Structural Analysis of Tunnel using FEA

Tunnels are typically built for transportation, such as roads, railways, or canals, but they can also be used for other purposes, such as mining, sewerage, or water supply. Tunnels allow us to travel safely and efficiently through difficult terrain, and they provide us with access to essential resources such as water and energy. The objective of current research is to evaluate the structural characteristics of tunnel structure under geo-mechanical loading conditions. The structural analysis of tunnel is conducted using techniques of FEA. The CAD modelling and FEA simulation of tunnel is conducted using ANSYS simulation package. The shear stress, normal stress and deformation data are generated. From the generated data, the critical regions are identified and the lateral zone of tunnel is one of them. This region is likely to induce damage in the form of crack

Regulation of Proteins Implicated in Alzheimer’s Disease by MicroRNAs

poster abstractAlzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the deposition of Amyloid-Beta (Aβ) peptide in the brain. This toxic peptide is generated by the sequential cleavage of Amyloid Precursor Protein (APP) by Beta-site APP-cleaving enzyme-1 (BACE-1) and γ-secretase. The disorder is also characterized by the perturbation of calcium homeostasis in neurons. MicroRNAs are short, single-stranded RNAs that are able to influence protein expression by targeting the 3’ Untranslated region (UTR) or 5’ UTR of mRNAs. Previous work in our laboratory has shown that miR-101, miR-153 and miR-346 can regulate APP whereas miR-339-5p can lower BACE1 expression. Here, we aim to reduce APP, BACE1 and Aβ levels, in vitro, by the addition of microRNAs that target the 3’ UTR of APP and BACE1. We show that in a human astrocytoma-glioblastoma (U373) cell line, the expression of BACE1 protein is significantly reduced compared to the mock condition upon transfecting miR-298, miR-328 and miR-144. miR-298 also reduces Aβ levels in these cells. Similarly, in HeLa cells, we show that miR-520c, miR-20b and miR-144 produce a reduction in APP expression compared to both mock and a negative control microRNA mimic. Additionally, we observed that knocking down APP using siRNA, but not knocking down BACE1, lowers basal intracellular calcium levels as well as changes the kinetics of Potassium Chloride (KCl)-induced intracellular calcium influx in a human fetal brain (HFB) culture, when compared to control. miR-346 increases basal calcium levels, but does not affect KCl-induced calcium transients in our HFB culture. Taken together, these results show that miRNAs can influence both the protein expression as well as calcium homeostasis in different human cell culture models. By reducing levels of proteins implicated in AD pathology and by reversing calcium dysregulation, our results will benefit AD research and generate possibilities for novel therapeutics

Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease

Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent

Rivastigmine Modifies the α-Secretase Pathway and Potentially Early Alzheimer\u27s Disease

Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer’s disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases– Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the non-amyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD

Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

BACKGROUND: Dysregulation of extracellular signal-related kinase (ERK) activity has been potentially implicated in the pathophysiology of autistic disorder (autism). ERK is part of a central intracellular signaling cascade responsible for a myriad of cellular functions. ERK is expressed in peripheral blood lymphocytes, and measurement of activated (phosphorylated) lymphocytic ERK is commonly executed in many areas of medicine. We sought to conduct the first study of ERK activation in humans with autism by utilizing a lymphocytic ERK activation assay. We hypothesized that ERK activation would be enhanced in peripheral blood lymphocytes from persons with autism compared to those of neurotypical control subjects. METHOD: We conducted an initial study of peripheral lymphocyte ERK activation in 45 subjects with autism and 26 age- and gender-matched control subjects (total n = 71). ERK activation was measured using a lymphocyte counting method (primary outcome expressed as lymphocytes staining positive for cytosolic phosphorylated ERK divided by total cells counted) and additional Western blot analysis of whole cell phosphorylated ERK adjusted for total ERK present in the lymphocyte lysate sample. RESULTS: Cytosolic/nuclear localization of pERK activated cells were increased by almost two-fold in the autism subject group compared to matched neurotypical control subjects (cell count ratio of 0.064 ± 0.044 versus 0.034 ± 0.031; p = 0.002). Elevated phosphorylated ERK levels in whole cell lysates also showed increased activated ERK in the autism group compared to controls (n = 54 total) in Western blot analysis. CONCLUSIONS: The results of this first in human ERK activation study are consistent with enhanced peripheral lymphocytic ERK activation in autism, as well as suggesting that cellular compartmentalization of activated ERK may be altered in this disorder. Future work will be required to explore the impact of concomitant medication use and other subject characteristics such as level of cognitive functioning on ERK activation

Security and Privacy in AI-Driven Industry 5.0: Experimental Insights and Threat Analysis

This empirical research offers important insights from simulated industrial situations as it examines security and privacy in AI-driven Industry 5.0. When responding to security problems, participants' remarkable average reaction time of 14 minutes demonstrated their preparedness. On a 5-point rating scale, the clarity and openness of privacy rules were scored 3.8 overall; however, differences between 3.5 and 4.2 indicated the range of privacy issues. These results highlight the need of well-defined security procedures, thorough training, and easily available, transparent privacy regulations in order to manage the ethical integration of AI into Industry 5.0 and promote stakeholder confidence and data protection

AI Evolution in Industry 4.0 and Industry 5.0: An Experimental Comparative Assessment

This paper provides a thorough analysis of the development of artificial intelligence (AI) in the context of Industry 4.0 and the soon-to-be Industry 5.0. Important conclusions come from the data, such as the startling 900% increase in AI applications between 2010 and 2018, which corresponds to a 60% rise in the proportion of industrial enterprises using AI at that time. Moreover, our analysis shows that Industry 4.0's AI integration has resulted in a notable 200% cost reduction and a cumulative 400% boost in production efficiency. Our study delves into the rapid deployment of critical technologies like 5G connectivity and quantum computing within the framework of Industry 5.0. The usage of 5G connectivity has increased by 200% in only two years, while quantum computing has seen a staggering 1000% growth in acceptance over the course of eight years. These findings demonstrate the fast technological transition occurring in Industry 5.0. Furthermore, by 2033, the research predicts a startling 400% increase in human-machine cooperation and an anticipated 133% decrease in mistake rates. The research highlights how Industry 4.0's deep consequences of AI development and Industry 5.0's revolutionary possibilities will impact manufacturing in the future

Impact of acamprosate on plasma amyloid-β precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker

BACKGROUND: Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-β precursor protein (APP), secreted APPα (sAPPα), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPα holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPPα function. METHODS: Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS)-associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. RESULTS: Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPPα levels but no change occurred in Aβ40 or Aβ42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPPα processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). CONCLUSIONS: Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPPα may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission

Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their inhibition of amyloid precursor protein, α-Synuclein synthesis, interleukin-1β release, and cholinergic action

A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques that are primarily composed of aggregated forms of β-amyloid peptide (Aβ) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Aβ levels by lowering the rate of APP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its three major metabolic products, (+)-N1-norPosiphen (15), (+)-N8-norPosiphen (17) and (+)-N1, N8-bisnorPosiphen (11), were required in high chemical and optical purity. The efficient transformation of Posiphen (1) into these metabolic products, 15, 17 and 11, is described. The biological activity of these metabolites together with Posiphen (1) and its enantiomer, the AD drug candidate (-)-phenserine (2), was assessed against APP,α-synuclein and classical cholinergic targets. All the compounds potently inhibited the generation of APP and α-synuclein in neuronal cultures. In contrast, metabolites 11 and 15, and (-)-phenserine (2) but not Posiphen (1) or 17, possessed acetyl cholinesterase inhibitory action and no compounds bound either nicotinic or muscarinic receptors. As Posiphen (1) lowered CSF markers of inflammation in a recent clinical trial, the actions of 1 and 2 on proinflammatory cytokine interleukin (IL)-1β release human peripheral blood mononuclear cells was evaluated, and found to be potently inhibited by both agents

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer's disease

Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer’s disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases– Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the non-amyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD