Pharmacokinetics/Pharmacodynamics and Analysis of the Effect of β-Amyloid Peptide on Acetylcholine Neurocycle and Alzheimer’s Disease Medications

The brain of Alzheimer’s disease (AD) is characterized by accumulations of β-amyloid peptide aggregates which promote neurodegentartive dysfunction. Comprehensive understanding of the interaction between β-amyloid aggregates and acetylcholine (ACh) neurocycle is required to uncover the physiological processes related to AD and might result in improving therapeutic approaches for AD. Pharmacokinetics (PK) and pharmacodynamics (PD) techniques were applied to allow predicting the extent of the interaction of certain doses of AD drugs and β-amyloid inhibitors and levels of ACh as well. Although many researchers focused on the β-amyloid interactions, the mechanisms by which β-amyloid affects cholinergic neurons and reduction of ACh are still unclear. The prediction of ACh and drug concentrations in the tissues and body needs an understanding of the physiology and mechanisms of β-amyloid aggregates processes and their compilation into a mechanistic model In this work, two hypotheses are proposed to investigate the dynamic behavior of the interaction between β-amyloid peptide aggregates and cholinergic neurocycle and the possible therapeutic approaches through proposing pharmacokinetic/pharmacodynamics (PK/PD) models to represent the impact of β-amyloid aggregates in AD. The effect of β-amyloid peptide aggregates is formulated through incorporating β- amyloid aggregates into non-linear model for the neurocycle of ACh where the presynaptic neuron is considered as compartment 1 and both synaptic cleft and postsynaptic neurons are considered as compartment 2. In the first hypothesis which is choline leakage hypothesis, β-amyloid peptide aggregates are considered to be located in the membrane of the presynaptic neuron and create pathways inside the membrane to allow for the intracellular choline to leak outside the cholinergic system. It is observed that β-amyloid aggregates via the choline leakage hypothesis could cause significant reductions of ACh and choline levels in both compartments. Furthermore, the process rates of ACh synthesis and hydrolysis have been affected negatively by a wide range of β-amyloid aggregate concentrations. It is found that as the input rate of β-amyloid aggregates to compartment 1 increases, the loss of choline from compartment 1 increases leading to an increase in the intracellular concentration of β-amyloid. In the second hypothesis, β-amyloid peptide aggregates are proposed to interact with the enzyme ChAT which is responsible for the synthesis of ACh in compartment 1; three different kinetic mechanisms are suggested to account for the interaction between β-amyloid aggregates and ChAT activity. In the first and second kinetic mechanisms, β-amyloid aggregate is supposed to attack different species in the enzyme. It is found that there is a significant decrease in the rate of ACh synthesis in compartment 1 and ACh concentrations in both compartments. However, it is observed that there is no effect on choline levels in both compartments, the rate of ACh hydrolysis in compartment 2, pH, and ACh levels in compartment 2. In the third kinetic mechanism, all species in ChAT are attacked by β-amyloid aggregates; it is observed that at very high input rates of β-amyloid aggregates, the oscillatory behavior dominates all components of the neurocycle of ACh. The disturbance observed in ACh levels in both compartments explains the harmful effect of the full attack of β-amyloid aggregates to all species of ChAT. It is found that to contribute significantly in ACh neurocycle, choline leakage hypothesis needs concentration of β-amyloid aggregates lower than that needed in ChAT activity hypothesis which is in agreement with experimental observations. The significant decrease in ACh levels observed in both choline leakage and loss of ChAT activity hypotheses leads to cognitive loss and memory impairment which were observed in individuals with AD. A one-compartment drug PK/PD model is proposed to investigate a therapeutic approach for inhibiting β-amyloid aggregation via choline leakage hypothesis where the maximum feed rate of β-amyloid (KL2 = 1) is considered. The drug is assumed to interact with the tissues of the presynaptic neurons where β-amyloid aggregates are located. The PK/PD model is built based on the effect of β-amyloid aggregates via choline leakage hypothesis where the maximum feed rate of β-amyloid aggregates is considered. The dynamic behavior of all concentrations of β-amyloid aggregates, choline, ACh, acetate, and pH in both compartments in addition to the rate of ACh synthesis in compartment 1 and ACh hydrolysis are investigated by monitoring the impacts of the drug on β-amyloid aggregates and cholinergic neurocycle over a wide range of the input drug dosage. The PK/PD model is able to predict the reduction in levels of β-amyloid aggregates and the increase in choline and ACh, in both compartments as well as both rates of ACh synthesis and hydrolysis catalyzed. The parameters of the PK/PD model such as maximum concentration (Cmax), maximum time (Tmax), area under the curve (AUC), and maximum effect (Emax) were investigated. It was found that it takes a longer time (Tmax) (3-5 h) to reach Emax as the drug dose increases. Furthermore, AUC was found to increase with increasing drug dosage. The results of the current work show that drugs / therapeutic agents inhibiting β- amyloid aggregation in the brain represent a likely successful therapeutic approach to give systematic highlights to develop future trials, new diagnostic techniques, and medications for AD. This study is helpful in designing PK and PD and developing experimental animal models to support AD drug development and therapy in the future

Voices From The United Arab Emirates: Engineering Graduates’ Labour Market Requisite Competencies

This study reports on engineering graduates’ labour market requisite communication competences and skills in the work environment in the United Arab Emirates (UAE). Its main purpose was to investigate whether internationally required engineering graduates’ communication competences were the same in third world countries or different. It used a survey to collect responses from major engineering companies operating in the seven emirates federation forming the UAE. The researchers conducted semi-structured interviews with some of the participants to seek clarifications on some of the survey responses. Results indicted similar market demands to those reported in international research with differences in preferences and ranking of competences. The conclusions reported are based on the responses given in the surveys. Future research may follow up some engineering graduates and find out how they perform in labor market environments. The findings show that although engineering labor market demands are in line with global market demands, they; nevertheless, indicate differences in the ranking and importance of the required competences and skills. This has significant implications for engineering course designers.

Degenerate Bogdanov-Takens bifurcations in a bulk viscous cosmology

Using the dynamical system theory we show that the Friedmann-Robertson-Walker (FRW) cosmological model with bulk viscous fluid in the presence of cosmological constant is equivalent to a degenerate two dimensional Bogdanov-Takens normal form. The equation of state parameter, $\omega$, the bulk viscosity coefficient, $\xi$, and the cosmological constant, $\Lambda$, define the necessary parameters for unfolding the degenerate Bogdanov-Takens system. The fixed points of the system are discussed together with the variation of their stability properties upon changing the relevant parameters $\omega$, $\Lambda$ and $\xi$. The variation of the stability properties are visualized by the appropriate bifurcation diagrams. Phase portrait for finite domain and global phase portrait are displayed and the issue of the structural stability are discussed. Typical issues such as late acceleration or inflation that can be induced by viscosity and could have relevance to observational cosmology are also discussed.Comment: 46 pages, 21 figures, 4 tables, typos are corrected, new references are added, new material is adde

Modeling the Interaction between β

The effect of β-amyloid aggregates on activity of choline acetyltransferase (ChAT) which is responsible for synthesizing acetylcholine (ACh) in human brain is investigated through the two-enzyme/two-compartment (2E2C) model where the presynaptic neuron is considered as compartment 1 while both the synaptic cleft and the postsynaptic neuron are considered as compartment 2 through suggesting three different kinetic mechanisms for the inhibition effect. It is found that the incorporation of ChAT inhibition by β-amyloid aggregates into the 2E2C model is able to yield dynamic solutions for concentrations of generated β-amyloid, ACh, choline, acetate, and pH in addition to the rates of ACh synthesis and ACh hydrolysis in compartments 1 and 2. It is observed that ChAT activity needs a high concentration of β-amyloid aggregates production rate. It is found that ChAT activity is reduced significantly when neurons are exposed to high levels of β-amyloid aggregates leading to reduction in levels of ACh which is one of the most significant physiological symptoms of AD. Furthermore, the system of ACh neurocycle is dominated by the oscillatory behavior when ChAT enzyme is completely inhibited by β-amyloid. It is observed that the direct inactivation of ChAT by β-amyloid aggregates may be a probable mechanism contributing to the development of AD

An improved long short term memory network for intrusion detection

Over the years, intrusion detection system has played a crucial role in network security by discovering attacks from network traffics and generating an alarm signal to be sent to the security team. Machine learning methods, e.g., Support Vector Machine, K Nearest Neighbour, have been used in building intrusion detection systems but such systems still suffer from low accuracy and high false alarm rate. Deep learning models (e.g., Long Short-Term Memory, LSTM) have been employed in designing intrusion detection systems to address this issue. However, LSTM needs a high number of iterations to achieve high performance. In this paper, a novel, and improved version of the Long Short-Term Memory (ILSTM) algorithm was proposed. The ILSTM is based on the novel integration of the chaotic butterfly optimization algorithm (CBOA) and particle swarm optimization (PSO) to improve the accuracy of the LSTM algorithm. The ILSTM was then used to build an efficient intrusion detection system for binary and multi-class classification cases. The proposed algorithm has two phases: phase one involves training a conventional LSTM network to get initial weights, and phase two involves using the hybrid swarm algorithms, CBOA and PSO, to optimize the weights of LSTM to improve the accuracy. The performance of ILSTM and the intrusion detection system were evaluated using two public datasets (NSL-KDD dataset and LITNET-2020) under nine performance metrics. The results showed that the proposed ILSTM algorithm outperformed the original LSTM and other related deep-learning algorithms regarding accuracy and precision. The ILSTM achieved an accuracy of 93.09% and a precision of 96.86% while LSTM gave an accuracy of 82.74% and a precision of 76.49%. Also, the ILSTM performed better than LSTM in both datasets. In addition, the statistical analysis showed that ILSTM is more statistically significant than LSTM. Further, the proposed ISTLM gave better results of multiclassification of intrusion types such as DoS, Prob, and U2R attacks

Poultry Production and Sustainability in Developing Countries under the COVID-19 Crisis: Lessons Learned

Poultry farming is a significant source of revenue generation for small farmers in developing countries. It plays a vital role in fulfilling the daily protein requirements of humans through meat and eggs consumption. The recently emerged pandemic Coronavirus Disease-19 (COVID-19) impacts the poultry production sector. Although the whole world is affected, these impacts may be more severe in developing countries due to their dependency on exporting necessary supplies such as feed, vaccines, drugs, and utensils. In this review, we have discussed poultry production in developing countries under the COVID-19 crisis and measures to regain the loss in the poultry industries. Generally, due to the lockdown, trade limitations have negatively impacted poultry industries, which might exacerbate global poverty. Coordinated activities have to be taken at the private and government levels to arrange soft loans so that these farms can restore their production and marketing to normal levels. In addition, here, we have focused on the supply of farm input, feed, other raw materials, management system, improved breeding efficiency, veterinary services, and marketing of egg and meat, which have to be ensured to secure a sustainable poultry production chain

Diversity of Coronaviruses with Particular Attention to the Interspecies Transmission of SARS-CoV-2

In December 2019, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China with serious impacts on global health and economy that is still ongoing. Although interspecies transmission of coronaviruses is common and well documented, each coronavirus has a narrowly restricted host range. Coronaviruses utilize different receptors to mediate membrane fusion and replication in the cell cytoplasm. The interplay between the receptor-binding domain (RBD) of coronaviruses and their coevolution are determinants for host susceptibility. The recently emerged SARS-CoV-2 caused the coronavirus disease 2019 (COVID-19) pandemic and has also been reported in domestic and wild animals, raising the question about the responsibility of animals in virus evolution. Additionally, the COVID-19 pandemic might also substantially have an impact on animal production for a long time. In the present review, we discussed the diversity of coronaviruses in animals and thus the diversity of their receptors. Moreover, the determinants of the susceptibility of SARS-CoV-2 in several animals, with special reference to the current evidence of SARS-CoV-2 in animals, were highlighted. Finally, we shed light on the urgent demand for the implementation of the One Health concept as a collaborative global approach to mitigate the threat for both humans and animals

Extending the shelf-life of fresh-cut green bean pods by ethanol, ascorbic acid, and essential oils

Green beans are a perishable crop, which deteriorate rapidly after harvest, particularly when minimally processed into ready-to-eat fresh-cut green beans. This study investigated the effectiveness of ethanol, ascorbic acid (AsA), tea tree essential oil (TTO), and peppermint essential oil (PMO) on the quality and storability of fresh-cut green bean pods samples stored at 5 °C for 15 days. Our results indicated that samples treated with ethanol, AsA, TTO, and PMO preserved appearance, firmness (except ethanol), chlorophyll content, and moisture compared with the samples without any treatment (control). Additionally, higher vitamin C, total soluble solids (TSS), total sugars, and total phenolic compounds (TPC) were observed in samples treated with ethanol, AsA, TTO, and PMO compared with the control. The most effective treatments for controlling microbial growth were ethanol followed by either TTO or PMO. All the treatments had positive effects on shelf life, maintained quality, and reducing microbial growth during 15 days of cold storage. A particular treatment can be selected based on the economic feasibility and critical control point in the value chain