Lipid binding properties of huntingtin as a novel therapeutic target

As protein aggregation is the defining hallmark of all amyloid diseases, a common therapeutic strategy is to develop molecules that inhibit aggregation. However, this approach has yielded limited success. Many amyloid proteins directly interact with lipid membranes. These interactions promote distinct aggregation pathways and often result in membrane damage leading to toxicity. As a result, directly targeting the ability of amyloids to bind lipid membranes represents a novel therapeutic strategy. As a proof of principle, the interaction between lipid membranes and mutant huntingtin protein (htt) aggregates was used to test this strategy. Mutant htt containing an expanded polygulatmine (polyQ) domain causes Huntington’s disease (HD). Using a colorimetric lipid binding assay over 1200 compounds were screened for their ability to block htt/lipid binding. The screen was set up to only identify compounds that directly interacted with htt, not the lipid membrane. Three compounds were identified having the ability to inhibit htt/lipid interaction, Ro-90-7501 (Ro), benzamil hydrochloride (ben) and ruthenium red. As these compounds directly interact with htt, ThT and AFM assays were performed to assess their impact on aggregation. Ro and ben did not inhibit fibril formation; however, oligomer precursors were significantly smaller when exposed to Benzamil. Molecular dynamic simulations (MD) revealed that the two compounds have unique mechanisms of interaction with htt aggregates. Unlike Ro and ben, ruthenium red altered htt aggregation and inhibit fibrilization. Having established that the compound prevented htt from binding membranes, a C. elegans model of HD was used to determine if this strategy could alleviate phenotype. Despite have a minimal impact on punctate formation, all three compounds reduced a thrashing deficit in animals caused by mutant htt expression, suggesting that this strategy reduces htt toxicity

Semi-parametric methods for personalized treatment selection and multi-state models.

This dissertation contains three research projects on personalized medicine and a project on multi-state modelling. The idea behind personalized medicine is selecting the best treatment that maximizes interested clinical outcomes of an individual based on his or her genetic and genomic information. We propose a method for treatment assignment based on individual covariate information for a patient. Our method covers more than two treatments and it can be applied with a broad set of models and it has very desirable large sample properties. An empirical study using simulations and a real data analysis show the applicability of the proposed procedure. We then extend this idea for treatment section for survival outcomes under right-censoring by introducing re-weighted estimation to adjust the bias caused by censoring. Series of empirical studies using simulations show the desirable performance of re-weighted estimation concept in treatment selection in finite sample cases. We provide a real data application of the proposed procedure to illustrate the applicability for right-censored data. Next we propose a novel method for individualized treatment selection when the treatment response is multivariate. The proposed method uses a rank aggregation technique to estimate an ordering of treatments based on ranked lists of treatment performance measures such as smooth conditional means and conditional probability of a response for one treatment dominating others. An empirical study demonstrates very desirable performances of the proposed method in finite sample cases. We also present a data analysis using a HIV clinical trial data to show the applicability of the proposed procedure for real data. Multi-state models are extensions of simple survival models that incorporate the progression of a subject in an interconnected system such as a disease network. An important measure arising from a mutistate model is the subjects’ state occupational probabilities given baseline covariates. In the final portion of this dissertation we introduce an inverse censoring probability re-weighted semi-parametric single index model based approach to estimate conditional state occupation probabilities of a given individual in an acyclic multistate model under right-censoring. Besides obtaining a temporal regression function, we also test the potentially time varying effect of a baseline covariate on future state occupations. We show that the proposed technique has desirable finite sample performances. Its performance is competitive when compared with two other existing approaches. We illustrate the proposed methodology using two different data sets. First we re-examine a well known data set on various event times tracking the progression of a sample of leukemia patients undergoing bone marrow transplant. Our second illustration is based on the functional status of a set of spinal cord injured patients undergoing a rehabilitation program

The epidemiology of frailty and its association with disability and quality of life among rural community-dwelling older adults in Kegalle district of Sri Lanka

Background and aim: Frailty is an important age related medical condition that predicts numerous adverse health outcomes. Many low-and middle-income countries (LMICs) are ageing rapidly but we know little about the epidemiology of frailty in these countries. This thesis describes the epidemiology of frailty and its association with disability and quality of life among rural community-dwelling older adults in Kegalle district of Sri Lanka. Methods: Part A) A systematic review and meta-analysis on prevalence of frailty and pre-frailty among community-dwelling older adults in LMICs. Part B) A population-based cross-sectional study conducted in 2016 to i) estimate the prevalence of frailty, ii) describe factors associated with frailty, and iii) evaluate the association of frailty with disability and quality of life among rural community-dwelling older adults in Kegalle district. A three stage probability sampling was used to recruit 746 older adults aged ≥60 years. Frailty was assessed using the Fried phenotype. Results: Part A) Limited evidence was found on the prevalence of frailty in low-income and lower middle-income countries. The random-effects pooled prevalence of frailty and pre-frailty in community-dwelling older adults in LMICs was 17.4% (95% CI: 14.4%, 20.7%) and 49.3% (95% CI: 46.4%, 52.2%) respectively. Part B) The prevalence of frailty and pre-frailty among rural community-dwelling older adults aged ≥60 years in Kegalle district of Sri Lanka was estimated as 15.2% (95% CI: 12.3%, 18.6%) and 48.5% (95% CI: 43.8%, 53.2%) respectively. The prevalence of limitations in instrumental activities of daily living (≥1 IADL) assessed with Lawton IADL scale was high (84.4%) in frail older adults. The prevalence of basic activities of daily living (≥1 BADL) assessed with Barthel index was 38.7% in frail older adults. Being frail lowered the odds of having no IADL limitations and was associated with a four times higher count of IADL limitations compared with non-frail counterparts. Frailty was associated with a small but significant lower quality of life in this rural Sri Lankan population. Conclusions: The prevalence of frailty appears higher in rural community-dwelling older adults in Sri Lanka compared with upper middle-income and high-income countries with a significant impact on IADL limitations but with lower than anticipated impact on BADL limitations and quality of life

Motivation of second language learners with particular reference to undergraduates of Sabaragamuwa University of Sri Lanka and Uva Wellassa University of Sri Lanka

Since motivation is an inevitable key to succeed in second language learning, this study aimed to investigate the motivation and the motivation orientation levels of the undergraduates in Sabaragamuwa University (SUSL) and Uva Wellassa University of Sri Lanka (UWU) towards learning English. The study was carried out with 110 secondyear and 69 first-year undergraduates in SUSL and UWU respectively. Results indicated that 72% undergraduates in SUSL and 100% in UWU possess high level of motivation and high instrumental orientation to learn Englis

Transforming the Pandemic into a gateway for zeroing waste-related emissions at the University of Colombo, Sri Lanka

The University of Colombo (UoC) has turned the Covid-19 pandemic into a win-win situation by adopting new measures to overcome limitations the pandemic has brought in while improving its overall waste management. It has incorporated a paperless system by conducting academic work online, including applying for new courses, distributing e-learning material and submitting assignments. Every lecture, meeting, and function has been held virtually, eliminating food, paper, plastic and decoration waste. Students now study from home and employees have been reporting to work according to rosters, reducing food and office waste generation significantly. The employees now adhere to the pre- and newly included post-pandemic environmental guidelines, litterless lunches, and have been provided with shuttle services for safer commuting, leading to lower greenhouse gas emissions. Identifying the potential environmental damage through improper disposal, using reusable masks is being promoted through regular online awareness programmes; eco-friendly sanitizers are used instead of liquid soap, which consumes water and generates wastewater. Although the amount of waste generated during the pandemic is low, the UoC-owned Waste Storage Center continues to function with waste segregation and recycling, and the composting facility is currently expanding its production. The waste reduction has also caused lowered waste-related greenhouse gas emissions.Keyword: Waste Management, Paperless System, Guidelines, Waste Storage Center, Segregation and Recyclin

Micro-Operator driven local 5G network architecture for industrial internet applications

Abstract. High degree of flexibility, customization and the rapid deployment methods are needed in future communication systems required by different vertical sectors. These requirements will be beyond the traditional mobile network operators’ offerings. The novel concept called micro-operator enables a versatile set of stakeholders to operate local 5G networks within spatially confined environment with a guaranteed quality and reliability to complement mobile network operators’ offerings. To enable the case specific requirements of different stakeholders, micro-operator architecture should be tailored to cater such requirements, so that the service is optimized. The novel micro-operator architecture proposed in this thesis using 5G access and core network functions, serves the communication needs of an Industry 4.0 environment having three use cases namely augmented reality, massive wireless sensor networks and mobile robots. Conceptual design of the proposed architecture is realized using simulation results for latency measurements, relating it with the results of a mobile network operator-based deployment. Latency analysis is carried out with respect to the core network distance and the processing delay of core network functions. Results demonstrate the advantages of the micro-operator deployment compared with mobile network operator deployment to cater specialized user requirements, thereby concluding that the micro-operator deployment is more beneficial

Aging and Stabilization of Pyrolitic Bio-Oils and Model Compounds

When compared to conventional liquid fuels, bio-oil has several undesired properties such as high viscosity, high acidity, high molecular weight, instability, and phase separation upon aging. Therefore, bio-oil needs further stabilization and upgrading before it can be used as a fuel in engines. Phase separation is considered as one of the major issues because it is detrimental to any fuel application and creates problems in storage, transportation and upgrading of bio-oils. This thesis investigates the phase separation of hardwood derived bio-oil under accelerated aging conditions. Different alcohols are used as stabilizing agents and the minimum required amount of alcohol for preventing phase separation for a given period of time is determined. The evolution in chemical composition of bio-oil during aging is studied using model compounds. Finally, this thesis explores the use of fractional condensation during bio-oil production to obtain a more stable bio-oil

NATURAL IRON SEQUESTERING AGENTS: THEIR ROLES IN NATURE AND THERAPEUTIC POTENTIAL

Iron is one of the essential elements involved in many cellular processes that are necessary for life, including oxygen sensing, oxygen transport, electron transfer, energy metabolism, DNA synthesis etc. Although, iron is not readily available in the naturally available iron III form, microorganisms have evolved to produce smaller high affinity chelating small organic molecules called siderophores for its acquisition. The study of siderophores has opened up investigations of small-molecule inhibitors, which can hinder the biosynthesis of siderophores and thereby suppress the growth and virulence of bacteria in iron-limiting backgrounds. One of the most important applications of siderophores is selective drug delivery to defeat drug-resistant bacteria. It uses the iron transport capabilities of siderophores in carrying drugs/molecules into cells, synthetic through conjugates between siderophores and antimicrobial agents forming sideromycins. Some siderophore such as Desferrioxamine B have been found to be useful in the treatment of malaria caused by Plasmodiumfalciparum through intracellular iron depletion mechanisms. Importantly, iron overload diseases can be efficiently treated with siderophore based drugs as they can quench iron effectively. Moreover, siderophores such as dexrazoxane, desferriexochelins, isonicotinoyl hydrazine derivatives are being used in cancer therapy, as they prevent the formation of free radicals by reducing iron and retard the tumor growth by disturbing the iron regulation in tumor cells. In addition to bacterial siderophores, it is reported that plant-derived polyphenols, phenolic acids,and flavonoid compounds show siderophores like activity scavenging iron which gives rise to their antioxidant and anticancer activity.Â