Epigenetics and chromatin remodeling play a role in lung disease

Epigenetics is defined as heritable changes that affect gene expression without altering the DNA sequence. Epigenetic regulation of gene expression is facilitated through different mechanisms such as DNA methylation, histone modifications and RNA-associated silencing by small non-coding RNAs. All these mechanisms are crucial for normal development, differentiation and tissue-specific gene expression. These three systems interact and stabilize one another and can initiate and sustain epigenetic silencing, thus determining heritable changes in gene expression. Histone acetylation regulates diverse cellular functions including inflammatory gene expression, DNA repair and cell proliferation. Transcriptional coactivators possess intrinsic histone acetyltransferase activity and this activity drives inflammatory gene expression. Eleven classical histone deacetylases (HDACs) act to regulate the expression of distinct subsets of inflammatory/immune genes. Thus, loss of HDAC activity or the presence of HDAC inhibitors can further enhance inflammatory gene expression by producing a gene-specific change in HAT activity. For example, HDAC2 expression and activity are reduced in lung macrophages, biopsy specimens, and blood cells from patients with severe asthma and smoking asthmatics, as well as in patients with chronic obstructive pulmonary disease (COPD). This may account, at least in part, for the enhanced inflammation and reduced steroid responsiveness seen in these patients. Other proteins, particularly transcription factors, are also acetylated and are targets for deacetylation by HDACs and sirtuins, a related family of 7 predominantly protein deacetylases. Thus the acetylation/deacetylation status of NF-κB and the glucocorticoid receptor can also affect the overall expression pattern of inflammatory genes and regulate the inflammatory response. Understanding and targeting specific enzymes involved in this process might lead to new therapeutic agents, particularly in situations in which current anti-inflammatory therapies are suboptimal

On the Role of Surface Roughness in Elastohydrodynamic Lubrication of Tribological Components

The present dissertation investigates the effect of surface roughness in the elastohydrodynamic lubrication (EHL). Since many essential components of the machinery such as gears, rolling element bearings, cam-followers, and heavily loaded journal bearings operate under the mixed EHL condition, and given the fact that nearly all engineering surfaces are rough to some extent, there is a need for an extensive research which can realistically quantify the effect of the surface roughness in such applications. We thus seek to develop an applied engineering approach for the treatment of the mixed EHL for prediction of the performance of machinery. Both line-contact and point-contact EHL are studied in this dissertation with a major focus on the line contact. In the present work, numerical solutions are developed to treat the problem of elastohydrodynamic lubrication of rough surfaces (referred to as the mixed EHL). The common EHL equations are solved in conjunction with the statistically-based elasto-plastic deformation of the surface asperities. Formulas are developed that can be readily applied to tribological contact involving both line and point contacts to predict the thickness of the lubricant’s film in such applications. For the line contact, a thermo-elastohydrodynamic approach is presented to predict the traction coefficient, where this model is also used to evaluate the wear rate. In addition, an engineering approach to estimate the traction coefficient and the wear rate with reasonable accuracy is presented. Since a rough surface does not necessarily have an isotropic orientation, a study on the effect of different surface pattern is also included to show how this factor influences the results. Also studied is the effect starvation where it is shown how inadequate lubricant supply at the inlet affects the film thickness, the traction, and the wear rate. To show the utility of the approach, the applications of the developed models in evaluating the performance of spur gear under the mixed EHL regime are presented

A Comparative Study on Calcification of Aortic Valves

Calcific Aortic Valve Disease (CAVD) is a major disorder in the developed countries among elderly. It is characterized by calcific deposition and stiffening of the aortic valve cusps. CAVD is a highly cell-mediated condition where valvular interstitial cells (VICs) become activated and differentiate into osteoblast-like cells. This is associated with upregulation of calcific markers like Alkaline phosphatase (ALP) and Runx2. ECM remodeling in another characteristic of stenotic aortic valves due to VIC activation. Reports show that CAVD initiates majorly on the noncoronary side of the aortic valves. Additionally, male sex is a significant risk factor of CAVD. Aortic valves are surrounded by a complicated hemodynamic environment. Pathological levels of mechanical forces applied to the aortic cusps interact with the VICs’ remodeling and differentiation and lead to abnormalities within the aortic cusps. In this dissertation, comparative studies were performed among VICs isolated from individual aortic cusps or between male and female to verify whether the differences in aortic calcification are observed at a cellular level. The calcification of VICs isolated from coronary and noncoronary aortic cusps was investigated in osteogenic culture condition to identify whether VICs show different amounts of calcific markers. Moreover, the osteogenic differentiation of VICs isolated separately from male and female aortic valves was analyzed to find if there are sex-related differences in their proliferation and calcification. Finally, both hypotheses were tested under cyclic strain to determine the impact of pathological vs. physiological strain on enhancing the VICs calcification among coronary and noncoronary cusps or between male and female valves. It was found that VICs isolated from noncoronary cusps demonstrated greater calcification potential than coronary cusps. Likewise, male VICs showed increased ECM remodeling compared to female. Pathological cyclic strain applied to VICs cultured in osteogenic condition enhanced their calcification, however VICs cultured in normal condition seem not to be affected by pathological cyclic strain. The results from this dissertation provide a new perspective on the biomolecular events associated with VICs calcification. It shows that VICs in different cusps of an aortic valve have heterogeneous populations. Furthermore, it confirms that sex of the cells matter in aortic valve calcification

Reduced Phagocytic Capacity of Blood Monocyte/Macrophages in Tuberculosis Patients Is Further Reduced by Smoking.

Tuberculosis (TB) and tobacco use are two major alarming global health issues posing immense threats to human populations. Mycobacterium tuberculosis (MTB) by activation of macrophages could induce the sequences of cells activation and releases of inflammatory cytokines such as CXCL-8, Il-12 and TNF-α which in turn induces the immune system network. However no information is available on other activity of cells by MTB and smoking. In the current study we aimed to investigate the serum levels TNF-a, CXCL-8 and phagocytosis capacity in tuberculosis patients with and without smoking. 103 subjects entered the study including 61 new diagnosed pulmonary TB patients (23 smokers and 38 nonsmokers) and 42 control healthy subjects. The phagocytosis of fluorescein isothiocyanate dextran (FITC-dextran) in blood monocytes/macrophages through flowcytometry was assessed. Serum levels of TNF-a and CXCL-8 were analyzed by ELISA methods. A lower percentage of cells from TB patients who smoked [50.29% (43.4-57.2), p<0.01] took up FITC-dextran after 2h compared to non-smoking TB subjects [71.62% (69.2-74.1)] and healthy cases [97.45% (95.9-99.1). Phagocytic capacity was inversely correlated with cigarette smoking as measured by pack years (r=-0.73, p<0.001). The serum levels of TNF-a and CXCL-8 were significantly higher in the TB patients who smoked compared to the TB non-smoker group (p<0.001, p<0.01 respectively). Blood monocytes/macrophages from TB patients have reduced phagocytic capacity which is further reduced in TB patients who smoke. Smoking enhanced serum levels of TNF-a and CXCL-8 suggesting a greater imbalance between the proinflammatory and anti-inflammatory factors in these patients

Chebyshev collocation method for the free vibration analysis of geometrically exact beams with fully intrinsic formulation

Peer reviewedPostprin

Impact of Skeletal Malocclusion on Quality of Life

Introduction: nowadays, one of the remarkable issues in dentistry is jaw growth pattern and tooth and mouth conditions (oral conditions) on patients' quality of life and daily activities. This study was done to evaluate skeletal malocclusion effect on the quality of life and oral health in Ahvaz. Methods: 80 people with skeletal malocclusion and 80 people with normal skeletal occlusion (control) participated in this cross-sectional study. Data collection tools included: demographic and oral health impact questionnaires. Results: there is not any significant difference between average quality of life of people with Cl III and Cl II skeletal (p=0.761), but there is a meaningful relation between Cl II skeletal and normal skeletal groups and also between Cl III skeletal and normal skeletal groups (p&lt;0.001). Conclusion: according to social and moral issues importance in raising the quality of life score and because study results showed that these patients are not in good condition of that, considering different moral and social aspects of oral condition in presenting dentistry services are suggested to develop general quality of lif

Large deflection of functionally graded porous beams based on a geometrically exact theory with a fully intrinsic formulation

Peer reviewedPostprin

Argon Plasma Coagulation in Treatment of Post Intubation Tracheal Stenosis

INTRODUCTION: Acquired tracheal stenosis can be created by various malignant or benign causes. The most common cause of acquired non-malignant tracheal stenosis is endotracheal intubation, even for a short period. Argon plasma coagulation is a non-contact method of thermal hemostasis. Argon plasma coagulation can be used easily and fast and has low depth of penetration. METHODS: This study is single blinded. Subjects are patients with tracheal stenosis after endotracheal intubation who were selected by non-probability sampling and were studied from March 2007 to November 2009 in bronchoscopy and laser center of Masih Daneshvari Hospital, Tehran. First, for each patient, a diagnostic flexible bronchoscopy was performed to identify the type, location, and severity of the stenosis. Then, under general anesthesia, patients underwent rigid bronchoscopy. Then, with Argon plasma coagulation device (ERBE VIO 200D) the stenosis was removed as possible. After two weeks, a new PFT (pulmonary function test) was done for checking the obstructive signs.RESULTS: Of these 34 patients, 24 were asymptomatic for more than 1 year and responded to treatment(70/6%), 5 were asymptomatic for more than 10 months and less than 12 months (14/7%) and 5 did not have asymptomatic periods more than 10 months, and did not respond to treatment. In PFT follow-ups, FEV1 in all patients who were asymptomatic for more than 10 months had a significant progress; therefore, in 27 out of 29 patients at the end of the study, FEV1 was more than 90% and 2 patients had FEV1 of 70-90%.CONCLUSION: In fact, although the surgical treatment remains the main treatment of tracheal stenosis after intubation (PITS), if this method is not possible for any reason, APC is very useful as a safe and effective method