OATP1A2 est un transporteur membranaire exprimé sur des organes importants, comme le cerveau et le rein. Plusieurs médicaments utilisés en clinique sont des substrats d’OATP1A2 et l’expression localisée de ce transporteur suggère un rôle important dans le devenir du médicament. Donc, mon projet de doctorat consistait à caractériser l’activité d’OATP1A2 en relation avec ses substrats et inhibiteurs, et de plus, à évaluer l’impact de différents variants génétiques d’OATP1A2 sur leur transport. Dans le premier article, la rosuvastatine a été utilisée comme substrat-type pour étudier le transport d’OATP1A2. Les expériences ont été menées en introduisant la rosuvastatine en compétition avec différent β-bloqueurs, une classe de médicaments rapportée dans la littérature comme substrats d’OATP1A2. Parmi les β-bloqueurs évalués, le carvédilol était l’inhibiteur le plus puissant. Dans la deuxième partie de l’étude, des médicaments ayant une structure similaire au carvédilol, tels que les antidépresseurs tricycliques, ont été évalués quant à leur potentiel d’inhibition sur OATP1A2. Une relation structure-activité a été définie à l’aide de ces données. Nous avons démontré que des composés tricycliques avec une courte chaîne aliphatique pouvaient inhiber OATP1A2. Dans le deuxième article, OATP1A2 a été étudié en considérant son expression et son rôle au sein de la barrière hémato-encéphalique (BHE). Des études précédentes ont démontré qu’OATP1A2 est exprimé sur la membrane luminale des cellules endothéliales formant la BHE. Nos données démontrent que les triptans, une classe de médicaments couramment utilisées pour traiter la crise migraineuse, sont des substrats d’OATP1A2 et que les composés tricycliques identifiés comme inhibiteurs d’OATP1A2 dans nos études précédentes peuvent inhiber le transport des triptans par OATP1A2. Ces résultats sont importants puisque: 1) il a été suggéré que les triptans peuvent agir au niveau du système nerveux central en se liant aux récepteurs trouvés sur les neurones centraux; 2) comme les triptans sont des molécules hydrophiles, un mécanisme de transport facilité est nécessaire pour qu’ils pénètrent la BHE et OATP1A2 pourrait être l’élément clé; 3) l’inhibition d’OATP1A2 par les composés tricycliques pourrait limiter l’accès des triptans à leur site d’action. Le troisième article caractérise l’activité associée à deux variants génétiques d’OATP1A2 (OATP1A2*2 et *3). Leur capacité à transporter les triptans et leur potentiel d’inhibition par les médicaments tricycliques ont été évalués. Des résultats supplémentaires caractérisant OATP1A2, mais sans liens directs avec les trois articles, seront présentés en annexe. Dans l’ensemble, les résultats présentés dans cette thèse servent à caractériser le transporteur membranaire OATP1A2 en relation avec ses substrats et inhibiteurs, et en fonction de ses variants génétiques.Drug transporters are important determinants in drug disposition, efficacy, and toxicity. They influence the pharmacokinetics and pharmacodynamics of drugs. Several clinically-observed drug-drug interactions are mediated through drug metabolizing enzymes and drug transporters. It is well known that there is an interindividual variability in the response to medications and polymorphisms found in genes encoding for drug transporters partially account for it. OATP1A2 is a membrane drug transporter expressed on important organs, such as the brain and the kidney. A wide spectrum of drugs used in the clinic are substrates of OATP1A2. Its localisation suggests an essential role in drug disposition. Thus, my PhD project consisted of characterizing the activity of OATP1A2 in regards to its substrates, inhibitors, and different protein variants due to genetic polymorphisms. In the first article, rosuvastatin was used as the probe substrate to study OATP1A2 transport activity. Experiments were conducted by putting rosuvastatin in competition with different β-blockers, a class of drugs known in the literature to be transported by OATP1A2. One of the drugs evaluated, carvedilol, inhibited OATP1A2 with much more potency than the others. In the second part of the study, drugs with a structure similar to carvedilol, such as tricyclic antidepressants, were tested for their potential to inhibit OATP1A2. A structure-activity relationship was defined using the data. It was demonstrated that drugs composed of a tricyclic ring with a short aliphatic amine chain were potent OATP1A2 inhibitors. In the second article presented, OATP1A2 was studied in the context of its localization at the blood-brain barrier (BBB). OATP1A2 expression at the luminal membrane of the endothelial cells making up the BBB was demonstrated in the literature. Our article showed that triptans, a class of commonly used anti-migraine drugs, were OATP1A2 substrates. The tricyclic drugs previously evaluated were shown to potently inhibit triptan transport through OATP1A2. These findings are important for three reasons: 1) it has been postulated that triptans may act at the central nervous system by binding to receptors found on central neurons; 2) as triptans are hydrophilic molecules, a facilitated transport mechanism is required for them to penetrate the BBB and OATP1A2 may be the key player; and 3) the inhibition of OATP1A2 by the tricyclic drugs may limit the entrance of triptans to their site of action. The third article characterized the transport activity of two OATP1A2 protein variants (OATP1A2*2 and *3). Their capacities to transport triptans and their potential of being inhibited by tricyclic drugs were evaluated. Additional data characterizing OATP1A2 but considered out of the scope of the three articles will be presented in appendices. In overall, the central theme of this thesis looks into the characterization of the OATP1A2 membrane drug transporter in regards to its substrates, inhibitors, and proteins variants

An Updated Overview of Low Back Pain Management in Primary Care

Currently, guidelines for lower back pain (LBP) treatment are needed. We reviewed the current guidelines and high-quality articles to confirm the LBP guidelines for the Korean Society of Spine Surgery. We searched available databases for high-quality articles in English on LBP published from 2000 to the present year. Literature searches using these guidelines included studies from MEDLINE, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Embase. We analyzed a total of 132 randomized clinical trials, 116 systematic reviews, 9 meta-analyses, and 4 clinical guideline reviews. We adopted the SIGN checklist for the assessment of article quality. Data were subsequently abstracted by a reviewer and verified. Many treatment options exist for LBP, with a variety of recommendation grades. We assessed the recommendation grade for general behavior, pharmacological therapy, psychological therapy, and specific exercises. This information should be helpful to physicians in the treatment of LBP patients

Saturated Hydrocarbon Analysis of Liberty State Park Soils

Contaminated soils have been a concern in New Jersey since the Industrial Revolution (Gallagher, 2008). One site in particular has a variety of contaminants and is near the coast of Jersey City in Liberty State Park. Liberty State Park has been impacted by three significant changes. It was first a wetland in the 1600s, then became a New York dump site, and finally a railyard for the Central Railroad of New Jersey (Stanislaw, 2013). The whole land mass has mixed contaminants, including trace elements, heavy metals, organic wastes, and organic compounds. Currently, most of the state park has been dredged out and filled with “reclaimed landfill”. Only 102 out of the park\u27s 490 hectares were left unremediated and this is the area that is under research. Even with this site still being highly contaminated, it has abundant plant life that has followed a relatively normal succession. In normal conditions, one might expect that contaminants would interfere with plant growth because they would impede different enzymatic functions of the plant. The goal of this study is to find out what contaminants are present in the LSP soils. There are four subplots and a reference site that my research group studied: HMF, 146, 43, 25F, and 25R. HMF or Hutcheson Memorial Forest is a natural preserve that Native Americans used for agriculture. The sites 146, 43, 25F, and 25R are in different locations within the restricted, unremediated section of Liberty State Park (LSP) and have different levels of contamination and plant life. This thesis reports on a category of organic compounds called saturated hydrocarbons. Depending on how contaminated each individual site is, the abundance of the specific saturated compounds may vary. The numerous findings prove that HMF is a natural site by having fewer hydrocarbons, as revealed by gas chromatography-mass spectrometry (GCMS). It also proves that 25R is the most organically contaminated site by its highest abundance of hydrocarbons out of all of the sites. Chapter 1 (Introduction): presents the background of the two site (HMF and LSP) and prepares the reader for the complex topics discussed in the following chapters and describes the significance of this study. Chapter 2 (Environmental Forensics): explains techniques used to investigate specific chemical compounds, how they relate to biotic processes, and how the chemical compounds affect the ecosystem. Chapter 3: (Experimental Methods): goes into the specifics of the analytical techniques and how they apply when examining soil contamination. Chapter 4: (Results and Discussions): shows the results from the experiment and interprets the data. Chapter 5: (Environmental Toxicology/Impacts): explains the health impact of each studied category of compounds, how the compounds enrich the actual sites, and compare overall contaminants (LSP) to the uncontaminated site (HMF). Chapter 6: (Conclusions): draws a final picture of what all the above evidence means, what we should do next, and how does the entire study relate to the people/communities that visit the LSP park now

Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs

BACKGROUND: The plasma membrane neurotransmitter transporters terminate neurotransmissions by the reuptake of the released neurotransmitters. The transporters for the monoamines dopamine, norepinephrine, and serotonin (DAT, NET, and SERT) are targets for several popular psychostimulant drugs of abuse. The potencies of the psychostimulant on the monoamine transporters have been studied by several laboratories. However, there are significant discrepancies in the reported data with differences up to 60-fold. In addition, the drug potencies of the 3 monoamine transporters from mouse have not been compared in the same experiments or along side the human transporters. Further studies and systematic comparisons are needed. RESULTS: In this study, we compared the potencies of five psychostimulant drugs to inhibit human and mouse DAT, SERT and NET in the same cellular background. The K(I )values of cocaine to inhibit the 3 transporters are within a narrow range of 0.2 to 0.7 μM. In comparison, methylphenidate inhibited DAT and NET at around 0.1 μM, while it inhibited SERT at around 100 μM. The order of amphetamine potencies was NET (K(I )= 0.07–0.1 μM), DAT (K(I )≈ 0.6 μM), and SERT (K(I )between 20 to 40 μM). The results for methamphetamine were similar to those for amphetamine. In contrast, another amphetamine derivative, MDMA (3–4 methylenedioxymethamphetamine), exhibited higher potency at SERT than at DAT. The human and mouse transporters were similar in their sensitivities to each of the tested drugs (K(I )values are within 4-fold). CONCLUSION: The current and previous studies support the following conclusions: 1) cocaine blocks all 3 monoamine transporters at similar concentrations; 2) methylphenidate inhibits DAT and NET well but a 1000-fold higher concentration of the drug is required to inhibit SERT; 3) Amphetamine and methamphetamine are most potent at NET, while being 5- to 9-fold less potent at DAT, and 200- to 500-fold less potent at SERT; 4) MDMA has moderately higher apparent affinity for SERT and NET than for DAT. The relative potencies of a drug to inhibit DAT, NET and SERT suggest which neurotransmitter systems are disrupted the most by each of these stimulants and thus the likely primary mechanism of drug action

The solute carrier 6 family of transporters

The solute carrier 6 (SLC6) family of the human genome comprises transporters for neurotransmitters, amino acids, osmolytes and energy metabolites. Members of this family play critical roles in neurotransmission, cellular and whole body homeostasis. Malfunction or altered expression of these transporters is associated with a variety of diseases. Pharmacological inhibition of the neurotransmitter transporters in this family is an important strategy in the management of neurological and psychiatric disorders. This review provides an overview of the biochemical and pharmacological properties of the SLC6 family transporters

Growth of unsaturated, cyclic, and polycyclic aromatic hydrocarbons: Reactions under the conditions of the interstellar medium

Hydrocarbons, in particular polycyclic aromatic hydrocarbons (PAHs), have been long discussed to be carriers of interstellar infrared (IR) emission and ultraviolet (UV) absorption features. Yet, their origin in dense phases of the interstellar medium (ISM), such as molecular clouds, remains unclear. In this work, growth mechanisms based on ion-molecule reactions between cationic PAHs/hydrocarbons and methyne (CH) were investigated. The reaction type and the precursor were derived and selected from known chemical and physical properties of the ISM. These chemical reactions were characterised by calculating branching ratios (based on cross sections) and capture rate coefficients, minimum reaction paths, reaction enthalpies, thermal equilibrium constants, and microcanonic isomerisation and radiative deactivation rate coefficients. In order to cope with the variety of reaction parameters, a hierarchic workflow scheme was set up. First, the reaction potential energy surface was sampled by molecular dynamics simulations. Then, minimum energy paths of the most probable reaction channels were investigated. Finally, molecular and kinetic properties of stationary points were calculated. The quantum chemical level of theory was increased at each step from DFTB (tight-binding density-functional), to DFT, and finally to post-Hartree-Fock methods. Results on CH based hydrocarbon growth showed the transition from non-cyclic hydrocarbons to cyclic and aromatic structures and from cyclic to polycyclic aromatic hydrocarbons. Additionally, the reactive collisions between hydrocarbons and CH were found to produce sufficient energy for isomerisation and fragmentation processes even at ultra low temperatures. In all, the results indicate that methyne might be a proper precursor for the formation of large interstellar PAHs.Kohlenwasserstoffe, insbesondere polyzyklische Kohlenwasserstoffe (engl. PAHs), werden seit einigen Jahren als Mitverursacher interstellar IR-Emissions- und UV-Absorptionsbanden angesehen und diskutiert. Dabei ist die Herkunft dieser Moleküle in den dichten Phasen des interstellaren Mediums (ISM) aber noch nicht aufgeklärt. In dieser Arbeit wurden daher die Bildungsmechanismen, welche auf Ion-Molekül-Reaktionen zwischen kationischen PAHs und Kohlenwasserstoffen und dem Molekül CH beruhen, untersucht. Sowohl der Reaktionstyp als auch der Präkursor wurden anhand von bekannten physikalischen und chemischen Eigenschaften des ISM abgeleitet und ausgewählt. Die Analyse der chemischen Reaktionen basierte auf Berechnungen zur Produktzusammensetzung und Einfangsratenkoeffizienten (welche wiederum aus berechneten Reaktionsquerschnitten hervorgingen) Minimumenergiepfade (MEP), Reaktionsenthalpien, thermische Gleichgewichtskonstanten und mikrokanonische Isomerisierungs- und Strahlungsdeaktivierungs-Ratenkoeffizienten. Um der Vielzahl an Reaktionsparameter gerecht zu werden, wurden die Berechnungsmethoden entsprechend eines hierarischen Fließschemas kombiniert. Hierzu wurden zuerst durch Molekulardynamik-Simulationen die Reaktionspotentialenergieflächen abgerastert. Auf der nächsten Stufe wurden statistisch bedeutsame Reaktionskanäle bezüglich ihrer Minimumenergiepfade untersucht. Den Abschluss bildete die Berechnung molekularer und kinetischer Charakteristika stationärer Punkte auf einem MEP. Entsprechend dieses Schemas wurde die quantenchemische Genauigkeit auf jeder Stufe von approximativer DFT über DFT zu post-Hartree-Fock verändert. Die Ergebnisse des CH-basierten Kohlenwasserstoffwachstums zeigten einen Übergang von nichtzyklischen zu zyklischen and aromatischen Strukturen, sowie von zyklischen zu polyzyklischen Kohlenwasserstoffen. Außerdem zeigte sich, dass reaktive Kollisionen zwischen Kohlenwasserstoffen und CH auch bei Tiefsttemperaturen immer ausreichend Energie für Isomerisierungs- und Fragmentationsprozesse liefert. Die Ergebnisse dieser Arbeit lassen den Schluss zu, dass CH ein geeigneter Präkursor für die Bildung großer interstellarer PAH ist

Racional terapêutico na escolha de antidepressivos: como optimizar a relação benefício-risco?

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.Com a prevalência de patologias do foro psicológico a crescer exponencialmente nas ultimas décadas, uma abordagem mais eficaz à saúde mental tem-se tornado essencial. Os transtornos depressivos são atualmente a maior causa de perda de saúde não fatal. Uma grande parte da população que sofre de distúrbios mentais não tem acesso a cuidados de saúde adequados. Da percentagem de população que tem acesso a terapêutica farmacológica, cerca de um terço é resistente à mesma, e apenas cerca de metade adere à terapêutica. A evolução na área terapêutica da psiquiatria trouxe alguma inovação, e principalmente progresso na relação benefício-risco dos fármacos. Ainda assim, esta encontra-se aquém das necessidades atuais da população que sofre de doenças mentais. Uma grande parte dos doentes tratados com antidepressivos sofre efeitos adversos gastrointestinais, sexuais, neurológicos, alterações no peso e no sono. Muitos destes efeitos são comuns, tendo um forte impacto sobre a qualidade de vida dos doentes. Também a eficácia dos mesmos é limitada, sendo estimado que apenas 50% dos doentes respondam ao tratamento inicial. Torna-se assim urgente não só o desenvolvimento e comercialização de novas opções terapêuticas, como também a otimização da utilização do arsenal terapêutico disponível. A presente monografia procura responder à questão: “Como otimizar a relação benefício-risco de antidepressivos?” abordando o estado da arte da terapêutica antidepressiva, e com base numa revisão de recomendações atuais de associações prestigiadas e publicações recentes. Com um foco na individualização da terapêutica, são reunidas as diferentes estratégias terapêuticas para o tratamento da depressão consoante as especificidades de cada população, nomeadamente para adultos, crianças, adolescentes, mulheres no período peri- e pós-natal, na menopausa, e em populações idosas. A pesquisa realizada tornou ainda evidente a utilidade da testagem farmacogenética para polimorfismos nos citocromos CYP2D6 e CYP2C19 como forma de detetar metabolizadores rápidos ou lentos de antidepressivos, permitindo melhorar os benefícios e reduzir riscos. Por fim, o papel do farmacêutico e dos serviços farmacêuticos prestados à população são colocados em destaque devido à sua importância na deteção de problemas relacionados com os fármacos, otimização da eficácia e aumento da adesão à terapêutica.With the prevalence of mental health disorders rising in the last decade, a more effective approach to addressing mental health is becoming essential. Depressive disorders are the single largest contributor to non-fatal health loss, yet a big percentage of the world’s population has low access to adequate mental care. Of those who do have access, about a third are resistant to pharmacological treatment, and about half do not adhere to therapy. Evolution in the psychiatric therapeutical area brought some innovation throughout the years and with it an improvement of the benefit-risk ratio of medicines. Nonetheless, this relation is still far from the current needs of people suffering from mental disorders. Adverse effects such as sexual dysfunction, weight, sleep, gastrointestinal and neurological disturbances impact the quality of life of many patients taking antidepressants. Efficacy is also limited, with only 50% of patients responding to initial treatment. It is therefore urgent not only to develop and commercialize new therapeutic options but also to optimize the use of the currently available therapeutic arsenal. The present dissertation aims to answer the question “How to maximize the benefit-risk ratio of antidepressants?”, by summarizing antidepressant therapy state of the art and based on a review of current recommendations from prestigious guidelines, as well as other recent publications. Focusing on therapy individualization, best practices for optimizing the use of antidepressants are gathered for specific populations: adults, children and adolescents, women during peri- and post-natal period, menopause, and in the elderly. The literature review also showed that pharmacogenetic testing for CYP2D6 and CYP2C19 polymorphisms is a promising way of detecting slow and fast drug metabolizers, thus enhancing the benefit and reducing risks. Finally, the major role of pharmacists and pharmaceutical care providence is highlighted as essential in the management of depression, to detect drug-related problems, and improve adherence and efficacy of therapy