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1.
ACS Med Chem Lett ; 10(11): 1573-1578, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-32038769

RESUMO

A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.

2.
J Med Chem ; 61(21): 9647-9665, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30272964

RESUMO

A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray cocrystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.


Assuntos
Inibidores de Catecol O-Metiltransferase/química , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Desenho de Fármacos , Oxiquinolina/química , Oxiquinolina/farmacologia , Animais , Encéfalo/metabolismo , Catecol O-Metiltransferase/química , Inibidores de Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacocinética , Masculino , Camundongos , Modelos Moleculares , Oxiquinolina/metabolismo , Oxiquinolina/farmacocinética , Conformação Proteica , Ratos , Distribuição Tecidual
3.
J Clin Psychol ; 74(6): 1034-1052, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29380877

RESUMO

OBJECTIVE: The Mental Health Continuum-Short Form (MHC-SF) is a brief scale measuring positive human functioning. The study aimed to examine the factor structure and to explore the cross-cultural utility of the MHC-SF using bifactor models and exploratory structural equation modelling. METHOD: Using multigroup confirmatory analysis (MGCFA) we examined the measurement invariance of the MHC-SF in 38 countries (university students, N = 8,066; 61.73% women, mean age 21.55 years). RESULTS: MGCFA supported the cross-cultural replicability of a bifactor structure and a metric level of invariance between student samples. The average proportion of variance explained by the general factor was high (ECV = .66), suggesting that the three aspects of mental health (emotional, social, and psychological well-being) can be treated as a single dimension of well-being. CONCLUSION: The metric level of invariance offers the possibility of comparing correlates and predictors of positive mental functioning across countries; however, the comparison of the levels of mental health across countries is not possible due to lack of scalar invariance. Our study has preliminary character and could serve as an initial assessment of the structure of the MHC-SF across different cultural settings. Further studies on general populations are required for extending our findings.


Assuntos
Saúde Global/estatística & dados numéricos , Saúde Mental/estatística & dados numéricos , Satisfação Pessoal , Escalas de Graduação Psiquiátrica/normas , Psicometria/normas , Adolescente , Adulto , Comparação Transcultural , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/instrumentação , Adulto Jovem
4.
Rev. Col. Méd. Cir. Guatem ; 156(2): 71-74, nov. 2017. tab
Artigo em Espanhol | LILACS | ID: biblio-995447

RESUMO

Objetivo: Determinar los conocimientos y actitudes sobre violencia sexual que poseen los adolescentes de Centros Educativos Públicos en el departamento de Chimaltenango en febrero y marzo 2017. Material y métodos: Estudio descriptivo transversal realizado en una muestra aleatoria de 386 sujetos, mediante un cuestionario auto aplicable posterior a consentimiento y asentimiento informado. Resultados: De los sujetos de estudio, 214 (55%) correspondían al sexo femenino, en promedio tenían 12.6 años de edad, 184 (48%) profesaban religión evangélica, 349 (90%) provenían de familias integradas, 292 (76%) pertenecían a la etnia Kaqchiquel. Conocimientos: 132 (34%) refirieron que la violencia sexual se define únicamente como el contacto físico de las partes íntima de otra persona, 116 (30%) identificaron al machismo y el consumo de drogas como factores de riesgo para violencia sexual, 83 (22%) consideraron adecuado el embarazo en menores de edad, 191 (50%) indicaron que en la mayoría de los casos los agresores son personas desconocidas de la víctima; 145 (38%) y 49 (13%) identificaron la calle y el hogar, respectivamente, como los principales lugares en los que se da este fenómeno. Actitudes: 304 (79%) no denunciarían si un compañero/a estuviera sufriendo violencia sexual, 218 (56%) están en desacuerdo con que los padres hablen sobre sexualidad con sus hijos, 202 (52%) no consideran importante que se imparta educación sexual en los centros educativos. Conclusiones: dos terceras partes desconocen conceptos básicos sobre el tema. Se evidencia una marcada indiferencia ante la necesidad de aprender del mismo y apoyar la denuncia de casos de compañeros que sufran algún tipo de violencia sexual.


Objective: To identify the knowledge and attitudes regarding sexual violence of adolescents in public schools of Chimaltenango, between February and March of 2017. Material and Methods: A descriptive cross sectional study conducted in a random sample of 386 subjects, based in a self-applicable questionnaire after student assent and parental consent (from parents or legal guardians). Results: 214 of 386 were female; with an average age of 12.6 years; 184 (48%) profess evangelical religion; 349 (90%) belonged to an integrated household; 292 (76%) belonged to the Kaqchiquel ethnic group. Knowledge: 132 (34%) reported that sexual violence is defined only as physical contact in intimate parts; 116 (30%) identified male chauvinist and drug abuse as risk factors for sexual violence; 83 (22%) considered pregnancy in underage teenagers as adequate; 191 (50%) indicated that in most cases the aggressors are unknown by the victims; students identify the street with 145 (38%) and the house with 49 (13%) as the main places where sexual violence occurs. Attitudes: 304 (79%) of the students would not report if a schoolmate is suffering from sexual violence, 218 (56%) disagree that parents should talk about sexuality with their children, 202 (52%) don't consider important to provide sex education in schools. Conclusions: Two thirds of the students are not aware of basic concepts regarding sexual violence, there is a considerable indifference to the need of learning of this topic and do not support the reporting of cases of classmates who suffer any type of sexual violence.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Estupro/prevenção & controle , Educação Sexual/tendências , Delitos Sexuais/prevenção & controle , Violência de Gênero/tendências , Opinião Pública , Estupro/estatística & dados numéricos , Epidemiologia Descritiva
5.
Rev. Col. Méd. Cir. Guatem ; 156(1): 43-46, 2017 jul. Tab
Artigo em Espanhol | LILACS | ID: biblio-982110

RESUMO

Objetivo: Determinar la prevalencia de ansiedad y depresión en pacientes con insuficiencia renal crónica en tratamiento sustitutivo de hemodiálisis en la Unidad Nacional de Atención al Enfermo Renal Crónico- UNAERC-Guatemala. Población y Métodos: Estudio descriptivo realizado en una muestra de 86 pacientes, mediante una entrevista elaborada con base al test de Hamilton para ansiedad y depresión. Resultados: De la muestra estudiada 80 (93%) pacientes presentaron ansiedad o depresión; en su mayoría las variantes más severas, 42 (49%) ansiedad mayor, y 34(39%) depresión muy grave; 68 (85%) evidenciaron la presencia de ambos trastornos de forma simultánea. Se observó asociación entre el tiempo mayor a 12 meses en tratamiento de hemodiálisis y la presencia de depresión; (X2):10.23; V de Cramer: 0.34 y P: 0.037. Conclusiones: En la Unidad de Atención al enfermo renal crónico-UNAERC-, según la escala de Hamilton, nueve de cada 10pacientes con insuficiencia renal crónica en tratamiento sustitutivo de hemodiálisis tienen algún grado de ansiedad o depresión, de los cuales más de tres cuartas partes presentan estos dos trastornos afectivos de forma simultánea y en su mayoría padecen sus variantes más severas (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Ansiedade/epidemiologia , Diálise Renal , Transtornos do Humor/diagnóstico , Depressão/tratamento farmacológico , Depressão/epidemiologia , Insuficiência Renal/tratamento farmacológico , Epidemiologia Descritiva , Guatemala
6.
Microbiome ; 4(1): 22, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27250991

RESUMO

BACKGROUND: For potential future human missions to the Moon or Mars and sustained presence in the International Space Station, a safe enclosed habitat environment for astronauts is required. Potential microbial contamination of closed habitats presents a risk for crewmembers due to reduced human immune response during long-term confinement. To make future habitat designs safer for crewmembers, lessons learned from characterizing analogous habitats is very critical. One of the key issues is that how human presence influences the accumulation of microorganisms in the closed habitat. RESULTS: Molecular technologies, along with traditional microbiological methods, were utilized to catalog microbial succession during a 30-day human occupation of a simulated inflatable lunar/Mars habitat. Surface samples were collected at different time points to capture the complete spectrum of viable and potential opportunistic pathogenic bacterial population. Traditional cultivation, propidium monoazide (PMA)-quantitative polymerase chain reaction (qPCR), and adenosine triphosphate (ATP) assays were employed to estimate the cultivable, viable, and metabolically active microbial population, respectively. Next-generation sequencing was used to elucidate the microbial dynamics and community profiles at different locations of the habitat during varying time points. Statistical analyses confirm that occupation time has a strong influence on bacterial community profiles. The Day 0 samples (before human occupation) have a very different microbial diversity compared to the later three time points. Members of Proteobacteria (esp. Oxalobacteraceae and Caulobacteraceae) and Firmicutes (esp. Bacillaceae) were most abundant before human occupation (Day 0), while other members of Firmicutes (Clostridiales) and Actinobacteria (esp. Corynebacteriaceae) were abundant during the 30-day occupation. Treatment of samples with PMA (a DNA-intercalating dye for selective detection of viable microbial population) had a significant effect on the microbial diversity compared to non-PMA-treated samples. CONCLUSIONS: Statistical analyses revealed a significant difference in community structure of samples over time, particularly of the bacteriomes existing before human occupation of the habitat (Day 0 sampling) and after occupation (Day 13, Day 20, and Day 30 samplings). Actinobacteria (mainly Corynebacteriaceae) and Firmicutes (mainly Clostridiales Incertae Sedis XI and Staphylococcaceae) were shown to increase over the occupation time period. The results of this study revealed a strong relationship between human presence and succession of microbial diversity in a closed habitat. Consequently, it is necessary to develop methods and tools for effective maintenance of a closed system to enable safe human habitation in enclosed environments on Earth and beyond.


Assuntos
Microbiologia do Ar , Archaea/classificação , Bactérias/classificação , Técnicas Microbiológicas/métodos , Voo Espacial , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Marte , Metagenoma , Viabilidade Microbiana , Lua , Filogenia , Análise de Sequência de DNA , Simulação de Ausência de Peso
7.
Bioorg Med Chem Lett ; 24(1): 258-61, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24332093

RESUMO

A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.


Assuntos
Alcenos/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Alcenos/síntese química , Alcenos/química , Amidas/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
8.
Artigo em Inglês | MEDLINE | ID: mdl-23366693

RESUMO

In this paper, we present preliminary results of subject's mental workload and task engagement assessment in an experimental space suit. We have quantified the mental workload and task engagement based on changes in electroencephalogram (EEG). EEG signals were collected from subjects scalp using a commercial wireless EEG device in two experimental conditions - when subjects did not wear space suit (control condition) and when subjects wore space suit. Brain state changes were estimated and compared with the direct responses for different tasks and different conditions. We found that the spacesuit experiment introduced a greater mental workload where subject's stress levels were higher than control experiment.


Assuntos
Encéfalo/fisiologia , Cognição , Eletroencefalografia/métodos , Trajes Espaciais , Análise e Desempenho de Tarefas , Humanos , Ondas de Rádio
9.
Bioorg Med Chem Lett ; 19(17): 4993-5, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19640712

RESUMO

During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Imidazóis/química , Inibidores de Proteases/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Conformação Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína
10.
Bioorg Med Chem Lett ; 19(1): 17-20, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19036583

RESUMO

A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico , Inibidores Enzimáticos/farmacocinética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Ligação Proteica
11.
Phys Rev E Stat Nonlin Soft Matter Phys ; 66(4 Pt 1): 042601, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12443238

RESUMO

An atomistic model for Cu electrodeposition under nonequilibrium conditions is presented. Cu electrodeposition takes place with a height-dependent deposition rate that accounts for fluctuations in the local Cu2+ ions concentration at the interface, followed by surface diffusion. This model leads to an unstable interface with the development of protrusions and grooves. Subsequently the model is extended to account for the presence of organic additives, which compete with Cu2+ for adsorption at protrusions, leading to a stable interface with scaling exponents consistent with those of the Edwards-Wilkinson equation. The model reproduces the interface evolution experimentally observed for Cu electrodeposition in the absence and in the presence of organic additives.

12.
Austin; ; 1948. 131 L p. tables.
Tese em Inglês | Porto Rico | ID: por-64475
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