9 research outputs found
Enhancing the solubility of SARS-CoV-2 inhibitors to increase future prospects for clinical development
No full textSARS-CoV-2 poses an ongoing threat to human health as variants con tinue to emerge. Several effective vaccines are available, but a diminishing number of Americans receive the updated vaccines (only 22% received the 2023 update). Public hesitancy towards vaccines and common occurrence of "breakthrough" infections (i.e., infections of vaccinated individuals) highlight the need for alternative methods to reduce viral transmission. SARS-CoV-2 enters cells by fusing its envelope with the target cell membrane in a process mediated by the viral spike protein, S. The S protein operates via a Class I fusion mechanism in which fusion between the viral envelope and host cell membrane is mediated by structural rearrangements of the S trimer. We previously reported lipopeptides derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibit fusion by SARS-CoV-2, both in vitro and in vivo. These lipopeptides bear an attached cholesterol unit to anchor them in the membrane. Here, to improve prospects for experimental development and future clinical utility, we employed structure-guided design to incorporate charged residues at specific sites in the peptide to enhance aqueous solubility. This effort resulted in two new, potent lipopeptide inhibitors
MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress
No full textPeer reviewe
Update on the Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Virus Infection
No full textChronic hepatitis B virus infection is an important cause of liver-related morbidity and mortality, with hepatocellular carcinoma being the most life-threatening complication. Because of the highly variable clinical course of the disease, enormous research efforts have been made with the aim of revealing the factors in the natural history that are relevant to hepatocarcinogenesis. These include epidemiological studies of predisposing risk groups, viral studies of mutations within the hepatitis B viral genome, and clinical correlation of these risk factors in predicting the likelihood of development of hepatocellular cancer in susceptible hosts. This update addresses these risks, with emphasis on the latest research relevant to hepatocarcinogenesis. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201
Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017
No full textAbstract: Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd
Global, regional, and national age-sex-specific mortality and life expectancy, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017
No full text© 2018 The Author(s). Background: Assessments of age-specifc mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Afairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specifc mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in diferent components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4-19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2-59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5-49·6) to 70·5 years (70·1-70·8) for men and from 52·9 years (51·7-54·0) to 75·6 years (75·3-75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5-51·7) for men in the Central African Republic to 87·6 years (86·9-88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3-238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6-42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2-5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specifc mortality shows that there are remarkably complex patterns in population mortality across countries. The fndings of this study highlight global successes, such as the large decline in under-5 mortality, which refects signifcant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing
Genome-wide trans-ethnic meta-analysis Identifies seven genetic loci influencing erythrocyte traits and a role for RBPMS in erythropoiesis
No full textGenome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits
Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis
No full textGenome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits
Estudio comparativo de interacciones supramoleculares en sales cuaternarias de amonio y el complejo proteína-ligando con la enzima colina quinasa
No full textIlustraciones, gráficas, fotos, tablasspa:Las sales cuaternarias de amonio (SCA) han mostrado gran potencial farmacológico para el tratamiento de diferentes enfermedades, razón por la cual, en el grupo de investigación de Química Teórica y Bioinformática (QTB) de la Universidad de Caldas, se han sintetizado diferentes SCA, y evaluado su potencial contra enfermedades como la leishmaniasis y el Chagas, además de, recientemente, evaluar su potencial anticancerígeno. Sin embargo, a pesar de la información experimental obtenida en los últimos años, aún no es claro el mecanismo de acción de las mismas, ni se tiene información sobre su interacción con diferentes blancos terapéuticos. El presente trabajo estudia las interacciones de un grupo de diez sales cuaternarias de amonio (SCA) de fórmula general [N(CH2X)(CH3)2R]I (X = I o Cl, R = (CH2)nCHC(Ar–pY)2 y pY = H o pF), tanto en sus estructuras cristalinas como haciendo parte de un complejo proteína-ligando entre dichas sales y la enzima Quinasa Colina (ChoK), la cual es un blanco anticancerígeno usual, dado que es sabido que la sobreexpresión de una de sus isoformas, se encuentra vinculada con desequilibrios en el ciclo de la fosfatidilcolina permitiendo la proliferación de diferentes neoplasias, razón por la cual, existe un interés en el potencial inhibitorio de diferentes SCA sobre la ChoK gracias a la similitud estructural de estas con la colina. Para ello, el estudio de los sistemas cristalinos se realizó mediante un análisis estructural de las diferentes sales apoyado en la teoría cuántica de átomos en moléculas (QTAIM) y el análisis de superficie de Hirshfeld, posteriormente, se realizaron estudios de acoplamiento molecular (Docking) y dinámica molecular entre las diferentes sales y la enzima ChoK, para luego, realizar un análisis estructural de los diferentes complejos proteína-ligando mediante la teoría QTAIM y de esta forma, identificar las interacciones presentes en los diferentes sistemas, y evaluar si existe o no una relación entre las mismas, encontrando que las principales interacciones presentes en ambos sistemas son aquellas de tipo hidrógeno como H – H e H – π, siendo relevante la presencia de otras interacciones de este tipo como H – I u otras como I – I o Cl – I en los sistemas cristalinos así como interacciones de tipo H – O o F – H en el complejo SCA-ChoK, a quienes se suman, aunque en menor medida, interacciones como π-π y I – π presentes en ambos sistemas, entre otras. Los diferentes cálculos mecano-cuánticos se realizaron a un nivel de teoría HF usando el set de base def2-TZVP para el átomo de yodo y 6-311++G(d,p) para el resto de los átomos.eng:Due to the biological significance of choline kinase enzyme (ChoK) as a antitumor target, a comparative study of its supramolecular interactions in protein-ligand complexes with ten quaternary ammonium salts (QAS) of general structure [(CH3)2(XCH2)N(CH2)nCH=C(Ar-pY)2]+ I- (where X = I or H; pY = H or F and n = 2 - 4) was carried out in silico for the first time. Initially a study of the crystalline system of QASs was performed by structural analysis supported by the Quantum Theory of Atoms in Molecules (QTAIM) and Hirshfeld surface analysis. Then, molecular docking and molecular dynamics between every QAS with ChoK enzyme were modeled and followed by a QTAIM structural analysis of the respective protein-ligand complexes in order to determine the likely interactions operating in these systems. The results suggest that the main interactions present in both systems are hydrogen-type ones such as H‧‧‧H and H‧‧‧π, being relevant the presence of other interactions of this type such as H‧‧‧I in the crystalline systems or H‧‧‧O in the ChoK-QAS complexes. Additionally, less frequent but very important interactions such as π‧‧‧π and others were identified in both crystalline and ligand-complex systems. Mechanical Quantum calculations were performed at HF level of theory using the def2-TZVP basis set for the iodine and 6-311++G(d,p) for the rest of the atoms.Lista de figuras / Lista de tablas / 1. Marco teórico / 1.1. Química supramolecular / 1.1.1. Interacciones intermoleculares / 1.2. Sales cuaternarias de amonio / 1.3. Antecedentes / 1.4. Teorías de enlace / 1.4.1. Reseña histórica / 1.4.2. Criterios para determinar un enlace químico / 1.5. Métodos ab initio / 1.5.1. Aproximación de Born-Oppenheimer / 1.5.2. Aproximación de la función de onda multielectrónica / 1.5.3. Antisimetría de la función de onda / 8 1.5.4. Teorema variacional / 1.6. Funciones base / 1.7. Análisis de la densidad electrónica / 1.7.1. Teoría cuántica de átomos en moléculas (QTAIM) / 1.8. Análisis de superficie de Hirshfeld / 1.9. Colina quinasa (ChoK) / 1.10. Modelado de estructura 3D en proteínas / 1.10.1. CASP / 1.10.2. CABS-fold / 1.10.3. AlphaFold / 1.11. Acoplamiento molecular (Docking) / 1.12. Dinámica molecular / 2. Planteamiento del problema y justificación / 3. Objetivos / 3.1. Objetivo general / 3.2. Objetivos específicos / 4. Materiales y métodos / 4.1. Determinación de interacciones en la estructura cristalina / 4.1.1. Análisis de superficie de Hirshfeld / 4.1.2. Teoría cuántica de átomos en moléculas (AIM) / 4.2. Enzima colina quinasa (ChoK) / 4.2.1. Modelado molecular / 4.2.2. Docking / 4.2.3. Dinámica molecular (DM) / 4.3. Determinación de las interacciones complejo enzima-sustrato / 4.3.1. Reducción del sistema / 4.4. Determinación de las interacciones del complejo / 5. Resultados y discusión 29 5.1. Análisis de interacciones en la familia C4 / 5.1.1. Análisis de superficie de Hirshfeld (HS) / 5.1.2. Teoría cuántica de átomos en moléculas (QTAIM) / 5.2. Análisis de interacciones en la familia C5 / 5.2.1. Análisis de superficie de Hirshfeld (HS) / 5.2.2. Teoría cuántica de átomos en moléculas (QTAIM) / 5.3. Análisis de interacciones en la familia C6 / 5.3.1. Análisis de superficie de Hirshfeld (HS) / 5.3.2. Teoría cuántica de átomos en moléculas (QTAIM) / 5.4. Quinasa de colina (ChoK): Determinación estructural / 5.4.1. Modelado por homología / 5.4.2. Comparación de estructuras / 5.5. Acoplamiento molecular: Docking ChoK-SCA / 5.5.1. Validación: Cross-Docking / 5.5.2. Acoplamiento molecular: Docking & SCA / 5.6. Dinámica molecular / 5.6.1. Clustering / 5.6.2. LigPlot: Familia C4 / 5.6.3. LigPlot: Familia C5 / 5.6.4. LigPlot: Familia C6 / 5.7. Análisis de interacciones complejo ChoK y familia C4 / 5.7.1. Generalidades familia C4 / 5.7.2. Interacciones en C4I / 5.7.3. Interacciones en C4pF / 5.7.4. Interacciones en C4IpF / 5.8. Análisis de interacciones complejo ChoK y familia C5 / 5.8.1. Generalidades familia C5 / 5.8.2. Interacciones en C5 / 91 5.8.3. Interacciones en C5pF / 5.8.4. Interacciones en C5I / 5.8.5. Interacciones en C5ClpF / 5.9. Análisis de interacciones complejo ChoK y familia C6 / 5.9.1. Generalidades familia C6 / 5.9.2. Interacciones en C6ClpF / 5.9.3. Interacciones en C6I / 5.9.4. Interacciones en C6IpF / 6. Conclusiones y recomendaciones 107 6.1. Conclusiones / 6.2. Recomendaciones / A. Distancias y ángulos de enlaces en el sitio activo del complejo ChoK y la familia C4 / B. Distancias y ángulos de enlaces en el sitio activo del complejo ChoK y la familia C5 / C. Distancias y ángulos de enlaces en el sitio activo del complejo ChoK y la familia C6 / ReferenciasMaestríaMagister en QuímicaQuímica teóric
Evaluar la alternativa de disposición del papel higiénico al sistema de drenaje hidrosanitario
No full textTrabajo de Investigación TecnológicaEl proyecto consistió en evaluar una alternativa experimental con el papel higiénico cuando es depositado en la red de drenaje hidrosanitario, para esto se diseñó un prototipo de aparato sanitario que simulara el proceso de descarga de un sanitario, con el fin de evaluar si luego de la descarga con el papel higiénico se afectan las funciones hidráulicas del sistema.PregradoIngeniero CivilRESUMEN
INTRODUCCIÓN
1. GENERALIDADES DEL PROYECTO
2. MARCO DE REFERENCIA
3. METODOLOGÍA
4. DISEÑO METODOLÓGICO
5. RESULTADOS
6. CONCLUSIONES
7. RECOMENDACIONES
BIBLIOGRAFÍA
ANEXO
