Hypoxia Inducible Factors in Alcoholic Liver Disease: A Dissertation

Chronic intake of alcohol can result in a range of pathology in the liver. Whilst the earliest changes observed with chronic ethanol, including the accumulation of lipid, or steatosis, are readily reversible upon cessation of alcohol consumption, longer exposure to ethanol may achieve more complex disease states including steatohepatitis, fibrosis, and cirrhosis that can cause irreversible damage and progress to fulminant hepatic failure. A key concept in the pathogenesis of alcoholic liver disease is that chronic ethanol primes the liver to increased injury through an interplay between hepatocytes and non-parenchymal cells, chiefly immune cells, of the liver. These relationships between hepatocytes and non-parenchymal cell types in alcoholic liver disease are reviewed in Chapter 1A. The Hypoxia Inducible Factors are a set of transcription factors that classically have been described as affecting a homeostatic response to conditions of low oxygen tension. Alcoholic liver disease is marked by increased hepatic metabolic demands, and some evidence exists for increased hepatic tissue hypoxia and upregulation of hypoxia-inducible factor mRNA with chronic alcohol. However, the biological significance of these findings is unknown. In Chapter 1B, we review the literature on recent investigations on the role of hypoxia inducible factors in a broad array of liver diseases, seeking to find common themes of biological function. In subsequent chapters, we investigate the hypothesis that a member of the hypoxia inducible- factor family, HIF1α, has a role in the pathogenesis of alcoholic liver disease. In Chapter 2, we establish a mouse model of alcoholic liver disease and report data confirming HIF1α activation with chronic ethanol. We demonstrate that HIF1α protein, mRNA, and DNA binding activity is upregulated in ethanol-fed mice versus pair-fed mice, and that some upregulation of HIF2α protein is observable as well. In Chapter 3, we utilize a mouse model of hepatocyte-specific HIF1α activation and demonstrate that such mice have exacerbated liver injury, including greater triglyceride accumulation than control mice. Using cre-lox technology, we introduce a degradation resistant mutant of HIF1α in hepatocytes, and after four weeks of ethanol feeding, we demonstrate that mice with the HIF1α transgene have increased liver-weight to body weight ratio and higher hepatic triglyceride levels. Additionally, several HIF1α target genes are upregulated. In Chapter 4, we examine the relationship between HIF1α activation and hepatic lipid accumulation using a recently published in vitro system, in which lipid accumulation was observed after treating Huh7 cells with the chemokine Monocyte Chemoattractant Protein-1 (MCP-1). We report that MCP-1 treatment induces HIF1α nuclear protein accumulation, that HIF1α overexpression in Huh7 cells induces lipid accumulation, and finally, that HIF1α siRNA prevents MCP-1 induced lipid accumulation. In Chapter 5, we use mouse models to investigate the hypothesis that suppression of HIF1α in hepatocytes or cells of the myeloid lineage may have differing effects on the pathogenesis of alcoholic liver disease. We find that ethanol-fed mice expressing a hepatocyte-specific HIF1α deletion mutant exhibit less elevation in liver-weight body ratio and diminished hepatic triglycerides versus wild-type mice; furthermore, we find that challenging these mice with lipopolysaccharide (LPS) results in less liver enzyme elevation and inflammatory cytokine secretion than in wild-type mice. In Chapter 6, we offer a final summary of our findings and some directions for future work

Thermal Management Of Electronics Experiencing Large Power Dissipation Transients.

Recent developments with micro-porous surfaces have led to the introduction of very high heat flux boiling surfaces. For example, Wirtz and coworkers have introduced a structured porous surface that achieves in excess of 1.5MW/m2 in saturated pool boiling of water at 0.2atm (Tsat = 60°C); and, this increases to 2.1MW/m2 at 1.0atm (Tsat = 100°C). In this case, onset of nucleate boiling (ONB) occurs at approximately 2K superheat, and the high heat flux noted occurs at 9K superheat, so the boiling curve slope is very high, approximately 0.3MW/m2 per Kelvin superheat. This suggests that a viable thermal management approach to systems that experience large transient heat loading would be to design the heat sink so that the heat sink-to-coolant heat transfer surface would “ride” its boiling curve. At baseline power dissipation levels, boiling would occur at near ONB; and, the heat transfer surface would climb the (very steep) boiling curve as the power dissipation level rises, so that there would be only a moderate electronics temperature excursion. Vented (constant pressure), sealed and hybrid immersion cooled electronics systems are considered. A thermal response model, based on boiling curves having differing ONB and CHF points (boiling curve slopes) and boiling correlation calculates the thermal response of the system. Response time constants and maximum temperature excursions are correlated with boiling curve characteristics, and system geometric and thermo physical properties. We have obtained the temperature response with respect to time were obtained with different system parameters and have been compared with each other

Life Estimation of a Steam Turbine Blade using Low Cycle Fatigue Analysis

This work is primarily focused in utilising a technique to assess low cycle fatigue life of steam turbine blade. Two approaches are employed here, first is based on the linear elastic finite element analysis. Fictive elastic results are recalculated using Neuber's rule. Second approach is based on elastic-plastic Finite Element analysis (FEA). Strain amplitude approach is followed through Universal slope method and Coffin-Manson equation to determine the number of start-up and shut down cycles Proper blade design with conservative stress levels is important for reliability in rotor blade design. Finite Element Analysis based fatigue tools enable reliable fatigue life calculations to be done at the design stage of a development process and a proper design methodology is important to predict the catastrophic failure of turbine blade due to fatigue

A comparative study to assess the awareness of antibiotic resistance amongst first and second year medical undergraduate students in a medical college

Background: With the rising instances of antibiotic resistance and decline in the discovery of newer antibiotics, it is high time to prevent the emergence of antibiotic resistance. One of the best measures regarding the above problem is education and creating awareness regarding antibiotic resistance, and that too primarily among healthcare professionals. The initiation should start at the basic level and that too in the early days of medical profession, so that there is greater awareness and strong foundation for antibiotic prescribing pattern. The present study is taken up to compare awareness among 1st year and 2nd year medical students in a private medical college with 2nd year medical students having prior education regarding antibiotics resistance and first year students representing general public without any education regarding antibiotics resistance.Methods: This study was a comparative, cross-sectional, questionnaire based study. The questionnaire was validated for face validity and content validity from subject experts. The two groups selected were 1st year and 2nd year medical undergraduates. Data was analysed using simple descriptive statistics.Results: 136 students from 1st year and 88 students from 2nd year participated in the study. In both the groups studied, majority of the respondents completed the full course of antibiotics. 77% of 1st year and all 2nd year students were aware of the antibiotic resistance. 99% of 2nd year students and only 49% of the 1st year students were aware of the reasons for it (p<0.01). Awareness regarding prophylactic usage of antibiotics, usage for simple common cold and usage of higher antibiotics for mid infection leading to Antibiotic Resistance was significantly less among first year students. 2nd year students were well aware of consequences of antibiotic resistance like ineffective treatment, prolongation of illness, emergence of bacterial resistance and additional cost burden than 1st year students. Awareness regarding other aspects of antibiotic resistance was not significant between two groups.Conclusions: Stressing upon awareness and education regarding antibiotic resistance in the early days of medical curriculum will help in change of behaviour and habits of antibiotic usage and rational prescribing of antibiotics by the future doctors.

Rajam Krishnan's novel Kootu Kunjugal

Rajam Krishnan's novels mostly deal with family, society, poverty and&nbsp; economics, caste related issues and about child labour. Novelist Rajam Krishnan would plan the theme foor a novel in advance and travel to the relevant places and stay there to find out the life of the people and writes the novel based on his experience This is his specialty. In the novel Kootu Kunjugal he talks about child labour. He has created a story centering on tribulations. The novel depicts the condition of people who send their children to the matchbox and firecracker factory to fill their stomachs when agriculture is stopped in a dry land because of lack of water and rain. Golam who went to work in a factory at an early age, got sick and Viji, the boss's wife who protests, fo all this things and leaves her husband. In this novel, Rajam Krishnan has said whether in present or past till the poverty did not get vanished child labour also will not come to an end

Learning-based content caching with time-varying popularity profiles

Content caching at the small-cell base stations (sBSs) in a heterogeneous wireless network is considered. A cost function is proposed that captures the backhaul link load called the "offloading loss", which measures the fraction of the requested files that are not available in the sBS caches. Previous approaches minimize this offloading loss assuming that the popularity profile of the content is time-invariant and perfectly known. However, in many practical applications, the popularity profile is unknown and time-varying. Therefore, the analysis of caching with non-stationary and statistically dependent popularity profiles (assumed unknown, and hence, estimated) is studied in this paper from a learning-theoretic perspective. A probably approximately correct (PAC) result is derived, in which a high probability bound on the offloading loss difference, i.e., the error between the estimated (outdated) and the optimal offloading loss, is investigated. The difference is a function of the Rademacher complexity of the set of all probability measures on the set of cached content items, the β-mixing coefficient, 1/√t (t is the number of time slots), and a measure of discrepancy between the estimated and true popularity profiles

Gas-to-gas heat exchanger design for high performance thermal energy storage

The mathematical modelling and optimization of a gas-to-gas heat exchanger with a non-constant cross sectional area is presented. The design of the cross sectional area of the heat exchanger analyzed is based on an hexagonal mesh, which would be highly impractical to fabricate in a conventional way but could be built relatively easily through modern manufacturing techniques. The geometric configuration proposed allows attaining a high exergy efficiency and a significant cost reduction, measured in terms of volume per unit of exergy transfer. The relationship that exists between the overall exergy efficiency of the heat exchanger and its cost is thoroughly explained throughout the study. The results obtained from the modelling demonstrate the premise that it is possible to realize designs for heat exchangers that are highly exergy-efficient and very cheap, owing to the small volume of material required, if the constrains imposed by the limitations of traditional manufacturing methods are set aside. Furthermore, the study reveals a very important fact: the volume of material in a heat exchanger increases in quadratic proportion to its characteristic dimension, which implies that scaling up the geometry has a strong impact on its cost-effectiveness