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1.
Nature ; 473(7347): 394-7, 2011 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-21552279

RESUMO

5-hydroxymethylcytosine (5hmC) is a modified base present at low levels in diverse cell types in mammals. 5hmC is generated by the TET family of Fe(II) and 2-oxoglutarate-dependent enzymes through oxidation of 5-methylcytosine (5mC). 5hmC and TET proteins have been implicated in stem cell biology and cancer, but information on the genome-wide distribution of 5hmC is limited. Here we describe two novel and specific approaches to profile the genomic localization of 5hmC. The first approach, termed GLIB (glucosylation, periodate oxidation, biotinylation) uses a combination of enzymatic and chemical steps to isolate DNA fragments containing as few as a single 5hmC. The second approach involves conversion of 5hmC to cytosine 5-methylenesulphonate (CMS) by treatment of genomic DNA with sodium bisulphite, followed by immunoprecipitation of CMS-containing DNA with a specific antiserum to CMS. High-throughput sequencing of 5hmC-containing DNA from mouse embryonic stem (ES) cells showed strong enrichment within exons and near transcriptional start sites. 5hmC was especially enriched at the start sites of genes whose promoters bear dual histone 3 lysine 27 trimethylation (H3K27me3) and histone 3 lysine 4 trimethylation (H3K4me3) marks. Our results indicate that 5hmC has a probable role in transcriptional regulation, and suggest a model in which 5hmC contributes to the 'poised' chromatin signature found at developmentally-regulated genes in ES cells.


Assuntos
Citosina/análogos & derivados , Células-Tronco Embrionárias/metabolismo , Genoma/genética , Análise de Sequência de DNA/métodos , 5-Metilcitosina/análogos & derivados , Animais , Biotinilação , Linhagem Celular , Citosina/análise , Citosina/isolamento & purificação , Citosina/metabolismo , Metilação de DNA , Éxons/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Glucose/metabolismo , Camundongos , Ácido Periódico/metabolismo , Regiões Promotoras Genéticas/genética , Sítio de Iniciação de Transcrição , Transcrição Gênica/genética
2.
Proc Natl Acad Sci U S A ; 111(4): 1361-6, 2014 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-24474761

RESUMO

Dioxygenases of the Ten-Eleven Translocation (TET) family are 5-methylcytosine oxidases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. We show that Tet1 and Tet2 have distinct roles in regulating 5hmC in mouse embryonic stem cells (mESC). Tet1 depletion diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is predominantly associated with decreased 5hmC in gene bodies. Enrichment of 5hmC is observed at the boundaries of exons that are highly expressed, and Tet2 depletion results in substantial loss of 5hmC at these boundaries. In contrast, at promoter/TSS regions, Tet2 depletion results in increased 5hmC, potentially because of the redundant activity of Tet1. Together, the data point to a complex interplay between Tet1 and Tet2 in mESC, and to distinct roles for these two proteins in regulating promoter, exon, and polyadenylation site usage in cells.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Células-Tronco Embrionárias/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Animais , Metilação de DNA , Proteínas de Ligação a DNA/genética , Dioxigenases , Éxons , Camundongos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Transcrição Gênica
3.
CMAJ ; 188(14): E342-E351, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27455981

RESUMO

BACKGROUND: The health burden caused by seasonal influenza is substantial. We sought to examine the effectiveness of influenza vaccination against admission to hospital for acute cardiovascular and respiratory conditions and all-cause death in people with type 2 diabetes. METHODS: We conducted a retrospective cohort study using primary and secondary care data from the Clinical Practice Research Datalink in England, over a 7-year period between 2003/04 and 2009/10. We enrolled 124 503 adults with type 2 diabetes. Outcome measures included admission to hospital for acute myocardial infarction (MI), stroke, heart failure or pneumonia/influenza, and death. We fitted Poisson regression models for influenza and off-season periods to estimate incidence rate ratios (IRR) for cohorts who had and had not received the vaccine. We used estimates for the summer, when influenza activity is low, to adjust for residual confounding. RESULTS: Study participants contributed to 623 591 person-years of observation during the 7-year study period. Vaccine recipients were older and had more comorbid conditions compared with nonrecipients. After we adjusted for covariates and residual confounding, vaccination was associated with significantly lower admission rates for stroke (IRR 0.70, 95% confidence interval [CI] 0.53-0.91), heart failure (IRR 0.78, 95% CI 0.65-0.92) and pneumonia or influenza (IRR 0.85, 95% CI 0.74-0.99), as well as all-cause death (IRR 0.76, 95% CI 0.65-0.83), and a nonsignificant change for acute MI (IRR 0.81, 95% CI 0.62-1.04) during the influenza seasons. INTERPRETATION: In this cohort of patients with type 2 diabetes, influenza vaccination was associated with reductions in rates of admission to hospital for specific cardiovascular events. Efforts should be focused on improvements in vaccine uptake in this important target group as part of comprehensive secondary prevention.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Hospitalização/estatística & dados numéricos , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Pneumonia/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Causas de Morte , Estudos de Coortes , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/mortalidade , Inglaterra/epidemiologia , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Humanos , Incidência , Influenza Humana/complicações , Influenza Humana/mortalidade , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Pneumonia/complicações , Pneumonia/mortalidade , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle
4.
Nature ; 468(7325): 839-43, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21057493

RESUMO

TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.


Assuntos
5-Metilcitosina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hidroxilação , Leucemia Mieloide Aguda/metabolismo , Proteínas Mutantes/metabolismo , Síndromes Mielodisplásicas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Biocatálise , Diferenciação Celular , Linhagem Celular , Ilhas de CpG/genética , Metilação de DNA , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Proteínas de Ligação a DNA/genética , Dioxigenases , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mutantes/genética , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Proteínas Proto-Oncogênicas/genética
5.
Proc Natl Acad Sci U S A ; 109(40): 16252-7, 2012 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-22991471

RESUMO

B cells and plasma cells possess distinct RNA processing environments that respectively promote the expression of membrane-associated Ig by B cells versus the secretion of Ig by plasma cells. Through a combination of transcriptional profiling and screening using a lentiviral short-hairpin RNA interference library, we show that both the splicing factor hnRNPLL and the transcription elongation factor ELL2 modulate the ratio of secreted versus membrane-encoding Ighg2b transcripts in MPC11 plasmacytoma cell lines. hnRNPLL and ELL2 are both highly expressed in primary plasma cells relative to B cells, but hnRNPLL binds Ighg2b mRNA transcripts and promotes an increase in levels of the membrane-encoding Ighg2b isoform at the expense of the secreted Ighg2b isoform, whereas ELL2 counteracts this effect and drives Ig secretion by increasing the frequency of the secreted Ighg2b isoform. As in T cells, hnRNPLL also alters the splicing pattern of mRNA encoding the adhesion receptor CD44, promoting exon inclusion, and decreasing the overall level of CD44 expression. Further characterization of ELL2-dependent transcription by RNA-Seq revealed that ∼12% of transcripts expressed by plasma cells were differentially processed because of the activities of ELL2, including B-cell maturation antigen BCMA, a receptor with a defined role in plasma cell survival. Taken together, our data identify hnRNPLL and ELL2 as regulators of pre-mRNA processing in plasma cells.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Plasmócitos/fisiologia , RNA Mensageiro/fisiologia , Fatores de Elongação da Transcrição/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Citometria de Fluxo , Receptores de Hialuronatos/metabolismo , Cadeias Pesadas de Imunoglobulinas/genética , Imunoprecipitação , Camundongos , Camundongos Endogâmicos BALB C , Análise em Microsséries , Plasmócitos/metabolismo , Isoformas de Proteínas/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA
6.
BMC Health Serv Res ; 14: 87, 2014 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-24568655

RESUMO

BACKGROUND: In England, the National Institute for Health and Care Excellence (NICE) produces guidelines for the management of hypertension. In 2006, the NICE guidelines introduced an ethnic-age group algorithm based on the 2004 British Hypertension Society guidelines to guide antihypertensive drug prescription. METHODS: A longitudinal retrospective study with 15933 hypertensive patients aged 18 years or over and registered with 28 general practices in Wandsworth, London in 2007 was conducted to assess variations in antihypertensive prescribing. Logistic models were used to measure variations in the odds of being prescribed the 2006 NICE first line recommended monotherapy among NICE patient groups over the period. RESULTS: From 2000 to 2007, the percentage of patients prescribed the recommended monotherapy increased from 54.2% to 61.4% (p < 0.0001 for annual trend). Over the study period, black patients were more likely to be prescribed the recommended monotherapy than younger non-black patients (OR 0.16, 95% CI 0.12-0.21) and older non-black patients (OR 0.49, 95% CI 0.37-0.65). After the introduction of the NICE guidelines there was an increase in the NICE recommended monotherapy (OR 1.44, 95% CI 1.19-1.75) compared with the underlying trend. Compared to black patients, an increase in the use of recommended monotherapy was observed in younger non-black patients (OR 1.49, 95% CI 1.17-1.91) but not in older non-black patients (OR 0.58, 95% CI 0.46-0.74). CONCLUSION: The introduction of the 2006 NICE guideline had the greatest impact on prescribing for younger non-black patients. Lower associated increases among black patients may be due to their higher levels of recommended prescribing at baseline. The analysis suggests that guidelines did not impact equally on all patient groups.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/etnologia , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/estatística & dados numéricos , Atenção Primária à Saúde/normas , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Fatores Etários , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/normas , População Negra/estatística & dados numéricos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diuréticos/uso terapêutico , Inglaterra/epidemiologia , Feminino , Fidelidade a Diretrizes/estatística & dados numéricos , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/normas , Atenção Primária à Saúde/métodos , Grupos Raciais/estatística & dados numéricos , Estudos Retrospectivos
7.
Nat Genet ; 37(5): 501-6, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15806101

RESUMO

Regulatory regions of plant genes tend to be more compact than those of animal genes, but the complement of transcription factors encoded in plant genomes is as large or larger than that found in those of animals. Plants therefore provide an opportunity to study how transcriptional programs control multicellular development. We analyzed global gene expression during development of the reference plant Arabidopsis thaliana in samples covering many stages, from embryogenesis to senescence, and diverse organs. Here, we provide a first analysis of this data set, which is part of the AtGenExpress expression atlas. We observed that the expression levels of transcription factor genes and signal transduction components are similar to those of metabolic genes. Examining the expression patterns of large gene families, we found that they are often more similar than would be expected by chance, indicating that many gene families have been co-opted for specific developmental processes.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Arabidopsis/genética , Perfilação da Expressão Gênica , Expressão Gênica/fisiologia , Marcadores Genéticos
8.
Herit Sci ; 12(1): 26, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38283177

RESUMO

The bronze doors of the Basilica of San Zeno in Verona, Italy, are a special case in art history research. They were made by several workshops during the twelfth century: stylistically, two to three workshops were assumed to produce the metal parts of the door. However, it is still unclear when exactly and if this interpretation can be supported by the chemical composition of the metal. In this research we aimed to verify the art history interpretation by identifying the alloy composition of each individual metal plate. The composition of the supporting wooden structures are discussed. A portable ED-XRF instrument and optical microscopes were used to analyse and document the doors non-invasively. The doors were also photographed to produce high resolution orthophotos and 3D models. We can confirm that the metal parts of the doors were made of leaded tin-bronze as well as leaded brass and mounted on a wooden structure mainly made of spruce and oak wood. Chemically, two/three different groups of alloys have been identified, which can be associated with two or three different workshops, and which largely correspond to the stylistic interpretation. Supplementary Information: The online version contains supplementary material available at 10.1186/s40494-024-01143-2.

9.
J Med Internet Res ; 14(5): e146, 2012 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-23076301

RESUMO

BACKGROUND: Patients are increasingly rating their family physicians on the Internet in the same way as they might rate a hotel on TripAdvisor or a seller on eBay, despite physicians' concerns about this process. OBJECTIVE: This study aims to examine the usage of NHS Choices, a government website that encourages patients to rate the quality of family practices in England, and associations between web-based patient ratings and conventional measures of patient experience and clinical quality in primary care. METHODS: We obtained all (16,952) ratings of family practices posted on NHS Choices between October 2009 and December 2010. We examined associations between patient ratings and family practice and population characteristics. Associations between ratings and survey measures of patient experience and clinical outcomes were examined. RESULTS: 61% of the 8089 family practices in England were rated, and 69% of ratings would recommend their family practice. Practices serving younger, less deprived, and more densely populated areas were more likely to be rated. There were moderate associations with survey measures of patient experience (Spearman ρ 0.37-0.48, P<.001 for all 5 variables), but only weak associations with measures of clinical process and outcome (Spearman ρ less than ± 0.18, P<.001 for 6 of 7 variables). CONCLUSION: The frequency of patients rating their family physicians on the Internet is variable in England, but the ratings are generally positive and are moderately associated with other measures of patient experience and weakly associated with clinical quality. Although potentially flawed, patient ratings on the Internet may provide an opportunity for organizational learning and, as it becomes more common, another lens to look at the quality of primary care.


Assuntos
Medicina de Família e Comunidade/normas , Internet , Programas Nacionais de Saúde/organização & administração , Pacientes/psicologia , Qualidade da Assistência à Saúde , Inglaterra , Humanos , Programas Nacionais de Saúde/normas
10.
CMAJ ; 183(12): E809-16, 2011 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-21810950

RESUMO

BACKGROUND: Not enough is known about the association between practice size and clinical outcomes in primary care. We examined this association between 1997 and 2005, in addition to the impact of the Quality and Outcomes Framework, a pay-for-performance incentive scheme introduced in the United Kingdom in 2004, on diabetes management. METHODS: We conducted a retrospective open-cohort study using data from the General Practice Research Database. We enrolled 422 general practices providing care for 154,945 patients with diabetes. Our primary outcome measures were the achievement of national treatment targets for blood pressure, glycated hemoglobin (HbA(1c)) levels and total cholesterol. RESULTS: We saw improvements in the recording of process of care measures, prescribing and achieving intermediate outcomes in all practice sizes during the study period. We saw improvement in reaching national targets after the introduction of the Quality and Outcomes Framework. These improvements significantly exceeded the underlying trends in all practice sizes for achieving targets for cholesterol level and blood pressure, but not for HbA(1c) level. In 1997 and 2005, there were no significant differences between the smallest and largest practices in achieving targets for blood pressure (1997 odds ratio [OR] 0.98, 95% confidence interval [CI] 0.82 to 1.16; 2005 OR 0.92, 95% CI 0.80 to 1.06 in 2005), cholesterol level (1997 OR 0.94, 95% CI 0.76 to 1.16; 2005 OR 1.1, 95% CI 0.97 to 1.40) and glycated hemoglobin level (1997 OR 0.79, 95% CI 0.55 to 1.14; 2005 OR 1.05, 95% CI 0.93 to 1.19). INTERPRETATION: We found no evidence that size of practice is associated with the quality of diabetes management in primary care. Pay-for-performance programs appear to benefit both large and small practices to a similar extent.


Assuntos
Diabetes Mellitus/terapia , Gerenciamento Clínico , Avaliação de Processos e Resultados em Cuidados de Saúde/economia , Atenção Primária à Saúde/normas , Qualidade da Assistência à Saúde/economia , Reembolso de Incentivo/economia , Adulto , Idoso , Distribuição de Qui-Quadrado , Diabetes Mellitus/economia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Atenção Primária à Saúde/economia , Análise de Regressão , Estudos Retrospectivos , Reino Unido/epidemiologia
11.
BMC Genomics ; 11: 364, 2010 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-20529381

RESUMO

BACKGROUND: Cell functions depend on molecules organized in the cellular society. Two basic components are mRNA molecules and proteins. The interactions within and between those two components are crucial for carrying out sophisticated cell functions. The interplay can be analyzed by comparing expression levels of mRNA and proteins. This is critical for understanding the molecular interactions, (post-) transcriptional regulations and conservation of co-expression between mRNAs and proteins. By using high-throughput transcriptome and proteome data, this study aims to systematically investigate the general picture of such expression correlations. We analyze four groups of correlations: (i) transcript levels of different genes, (ii) protein levels of different genes, (iii) mRNA levels with protein levels of different genes and (iv) mRNA levels with protein levels of same genes. This helps to obtain global insights into the stability and variability of co-expression and correlation of mRNA and protein levels. RESULTS: Analysis of the simultaneous co-expression of mRNAs and proteins yields mainly weak correlations. Therefore we introduce the concept of time-delayed co-expression patterns. Based on a time-course dataset, we obtain a high fraction of time-delayed correlations. In group (i), 67% of different transcripts are significantly correlated. At the protein level (ii), 68% of different proteins are significantly correlated. Comparison of the different molecular levels results in a 74% fraction of correlated transcript and protein levels of different genes (iii) and 56% for the same genes (iv). Furthermore, a higher fraction of protein levels (simultaneously 20% and short time-delayed 29%) is correlated than at the transcript level (10% and 18% respectively). Analysis of the dynamics of the correlation shows that correlation at the transcript level is largely passed to the protein level. In contrast, specific co-expression patterns are changed in multiple ways. CONCLUSIONS: Our analysis reveals that the regulation of transcription and translation contains a time-delayed component. The correlation at the protein level is more synchronous or delayed by shorter time than those at the transcript level. This supports the hypothesis that a higher degree of direct physical interactions require a higher synchronicity between the interacting partners. The conservation of correlation between the transcript level (i) and the protein level (ii) sheds light on the processes underlying transcription, translation and regulation. A future investigation of the conditions of conservation will give comprehensive insights in the complexity of the regulatory mechanisms.


Assuntos
Biologia Computacional , Perfilação da Expressão Gênica , Proteínas/metabolismo , Humanos , Plasmodium falciparum/citologia , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo , Transcrição Gênica
12.
Bioinformatics ; 25(16): 2103-9, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19286833

RESUMO

MOTIVATION: Statistical assessment of cis-regulatory modules (CRMs) is a crucial task in computational biology. Usually, one concludes from exceptional co-occurrences of DNA motifs that the corresponding transcription factors (TFs) are cooperative. However, similar DNA motifs tend to co-occur in random sequences due to high probability of overlapping occurrences. Therefore, it is important to consider similarity of DNA motifs in the statistical assessment. RESULTS: Based on previous work, we propose to adjust the window size for co-occurrence detection. Using the derived approximation, one obtains different window sizes for different sets of DNA motifs depending on their similarities. This ensures that the probability of co-occurrences in random sequences are equal. Applying the approach to selected similar and dissimilar DNA motifs from human TFs shows the necessity of adjustment and confirms the accuracy of the approximation by comparison to simulated data. Furthermore, it becomes clear that approaches ignoring similarities strongly underestimate P-values for cooperativity of TFs with similar DNA motifs. In addition, the approach is extended to deal with overlapping windows. We derive Chen-Stein error bounds for the approximation. Comparing the error bounds for similar and dissimilar DNA motifs shows that the approximation for similar DNA motifs yields large bounds. Hence, one has to be careful using overlapping windows. Based on the error bounds, one can precompute the approximation errors and select an appropriate overlap scheme before running the analysis. AVAILABILITY: Software to perform the calculation for pairs of position frequency matrices (PFMs) is available at http://mosta.molgen.mpg.de as well as C++ source code for downloading.


Assuntos
Algoritmos , Biologia Computacional/métodos , Análise de Sequência de DNA , Fatores de Transcrição/metabolismo , DNA/química , Alinhamento de Sequência/métodos
13.
Bioinformatics ; 24(3): 350-7, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18174183

RESUMO

MOTIVATION: Transcription factors (TFs) play a key role in gene regulation by binding to target sequences. In silico prediction of potential binding of a TF to a binding site is a well-studied problem in computational biology. The binding sites for one TF are represented by a position frequency matrix (PFM). The discovery of new PFMs requires the comparison to known PFMs to avoid redundancies. In general, two PFMs are similar if they occur at overlapping positions under a null model. Still, most existing methods compute similarity according to probabilistic distances of the PFMs. Here we propose a natural similarity measure based on the asymptotic covariance between the number of PFM hits incorporating both strands. Furthermore, we introduce a second measure based on the same idea to cluster a set of the Jaspar PFMs. RESULTS: We show that the asymptotic covariance can be efficiently computed by a two dimensional convolution of the score distributions. The asymptotic covariance approach shows strong correlation with simulated data. It outperforms three alternative methods. The Jaspar clustering yields distinct groups of TFs of the same class. Furthermore, a representative PFM is given for each class. In contrast to most other clustering methods, PFMs with low similarity automatically remain singletons. AVAILABILITY: A website to compute the similarity and to perform clustering, the source code and Supplementary Material are available at http://mosta.molgen.mpg.de.


Assuntos
Algoritmos , Análise por Conglomerados , Reconhecimento Automatizado de Padrão/métodos , Alinhamento de Sequência/métodos , Análise de Sequência de DNA/métodos , Fatores de Transcrição/genética , Inteligência Artificial , Sequência de Bases , Sítios de Ligação , Dados de Sequência Molecular , Ligação Proteica , Homologia de Sequência do Ácido Nucleico
14.
Genome Inform ; 17(1): 134-40, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17503363

RESUMO

Transcription factors (TFs) play a key role in gene regulation by binding to target sequences. In silico prediction of potential binding to a sequence is a main task in computational biology. Although many methods have been proposed to tackle this problem, the statistical significance of the prediction is still not solved. We propose an approach to give a good approximation for the potential of a sequence to be bound by a TF. Instead of assessing distinct binding sites, we motivate to focus on the number of binding sites. Based on a suitable statistical model, probabilities for scoring are approximated for a TF to bind to a sequence. Two examples show the necessity of such a model as well as the superiority of the proposed method compared to standard approaches.


Assuntos
DNA/genética , Modelos Genéticos , Modelos Estatísticos , Análise de Sequência de DNA , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação/genética , DNA/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Fatores de Transcrição MEF2 , Camundongos , Fatores de Regulação Miogênica/genética , Fatores de Regulação Miogênica/metabolismo , Fatores de Transcrição/genética
15.
Arch Intern Med ; 136(4): 444-8, 1976 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-944559

RESUMO

In 17 previously reported cases of cladosporiosis, no reliable therapy was described, and death occurred usually within one year of diagnosis. Pretreatment isolates from our two patients were inhibited by 6.2 mug/ml and 3.1mug/ml of flucytosine, respectively. Although both patients died, postmortem examination results showed that in one patient, the fungus had been eradicated. In the other patient, C trichoides that was isolated at postmortem examination was resistant to flucytosine treatment.


Assuntos
Abscesso Encefálico/etiologia , Cladosporium/isolamento & purificação , Fungos Mitospóricos/isolamento & purificação , Micoses/complicações , Adolescente , Adulto , Autopsia , Abscesso Encefálico/microbiologia , Abscesso Encefálico/patologia , Cladosporium/efeitos dos fármacos , Feminino , Flucitosina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/patologia
16.
PLoS One ; 10(3): e0119185, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25811487

RESUMO

Pay-for-performance programs are often aimed to improve the management of chronic diseases. We evaluate the impact of a local pay for performance programme (QOF+), which rewarded financially more ambitious quality targets ('stretch targets') than those used nationally in the Quality and Outcomes Framework (QOF). We focus on targets for intermediate outcomes in patients with cardiovascular disease and diabetes. A difference-in-difference approach is used to compare practice level achievements before and after the introduction of the local pay for performance program. In addition, we analysed patient-level data on exception reporting and intermediate outcomes utilizing an interrupted time series analysis. The local pay for performance program led to significantly higher target achievements (hypertension: p-value <0.001, coronary heart disease: p-values <0.001, diabetes: p-values <0.061, stroke: p-values <0.003). However, the increase was driven by higher rates of exception reporting (hypertension: p-value <0.001, coronary heart disease: p-values <0.03, diabetes: p-values <0.05) in patients with all conditions except for stroke. Exception reporting allows practitioners to exclude patients from target calculations if certain criteria are met, e.g. informed dissent of the patient for treatment. There were no statistically significant improvements in mean blood pressure, cholesterol or HbA1c levels. Thus, achievement of higher payment thresholds in the local pay for performance scheme was mainly attributed to increased exception reporting by practices with no discernable improvements in overall clinical quality. Hence, active monitoring of exception reporting should be considered when setting more ambitious quality targets. More generally, the study suggests a trade-off between additional incentive for better care and monitoring costs.


Assuntos
Doenças Cardiovasculares/epidemiologia , Planos de Incentivos Médicos , Qualidade da Assistência à Saúde , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Comorbidade , Gerenciamento Clínico , Etnicidade , Feminino , Humanos , Londres/epidemiologia , Londres/etnologia , Masculino , Avaliação de Resultados em Cuidados de Saúde , Atenção Primária à Saúde , Indicadores de Qualidade em Assistência à Saúde
17.
PLoS One ; 10(4): e0122747, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25849356

RESUMO

BACKGROUND: Understanding how urbanisation and rural-urban migration influence risk-factors for non-communicable disease (NCD) is crucial for developing effective preventative strategies globally. This study compares NCD risk-factor prevalence in urban, rural and migrant populations in China, Ghana, India, Mexico, Russia and South Africa. METHODS: Study participants were 39,436 adults within the WHO Study on global AGEing and adult health (SAGE), surveyed 2007-2010. Risk ratios (RR) for each risk-factor were calculated using logistic regression in country-specific and all country pooled analyses, adjusted for age, sex and survey design. Fully adjusted models included income quintile, marital status and education. RESULTS: Regular alcohol consumption was lower in migrant and urban groups than in rural groups (pooled RR and 95%CI: 0.47 (0.31-0.68); 0.58, (0.46-0.72), respectively). Occupational physical activity was lower (0.86 (0.72-0.98); 0.76 (0.65-0.85)) while active travel and recreational physical activity were higher (pooled RRs for urban groups; 1.05 (1.00-1.09), 2.36 (1.95-2.83), respectively; for migrant groups: 1.07 (1.0 -1.12), 1.71 (1.11-2.53), respectively). Overweight, raised waist circumference and diagnosed diabetes were higher in urban groups (1.19 (1.04-1.35), 1.24 (1.07-1.42), 1.69 (1.15-2.47), respectively). Exceptions to these trends exist: obesity indicators were higher in rural Russia; active travel was lower in urban groups in Ghana and India; and in South Africa, urban groups had the highest alcohol consumption. CONCLUSION: Migrants and urban dwellers had similar NCD risk-factor profiles. These were not consistently worse than those seen in rural dwellers. The variable impact of urbanisation on NCD risk must be considered in the design and evaluation of strategies to reduce the growing burden of NCDs globally.


Assuntos
Envelhecimento , Obesidade/epidemiologia , Fumar/epidemiologia , Adolescente , Adulto , Estudos Transversais , Países Desenvolvidos , Comportamento Alimentar , Feminino , Migração Humana , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , População Rural , Migrantes , População Urbana , Organização Mundial da Saúde , Adulto Jovem
18.
J Nucl Med ; 21(8): 747-9, 1980 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-6249896

RESUMO

Tc-99m sulfur colloid is concentrated in Kupffer cells of the liver, whereas the new biliary agents are processed by hepatic parenchymal cells. A case of primary hepatocellular carcinoma, appearing as a defect on sulfur-colloid liver scan and visualized on a biliary scan, is presented. The possible role of biliary scanning in the evaluation of a defect on sulfur-colloid liver scan is discussed.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Glutamatos , Neoplasias Hepáticas/diagnóstico por imagem , Compostos de Organotecnécio , Piridoxal/análogos & derivados , Tecnécio , Idoso , Carcinoma Hepatocelular/patologia , Coloides , Diagnóstico Diferencial , Vesícula Biliar/diagnóstico por imagem , Radioisótopos de Gálio , Humanos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Cintilografia , Enxofre
19.
Semin Nucl Med ; 10(3): 302-10, 1980 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-6106288

RESUMO

Nuclear medicine imaging techniques are being more widely applied to study a variety of lung injuries. Ventilation and perfusion imaging is often superior to other roentgenographic techniques for establishing the diagnosis and demonstrating the extent of such injuries. At several large burn centers, the Xe-133 washout technique has become the cornerstone for diagnosing early inhalation injury. The overall accuracy of this procedure is 92%. Regional decreases in ventilation and perfusion can reliably localize aspirated radiolucent foreign bodies. Disproportionate perfusion changes are often the earliest indicator of radiation pneumonitis and other forms of vascular injury. Other types of injury, such as gastropulmonary aspiration, blunt trauma, and near-drowning, require further evaluation before the ultimate role of nuclear imaging is defined. An imaging technique to assess capillary permeability in the adult respiratory distress syndrome would be of great clinical benefits.


Assuntos
Lesão Pulmonar , Traumatismos por Explosões/diagnóstico por imagem , Queimaduras por Inalação/diagnóstico por imagem , Criança , Corpos Estranhos/diagnóstico por imagem , Humanos , Pneumonia Aspirativa/diagnóstico por imagem , Lesões por Radiação/diagnóstico por imagem , Cintilografia , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Albumina Sérica , Arterite de Takayasu/diagnóstico por imagem , Tecnécio , Vasculite/diagnóstico por imagem , Ferimentos não Penetrantes/diagnóstico por imagem , Radioisótopos de Xenônio
20.
Biochem Pharmacol ; 41(8): 1195-201, 1991 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-1672594

RESUMO

The reported relaxing effect of CO on various smooth muscle tissues could also be found in guinea pig ileal strips. The effect was pronounced after precontraction with 10-100 nM acetylcholine and rather small with KCl. Based on the photoreversibility of the CO-dependent relaxation, a photochemical action spectrum was established which showed a maximum at around 422 nm. This definitely rules out the participation of a cytochrome P450 dependent process as postulated for the CO induced relaxation of lamb ductus arteriosus. With regard to the potency of KCN and antimycin A to relax ileal smooth muscle, the involvement of respiratory chain inhibition was reinvestigated, but no indication for such a mechanism could be obtained. In analogy to the mechanism of CO-inhibition of platelet activation we found that CO about doubles cGMP levels in guinea pig ileal strips. This is similar to NO which also leads to effective relaxation. We propose that CO can be considered and experimentally used as a convenient activator of soluble G-cyclase in smooth muscle and platelets.


Assuntos
Monóxido de Carbono/farmacologia , Guanilato Ciclase/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , GMP Cíclico/fisiologia , Cobaias , Técnicas In Vitro , Luz , Nitroprussiato/farmacologia , Fotoquímica , Cianeto de Potássio/farmacologia
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