Global Existence of Cylinder Symmetric Solutions for the Nonlinear Compressible Navier-Stokes Equations

We prove the global existence of cylinder symmetric solutions to the compressible Navier-Stokes equations with external forces and heat source in R3 for any large initial data. Some new ideas and more delicate estimates are used to prove this result

Sphere-forming cell subpopulations with cancer stem cell properties in human hepatoma cell lines

<p>Abstract</p> <p>Background</p> <p>Cancer stem cells (CSCs) are regarded as the cause of tumor formation and recurrence. The isolation and identification of CSCs could help to develop novel therapeutic strategies specifically targeting CSCs.</p> <p>Methods</p> <p>Human hepatoma cell lines were plated in stem cell conditioned culture system allowed for sphere forming. To evaluate the stemness characteristics of spheres, the self-renewal, proliferation, chemoresistance, tumorigenicity of the PLC/PRF/5 sphere-forming cells, and the expression levels of stem cell related proteins in the PLC/PRF/5 sphere-forming cells were assessed, comparing with the parental cells. The stem cell RT-PCR array was performed to further explore the biological properties of liver CSCs.</p> <p>Results</p> <p>The PLC/PRF/5, MHCC97H and HepG2 cells could form clonal nonadherent 3-D spheres and be serially passaged. The PLC/PRF/5 sphere-forming cells possessed a key criteria that define CSCs: persistent self-renewal, extensive proliferation, drug resistance, overexpression of liver CSCs related proteins (Oct3/4, OV6, EpCAM, CD133 and CD44). Even 500 sphere-forming cells were able to form tumors in NOD/SCID mice, and the tumor initiating capability was not decreased when spheres were passaged. Besides, downstream proteins DTX1 and Ep300 of the CSL (CBF1 in humans, Suppressor of hairless in Drosophila and LAG1 in C. elegans) -independent Notch signaling pathway were highly expressed in the spheres, and a gamma-secretase inhibitor MRK003 could significantly inhibit the sphere formation ability.</p> <p>Conclusions</p> <p>Nonadherent tumor spheres from hepatoma cell lines cultured in stem cell conditioned medium possess liver CSC properties, and the CSL-independent Notch signaling pathway may play a role in liver CSCs.</p

Molecular and cellular mechanisms regulating cross-talk between cyclooxygenase and lipoxygenase biosynthetic axes

Rheumatoid arthritis (RA) is characterized by chronic inflammation, synovial hyperplasia and joint destruction. The pathogenic mechanisms responsible for RA remain poorly understood both systemically and in the microenvironment of diarthrodial joint. Here we hypothesized, based on previous observations, that there is a positive interaction between resident mast cells and synovial fibroblasts (SF) within the rheumatoid synovial compartment. Our principal objectives were to define the cellular and molecular interactions between infiltrating mast cells and resident human synovial fibroblasts (HSF), and we focused our efforts on two genes, cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), both implicated in the inflammatory response associated with RA. Furthermore, our research led to the discovery of novel epigenetic mechanisms governing the regulation of 5-LO gene expression in RA-affected SF. Epigenetics refers to heritable changes in gene expression regulated by DNA methylation, histone modifications and RNA interference. Epigenetic regulation is critical for normal development and differentiation. But environmental factors can trigger epigenetic dysregulation, leading to the development of many diseases, including cancer and autoimmune diseases. Using Western and Northern blot analyses in addition to reporter assays, we demonstrated that mast cell-derived leukotriene B4 (LTB4) contributes to the modulation of inflammatory response in part through stabilization of COX-2 mRNA and protein expression in SF, the key enzyme in prostaglandin biosynthesis and the target of all non-steroidal anti-inflammatory drugs (NSAIDs). Further transient and stable transfection experiments verified that LTB4 exerted this COX-2 stabilization effect at the post-transcriptional level through Ras/c-Raf/MEK1/2/ERK1/2/p42 AUF1 signaling pathway. Genomic bisulfite sequencing was used to detect DNA methylation profiles of 5-LO gene (rate limiting in LTB4 synthesis) in HSF, mast cells and other cell types. The 5-LO gene promoter (DNA CpG islands) was heavily methylated in U937 cells (5-LO negative), but unmethylated in HL-60 cells (5-LO positive). Compared to the 5-LO-positive HMC-1 cells, the 5-LO-negative HMC-1 cells had much higher methylation levels of CpG islands in the promoter region. We found a strong correlation between 5-LO gene expression and DNA methylation in HMC-1 cells. Dexamethasone (DEX) treatment of HMC-1 cells increased the expression of 5-LO, a process associated with reduced methylation of histone H3 on lysines 9 and 27. Interestingly, osteoarthritic (OA)/RA HSF are 5-LO negative; though the promoter region is CpG hypomethylated, histone H3 is hypermethylated at Lys-9 and -27 residues.The research in this thesis provided innovative insights into the understanding of the pathophysiological mechanisms involved in inflammatory diseases like RA. The elucidation of the cellular and molecular mechanisms involved in these studies may help to establish new therapeutical targets in the treatment of RA patients. Moreover, the bisulfite sequencing and chromatin immunoprecipitation (ChIP) techniques used in this thesis provide reliable procedures for DNA methylation and histone modification studies in various inflammatory diseases and cancers.L'arthrite rhumatoïde est caractérisée par une inflammation chronique, une hyperplasie de la membrane synoviale et la destruction des jointures. Notre hypothèse, basé sur des observations précédentes, qu'il y avait une interaction positive entre les cellules mastocytes résidentielles et les fibroblastes synoviaux dans le compartiment de la synovial rhumatoïde. Nos objectifs principaux étaient de définir les interactions cellulaires et moléculaires entre les cellules mastocytes infiltrantes et les fibroblastes synoviaux résidentielles, en particulier deux gènes, la cyclooxygénase-2 et la 5-lipoxygénase (5-LO), tous deux impliquées dans la réponse inflammatoire associée à l'arthrite rhumatoïde. De plus, notre recherche a abouti à la découverte de mécanismes épigénétiques gouvernant la régulation de l'expression du gène de la 5-LO chez les fibroblastes synoviales atteint d'arthrite rhumatoïde. L'épigénétique est l'ensemble des modifications de l'expression des gènes contrôlés par la méthylation de l'ADN, les modifications aux histones liées à l'ADN et par interférence ARN transmissibles d'une génération de cellule à l'autre. La régulation épigénétique est indispensable pour la différentiation et le développement normal. Cependant, des facteurs environnementaux peuvent entamer un désordre épigénétique causant ainsi plusieurs maladies, tels que le cancer et des maladies auto-immunes.Avec les méthodes d'analyse par buvardage Western et Northern, en plus des essais rapporteurs, nous avons démontré que le leukotriène B4 (LTB4) produit par les cellules mastocytes contribues à la modulation de la réponse inflammatoire en parti par la stabilisation de l'ARN messager de la cyclooxygénase-2 (COX-2) et de l'expression de la protéine chez les fibroblastes synoviaux, l'enzyme clé de la biosynthèse des prostaglandines et la cible de tous les drogues anti-inflammatoires non stéroïdiens. De plus, les expériences de transfections transitoires et stables ont démontré que le LTB4 a exercé cet effet de stabilisation de la COX-2 au niveau post-transcriptionnelle par l'intermédiaire de la voie de signalisation de Ras/c-Raf/MEK1/2/ERK1/2/p42 AUF1. Le séquençage génomique avec traitement au bisulfite a été utilisé pour déterminer le profile de méthylation de l'ADN du gène de la 5-LO (enzyme clé dans la synthèse du LTB4) chez les fibroblastes synoviaux humains, les cellules mastocytes et d'autres types cellulaires. Le promoteur du gène 5-LO (îlots d'ADN CpG) était fortement méthylé chez les cellules U937 (5-LO négatif), cependant chez les cellules HL-60 le promoteur n'était pas méthylé (5-LO positif). En comparant les cellules HMC-1 qui expriment la 5-LO aux cellules HMC-1 qui n'expriment pas la 5-LO, ces derniers avaient de fort niveaux de méthylation des îlots CpG dans la région du promoteur. Nous avons trouvé une forte corrélation entre l'expression du gène 5-LO et la méthylation de l'ADN chez les cellules HMC-1. Le traitement des cellules HMC-1 avec la dexamethasone (DEX) augmente l'expression de la 5-LO, un processus associé à la réduction de la méthylation de l'histone H3 sur les lysines 9 et 27. Il est intéressant de voir que les fibroblastes synoviaux humains ostéoarthritique (OA)/RA sont 5-LO négatif; quoique la région du promoteur CpG est hypométhylé alors que l'histone H3 est hyperméthylé aux lysines 9 et 27.La recherche de cette thèse propose un cheminement innovateur à la compréhension des mécanismes physiopathologique impliqué dans les maladies inflammatoires telle que l'arthrite rhumatoïde. L'élucidation des mécanismes cellulaires et moléculaires impliqués dans ses études peuvent aider à l'établissement de nouvelles cibles thérapeutiques pour le traitement de l'arthrite rhumatoïde. De plus, la technique de séquençage de l'ADN avec le traitement au bisulfite utilisé dans cette thèse est fiable pour des études de méthylation de l'ADN et la modification des histones chez plusieurs maladies inflammatoires ainsi que les cancers

Relation Extraction Based on Fusion Dependency Parsing from Chinese EMRs

The Electronic Medical Record (EMR) contains a great deal of medical knowledge related to patients, which has been widely used in the construction of medical knowledge graphs. Previous studies mainly focus on the features based on surface semantics of EMRs for relation extraction, such as contextual feature, but the features of sentence structure in Chinese EMRs have been neglected. In this paper, a fusion dependency parsing-based relation extraction method is proposed. Specifically, this paper extends basic features with medical record feature and indicator feature that are applicable to Chinese EMRs. Furthermore, dependency syntactic features are introduced to analyse the dependency structure of sentences. Finally, the F1 value of relation extraction based on extended features is 4.87% higher than that of relation extraction based on basic features. And compared with the former, the F1 value of relation extraction based on fusion dependency parsing is increased by 4.39%. The results of experiments performed on a Chinese EMR data set show that the extended features and dependency parsing all contribute to the relation extraction

Hepatoma-derived growth factor-related protein 2 promotes DNA repair by homologous recombination

We have recently identified lens epithelium-derived growth factor (LEDGF/p75, also known as PSIP1) as a component of the homologous recombination DNA repair machinery. Through its Pro-Trp-Trp-Pro (PWWP) domain, LEDGF/p75 binds to histone marks associated with active transcription and promotes DNA end resection by recruiting DNA endonuclease retinoblastoma-binding protein 8 (RBBP8/CtIP) to broken DNA ends. Here we show that the structurally related PWWP domain-containing protein, hepatoma-derived growth factor-related protein 2 (HDGFRP2), serves a similar function in homologous recombination repair. Its depletion compromises the survival of human U2OS osteosarcoma and HeLa cervix carcinoma cells and impairs the DNA damage-induced phosphorylation of replication protein A2 (RPA2) and the recruitment of DNA endonuclease RBBP8/CtIP to DNA double strand breaks. In contrast to LEDGF/p75, HDGFRP2 binds preferentially to histone marks characteristic for transcriptionally silent chromatin. Accordingly, HDGFRP2 is found in complex with the heterochromatin-binding chromobox homologue 1 (CBX1) and Pogo transposable element with ZNF domain (POGZ). Supporting the functionality of this complex, POGZ-depleted cells show a similar defect in DNA damage-induced RPA2 phosphorylation as HDGFRP2-depleted cells. These data suggest that HDGFRP2, possibly in complex with POGZ, recruits homologous recombination repair machinery to damaged silent genes or to active genes silenced upon DNA damage

Theoretical Studies on Isomerization and Decomposition Reactions of 2‑Methyl-1-butanol Radicals

2-Methyl-1-butanol (2M1B) is a favorable candidate of substitute fuels characterized with high energy density and low hygroscopicity. 2M1B radicals, which are the products of H-abstraction reactions of 2M1B, and their isomerization and decomposition reactions play a cardinal impact on the distribution of combustion products. In this work, the primary isomerization and decomposition reaction channels of 2M1B radicals were investigated by using QCISD­(T)/CBS//M062x/cc-pVTZ and CBS-QB3 method, respectively. The accurate phenomenological temperature- and pressure-dependent rate constants covering temperatures of 250–2500 K and pressures from 1 × 10^–3 to 1 × 10³ bar along with high-pressure limit rate constants for these channels were computed by solving the RRKM/master equation. The calculations revealed that the isomerization reaction of RC2 → RC6 has the highest energy barrier among these reactions, while the decomposition reaction RC6 → CH₃CH₂CHCH₃ + CH₂O has the lowest energy barrier. Furthermore, the computed rate coefficients were also validated by using the previous pyrolysis experiment. The modeling results reproduce the experimental results satisfactorily. The current work not only provides reasonable kinetic data for the development of 2M1B combustion models but also lays a foundation to extend the kinetic mechanisms of alcohol with a longer chain