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Neural Regeneration Research 2018年第7期13卷 1156-1158页

作者： Jingyi Liang don kulasiri Centre for Advanced Computational Solutions(C-fACS) Lincoln University

Ca^2＋ dysregulation is an early event observed in Alzheimer＇s disease（AD） patients preceding the presence of its clinical *** of neuronalCa^2＋ will cause synaptic loss and neuronal death,eventually leading to memory impairments and cognitive *** targetingCa^2＋ signaling pathways are potential therapeutic strategies against *** complicated interactions make it challenging and expensive to study the underlying mechanisms as to how Ca^2＋ signaling contributes to the pathogenesis of *** modeling offers new opportunities to study the signaling pathway and test proposed *** this mini-review,we present some computational approaches that have been used to study Ca^2＋ dysregulation of AD by simulating Ca^2＋signaling at various *** also pointed out the future directions that computational modeling can be done in studying the Ca^2＋ dysregulation in AD.

关键词： Alzheimer's disease amyloid-beta Ca^2+ hypothesis Ca^2+ dysregulation computational modeling computational neuroscience

Functional repertoire of protein kinases and phosphatases in synaptic plasticity and associated neurological disorders

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Neural Regeneration Research 2021年第6期16卷 1150-1157页

作者： Raheel Khan don kulasiri Sandhya Samarasinghe Centre for Advanced Computational Solutions(C-fACS) Lincoln UniversityChristchurchNew Zealand Department of Molecular Biosciences Lincoln UniversityChristchurchNew Zealand

Protein phosphorylation and dephosphorylation are two essential and vital cellular mechanisms that regulate many receptors and enzymes through kinases and ***^2+- dependent kinases and phosphatases are responsible for controlling neuronal processing;balance is achieved through *** molecular mechanisms of learning and memory,kinases generally modulate positively while phosphatases modulate *** review outlines some of the critical physiological and structural aspects of kinases and phosphatases involved in maintaining postsynaptic structural *** also explores the link between neuronal disorders and the deregulation of phosphatases and kinases.

关键词： Alzheimer’s disease autism spectrum disorder CaMKII calcineurin longterm depression long-term potentiation protein kinase A protein phosphatase 1 protein dephosphorylation protein phosphorylation

Detection of Alzheimer’s disease onset using MRI and PET neuroimaging:longitudinal data analysis and machine learning

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Neural Regeneration Research 2023年第10期18卷 2134-2140页

作者： Iroshan Aberathne don kulasiri Sandhya Samarasinghe Centre for Advanced Computational Solutions(C-fACS) Lincoln UniversityChristchurchNew Zealand

The scientists are dedicated to studying the detection of Alzheimer’s disease onset to find a cure, or at the very least, medication that can slow the progression of the disease. This article explores the effectiveness of longitudinal data analysis, artificial intelligence, and machine learning approaches based on magnetic resonance imaging and positron emission tomography neuroimaging modalities for progression estimation and the detection of Alzheimer’s disease onset. The significance of feature extraction in highly complex neuroimaging data, identification of vulnerable brain regions, and the determination of the threshold values for plaques, tangles, and neurodegeneration of these regions will extensively be evaluated. Developing automated methods to improve the aforementioned research areas would enable specialists to determine the progression of the disease and find the link between the biomarkers and more accurate detection of Alzheimer’s disease onset.

关键词： deep learning image processing linear mixed effect model neuroimaging neuroimaging data sources onset of Alzheimer’s disease detection pattern recognition

Modeling protein-protein interactions in axon initial segment to understand their potential impact on action potential initiation

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Neural Regeneration Research 2021年第4期16卷 700-706页

作者： Piyush Bhardwaj don kulasiri Sandhya Samarasinghe Centre of Advanced Computational Solutions(C-fACS) Lincoln UniversityChristchurchNew Zealand Department of Molecular Biosciences Lincoln UniversityChristchurchNew Zealand

The axon initial segment(AIS)region is crucial for action potential initiation due to the presence of high-density AIS protein voltage-gated sodium channels(Nav).Nav channels comprise several serine residues responsible for the recruitment of Nav channels into the structure of AIS through interactions with ankyrin-G(AnkG).In this study,a series of computational experiments are performed to understand the role of AIS proteins casein kinase 2 and AnkG on Nav channel recruitment into the *** computational simulation results using Virtual cell software indicate that Nav channels with all serine sites available for phosphorylation bind to AnkG with strong *** the low initial concentration of AnkG and casein kinase 2,the concentration of Nav channels reduces significantly,suggesting the importance of casein kinase 2 and AnkG in the recruitment of Nav channels.

关键词： Alzheimer’s disease ankyrin-G axon initial segment casein kinase-2 microtubules voltage-gated potassium channel voltage-gated sodium channel

A mathematical model of synaptotagmin 7 revealing functional importance of short-term synaptic plasticity

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Neural Regeneration Research 2019年第4期14卷 621-631页

作者： Yao He don kulasiri Jingyi Liang Center for Advanced Computational Solutions (C-fACS) Lincoln UniversityChristchurch New Zealand

Synaptotagmin 7(Syt7), a presynaptic calcium sensor, has a significant role in the facilitation in shortterm synaptic plasticity: Syt7 knock out mice show a significant reduction in the facilitation. The functional importance of short-term synaptic plasticity such as facilitation is not well understood. In this study, we attempt to investigate the potential functional relationship between the short-term synaptic plasticity and postsynaptic response by developing a mathematical model that captures the responses of both wild-type and Syt7 knock-out mice. We then studied the model behaviours of wild-type and Syt7 knock-out mice in response to multiple input action potentials. These behaviors could establish functional importance of short-term plasticity in regulating the postsynaptic response and related synaptic properties. In agreement with previous modeling studies, we show that release sites are governed by non-uniform release probabilities of neurotransmitters. The structure of non-uniform release of neurotransmitters makes shortterm synaptic plasticity to act as a high-pass filter. We also propose that Syt7 may be a modulator for the long-term changes of postsynaptic response that helps to train the target frequency of the filter. We have developed a mathematical model of short-term plasticity which explains the experimental data.

关键词： synapse short-term plasticity short-term facilitation and depression mathematical model low-frequency stimulation high-frequency stimulation

Alleviating the unwanted effects of oxidative stress on Aβclearance:a review of related concepts and strategies for the development of computational modelling

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Translational Neurodegeneration 2023年第1期12卷 702-721页

作者： Sarawoot Somin don kulasiri Sandhya Samarasinghe Centre for Advanced Computational Solutions(C-fACS) Lincoln UniversityChristchurch 7647New Zealand Department of Wine Food and Molecular BiosciencesLincoln UniversityChristchurch 7647New Zealand

Treatment for Alzheimer’s disease(AD)can be more effective in the early *** we do not completely understand the aetiology of the early stages of AD,potential pathological factors(amyloid beta[Aβ]and tau)and other co-factors have been identified as causes of AD,which may indicate some of the mechanism at work in the early stages of ***,one of the primary techniques used to help delay or prevent AD in the early stages involves alleviating the unwanted effects of oxidative stress on Aβclearance.4-Hydroxynonenal(HNE),a product of lipid peroxidation caused by oxidative stress,plays a key role in the adduction of the degrading *** HNE employs a mechanism which decreases catalytic *** process ultimately impairs Aβ*** degradation of HNE-modified proteins helps to alleviate the unwanted effects of oxidative *** a clear understanding of the mechanisms associated with the degradation of the HNE-modified proteins is essential for the development of strategies and for alleviating the unwanted effects of oxidative *** strategies which could be employed to decrease the effects of oxidative stress include enhancing antioxidant activity,as well as the use of nanozymes and/or specific *** area which shows promise in reducing oxidative stress is protein ***,more research is needed to improve the effectiveness and accuracy of this *** paper discusses the interplay of potential pathological factors and *** particular,it focuses on the effect of oxidative stress on the expression of the Aβ-degrading proteases through adduction of the degrading proteases caused by *** paper also elucidates other strategies that can be used to alleviate the unwanted effects of oxidative stress on Aβ*** improve the effectiveness and accuracy of protein design,we explain the application of quantum mechanical/molecular mechanical approach.

关键词： Alzheimer’s disease Oxidative stress Amyloid beta clearance Protein design

Fundamental Boolean network modelling for childhood acute lymphoblastic leukaemia pathways

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Quantitative Biology 2022年第1期10卷 94-121页

作者： Leshi Chen don kulasiri Sandhya Samarasinghe Computational Systems Biology Laboratory Centre for Advanced Computational Solutions(C-fACS)Lincoln UniversityLincolnCanterbury 7647New Zealand Integrated Systems Modelling Group Centre for Advanced Computational Solutions(C-fACS)Lincoln UniversityLincolnCanterbury 7647New Zealand

Background:A novel data-driven Boolean model,namely,the fundamental Boolean model(FBM),has been proposed to draw genetic regulatory insights into gene activation,inhibition,and protein decay,published in *** novel Boolean model facilitates the analysis of the activation and inhibition ***,the novel model does not handle the situation well,where genetic regulation might require more time steps to ***:Here,we propose extending the fundamental Boolean modelling to address the issue that some gene regulations might require more time steps to complete than *** denoted this extension model as the temporal fundamental Boolean model(TFBM)and related networks as the temporal fundamental Boolean networks(TFBNs).The leukaemia microarray datasets downloaded from the National Centre for Biotechnology Information have been adopted to demonstrate the utility of the proposed TFBM and ***:We developed the TFBNs that contain 285 components and 2775 Boolean rules based on TFBM on the leukaemia microarray datasets,which are in the form of short-time *** data contain gene expression measurements for 13 GC-sensitive children under therapy for acute lymphoblastic leukaemia,and each sample has three time points:0 hour(before GC treatment),6/8 hours(after GC treatment)and 24 hours(after GC treatment).Conclusion:We conclude that the proposed TFBM unlocks their predecessor’s limitation,Le.,FBM,that could help pharmaceutical agents identify any side effects on clinic-related *** hypotheses could be identified by analysing the extracted fundamental Boolean networks and analysing their up-regulatory and down-regulatory pathways.

关键词： Boolean modelling Boolean network time series data network inference data-driven boolean modelling fundamental boolean model fundamental boolean networks orchard cube

On electrostatic interactions of adenosine triphosphate-insulin-degrading enzyme revealed by quantum mechanics/molecular mechanics and molecular dynamics

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Quantitative Biology 2024年第4期12卷 414-432页

作者： Sarawoot Somin don kulasiri Sandhya Samarasinghe Centre for Advanced Computational Solutions(C‐fACS) Lincoln UniversityChristchurchNew Zealand Department of Molecular Biosciences Lincoln UniversityChristchurchNew Zealand

The insulin-degrading enzyme(IDE)plays a significant role in the degradation of the amyloid beta(Aβ),a peptide found in the brain regions of the patients with early Alzheimer’s *** triphosphate(ATP)allosterically regulates the Aβ-degrading activity of *** present study investigates the electrostatic interactions between ATP-IDE at the allosteric site of IDE,including thermostabilities/flexibilities of IDE residues,which have not yet been explored *** study applies the quantum mechanics/molecular mechanics(QM/MM)to the proposed computational model for exploring electrostatic interactions between ATP and *** dynamic(MD)simulations are performed at different temperatures for identifying flexible and thermostable residues of *** proposed computational model predicts QM/MM energy-minimised structures providing the IDE residues(Lys530 and Asp385)with high binding *** root mean square fluctuation values during the MD simulations at 300.00 K including heat-shock temperatures(321.15 K and 315.15 K)indicates that Lys530 and Asp385 are also the thermostable residues of IDE,whereas Ser576 and Lys858 have high flexibilities with compromised *** present study sheds light on the phenomenon of biological recognition and interactions at the ATP-binding domain,which may have important implications for pharmacological drug *** proposed computational model may facilitate the development of allosteric IDE activators/inhibitors,which mimic ATP interactions.

关键词： electrostatic interactions molecular dynamic simulation QM/MM calculation method thermostability/flexibility