Multiscale Modelling of Brain Networks and the Analysis of Dynamic Processes in Neurodegenerative Disorders

The complex nature of the human brain, with its intricate organic structure and multiscale spatio-temporal characteristics ranging from synapses to the entire brain, presents a major obstacle in brain modelling. Capturing this complexity poses a significant challenge for researchers. The complex interplay of coupled multiphysics and biochemical activities within this intricate system shapes the brain\u27s capacity, functioning within a structure-function relationship that necessitates a specific mathematical framework. Advanced mathematical modelling approaches that incorporate the coupling of brain networks and the analysis of dynamic processes are essential for advancing therapeutic strategies aimed at treating neurodegenerative diseases (NDDs), which afflict millions of individuals worldwide. This thesis aims to develop novel multiscale brain network models to investigate the properties of biological processes spanning multiple spatial and temporal scales, potentially offering new insights into the fundamental aspects of brain networks in healthy and diseased states. Among various factors, our particular attention is devoted to brain electrical activity, which serves as a significant characteristic of NDDs such as Alzheimer\u27s disease (AD), cortical spreading depression (CSD), and Parkinson\u27s disease (PD). Our analysis starts with a focus on large-scale brain network models within the context of AD and PD. Importantly, AD is characterized by pathological accumulations of amyloid-beta plaques ($A\beta$) and neurofibrillary tangles ($\tau$). Specifically, the propagation of intracellular calcium ($Ca^{2+}$) signalling within non-neuronal cells, such as astrocytes, has an impact on the tripartite synapse propagation in neuronal cells, leading to synaptic failure and neuronal death. To gain insights into the pathogenesis of AD, particularly the role of astrocytes in the presence of misfolded proteins ($A\beta$ and $\tau$), we propose an improved large-scale brain network model. This model incorporates the concept of astrocytic clearance, which aids in the fragmentation and elimination of toxic $A\beta$. We obtained the data from the Human Connectome Project (HCP) and proposed a hybrid multiscale modelling strategy based on a large-scale brain network model. Furthermore, PD is characterized by involuntary or uncontrolled movements such as shaking, stiffness, and difficulties with balance and coordination. In our study, we have developed a small-scale brain network model that aims to shed light on the intricate dynamics of PD and its impact on the brain. Within the context of PD, we have explored the optimization of deep brain stimulation (DBS) procedures, a well-established neuromodulation technique for managing PD symptoms. By leveraging data from the HCP, we propose a closed-loop DBS approach based on a brain network model. Additionally, CSD is characterized by a slowly propagating wave that disrupts the brain\u27s homeostasis, leading to a temporary impairment in the normal functioning of neurons. In this thesis, our focus is to model the propagation of CSD in the brain using two different approaches found in the literature. Firstly, we employ a simplified model consisting of six coupled equations of the reaction-diffusion type in two spatial dimensions. Secondly, we utilize a more complex one-dimensional neuronal model that incorporates ionic currents and ionic pumps. Furthermore, we have developed a comprehensive coupled neuronal-glial model to investigate the impact of temperature on the activation and inactivation of ionic channels, specifically focusing on their influence on calcium-mediated exosomal dynamics in PD and AD. This model specifically examines controlled therapeutic exosomal release by evaluating the modulated release rate and the concentration of released exosomes. Importantly, it considers the temperature threshold dependence on $Ca^{2+}$ dynamics by incorporating cold-sensing neurons. The outcomes of our investigation highlight the significant role played by $TRPM8$ and voltage-gated $Ca^{2+}$ channels in determining temperature-dependent activation and inactivation at various threshold levels. Notably, the primary objective of this thesis is to develop multiscale deterministic and stochastic models that can capture the overall trends and average behaviour of the system, providing insights into the mechanisms underlying these diseases. The etiology of AD can be described as a multi-state disease process utilizing the approximate Bayesian computation (ABC) method. In this context, we employ ADNI data from 2-year visits for AD patients and apply this method to investigate the interplay between $A\beta$ and $Ca^{2+}$ levels at different stages of disease development. Astrocytes play a crucial role in NDDs as they secrete neurotrophins, regulate synaptogenesis, facilitate the formation of neural networks, and influence synaptic plasticity underlying learning, memory, and disease progression. Thus, we employ strong and weak astrocyte effect models on $A\beta$ dynamics to explore the biological mechanisms within the central nervous system. In this regard, we analyze ADNI data for $A\beta$ concentration and fit it to the developed stochastic models using the ABC technique, allowing us to refine and validate the model based on clinical data. It is expected that the coupled multiscale models developed in this thesis will provide novel insight into disease origin and progression and a better understanding of the key mechanisms underlying the dynamics of the pathological brain

Data-driven Stochastic Model for Quantifying the Interplay Between Amyloid-beta and Calcium Levels in Alzheimer's Disease

The abnormal aggregation of extracellular amyloid-$\beta$ (A\beta) in senile plaques resulting in calcium (Ca^{+2}) dyshomeostasis is one of the primary symptoms of Alzheimer's disease (AD). Significant research efforts have been devoted in the past to better understand the underlying molecular mechanisms driving A\beta deposition and Ca^{+2} dysregulation. To better understand this interaction, we report a novel stochastic model where we analyze the positive feedback loop between A\beta and Ca^{+2} using ADNI data. A good therapeutic treatment plan for AD requires precise predictions. Stochastic models offer an appropriate framework for modelling AD since AD studies are observational in nature and involve regular patient visits. The etiology of AD may be described as a multi-state disease process using the approximate Bayesian computation method. So, utilizing ADNI data from $2$-year visits for AD patients, we employ this method to investigate the interplay between A\beta and Ca^{+2} levels at various disease development phases. Incorporating the ADNI data in our physics-based Bayesian model, we discovered that a sufficiently large disruption in either A\beta metabolism or intracellular Ca^{+2} homeostasis causes the relative growth rate in both Ca^{+2} and A\beta, which corresponds to the development of AD. The imbalance of Ca^{+2} ions causes A\beta disorders by directly or indirectly affecting a variety of cellular and subcellular processes, and the altered homeostasis may worsen the abnormalities of Ca^{+2} ion transportation and deposition. This suggests that altering the Ca^{+2} balance or the balance between A\beta and Ca^{+2} by chelating them may be able to reduce disorders associated with AD and open up new research possibilities for AD therapy.Comment: 20 pages, 6 figure

Epidemiology of pseudoexfoliation syndrome: a hospital based comparative study

Background: Pseudoexfoliation syndrome (PEX), is an age-related condition with generalized disorder of the extracellular matrix (ECM) characterized by a pathological accumulation of polymorphic fibrillar extracellular material in ocular tissue and various visceral organs. The search for the etiology of pseudoexfoliation syndrome has been directed towards both genetic and environmental factors. It is associated with many ocular and systemic complications.Methods: The study was a hospital based comparative clinical study with 100 consecutive patients with pseudoexfoliation and age and sex matched 100 patients as control without pseudoexfoliation. The patients were registered on a Pre-structured Proforma which included patients’ demographic detail, history and examination. Examination protocol including visual acuity with snellen’s chart for literate patients and E-Chart for illiterate patients, intraocular pressure (by Goldmann applanation tonometry), slit lamp examination and fundus examination.Results: The mean age of cases was 65.93± 7.82 years ranging from 49 to 85 years. The mean age of controls was 63.98± 7.06 years ranging from 50 to 80 years (p=0.139). 72% of cases were more than 60 years old. Male female ratio was 1.63:1. Most of the cases were from Budgam, Bandipora and Ganderbal areas. Spring water was proportionately more frequently used as water source in cases (χ2 =18.5, p=0.000), and tube well water in controls. The mean duration of smoking was 26.63±24.74 pack years for cases and 14.88±17.10 pack years for controls (p=0.000). Average duration of daytime exposure for cases was 6.68±2.13 hours and for controls it was 4.52±2.53 hours. Among cases 12 patients (12%) were on treatment for glaucoma whereas among controls, 1 patient (1%) was on treatment for glaucoma. With respect to dietary habits, there was no difference between cases and controls. Farmers comprised of 49% of cases, followed by House wives and government employees.Conclusions: The study concludes that PEX is very common in our region, increasing with age and more in men. Smoking, occupations involved with sunlight exposure, spring water as water source are possible risk factors for PEX. Glaucoma and cataract are common ocular complications of the syndrome

Bayesian inference and role of astrocytes in amyloid-beta dynamics with modelling of Alzheimer's disease using clinical data

Alzheimer's disease (AD) is a prominent, worldwide, age-related neurodegenerative disease that currently has no systemic treatment. Strong evidence suggests that permeable amyloid-beta peptide (Abeta) oligomers, astrogliosis and reactive astrocytosis cause neuronal damage in AD. A large amount of Abeta is secreted by astrocytes, which contributes to the total Abeta deposition in the brain. This suggests that astrocytes may also play a role in AD, leading to increased attention to their dynamics and associated mechanisms. Therefore, in the present study, we developed and evaluated novel stochastic models for Abeta growth using ADNI data to predict the effect of astrocytes on AD progression in a clinical trial. In the AD case, accurate prediction is required for a successful clinical treatment plan. Given that AD studies are observational in nature and involve routine patient visits, stochastic models provide a suitable framework for modelling AD. Using the approximate Bayesian computation (ABC) approach, the AD etiology may be modelled as a multi-state disease process. As a result, we use this approach to examine the weak and strong influence of astrocytes at multiple disease progression stages using ADNI data from the baseline to 2-year visits for AD patients whose ages ranged from 50 to 90 years. Based on ADNI data, we discovered that the strong astrocyte effect (i.e., a higher concentration of astrocytes as compared to Abeta) could help to lower or clear the growth of Abeta, which is a key to slowing down AD progression.Comment: 10, figures and 30 page

The Problem-Based Learning Approach towards Developing Soft Skills: A Systematic Review

In this paper, we review systematically the role of problem-based learning (PBL) in developing soft skills in Technical and Vocational Education and Training (TVET) and other fields of studies. The Systematic Literature Review (SLR) includes the most recent empirical, review, and conceptual studies from TVET and other multiple fields of studies including medicine, humanities, and engineering between the years of 2001 and 2016 collected from four databases. A qualitative method was used to accomplish the systematic review. After the collection of articles, the selected studies were analyzed through thematic analysis. From this review, we concluded that PBL as an instructional approach has a significant role in the development of soft skills among students of various disciplines including TVET; empirical evidence is predominantly conclusive in identifying the acquisitions of various soft skills including communication skills, conflict resolution skills, leadership skills, and interpersonal skills, and finally, several factors might influence the relationship of PBL and soft skills such as duration and process of PBL instruction, role of facilitator, and awareness and training of learners. Moreover, there are fewer number of empirical studies on the role and effects of PBL approach to developing soft skills in TVET

Foreign Direct Investment and Sustainable Long Run Economic Growth Nexus: A Case Study of Pakistan

The present study examined the relationship between economic growth and FDI in Pakistan by utilizing the data for the time period 1975-2015. The study employed a number of statistical and econometric tools for the analysis. ADF test for stationarity of data, and ARDL approach to cointegration is used for parameter estimations. The study includes GDP growth rate, foreign direct investment, trade openness, inflation and labour force as the variables of the study. The results indicated that the association between FDI and GDP growth is negative, for Pakistan, in the long run, while the results illustrated the positive association among variables in short run. Trade openness enhances GDP growth both in the long and short run, the result also revealed

Un estudio sobre el uso de combinaciones de palabras en estudiantes de administración

Previous studies have reported lack of collocational competence and difficulties among English as a second language (ESL) learners. However, collocation is crucial in second language acquisition. This research examined the receptive and productive knowledge of collocations among the business students of COMSATS University Islamabad Vehari Campus who studied ESL. It also investigated the gap in the use of collocations at a receptive and productive level. The sample included 61 males and 39 females out of the total sample size of 100. Employing a quantitative approach, we gathered the data through a questionnaire and two collocations tests, and we analysed them via SPSS version 20. The overall result of the collocation test indicated that 66.4% of the respondents had the correct answer at the receptive level compared with only 33.7% at the productive level. Moreover, the statistical result presented a great gap in the ability to utilise collocations at the productive and receptive levels. This result also affirmed that despite their ability to understand the collocations, the students had difficulties in identifying proper English collocations confidently. Local and native language experiences might be one of the reasons that caught the students from being more confident in identifying the English collocations.Previos estudios han informado de la falta de competencia en la ubicación y las dificultades entre los estudiantes de inglés como segunda lengua (ESL). Sin embargo, las combinaciones de palabras son cruciales en la adquisición de un segundo idioma. Esta investigación examinó el conocimiento receptivo y productivo de las combinaciones de palabras entre los estudiantes de administración de la Universidad COMSATS de Islamabad (Campus de Vehari) que estudiaron ESL. También investigó la brecha en el uso de estas combinaciones a nivel receptivo y productivo. La muestra incluyó 61 hombres y 39 mujeres, de un total de 100. Empleando un enfoque cuantitativo, recopilamos los datos mediante un cuestionario y dos pruebas de colocaciones, y los analizamos por medio del programa SPSS versión 20. El resultado general de la prueba de colocación indicó que el 66,4 % de los encuestados tenía la respuesta correcta a nivel receptivo y solo el 33,7 % a nivel productivo. Además, el resultado estadístico presentó una gran brecha en la capacidad de utilizar combinaciones de palabras en los niveles productivo y receptivo. Este resultado también afirmó que, a pesar de su capacidad para comprender las combinaciones de palabras, los estudiantes tenían dificultades para identificar con seguridad (...

Correlation between correctly sized uncuffed endotracheal tube and ultrasonographically determined subglottic diameter in pediatric population

Background: The size of the airway varies greatly in pediatric patients, making it difficult to predict an appropriate size Endotracheal tube (ETT) for securing the airway. Several formulae are used to predict approximate ETT size. With the wider availability of ultrasonography (USG), many clinicians have suggested it as a useful tool for airway management and have used USG to measure tracheal dimensions in adults and children. Aims and Objectives: The primary aim of this study was to evaluate the usefulness of USG for the selection of correct sized uncuffed ETT in pediatric patients and the secondary aim was to correlate the age-based formula with ultrasound measured subglottic diameter for predicting the size of ETT. Materials and Methods: A total of 64 patients of either gender in the age group of 2–6 years were enrolled in the study. Standard anesthetic induction was done and transverse subglottic diameter was measured using USG. The minimal transverse subglottic diameter was measured and noted and the patient was intubated with the tube size as determined by modified Cole’s age-based formula. Results: Out of 64 patients, 33 were male and 31 female. Average age was 3.9 (±1.47) years, 42.2% belonged to the age group of (2–3) years, average weight of the patients was 20.3 (±10.45) kg. The mean ETT outer diameters (OD) based on age-based formula was 6.81 mm compared to 6.91 mm and 6.78 mm by USG based and actual ETT OD, respectively. Both the age based ETT OD and USG-based ETT OD showed good correlation with actual ETT OD used with r-value of 0.891 and 0.876, respectively. Conclusion: Although USG is a non-invasive, cost-effective, and reproducible technique its routine use for estimating ETT size in pediatric patients could not be justified over age-based formula as both of them have comparable results (statistically insignificant). The success rate of age-based formula and USG in precisely predicting ETT outer diameter is comparable with the size of actual ETT outer diameter (78% vs. 75%, P=0.86)

Arsenic speciation and biotransformation pathways in the aquatic ecosystem: The significance of algae

© 2020 Elsevier B.V. The contamination of aquatic systems with arsenic (As) is considered to be an internationally-important health and environmental issue, affecting over 115 countries globally. Arsenic contamination of aquatic ecosystems is a global threat as it can enter the food chain from As-rich water and cause harmful impacts on the humans and other living organisms. Although different factors (e.g., pH, redox potential, iron/manganese oxides, and microbes) control As biogeochemical cycling and speciation in water systems, the significance of algal species in biotransformation of As is poorly understood. The overarching attribute of this review is to briefly elaborate various As sources and its distribution in water bodies and factors affecting As biogeochemical behavior in aqueous ecosystems. This review elucidates the intriguing role of algae in biotransformation/volatilization of As in water bodies under environmentally-relevant conditions. Also, we critically delineate As sorption, uptake, oxidation and reduction pathways of As by algae and their possible role in bioremediation of As-contaminated water (e.g., drinking water, wastewater). The current review provides the updated and useful framework for government and water treatment agencies to implement algae in As remediation programs globally

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation