UNDERSTANDING CONDITIONAL MODES OF ACTIONS IN CHEMICAL-INDUCED TOXICITY USING RULE MODELS

It is estimated that 115 million animals are used in experimental testing each year. Hence, shifting efforts toward alternative methods for toxicity assessment is essential. However, slow regulatory acceptance of new approaches is governed by knowledge gaps in toxicity modes of action. In this thesis, I describe these challenges and the use of in vitro screening as an alternative of animal testing. I also discuss common data-based methods to derive hypotheses about toxicity modes of actions, and the associated limitations in capturing multiple biological perturbations. I applied novel data-based workflows, using rule models, to prioritize in vitro assays predictive of toxicity as well as to detect significant polypharmacology profiles. I explain how constraints were applied to rule-based models to inform meaningful mechanistic interpretation for two toxicity endpoints: rat hepatotoxicity and acute toxicity. I compared assays selected, by rules, for predicting hepatotoxicity with endpoints used in in vitro models from commercial sources. An overlap was observed including cytochrome activity, mitochondrial toxicity and immunological responses. However, nuclear receptor activity, identified in rules, is not currently covered in commercial setups. I also demonstrate that endocrine disruption endpoints extrapolate better into in vivo toxicity when a set of specific conditions are met, such as physicochemical properties associated with good bioavailability. Next, I examined synergistic interactions between conditions in rules describing acute toxicity. I gained novel insights into how specific stressors potentiate the perturbation by known key events, such as acetylcholinesterase inhibition and neuro-signalling disruption. I show that examining polypharmacology profiles is particularly important at low bioactive potencies. Further, the overall predictive performance of rules describing acute toxicity was tested against a benchmark Random Forest model in a conformal prediction framework. Irrespective to the data type used in the training, the models were prone to bias over compounds promiscuity, by which high promiscuous compounds were more likely to be predicted as toxic. Overall, the studies conducted in this thesis provide novel insights into molecular mechanisms of toxicity, namely hepatotoxicity and acute toxicity, and with regards to chemical properties and polypharmacology. This knowledge can be used to improve the utility and design of alternative methods for toxicity, and hence, accelerate the regulatory acceptance.Islamic Development Bank Cambridge Trust Fun

Principles of AAA+ Proteases

ATPases associated with diverse cellular activities (AAA+) proteases in bacteria help maintain protein homeostasis by degrading misfolded and regulatory proteins. While a handful of protein targets for these proteases have been identified in Caulobacter crescentus and other organisms, more research is needed to elucidate mechanisms that govern substrate specificity. In the second chapter of this thesis, I will elaborate on how AAA+ substrate specificity is less rigid than previous work has suggested and how limiting ATP or mutations can alter substrate preferences of the ClpXP protease. In the third chapter, I will highlight our efforts to use a quantitative proteomics approach and how this approach has provided us with insights on new phenotypes. The fourth chapter of this thesis is a compilation of our efforts to identify suppressors of Dlon defects. Lastly, the remainder of this thesis will present additional data that was generated in the pursuit of these three projects and other endeavors

ATP hydrolysis tunes specificity of a AAA+ protease

In bacteria, AAA+ proteases such as Lon and ClpXP degrade substrates with exquisite specificity. These machines capture the energy of ATP hydrolysis to power unfolding and degradation of target substrates. Here, we show that a mutation in the ATP binding site of ClpX shifts protease specificity to promote degradation of normally Lon-restricted substrates. However, this ClpX mutant is worse at degrading ClpXP targets, suggesting an optimal balance in substrate preference for a given protease that is easy to alter. In vitro, wild-type ClpXP also degrades Lon-restricted substrates more readily when ATP levels are reduced, similar to the shifted specificity of mutant ClpXP, which has altered ATP hydrolysis kinetics. Based on these results, we suggest that the rates of ATP hydrolysis not only power substrate unfolding and degradation, but also tune protease specificity. We consider various models for this effect based on emerging structures of AAA+ machines showing conformationally distinct states

盲腸結紮穿刺誘発性敗血症マウスモデルの臓器傷害および生存率に対するSTAT3デコイ核酸導入効果に関する分子薬理学的研究

富山大学・富医薬博甲第331号・Samar Mahmoud Mohamed Mahmoud Ahmed Imbaby・2020/03/24・★論文非公開★富山大

ثلاثية الابداع ومدى فاعلية المسؤولية الاجتماعية لبعض المؤسسات الكبرى بقطاع غزة: الواقع وسيناريو المستقبل.

تهدف هذه الدراسة إلى معرفة ماهية المسؤولية الاجتماعية للقطاع الخاص وأثرها ودورها في الاقتصاد الكلي، حيث أن المسئولية الاجتماعية تشغل العديد من المجالات، وترتبط بالعديد من المحددات التي قد تؤثر أو تتأثر بها. وقد استخدم الباحثان الاسلوب النقدي التحليلي لعرض الادبيات السابقة الخاصة بالموضوع ولعرض نموذج The Triple Helix of University-Industry-Government Relations والذي يمكن ان يحقق دعامة اساسية لتحقيق التنمية المستدامة والتكاملية لتخدم الاهداف والأولويات التنموية الوطنية. كما استخدم الباحثان المنهج الاستنباطي والاستقرائي لبحث نشاط المسئولية الاجتماعية التي تقوم به العديد من المؤسسات الاقتصادية المحلية الكبرى والتي تعتبر ريادية في مجالها – في ظل النقص الحاد للبيانات. وقد استخدم الباحثان اسلوب السيناريو لعرض تصور للدور الحقيقي والمسئولية الاجتماعية التي يمكنان تشكل مساهمة فاعلة في تحقيق التنمية المستدامة. وقد استنتج البحث أن الدور الذي تلعبه العديد من المؤسسات المحلية كشكل من المسئولية الاجتماعية ما هو إلا دور دعائي ويخدم بالأساس ربحية المنشأة وحماية مصالحها وغير منطوي ضمن اطار الاولويات الوطنية. وقد خرج البحث بالعديد من التوصيات والمقترحات التي قد تخدم المساهمة التنموية الفاعلة والمستدامة في الاقتصاد ضمن اطار الاحتياجات والأولويات القومية. Purpose: To understand the nature of the social responsibility of the private sector, and its impact and role in the macro economy, whereas the social responsibility occupies many areas, and is linked to many of the determinants that may affect or be affected by it. The researchers used the analytical method to present the previous studies on the subject and to present the model of The Triple Helix of University-Industry-Government Relations, Which can achieve a basic pillar for sustainable development and complementary to serve the national development goals and priorities. Methodology: The researchers used the deductive and inductive approach to investigate the social responsibility activity carried out by many major local economic institutions, which are pioneering in their field, in light of the severe data shortage. The researchers used the scenario style to present a perception of the real role and social responsibility, which can be an effective contribution to sustainable development. Results: The research concluded that the role played by many local institutions as a form of social responsibility, is only a propaganda role that serves primarily the profitability of the business, and protects their interests. It is non-intrusive within the framework of national priorities. The research has produced many recommendations and proposals that may serve the active and sustainable development contribution in the economy within the framework of national needs and priorities

COMESA-EAC-SADC trepertite free trade area: challenges and prospects

In Sharm ElShiekh, Egypt, 2015 the member states of three major African regional economic blocks: COMESA, SADC and EAC, agreed on establishing a common free trade area called COMESA-EAC-SADC TFTA. Establishing this FTA is considered as a major step towards Africa’s Continental trade integration which is one of the main objectives of Africa 2063 Agenda. This paper aims to identify the potential impacts of the integration among those three RECs on various aspects of economic growth including welfare, trade, price effects, and government’s revenues and to identify the main obstacles and challenges that may hinder achieving these potentials

Dual buoyant/mucoadhesive macroporous polypropylene microparticles for gastric delivery of repaglinide

Preparation and characterization of dual buoyant/mucoadhesive polypropylene microparticles (MPs) loaded with repaglinide (REP) for gastric drug delivery in order to augment the weak mucoadhesion in the stomach.Porous foam powder MPs were prepared using coating polymers with variable permeability (Eudragit L100, Eudragit RSPO) alone or in combination by the soaking method. Thiolated Eudragit L100 (Eudragit L100-SH) was also synthesized and tried in an attempt to enhance the mucoadhesive properties of MPs. All formulae were characterized for their yield, flow properties, particle size, encapsulation efficiency (EE %), morphology, and drug release and its mechanistics. Possible interactions inside MPs matrix were also elucidated using FTIR study. The suitability of the selected formulae for gastroretention was evaluated by in vitro buoyancy and ex-vivo mucoadhesion studies.All REP-loaded MPs demonstrated a passable powder flow, high yield values, promising floatation and mucoadhesion. Encapsulation efficiency % values were nearly tripled upon addition of Eudragit polymers. Compared to the Eudragit free REP loaded foam powder, all formula showed more sustained release features. Eudragit L100-SH was synthesized and confirmed by FTIR. Furthermore, its incorporation, alone or in combination, exhibited a significant increase in mucoadhesion strength compared to the unmodified one.Dual buoyant/mucoadhesive MPs loaded with REP encourage planning for future in-vivo performance studies for the management of diabetes

Imputation versus prediction: applications in machine learning for drug discovery

Imputation is a powerful statistical method that is distinct from the predictive modelling techniques more commonly used in drug discovery. Imputation uses sparse experimental data in an incomplete dataset to predict missing values by leveraging correlations between experimental assays. This contrasts with quantitative structure–activity relationship methods that use only descriptor – assay correlations. We summarize three recent imputation strategies – heterogeneous deep imputation, assay profile methods and matrix factorization – and compare these with quantitative structure–activity relationship methods, including deep learning, in drug discovery settings. We comment on the value added by imputation methods when used in an ongoing project and find that imputation produces stronger models, earlier in the project, over activity and absorption, distribution, metabolism and elimination end points. </jats:p

FREQUENCY OF BLOOD GROUPS AMONGA SAMPLE OF PATIENTSWITH RENAL FAILURE AT ROYAL MEDICAL SERVICES

Introduction: Renal failure underlies various etiologies among which are infectious and autoimmune origins which may link directly or indirectly with blood groups. Objectives: To determine the frequency of blood groups among a sample of patients with renal failure at Royal medical services, and to investigate the association of renal function tests with blood groups. Methodology: A retrospective study design was followed to collect data from files of patients with renal failure. Files of renal patients was included if blood groups were written and kidney function tests were provided. A data sheet was made for each patient that included relevant information about renal patients. A total of 197 files were reviewed. Data were entered into excel sheet to make raw data for all patients. Data analysis was conducted using SPSS V20. Data were presented as frequencies and percentages. The relationships between blood groups and renal function tests were investigated using T-independent test. Significance was considered at alpha level &lt; 0.05. Results: the most prevalent blood group among renal failure patients was blood group A (45.7%), blood group O (30.4%), blood group B (17.3%), and blood group AB (6.6%). When biochemical tests including renal function tests were compared between renal failure patients according their blood groups, results showed slight variations, which were not statistically significant (p&gt;0.05), except for potassium level which was observed in its maximal level among patients with blood group A, and its minimal levels were observed among patients with blood group AB (p=0.032). Conclusions: The present study showed that renal failure patients exhibited more frequency with blood groups A and O and agreed with other studies in which blood group AB is the least associated blood group with renal failure. The level of potassium was highest in patients with blood group A and lowest in patients with blood group AB and this was statistically significant (p=0.032)