RESUMEN
BACKGROUND: Reactivation of the varicella-zoster virus (VZV), which causes herpes zoster (HZ, synonym: shingles) in humans, can be a rare adverse reaction to vaccines. Recently, reports of cases after COVID-19 vaccination have arisen. OBJECTIVES: The aim of this study was to assess whether the frequency of HZ is found to increase after COVID-19 vaccination in a large cohort, based on real-world data. As a hypothesis, the incidence of HZ was assumed to be significantly higher in subjects who received a COVID-19 vaccine (Cohort I) vs. unvaccinated individuals (Cohort II). METHODS: The initial cohorts of 1 095 086 vaccinated and 16 966 018 unvaccinated patients were retrieved from the TriNetX database and were matched on age and gender in order to mitigate confounder bias. RESULTS: After matching, each cohort accounted for 1 095 086 patients. For the vaccinated group (Cohort I), 2204 subjects developed HZ within 60 days of COVID-19 vaccination, while among Cohort II, 1223 patients were diagnosed with HZ within 60 days after having visited the clinic for any other reason (i.e. not vaccination). The risk of developing shingles was calculated as 0.20% and 0.11% for cohort I and cohort II, respectively. The difference was statistically highly significant (P < 0.0001; log-rank test). The risk ratio and odds ratio were 1.802 (95% confidence interval [CI] = 1.680; 1.932) and 1.804 (95% CI = 1.682; 1.934). CONCLUSIONS: Consistent with the hypothesis, a higher incidence of HZ was statistically detectable post-COVID-19 vaccine. Accordingly, the eruption of HZ may be a rare adverse drug reaction to COVID-19 vaccines. Even though the molecular basis of VZV reactivation remains murky, temporary compromising of VZV-specific T-cell-mediated immunity may play a mechanistic role in post-vaccination pathogenesis of HZ. Note that VZV reactivation is a well-established phenomenon both with infections and with other vaccines (i.e. this adverse event is not COVID-19-specific).
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Vacunas contra la COVID-19 , COVID-19 , Herpes Zóster , Herpesvirus Humano 3 , Activación Viral , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Herpes Zóster/epidemiología , Herpes Zóster/etiología , Herpesvirus Humano 3/fisiología , Humanos , Vacunación/efectos adversosRESUMEN
The bacterial burden on human health is quickly outweighing available therapeutics. Our long-term goal is the development of antimicrobials with the potential for broad-spectrum activity. We previously reported phthalazine-based inhibitors of dihydrofolate reductase (DHFR) with potent activity against Bacillus anthracis, a major component of Project BioShield. The most active molecule, named RAB1, performs well in vitro and, in a cocrystal structure, was found deep within the active site of B. anthracis DHFR. We have now examined the activity of RAB1 against a panel of bacteria relevant to human health and found broad-spectrum applicability, particularly with regard to gram-positive organisms. RAB1 was most effective against Staphylococcus aureus, including methicillin- and vancomycin-resistant (MRSA/VRSA) strains. We have determined the cocrystal structure of the wild-type and trimethoprim-resistant (Phe 98 Tyr) DHFR enzyme from S. aureus with RAB1, and we found that rotational freedom of the acryloyl linker region allows the phthalazine moiety to occupy two conformations. This freedom in placement also allows either enantiomer of RAB1 to bind to S. aureus, in contrast to the specificity of B. anthracis for the S-enantiomer. Additionally, one of the conformations of RAB1 defines a unique surface cavity that increases the strength of interaction with S. aureus. These observations provide insights into the binding capacity of S. aureus DHFR and highlight atypical features critical for future exploitation in drug development.
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Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Tetrahidrofolato Deshidrogenasa/metabolismo , Antibacterianos/química , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Tetrahidrofolato Deshidrogenasa/químicaRESUMEN
INTRODUCTION: A comprehensive literature review revealed a gap in health research regarding the determinants of good health for rural men in Jamaica. This study seeks to fill this void by examining cross-sectional survey data to model the social determinants of the self-reported good health status of rural men in Jamaica. METHOD: A sample of 5041 males (> or = 15 years) was extracted from a national cross-sectional survey of 25 018 respondents. A stratified random probability sampling technique was used to draw the sample. Data were stored, retrieved and analyzed using SPSS for Windows 16.0 (SPSS; Chicago, IL, USA). Descriptive statistics were used to provide pertinent socio-demographic characteristics of the sample, and logistic regression was used to establish a predictive model for good self-reported health status in rural Jamaican males. RESULTS: Seventeen percent of rural men claimed that they had poor health, 4.9% had health insurance, 61.6% visited a healthcare practitioner, 96.0% purchased prescribed medications and 45.3% completed the course of prescribed medications. The social determinants of good health status of rural men in Jamaica are cost of medical care (OR = 0.916, 95% CI = 0.841-0.997); retirement income (OR = 0.0.382, 95% CI = 0.206-0.707); marital status: separated, divorced or widowed with reference to those never married (OR = 0.270, 95% CI = 0.178-0.410), and married with reference to never married men (OR = 0.465, 95% CI = 0.356-0.609); health insurance coverage (OR = 0.041, 95% CI = 0.027-0.063); number of children in household (OR = 1.200, 95% CI = 1.069-1.347); and number of durable goods owned (OR = 1.107, 95% CI = 1.050-1.166). CONCLUSION: Children continue to be not only futuristic assets to parents, but they also currently improve the health status of rural men.
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Estado de Salud , Salud del Hombre/etnología , Salud Rural/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Anciano , Estudios Transversales , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Humanos , Cobertura del Seguro/estadística & datos numéricos , Seguro de Salud/estadística & datos numéricos , Jamaica , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud/etnología , Aceptación de la Atención de Salud/estadística & datos numéricos , Apoyo Social , Factores Socioeconómicos , Adulto JovenRESUMEN
OBJECTIVE: During 1880-1882, life expectancy for Jamaican males was 37.02 years and 39.80 for their female counterparts and 100 years later, the figures had increased to 69.03 for males and 72.37 for females. Despite the achievements in increased life expectancies of the general populace and the postponement of death, non-communicable diseases are on the rise. Hence, this means that prolonged life does not signify better quality life. Thus, this study seeks to examine the quality of life of Jamaicans by broadening the measure of well-being from the biomedical to the biopsychosocial and ecological model METHOD: Secondary data were used for this study. The sample was a nationally representative one collected by the Statistical Institute of Jamaica and the Planning Institute of Jamaica in 2002. The total sample is 25,018 respondents of which the model used 1147. Data were stored and analysed using the Statistical Packages for the Social Sciences (SPSS). Multivariate regression was used to test the general hypothesis that well-being is a function of psychosocial, biological, environmental and demographic variables. RESULTS: The model explains 39.3 percentage of the variance in well-being (adjusted r2). Among those 10, the 5 most significant determinants of well-being in descending order are average number of persons per room (beta = -0.254, p < 0.001), area of residence (1 = KMA) (beta = -0.223, p < 0.001), area of residence [1 = Other Towns] (beta = -0.209, p < 0.001) and age of respondents (beta = -0.207, p < 0.001). These five variables accounted for 27.2 percentage of the model, with average occupancy and area of residence (being KMA) accounting for 7 per cent each. CONCLUSION: This study has shown that well-being is indeed a multidimensional concept involving psychosocial, environmental and demographic variables.
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Esperanza de Vida/tendencias , Modelos Econométricos , Psicometría , Calidad de Vida , Estrés Psicológico , Adulto , Factores Epidemiológicos , Femenino , Humanos , Jamaica , Masculino , Análisis Multivariante , Valor Predictivo de las Pruebas , Calidad de Vida/psicología , Análisis de Regresión , Medio SocialRESUMEN
OBJECTIVE: Advances in nutrition, sanitation, water supply, technology and drugs have managed to add years to life. However, with the continuing increase in the non-communicable diseases, the World Health Organization (WHO) has said that disabilities have eroded nine years from the healthy quality of life of Jamaicans. The current study aims to provide factors that will explain how to attain 'good' health. METHOD: The research design for this study is an explanatory one. This research utilizes cross-sectional data taken from the Jamaica Survey of Living Conditions (JSLC) 2002 in order to identify and explain some of the determinants of well-being among the Jamaican elderly. Information collected used self-administered questionnaire. Multivariate regression was used to establish the well-being model. The surveyedpopulation was 3009 respondents ages 60 years and older, with 52.7% females (n=1423) and 47.3% males (n=1423). The average age of the surveyed population was 71 years 10 months +/- 8 years six months. RESULT: Of the 14 predisposed variables that were used to test the general hypothesis, 11 were found to be statistically significant. From the selected variables of this study, the six most important factors that impact on the well-being of the Jamaican elderly in descending order are as follows: social support (beta = 0.486), average occupancy per room (beta = -0.428), area of residence--living in Kingston Metropolitan Area (KMA) with reference to rural areas (beta = 0.179) or dwelling in other towns with reference to rural area (beta = 0.157), education (beta = 0.155) followed by the physical environment (beta = -0.138) and age of respondents (beta = -0.129). CONCLUSION: The predisposed variables used in this study explain 45.9% of the variance in quality of life. The variable that has the most influential impact on well-being is social support. The general wellbeing of the Jamaican elderly is low (mean of 3.9/14 +/- 2.3). The model provides a basis upon which we can address patient care and 'good' health.
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Evaluación Geriátrica , Estado de Salud , Sociología Médica , Anciano , Femenino , Humanos , Jamaica , Esperanza de Vida , Masculino , Persona de Mediana Edad , Calidad de Vida , Apoyo SocialRESUMEN
MOTIVATION: Analysis of large biological data sets using a variety of parallel processor computer architectures is a common task in bioinformatics. The efficiency of the analysis can be significantly improved by properly handling redundancy present in these data combined with taking advantage of the unique features of these compute architectures. RESULTS: We describe a generalized approach to this analysis, but present specific results using the program CEPAR, an efficient implementation of the Combinatorial Extension algorithm in a massively parallel (PAR) mode for finding pairwise protein structure similarities and aligning protein structures from the Protein Data Bank. CEPAR design and implementation are described and results provided for the efficiency of the algorithm when run on a large number of processors. AVAILABILITY: Source code is available by contacting one of the authors.
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Algoritmos , Biología Computacional/métodos , Almacenamiento y Recuperación de la Información/métodos , Proteínas/química , Proteínas/clasificación , Alineación de Secuencia/métodos , Análisis de Secuencia de Proteína/métodos , Metodologías Computacionales , Modelos Moleculares , Conformación Proteica , Homología de Secuencia de AminoácidoRESUMEN
Structural genomics--large-scale macromolecular 3-dimenional structure determination--is unique in that major participants report scientific progress on a weekly basis. The target database (TargetDB) maintained by the Protein Data Bank (http://targetdb.pdb.org) reports this progress through the status of each protein sequence (target) under consideration by the major structural genomics centers worldwide. Hence, TargetDB provides a unique opportunity to analyze the potential impact that this major initiative provides to scientists interested in the sequence-structure-function-disease paradigm. Here we report such an analysis with a focus on: (i) temporal characteristics--how is the project doing and what can we expect in the future? (ii) target characteristics--what are the predicted functions of the proteins targeted by structural genomics and how biased is the target set when compared to the PDB and to predictions across complete genomes? (iii) structures solved--what are the characteristics of structures solved thus far and what do they contribute? The analysis required a more extensive database of structure predictions using different methods integrated with data from other sources. This database, associated tools and related data sources are available from http://spam.sdsc.edu.
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Biología Computacional , Genómica/estadística & datos numéricos , Bases de Datos de Proteínas , Modelos Moleculares , Proteínas/química , Proteínas/genética , Proteómica/estadística & datos numéricosRESUMEN
The apoptosis database is a public resource for researchers and students interested in the molecular biology of apoptosis. The resource provides functional annotation, literature references, diagrams/images, and alternative nomenclatures on a set of proteins having 'apoptotic domains'. These are the distinctive domains that are often, if not exclusively, found in proteins involved in apoptosis. The initial choice of proteins to be included is defined by apoptosis experts and bioinformatics tools. Users can browse through the web accessible lists of domains, proteins containing these domains and their associated homologs. The database can also be searched by sequence homology using basic local alignment search tool, text word matches of the annotation, and identifiers for specific records. The resource is available at http://www.apoptosis-db.org and is updated on a regular basis.
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Apoptosis/fisiología , Bases de Datos de Proteínas/tendencias , Proteínas/clasificación , Animales , Biología Computacional/métodos , Biología Computacional/tendencias , Humanos , Filogenia , Estructura Terciaria de Proteína/fisiología , Proteínas/química , Proteínas/fisiología , Homología de Secuencia de Ácido Nucleico , Programas Informáticos/tendenciasRESUMEN
Procedures are presented for the assessment of the phytoecdysteroid profiles in small plant samples (ca. 25 mg), using seeds of Sida spp. as an example. The procedures are suitable for the analysis of minute or valuable samples and provide copious information for chemotaxonomic purposes. Methanolic extracts of the plant material, after partitioning against hexane, were separated by reversed-phase gradient HPLC monitored by PAD, RIA and bioassay. Aliquots of the fractions were also treated with Helix pomatia hydrolases, followed by RIA and bioassay, in order to assess the presence of hydrolysable ecdysteroid conjugates. Further information could also be obtained by separation of samples using normal-phase gradient HPLC. Among 11 species of Sida examined, seed extracts of S. acuta (= S. carpinifolia) and S. rhombifolia were found to contain significant amounts of ecdysteroids, seed extracts of S. filicaulis contained only moderate levels, whilst the remaining species showed no detectable levels of ecdysteroids. The ecdysteroid profiles of the extracts of the three positive species were significantly different, demonstrating that phytoecdysteroids have chemotaxonomic value in this genus.
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Cromatografía Líquida de Alta Presión/métodos , Ecdisteroides/análisis , Malvaceae/química , Semillas/química , Animales , Caracoles Helix/enzimología , Radioinmunoensayo , Espectrofotometría UltravioletaRESUMEN
The B(II) bioassay was developed as a rapid and reliable tool for detecting potential insect growth regulators acting as ecdysteroid receptor (ant)agonists. Based on an ecdysteroid-responsive cell line from Drosophila melanogaster, this microplate assay is ideally suited to the evaluation of environmental contaminants as potential endocrine disrupters. Data are presented for about 80 potential environmental contaminants, including industrial chemicals, pesticides, pharmaceuticals, phytoestrogens, and vertebrate steroids, and are compared with data for known (ant)agonists. Apart from androst-4-ene-3,17-dione (a weak antagonist), vertebrate steroids were inactive at concentrations up to 10(-3) M. The vast majority of xenobiotics also showed no (ant)agonist activity. Among the industrial chemicals, antagonistic activity was observed for bisphenol A median effective concentration (EC50) of 1.0 x 10(-4) M and diethylphthalate (EC50 of 2.0 x 10(-3) M). Some organochlorine compounds also showed weak antagonistic activity, including o,p'-dichlorodiphenyldichloroethylene (DDE), p,p'-DDE, dieldrin, and lindane (EC50 of 3.0 x 10(-5) M). For lindane, bisphenol A, and diethylphthalate, activity is not associated with impurities in the samples and, for lindane and bisphenol A at least, the compounds are able to compete with ecdysteroids for the ligand binding site on the receptor complex, albeit at concentrations very much higher than those found in the environment. The only pharmaceutical showing any detectable antagonist activity was 17alpha-ethynylestradiol. In the context of recent publications on potential endocrine disruption in marine and freshwater arthropods, these findings suggest that, for some compounds (e.g., diethylstilbestrol), ecdysteroid receptor-mediated responses are unlikely to be involved in producing chronic effects. The B(II) assay has a potentially valuable role to play in distinguishing between endocrine-mediated, which normally occur at submicromolar concentrations, and pharmacological effects in insects and crustaceans.
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Ecdisteroides/farmacología , Monitoreo del Ambiente/métodos , Muda/efectos de los fármacos , Contaminantes Químicos del Agua/efectos adversos , Xenobióticos/efectos adversos , Animales , Bioensayo , Línea Celular , Crustáceos , Drosophila melanogaster/fisiología , Ecdisteroides/análogos & derivados , Ecdisteroides/antagonistas & inhibidores , InsectosRESUMEN
We have reinvestigated the activity of 8-O-acetylharpagide, an iridoid glucoside, as an ecdysteroid agonist. Elbrecht et al. (Insect Biochem. Mol. Biol. 26 (1996) 519) isolated a preparation of this compound from Ajuga reptans L. and ascribed ecdysteroid agonist activity on the basis of the induction of an ecdysteroid-like response in Drosophila melanogaster KcO cells, the displacement of [3H]ponasterone A from the Drosophila receptor and the activation of an ecdysteroid-regulated gene in a transactivation assay. We provide evidence that the agonist activity derives from contaminating ecdysteroids; A. reptans is a species rich in ecdysteroids. Purified 8-O-acetylharpagide is not active in the D. melanogaster B(II) cell bioassay, neither as an agonist nor as an antagonist, nor does it displace [3H]ponasterone A from dipteran or lepidopteran ecdysteroid receptor complexes.
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Ecdisteroides/agonistas , Piranos/metabolismo , Animales , Bioensayo , Línea Celular , Cromatografía Líquida de Alta Presión/métodos , Drosophila melanogaster , Estructura Molecular , Piranos/química , Piranos/aislamiento & purificación , Radioinmunoensayo , Espectrofotometría UltravioletaAsunto(s)
Ingeniería de Proteínas , Animales , Humanos , Internet , Proteínas de la Membrana , Membranas/química , Membranas/ultraestructuraRESUMEN
During the determination of macromolecular structures, scientists routinely use complex graphics software to display various representations of the molecule of interest. Once the structure determination is complete, coordinates are deposited in the Protein Data Bank (PDB), from where anyone with an Internet connection may download and view them or request them on CD-ROM. However, the currently available visualization software is such that causal users, whose expertise may not be in structure determination, often cannot obtain useful images of interesting molecules without expending considerable time and effort. Existing visualization software is generally very complex, requiring a high degree of familiarity to obtain the best results, or else it is too simplistic to provide users with the level of customizability needed to get the most out of the atomic coordinates. Few of the existing software packages have the capability for collaborative visualization via the Internet. These and other issuses are being addressed by the Molecular Interactive Collaborative Environment (MICE) project (http://mice.sdsc.edu/). The core of the MICE project is the MICE application, an interactive molecular structure viewer with built-in collaborative capabilities. MICE not only addresses the issues of usability and flexibility but also extends the role of traditional visualization tools by allowing multiple users to view, manipulate, and interact with a single representation of a macromolecular structure. MICE is written entirely in Java, using the Java3D extensions for rendering and manipulation of the three-dimensional scene, and the Common Object Request Broker Architecture (CORBA) communications suite to enable collaborative manipulation of that scene.
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Gráficos por Computador , Simulación por Computador , Modelos Moleculares , Animales , Sistemas de Computación , Bases de Datos de Proteínas , Humanos , Sustancias Macromoleculares , Conformación Proteica , Proteínas/química , Programas Informáticos , Interfaz Usuario-ComputadorRESUMEN
Methanolic extracts of seeds of several (Carex species were found to antagonise the action of 20-hydroxyecdysone in the Drosophila melanogaster microplate-based B(II) cell bioassay. Bioassay-guided HPLC analysis of seeds of Carex pendula (drooping sedge) provided one previously unknown tetrastilbene (cis-miyabenol A) and two known oligostilbenes (kobophenol B and cis-miyabenol C) as the biologically active compounds (EC50 values were 31, 37 and 19 microM, respectively, vs. 5 x 10(-8) M 20-hydroxyecdysone). The structures and relative stereochemistries of these compounds were deduced by comprehensive ID- and 2D-NMR experiments. These compounds are isolated from Carex pendula for the first time. In vitro experiments with dipteran and lepidopteran ecdysteroid receptor proteins demonstrate that the oligostilbenes are able to compete with radiolabelled ecdysteroid ([3H]ponasterone A) for occupancy of the ligand binding site. IC50/Ki values are similar to the EC50 values obtained in the B(II) bioassay.
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Ecdisterona/análogos & derivados , Ecdisterona/farmacología , Magnoliopsida/química , Receptores de Esteroides/fisiología , Semillas/química , Esteroides/antagonistas & inhibidores , Estilbenos/farmacología , Animales , Bioensayo , Cromatografía Líquida de Alta Presión , Dípteros , Drosophila melanogaster , Ecdisteroides , Ecdisterona/antagonistas & inhibidores , Ecdisterona/farmacocinética , Lepidópteros , Magnoliopsida/clasificación , Receptores de Esteroides/antagonistas & inhibidores , Receptores de Esteroides/efectos de los fármacos , Especificidad de la Especie , Esteroides/agonistas , Estilbenos/química , Estilbenos/aislamiento & purificaciónRESUMEN
Ecdysteroid agonist and antagonist activities can be detected and quantified with the Drosophila melanogaster B(II) cell bioassay. This bioassay is convenient, sensitive and robust. We report the assessment with this bioassay of the activities of a wide range of compounds representing a number of classes of natural products. Many compounds were inactive over a wide concentration range (10(-8) to 10(-4) or 10(-3) M) or cytotoxic at high concentrations. However, antagonisitic activity was associated with several classes of compounds: cucurbitacins and withanolides (extending previous findings) and phenylalkanoids and certain alkaloids (described for the first time). A withanolide (withaperuvin D) is identified which possesses agonistic activity. Brassinosteroids, which have been ascribed (ant)agonistic properties in the past, were not found to be active in the B(II) bioassay, either as agonists or antagonists. Possible reasons for the prevalence of antagonists and for the low potency of the majority of them are discussed.
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Bioensayo/métodos , Productos Biológicos/farmacología , Isoflavonas , Esteroides/agonistas , Esteroides/antagonistas & inhibidores , Alcaloides/química , Alcaloides/farmacología , Animales , Unión Competitiva , Productos Biológicos/química , Productos Biológicos/metabolismo , Bufanólidos/química , Bufanólidos/farmacología , Cardenólidos/química , Cardenólidos/farmacología , Línea Celular , Cucurbitacinas , Drosophila melanogaster/citología , Ecdisteroides , Estrógenos no Esteroides/química , Estrógenos no Esteroides/farmacología , Hormonas de Insectos/química , Hormonas de Insectos/farmacología , Ligandos , Lignanos/química , Lignanos/farmacología , Neurotransmisores/química , Neurotransmisores/farmacología , Fitoestrógenos , Preparaciones de Plantas , Receptores de Esteroides/efectos de los fármacos , Receptores de Esteroides/metabolismo , Saponinas/química , Saponinas/farmacología , Esteroides/química , Esteroides/farmacología , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
We have developed a new algorithm for the alignment of multiple protein structures based on a Monte Carlo optimization technique. The algorithm uses pair-wise structural alignments as a starting point. Four different types of moves were designed to generate random changes in the alignment. A distance-based score is calculated for each trial move and moves are accepted or rejected based on the improvement in the alignment score until the alignment is converged. Initial tests on 66 protein structural families show promising results, the score increases by 69% on average. The increase in score is accompanied by an increase (12%) in the number of residue positions incorporated into the alignment. Two specific families, protein kinases and aspartic proteinases were tested and compared against curated alignments from HOMSTRAD and manual alignments. This algorithm has improved the overall number of aligned residues while preserving key catalytic residues. Further refinement of the method and its application to generate multiple alignments for all protein families in the PDB, is currently in progress.
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Algoritmos , Proteínas/genética , Alineación de Secuencia/estadística & datos numéricos , Secuencia de Aminoácidos , Ácido Aspártico Endopeptidasas/química , Ácido Aspártico Endopeptidasas/genética , Bases de Datos Factuales , Datos de Secuencia Molecular , Método de Montecarlo , Proteínas Quinasas/química , Proteínas Quinasas/genética , Proteínas/química , Homología de Secuencia de AminoácidoRESUMEN
Androgens have been shown to modulate the haematopoietic and immune systems and have been used clinically for stimulating haematopoiesis in bone marrow failure conditions. To identify the bone marrow cell types as potential targets of androgens, an androgen receptor (AR)-specific antibody was used to localize the AR in normal human bone marrow biopsies. The results show that AR was ubiquitously expressed in the bone marrow of both males and females. Furthermore, the AR expression pattern did not change with age. Stromal cells, macrophages, endothelial cells, myeloblasts, myelocytes, neutrophils, and megakaryocytes expressed AR. In contrast, AR was not detected in the lymphoid and erythroid cells, or in eosinophils. These results indicate that androgens may exert direct modulating effects on a wide spectrum of bone marrow cell types via AR-mediated responses.
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Células de la Médula Ósea/metabolismo , Receptores Androgénicos/metabolismo , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Hematopoyesis/fisiología , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Distribución por SexoRESUMEN
An all-against-all protein structure comparison using the Combinatorial Extension (CE) algorithm applied to a representative set of PDB structures revealed a gallery of common substructures in proteins (http://cl.sdsc.edu/ce.html). These substructures represent commonly identified folds, domains, or components thereof. Most of the subsequences forming these similar substructures have no significant sequence similarity. We present a method to identify conserved amino acid positions and residue-dependent property clusters within these subsequences starting with structure alignments. Each of the subsequences is aligned to its homologues in SWALL, a nonredundant protein sequence database. The most similar sequences are purged into a common frequency matrix, and weighted homologues of each one of the subsequences are used in scoring for conserved key amino acid positions (CKAAPs). We have set the top 20% of the high-scoring positions in each substructure to be CKAAPs. It is hypothesized that CKAAPs may be responsible for the common folding patterns in either a local or global view of the protein-folding pathway. Where a significant number of structures exist, CKAAPs have also been identified in structure alignments of complete polypeptide chains from the same protein family or superfamily. Evidence to support the presence of CKAAPs comes from other computational approaches and experimental studies of mutation and protein-folding experiments, notably the Paracelsus challenge. Finally, the structural environment of CKAAPs versus non-CKAAPs is examined for solvent accessibility, hydrogen bonding, and secondary structure. The identification of CKAAPs has important implications for protein engineering, fold recognition, modeling, and structure prediction studies and is dependent on the availability of structures and an accurate structure alignment methodology. Proteins 2001;42:148-163.