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Objective This report on the third round of the Research and Development Survey (RANDS 3) provides a general description of RANDS 3 and presents percentage estimates of selected demographic and health-related variables from the overall sample and by one set of experimental groups embedded in the survey. Statistical tests comparing estimates for the two randomized groups were conducted to evaluate the randomization. Methods NORC at the University of Chicago conducted RANDS 3 for the National Center of Health Statistics in 2019 using its AmeriSpeak Panel in web-only mode. To assess question-response patterns, probe questions and four sets of experiments were embedded in RANDS 3, with panelists randomized into two groups for each set of experiments. Participants in each group received questions with differences in wording, question-andresponse formats, or question order. Results Of the 4,255 people sampled, 2,646 completed RANDS 3 for a completion rate of 62.2% and a weighted cumulative response rate of 18.1%. Iterative raking was performed using demographic and selected health condition variables to calibrate the RANDS 3 sample to 2019 National Health Interview Survey (NHIS) estimates. As a result, the overall demographic distribution and percentages of asthma, diabetes, hypertension, and high cholesterol for the calibrated RANDS 3 sample aligned with the percentages estimated from the 2019 NHIS. The distributions of demographic and healthrelated variables were comparable between the two randomized groups examined except for ever-diagnosed hypertension. Conclusion As part of a research series using probability-based survey panels, RANDS 3 included health-related questions with a focus on disability and opioids. Because RANDS is an ongoing research platform, a variety of persistent and emergent research questions relating to survey methodology will continue to be examined in current and future rounds of RANDS.
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Hipertensión , Investigación , Estados Unidos/epidemiología , Humanos , National Center for Health Statistics, U.S. , Analgésicos Opioides , Encuestas y CuestionariosRESUMEN
BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Microambiente Tumoral , Recurrencia Local de Neoplasia , Inmunoterapia/métodos , Neoplasias Encefálicas/tratamiento farmacológicoRESUMEN
Obscurin is a giant cytoskeletal protein with structural and regulatory roles encoded by the OBSCN gene. Recently, mutations in OBSCN were associated with the development of different forms of cardiomyopathies, including hypertrophic cardiomyopathy (HCM). We previously reported that homozygous mice carrying the HCM-linked R4344Q obscurin mutation develop arrhythmia by 1-year of age under sedentary conditions characterized by increased heart rate, frequent incidents of premature ventricular contractions, and episodes of spontaneous ventricular tachycardia. In an effort to delineate the molecular mechanisms that contribute to the observed arrhythmic phenotype, we subjected protein lysates prepared from left ventricles of 1-year old R4344Q and wild-type mice to comparative proteomics analysis using tandem mass spectrometry; raw data are available via ProteomeXchange with identifier PXD017314. We found that the expression levels of proteins involved in cardiac function and disease, cytoskeletal organization, electropotential regulation, molecular transport and metabolism were significantly altered. Moreover, phospho-proteomic evaluation revealed changes in the phosphorylation profile of Ca2+ cycling proteins, including sAnk1.5, a major binding partner of obscurin localized in the sarcoplasmic reticulum; notably, this is the first report indicating that sAnk1 undergoes phosphorylation. Taken together, our findings implicate obscurin in diverse cellular processes within the myocardium, which is consistent with its multiple binding partners, localization in different subcellular compartments, and disease association.
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Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP-dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein-C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631-709, 2018.
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Proteínas Musculares/fisiología , Miofibrillas/metabolismo , Sarcómeros/fisiología , Animales , Humanos , Contracción Muscular/fisiología , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Enfermedades Musculares/metabolismo , Mutación , Miofibrillas/fisiología , Miosinas/genética , Miosinas/fisiologíaRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0088162.].
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Obscurins are cytoskeletal proteins with structural and regulatory roles encoded by OBSCN. Mutations in OBSCN are associated with the development of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Specifically, the R4344Q mutation present in immunoglobulin domain 58 (Ig58) was the first to be linked with the development of HCM. To assess the effects of R4344Q in vivo, we generated the respective knock-in mouse model. Mutant obscurins are expressed and incorporated normally into sarcomeres. The expression patterns of sarcomeric and Ca2+-cycling proteins are unaltered in sedentary 1-year-old knock-in myocardia, with the exception of sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase 2 (SERCA2) and pentameric phospholamban whose levels are significantly increased and decreased, respectively. Isolated cardiomyocytes from 1-year-old knock-in hearts exhibit increased Ca2+-transients and Ca2+-load in the sarcoplasmic reticulum and faster contractility kinetics. Moreover, sedentary 1-year-old knock-in animals develop tachycardia accompanied by premature ventricular contractions, whereas 2-month-old knock-in animals subjected to pressure overload develop a DCM-like phenotype. Structural analysis revealed that the R4344Q mutation alters the distribution of electrostatic charges over the Ig58 surface, thus interfering with its binding capabilities. Consistent with this, wild-type Ig58 interacts with phospholamban modestly, and this interaction is markedly enhanced in the presence of R4344Q. Together, our studies demonstrate that under sedentary conditions, the R4344Q mutation results in Ca2+ deregulation and spontaneous arrhythmia, whereas in the presence of chronic, pathological stress, it leads to cardiac remodeling and dilation. We postulate that enhanced binding between mutant obscurins and phospholamban leads to SERCA2 disinhibition, which may underlie the observed pathological alterations.
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Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Señalización del Calcio , Calcio/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Cardiopatías/genética , Cardiopatías/metabolismo , Proteínas Musculares/genética , Mutación , Animales , Arritmias Cardíacas/diagnóstico , Modelos Animales de Enfermedad , Ecocardiografía , Electrocardiografía , Cardiopatías/diagnóstico , Espectroscopía de Resonancia Magnética , Ratones , Ratones Transgénicos , Proteínas Serina-Treonina Quinasas , Factores de Intercambio de Guanina Nucleótido RhoRESUMEN
Tyrosine kinase inhibitor (TKI) therapies induce clinical remission with remarkable effects on chronic myeloid leukemia (CML). However, very few TKIs completely eradicate the leukemic clone and persistence of leukemic stem cells (LSCs) remains challenging, warranting new, distinct targets for improved treatments. We demonstrated that the scaffold protein AHI-1 is highly deregulated in LSCs and interacts with multiple proteins, including Dynamin-2 (DNM2), to mediate TKI-resistance of LSCs. We have now demonstrated that the SH3 domain of AHI-1 and the proline rich domain of DNM2 are mainly responsible for this interaction. DNM2 expression was significantly increased in CML stem/progenitor cells; knockdown of DNM2 greatly impaired their survival and sensitized them to TKI treatments. Importantly, a new AHI-1-BCR-ABL-DNM2 protein complex was uncovered, which regulates leukemic properties of these cells through a unique mechanism of cellular endocytosis and ROS-mediated autophagy. Thus, targeting this complex may facilitate eradication of LSCs for curative therapies.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Autofagia , Dinaminas/fisiología , Endocitosis , Proteínas de Fusión bcr-abl/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Especies Reactivas de Oxígeno/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras del Transporte Vesicular , Línea Celular Tumoral , Dinamina II , Dinaminas/genética , Dinaminas/metabolismo , Endosomas/metabolismo , Proteínas de Fusión bcr-abl/metabolismo , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Fosforilación , ARN Mensajero/metabolismoRESUMEN
In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400-800 µM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation, and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 µM lovastatin for three days prior to addition of Tumor necrosis factor - α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.
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Vasos Sanguíneos/fisiología , Evaluación Preclínica de Medicamentos/métodos , Fibroblastos/citología , Óxido Nítrico/metabolismo , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Acetilcolina/farmacología , Vasos Sanguíneos/efectos de los fármacos , Células Cultivadas , Humanos , Lovastatina/farmacología , NG-Nitroarginina Metil Éster/farmacología , Fenilefrina/farmacología , Ingeniería de Tejidos , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
The sarcomeric M-region anchors thick filaments and withstands the mechanical stress of contractions by deformation, thus enabling distribution of physiological forces along the length of thick filaments. While the role of the M-region in supporting myofibrillar structure and contractility is well established, its role in mediating additional cellular processes has only recently started to emerge. As such, M-region is the hub of key protein players contributing to cytoskeletal remodeling, signal transduction, mechanosensing, metabolism, and proteasomal degradation. Mutations in genes encoding M-region related proteins lead to development of severe and lethal cardiac and skeletal myopathies affecting mankind. Herein, we describe the main cellular processes taking place at the M-region, other than thick filament assembly, and discuss human myopathies associated with mutant or truncated M-region proteins.
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Citoesqueleto/metabolismo , Proteínas Musculares/química , Miocardio/metabolismo , Sarcómeros/metabolismo , Humanos , Contracción Muscular , Proteínas Musculares/metabolismo , Sarcómeros/química , Estrés MecánicoRESUMEN
Obscurins comprise a family of proteins originally identified in striated muscles, where they play essential roles in myofibrillogenesis, cytoskeletal organization, and Ca(2+) homeostasis. They are encoded by the single OBSCN gene, and are composed of tandem adhesion domains and signaling motifs. To date, two giant obscurin isoforms have been described in detail that differ only at the extreme COOH-terminus; while obscurin-A (â¼720 kDa) contains a non-modular COOH-terminus that harbors binding sites for the adaptor proteins ankyrins, obscurin-B (â¼870 kDa) contains two COOH-terminal serine-threonine kinase domains preceded by adhesion motifs. Besides the two known giant obscurins, a thorough search of transcript databases suggests that complex alternative splicing of the obscurin transcript results in the generation of additional giant as well as small isoforms with molecular masses ranging between â¼50-970 kDa. These novel isoforms share common domains with the characterized isoforms, but also contain unique regions. Using a panel of highly specific antibodies directed against epitopes spanning the entire length of giant obscurins, we employed western blotting and immunohistochemistry to perform a systematic and comprehensive characterization of the expression profile of obscurins in muscle and non-muscle tissues. Our studies demonstrate for the first time that obscurins are not restricted to striated muscles, but are abundantly expressed in several tissues and organs including brain, skin, kidney, liver, spleen, and lung. While some obscurin isoforms are ubiquitously expressed, others are preferentially present in specific tissues and organs. Moreover, obscurins are present in select structures and cell types where they assume nuclear, cytosolic, and membrane distributions. Given the ubiquitous expression of some obscurins, along with the preferential expression of others, it becomes apparent that obscurins may play common and unique roles, respectively, in the regulation and maintenance of cell homeostasis in various tissues and organs throughout the body.
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Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas Musculares/metabolismo , Músculos/metabolismo , Animales , Epítopos/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Músculo Estriado/metabolismo , Especificidad de Órganos/genética , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinasas , Transporte de Proteínas , Ratas Sprague-Dawley , Factores de Intercambio de Guanina Nucleótido Rho , Fracciones Subcelulares/metabolismoRESUMEN
Boolean networks are a simple but efficient model for describing gene regulatory systems. A number of algorithms have been proposed to infer Boolean networks. However, these methods do not take full consideration of the effects of noise and model uncertainty. In this paper, we propose a full Bayesian approach to infer Boolean genetic networks. Markov chain Monte Carlo algorithms are used to obtain the posterior samples of both the network structure and the related parameters. In addition to regular link addition and removal moves, which can guarantee the irreducibility of the Markov chain for traversing the whole network space, carefully constructed mixture proposals are used to improve the Markov chain Monte Carlo convergence. Both simulations and a real application on cell-cycle data show that our method is more powerful than existing methods for the inference of both the topology and logic relations of the Boolean network from observed data.
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Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Modelos Genéticos , Algoritmos , Teorema de Bayes , Ciclo Celular/genética , Simulación por Computador , Cadenas de Markov , Método de MontecarloRESUMEN
Discovered about a decade ago, obscurin (~720 kDa) is a member of a family of giant proteins expressed in striated muscle that are essential for normal muscle function. Much of what we understand about obscurin stems from its functions in cardiac and skeletal muscle. However, recent evidence has indicated that variants of obscurin ("obscurins") are expressed in diverse cell types, where they contribute to distinct cellular processes. Dysfunction or abrogation of obscurins has also been implicated in the development of several pathological conditions, including cardiac hypertrophy and cancer. Herein, we present an overview of obscurins with an emphasis on novel findings that demonstrate their heretofore-unsuspected importance in cell signaling and disease progression.
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Factores de Intercambio de Guanina Nucleótido Rho/fisiología , Animales , Cardiomiopatía Hipertrófica Familiar/genética , Humanos , Desarrollo de Músculos , Músculo Esquelético/metabolismo , Mutación Missense , Neoplasias/genética , Especificidad de Órganos , Mapas de Interacción de Proteínas , Proteínas Serina-Treonina QuinasasRESUMEN
Obscurins comprise a family of giant (~870- to 600-kDa) and small (~250- to 55-kDa) proteins that play important roles in myofibrillogenesis, cytoskeletal organization, and cell adhesion and are implicated in hypertrophic cardiomyopathy and tumorigenesis. Giant obscurins are composed of tandem structural and signaling motifs, including 2 serine/threonine kinase domains, SK1 and SK2, present at the COOH terminus of giant obscurin-B. Using biochemical and cellular approaches, we show for the first time that both SK1 and SK2 possess enzymatic activities and undergo autophosphorylation. SK2 can phosphorylate the cytoplasmic domain of N-cadherin, a major component of adherens junctions, and SK1 can interact with the extracellular domain of the ß1-subunit of the Na(+)/K(+)-ATPase, which also resides in adherens junctions. Immunostaining of nonpermeabilized myofibers and cardiocytes revealed that some obscurin kinase isoforms localize extracellularly. Quantification of the exofacial expression of obscurin kinase proteins indicated that they occupy ~16 and ~5% of the sarcolemmal surface in myofibers and cardiocytes, respectively. Treatment of heart lysates with peptide-N-glycosidase F revealed that while giant obscurin-B localizes intracellularly, possessing dual kinase activity, a small obscurin kinase isoform that contains SK1 localizes extracellularly, where it undergoes N-glycosylation. Collectively, our studies demonstrate that the obscurin kinase domains are enzymatically active and may be involved in the regulation of cell adhesion.
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Adhesión Celular/fisiología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas Musculares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Animales , Cadherinas/metabolismo , Femenino , Glicosilación , Factores de Intercambio de Guanina Nucleótido/inmunología , Isoenzimas/metabolismo , Ratones , Proteínas Musculares/inmunología , Miocitos Cardíacos/enzimología , Miofibrillas/enzimología , Fosforilación , Transporte de Proteínas/fisiología , Factores de Intercambio de Guanina Nucleótido Rho , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Especificidad por SustratoRESUMEN
Tandem repeats occur frequently in biological sequences. They are important for studying genome evolution and human disease. A number of methods have been designed to detect a single tandem repeat in a sliding window. In this article, we focus on the case that an unknown number of tandem repeat segments of the same pattern are dispersively distributed in a sequence. We construct a probabilistic generative model for the tandem repeats, where the sequence pattern is represented by a motif matrix. A Bayesian approach is adopted to compute this model. Markov chain Monte Carlo (MCMC) algorithms are used to explore the posterior distribution as an effort to infer both the motif matrix of tandem repeats and the location of repeat segments. Reversible jump Markov chain Monte Carlo (RJMCMC) algorithms are used to address the transdimensional model selection problem raised by the variable number of repeat segments. Experiments on both synthetic data and real data show that this new approach is powerful in detecting dispersed short tandem repeats. As far as we know, it is the first work to adopt RJMCMC algorithms in the detection of tandem repeats.
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Algoritmos , Repeticiones de Microsatélite , Análisis de Secuencia de ADN , Cadenas de Markov , Método de MontecarloRESUMEN
Treatment strategy of esophageal cancer mainly depends on accurate staging. At present, no single ideal staging modality is superior to another in preoperative tumor-node-metastasis (TNM) staging of patients with esophageal cancer. We aimed to investigate the efficacy of endoscopic ultrasonography (EUS) and positron emission tomography-computed tomography (PET-CT) for staging of esophageal cancer. We retrospectively studied 118 consecutive patients with esophageal squamous cell carcinoma who underwent esophagectomy with or without neoadjuvant chemoradiotherapy (CRT) over a near 3-year period between January 2005 and November 2008 at a tertiary hospital in Taiwan. Patients were separated into two groups: without neoadjuvant CRT (group 1, n= 28) and with CRT (group 2, n= 90). Medical records of demographic data and reports of EUS and PET-CT of patients before surgery were reviewed. A database of clinical staging by EUS and PET-CT was compared with one of pathological staging. The accuracies of T staging by EUS in groups 1 and 2 were 85.2% and 34.9%. The accuracies of N staging by EUS in groups 1 and 2 were 55.6% and 39.8%. The accuracies of T and N staging by means of PET-CT scan were 100% and 54.5% in group 1, and were 69.4% and 86.1% in group 2, respectively. In group 2, 38 of 90 patients (42.2%) achieved pathologic complete remission. Among them, two of 34 (5.9%) and 12 of 17 (70.6%) patients were identified as tumor-free by post-CRT EUS and PET-CT, respectively. EUS is useful for initial staging of esophageal cancer. PET-CT is a more reliable modality for monitoring treatment response and restaging. Furthermore, the accuracy of PET-CT with regard to N staging is higher in patients who have undergone CRT than those who have not.
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Carcinoma de Células Escamosas/diagnóstico , Endosonografía , Neoplasias Esofágicas/diagnóstico , Imagen Multimodal , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Quimioradioterapia Adyuvante , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Esofagectomía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estudios Retrospectivos , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
The objective of our study was to develop a computing program for computing the transit time frequency distributions of red blood cell in human pulmonary circulation, based on our anatomic and elasticity data of blood vessels in human lung. A stochastic simulation model was introduced to simulate blood flow in human pulmonary circulation. In the stochastic simulation model, the connectivity data of pulmonary blood vessels in human lung was converted into a probability matrix. Based on this model, the transit time of red blood cell in human pulmonary circulation and the output blood pressure were studied. Additionally, the stochastic simulation model can be used to predict the changes of blood flow in human pulmonary circulation with the advantage of the lower computing cost and the higher flexibility. In conclusion, a stochastic simulation approach was introduced to simulate the blood flow in the hierarchical structure of a pulmonary circulation system, and to calculate the transit time distributions and the blood pressure outputs.
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Pulmón/irrigación sanguínea , Modelos Cardiovasculares , Circulación Pulmonar/fisiología , Programas Informáticos , Presión Sanguínea/fisiología , Elasticidad , Eritrocitos/fisiología , Humanos , Pulmón/anatomía & histologíaRESUMEN
MOTIVATION: Repeats detection problems are traditionally formulated as string matching or signal processing problems. They cannot readily handle gaps between repeat units and are incapable of detecting repeat patterns shared by multiple sequences. This study detects short adjacent repeats with interunit insertions from multiple sequences. For biological sequences, such studies can shed light on molecular structure, biological function and evolution. RESULTS: The task of detecting short adjacent repeats is formulated as a statistical inference problem by using a probabilistic generative model. An Markov chain Monte Carlo algorithm is proposed to infer the parameters in a de novo fashion. Its applications on synthetic and real biological data show that the new method not only has a competitive edge over existing methods, but also can provide a way to study the structure and the evolution of repeat-containing genes. AVAILABILITY: The related C++ source code and datasets are available at http://ihome.cuhk.edu.hk/%7Eb118998/share/BASARD.zip. CONTACT: xfan@sta.cuhk.edu.hk
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Algoritmos , Cadenas de Markov , Método de Montecarlo , Secuencias Repetidas en Tándem , Secuencia de Bases , Teorema de Bayes , Biología Computacional , Modelos EstadísticosRESUMEN
A continuum model was introduced to analyze the pressure-flow relationship for steady flow in human pulmonary circulation. The continuum approach was based on the principles of continuum mechanics in conjunction with detailed measurement of vascular geometry, vascular elasticity and blood rheology. The pulmonary arteries and veins were considered as elastic tubes and the "fifth-power law" was used to describe the pressure-flow relationship. For pulmonary capillaries, the "sheet-flow" theory was employed and the pressure-flow relationship was represented by the "fourth-power law". In this paper, the pressure-flow relationship for the whole pulmonary circulation and the longitudinal pressure distribution along the streamlines were studied. Our computed data showed general agreement with the experimental data for the normal subjects and the patients with mitral stenosis and chronic bronchitis in the literature. In conclusion, our continuum model can be used to predict the changes of steady flow in human pulmonary circulation.
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Presión Sanguínea/fisiología , Pulmón/irrigación sanguínea , Modelos Biológicos , Arteria Pulmonar , Venas Pulmonares , Elasticidad , Humanos , Matemática , Arteria Pulmonar/anatomía & histología , Arteria Pulmonar/fisiología , Venas Pulmonares/anatomía & histología , Venas Pulmonares/fisiología , Flujo Sanguíneo Regional , VasoconstricciónRESUMEN
The tumor suppressor gene hypermethylated in cancer 1 (HIC1), which encodes a transcriptional repressor, is epigenetically inactivated in various human cancers. In this study, we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers. We also show that mouse embryos lacking both Hic1 alleles manifest developmental defects spatially associated with the misexpression of ephrin-A1, and that overexpression of ephrin-A1 is a feature of tumors arising in Hic1 heterozygous mice in which the remaining wild-type allele is epigenetically silenced. In breast cancer, we find that ephrin-A1 expression is common in vivo, but that in cell culture, expression of the EphA receptors is predominant. Restoration of HIC1 function in breast cancer cells leads to a reduction in tumor growth in vivo, an effect that can be partially rescued by co-overexpression of ephrin-A1. Interestingly, overexpression of ephrin-A1 in vitro triggers downregulation of EphA2 and EphA4 levels, resulting in an expression pattern similar to that seen in vivo. We conclude that Hic1 spatially restricts ephrin-A1 expression in development, and that upregulated expression of ephrin-A1 resulting from epigenetic silencing of HIC1 in cancer cells may be an important mechanism in epithelial malignancy.