The role of Wnt/β-catenin signalling in the regulation of liver progenitor cell responses in non-alcoholic fatty liver disease

This study established a regulatory role for the Wnt/ß-catenin pathway in liver progenitor cells (LPCs) in cell culture and in vivo models of non-alcoholic fatty liver disease and demonstrated a significant potential for therapeutic targeting of LPCs with the Wnt inhibitor PRI-724 to inhibit chronic liver disease progression

Modeling Epidemiological Spread on Contact Networks

The rapid diffusion of a contagion amongst a population has detrimental impacts on both public health and economic stability. As individuals of a population come into contact, they can spread tangible materials, such as bacteria and viruses, through probabilistic diffusion of the resulting contact network. The probabilistic branching process of disease relies on the basic reproductive number, or the average contagiousness of the pathogen - a crude measure of the true impact of the virus. Multiple precautionary measures can be taken to reduce the reproductive number in the case of an epidemic. Stochastic agent-based modeling was used in this study to emulate and analyze the impacts of various public health measures on the coronavirus epidemic. These ABM simulations are carried out using the EpiModel package within R, implemented by the ERGM (Exponential Random Graph Model) package. This algorithm allows the network model to vary stochastically (randomly) over time. The following protocols implemented during the coronavirus epidemic were assessed: the mask mandate, the social distancing protocol, the reduction of initial infected population size (ex. travel restrictions), and national vaccination. The simulated examples within this study followed the susceptible-infectious-recovered/immune (SIR) compartmental model type. These simulations serve to model the spread of the coronavirus contagion through a connected network of 1,000 nodes and 4,000 edges over a span of 100 days. The findings of this study could point towards a tool for future researchers tasked with the difficult job of updating national safety standards and precautionary health measures to inhibit contagion spread.Bachelor of Scienc

FORMULATION AND OPTIMIZATION OF FLOATING TABLETS OF CLOPIDOGREL BISULPHATE USING DESIGN OF EXPERIMENTS

Objective: The present study aimed at designing of floating matrix tablet of clopidogrel bisulphate by design of experiments.Methods: The tablets were prepared by direct compression technique using hydroxypropyl methylcellulose K15 (HPMC) as a matrix polymer and sodium bicarbonate as a gas generating agent. In order to optimize the concentration of HPMC (X1) and sodium bicarbonate (X2), a 32 full factorial design was employed. The tablet formulations were evaluated for floating lag time (Y1), floating or buoyancy time (Y2), percent water uptake, and differential scanning calorimetry (DSC) and in vitro drug release (Y3).Results: The formulation variables, HPMC concentration, and sodium bicarbonate concentration exerted a significant effect on floating behavior and drug release characteristics of the tablet. The optimized formulation, with 15% sodium bicarbonate concentration and 30 % HPMC concentration resulted in 5±2.6 sec of floating lag time, 22.0±0.6 h of floating time and 42.0±0.99% of clopidogrel bisulphate release in 8 h of dissolution study. The drug release mechanism was identified as nonfickian. The water uptake studies revealed that with an increase in HPMC concentration, there was an increase in swelling index of tablet whereas higher sodium bicarbonate concentration supported the faster erosion of matrix tablets. DSC study revealed no interaction of drug and polymers. The lower percentage error between predicted and observed responses of the optimized formulation validated the design.Conclusion: The study demonstrated successful designing of floating clopidogrel bisulphate tablet with factorial design

Development of High-Performance Carbon Fibers: Accelerating Paradigm Shifts

This work details the development of three technological pathways to accelerate paradigm shifts in the way carbon fibers are developed and manufactured. The first two, viz. hollow carbon fibers and small diameter carbon fibers, provide a comprehensive understanding of the process, structure, and property relationship for these continuous carbon fibers. The third pathway provides insights into the challenges and opportunities to employ machine learning models to predict carbon fiber properties by leveraging experimental data and accelerate the improvement in tensile properties in a cost-efficient manner. Multifilament continuous hollow carbon fiber tows with a honeycomb cross-section have been produced using a gel-spun bicomponent islands-in-a-sea precursor with polyacrylonitrile (PAN) as the sea component and polymethylmethacrylate (PMMA) as the sacrificial island component. Over 80% improvement in tensile strength has been achieved for these fibers compared to the previously reported batch processed hollow carbon fibers, along with a manufacturing scale up from single filament to 740 filament tow. The effect of precursor and carbon fiber manufacturing parameters on the structure and tensile properties of the hollow carbon fibers has been studied. Furthermore, mechanical properties of hollow carbon fiber-epoxy composites have been tested and compared with commercial aerospace grade carbon fiber composites. The effect of adhesion between the fiber and epoxy matrix, alignment of fibers in the composite along the testing direction, and various testing environments, on the composite mechanical properties has been explored. The properties of hollow carbon fibers and their composites show great promise to replace conventional aerospace grade carbon fibers in the foreseeable future. Continuous multifilament carbon fiber tows with 2-3μm fiber diameter have been developed from a PAN (island) - PMMA (sea) bicomponent precursor. These small diameter carbon fibers have tensile strength as high as 5.1 GPa and tensile modulus as high as 434 GPa in different trials. The size of the defects in these fibers is estimated to be in the range of 35-70 nm. The role of smaller diameter in improving the tensile properties of these fibers is explored and the nano scale defects in these fibers have been characterized. Finally, the efficacy of four supervised machine learning techniques, in establishing a mathematical relationship to model the continuous stabilization and carbonization process and predicting the tensile strength and modulus of the fibers, based on the manufacturing process parameters, has been investigated. The data set consisted of 600 data points with 31 features each. The results indicate that machine learning can be used to approximate the underlying function describing the effect of the manufacturing process parameters on the carbon fiber tensile properties This thesis develops a comprehensive understanding of the three technologies that can each accelerate the development high performance structural carbon fibers. Pursuing these studies separately or in conjunction with each other will likely bring about a paradigm shift in the way high performance carbon fibers and composites are developed.Ph.D

FORMULATION OPTIMIZATION OF PROMETHAZINE THEOCLATE IMMEDIATE RELEASE PELLETS BY USING EXTRUSION-SPHERONIZATION TECHNIQUE

Objective: Promethazine theoclate is a BCS Class II drug having anti-histaminic property and mainly used for the treatment of motion sickness and postoperative emesis. The main objective of the research work was to formulate and optimize immediate release pellets of promethazine theoclate by using the extrusion-spheronization technique to offer immediate release dosage form suitable for treatment of nausea and vomiting associated with motion sickness and post-operative conditions.Methods: Immediate release pellets of promethazine theoclate were prepared by using microcrystalline cellulose (MCC) and corn starch as filler and disintegrant respectively along with other excipients. Pellet formulation was further optimized for bulk density, disintegration time and percent drug release after 10 min. using 32 factorial design. Formulations were also characterized for drug-polymer interactions using Differential Scanning Calorimetry (DSC), surface morphology by Scanning Electron Microscopy (SEM) and other physicochemical properties.Results: Optimised pellet formulation contains 2.5:4.5:1 ratio of MCC: Corn Starch: Drug and spheronization time of 60 seconds showing highest percent yield of 78% and immediate drug release of 100.52±0.65% after 10 min.Conclusion: Promethazine theoclate pellets formulated in this study can serve as an alternative to tablet dosage form which can give immediate drug release for treatment of motion sickness and postoperative emesis

Designing supportability into software

Thesis (S.M.)--Massachusetts Institute of Technology, System Design & Management Program, February 2004.Includes bibliographical references (p. 114-116).Background: Despite the identification of a "software crisis" in the 1960s, large software projects are full of defects even today [19]. These defects cause the software to behave unexpectedly. The cause generally is attributed to the inherent property of software to possess arbitrary complexity [20]. Additionally, computer software is becoming all pervading. There is literally an explosion of software automating things that were considered impossible to automate only a few years ago. Essentially, software is growing to encompass anything and everything with such speed that we don't have the time to reflect on 'what happens when the software does something that it was not intended to do?' In other words, the software encounters an anomaly or a defect something customers encounter everyday. In any case, whenever customers encounter problems caused by defects they need help to solve these problems. They generally seek such help at a software vendor's product support services. With software getting more and more complex it is getting extremely difficult to support customers in a timely and cost effective manner. There is a constant struggle to ensure high Quality of Service (QoS) with low Total Cost of Ownership (TCO), which in turn affects Return on Investment; in such a scenario considering nearly 80% of the costs associated with software occur after it is shipped to the customer. Currently, there are two solutions to such problems caused by defects: First, if the source of the problem itself is found to be a defect in the software then the software vendor generally fixes the problem by modifying their code. Such a problem is generally classified as a bug. By now it is known that software applications have such bugs or defects or anomalies. These bugs cause the software to behave unexpectedly. Depending on its severity this behavior can on one extreme go unnoticed or one the other end produce catastrophic results. It pervades all software whether it is the AT&T long distance switching node crash in 01/15/90, the well known Y2K bug in database related software, Microsoft Passport Security defect, Mars Polar Lander defect, or the Ariane 5 rocket defect. These are just a few examples of well known software bugs. For each well known bug there are untold numbers of bugs that may not see the limelight. These defects can arise due to many reasons during the design and development of the software however they primarily arise due the essence of software to possess inherent properties of complexity, conformity, changeability, and invisibility [20]. Hence, a question arises, "Do we still try to single-mindedly go for the elusory 0 bug product? OR Do we accept that there are going to be bugs and try incorporate / accommodate for this directly into the product or otherwise?" Second, if the source of the problem is such that the vendor cannot simply fix the product, then it is classified as a limitation of the software product itself. In such a case the support organization works with the customer to find a workaround. Additionally, if many customers encounter the same problem then the product needs to be modified based on the workarounds their support services have provided to customers. In other words the product evolves based on how its customers use it. Product support services also receive numerous problems that are non-defect related where the source could be customer error or ignorance, improper documentation etc and their solutions generally require end-user education and training, better documentation etc. However such nondefect related support incidences fall outside the scope of this thesis. In the defect related scenarios illustrated above most of the contemporary efforts to determine the root cause of a customer's problem, requires in-depth knowledge of the product, extensive debugging that is extremely tedious, painstaking, and manual. Resolution of a problem depends solely on the troubleshooting skills, experience and subjectivity of the Support Personal that the customer is able to get a hold of. Products have all along incorporated functionality such as better features, performance, scalability etc. into their designs however none explicitly addresses how to tackle a software application's problems. This is unfortunate since such problems deeply affect customers and software development organization alike. The former looses productivity, effectiveness, time and money while the latter expends dedicated monetary and human resources for troubleshooting software products for a number of years until the product is declared obsolete or the customer's license expires. Problems affect overall customer satisfaction with the software making them more skeptical of future releases. The bottom-line is that there is a strong need to innovate software design and development itself to address how to deal with software problems so that customers should not have to loose their time, money or their life because the software application they are using has problems.by Prashant A. Shirolkar.S.M

A COMPARATIVE ASSESSMENT OF PHARMACOLOGICALLY ACTIVE PRINCIPLES AND ANTIOXIDANT ACTIVITY OF COMMONLY OCCURRING MUCUNA SPS. IN INDIA

The genus Mucuna (Fabaceae) includes about 150 species and almost all the species are reported to contain L-3,4-dihydroxy phenylalanine (L-Dopa), a non-protein amino acid that acts as precursor for the neurotransmitter dopamine, used in the treatment of Parkinsons disease. The present study was aimed to assess the pharmacologically active principles and antioxidant activities of Mucuna pruriens (L.) DC., Mucuna bracteata DC., Mucuna cochinchinensis (Lour.) A. Chev. black seeds sp. and Mucuna cochinchinensis (Lour.) A. Chev. white seeds sp. The aqueous extract of plant material was subjected to assess the pharmacologically active principles by using L-dopa quantification, determination of protein and flavonoids, total phenolic content, Inhibition of DPPH radical and Reducing power/Ferric reducing antioxidant potential (FRAP) assays. The results obtained showed that, Mucuna cochinchinensis black seeds sp. has highest protein, total phenolic content, L-dopa content and DPPH radical scavenging activity. Mucuna bracteata seeds showed highest flavonoid content whereas, in FRAP assay Mucuna pruriens extract showed highest potential to reduce the ferric ions. It can be concluded from this study that, L-DOPA possesses antioxidant activity which was supported by in-vitro antioxidant assays. This indicates that the antioxidant activity of the aqueous extracts of all the Mucuna sps. may be due to the presence of L-Dopa content in its seed

Wnt/B-Catenin signalling during liver metabolism, chronic liver disease and hepatocarcinogenesis

Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their sig­nalling to fibrosis-driving hepatic stellate cells. The Wnt/β-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/β-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis

Wnt/B-Catenin signalling during liver metabolism, chronic liver disease and hepatocarcinogenesis

Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their sig­nalling to fibrosis-driving hepatic stellate cells. The Wnt/β-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/β-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis