Tau truncation in the pathogenesis of Alzheimer's disease:a narrative review

Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein.Recent studies suggest that dysregulation of the microtubuleassociated protein Tau,especially specific proteolysis,could be a driving force for Alzheimer's disease neurodegeneration.Tau physiologically promotes the assembly and stabilization of microtubules,whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers,resulting in them gaining prion-like characteristics.In addition,Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner.This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments,investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease,and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.

Tangling and instability effect analysis of initial in-plane/out-of-plane angles on electrodynamic tether deployment under gravity gradient

The space debris occupies the orbit resources greatly,which seriously threats the safety of spacecraft for its high risks of collisions.Many theories about space debris removal have been put forward in recent years.The Electro Dynamic Tether(EDT),which can be deployed under gravity gradient,is considered to be an effective method to remove debris in low orbit for its low power consumption.However,in order to generate sufficient Lorentz force,the EDT needs to be deployed to several kilometers,which increases the risks of tangling and the instability of the EDT system.In the deployment process,different initial in-plane/out-of-plane angles,caused by direction error at initial release or the initial selection of ejection,affect the motion of EDT system seriously.In order to solve these problems,firstly,this paper establishes the dynamic model of the EDT system.Then,based on the model,safety metrics of avoiding tangling and assessing system stability during EDT deployment stage are designed to quantitatively evaluate the EDT system security.Finally,several numerical simulations are established to determine the safety ranges of the initial in-plane/out-of-plane angles on the EDT deployment.

A blockchain-empowered authentication scheme for worm detection in wireless sensor network

Wireless Sensor Network(WSN)is a distributed sensor network composed a large number of nodes with low cost,low performance and self-management.The special structure of WSN brings both convenience and vulnerability.For example,a malicious participant can launch attacks by capturing a physical device.Therefore,node authentication that can resist malicious attacks is very important to network security.Recently,blockchain technology has shown the potential to enhance the security of the Internet of Things(IoT).In this paper,we propose a Blockchain-empowered Authentication Scheme(BAS)for WSN.In our scheme,all nodes are managed by utilizing the identity information stored on the blockchain.Besides,the simulation experiment about worm detection is executed on BAS,and the security is evaluated from detection and infection rate.The experiment results indicate that the proposed scheme can effectively inhibit the spread and infection of worms in the network.

基于Tangle网络的移动群智感知数据安全交付模型

针对现有群智感知平台在数据和酬金交付过程中存在的安全风险和隐私泄露问题,该文提出一种基于Tangle网络的分布式群智感知数据安全交付模型。首先,在数据感知阶段,调用局部异常因子检测算法剔除异常数据,聚类获取感知数据并确定可信参与者节点。然后,在交易写入阶段,使用马尔科夫蒙特卡洛算法选择交易并验证其合法性,通过注册认证中心登记完成匿名身份数据上传,并将交易同步写入分布式账本。最后,结合Tangle网络的累计权重共识机制,当交易安全性达到阈值时,任务发布者可进行数据和酬金的安全交付。仿真试验表明,在模型保护用户隐私的同时,增强了数据和酬金的安全交付能力,相比现有感知平台降低了时间复杂度和任务发布成本。

基于Tangle网络的群智感知用户可信激励方法

随着群智感知技术的广泛应用,用户参与度成为影响群智感知技术发展的关键问题,提出一种基于Tangle网络的群智感知用户可信激励方法.首先,基于Tangle网络构建群智感知网络模型,通过去中心化的Tangle网络来克服群智感知平台面临可信第三方参与的安全隐患,制定Tangle网络的可信度标准.然后,通过可信度来衡量用户权重,借此来评估交易的可信性,将感知任务分配给更可信的用户.最后,对用户上传的感知数据使用蒙特卡洛最大期望算法量化用户的工作量,支付相应报酬.通过基于真实数据集的仿真实验表明,所提方法能有效激励用户参与感知任务,同RSFP方法和CSII方法相比,所提方法在用户参与度上分别提升了0.379和0.067.

Potential therapeutic roles of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease

All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to activate specific signaling pathways in the cells. Retinoic acid signaling is extremely important in the central nervous system. Impairment of retinoic acid signaling pathways causes severe pathological processes in the central nervous system, especially in the adult brain. Retinoids have major roles in neural patterning, differentiation, axon outgrowth in normal development, and function of the brain. Impaired retinoic acid signaling results in neuroinflammation, oxidative stress, mitochondrial malfunction, and neurodegeneration leading to progressive Alzheimer’s disease, which is pathologically characterized by extra-neuronal accumulation of amyloid plaques(aggregated amyloid-beta) and intra-neurofibrillary tangles(hyperphosphorylated tau protein) in the temporal lobe of the brain. Alzheimer’s disease is the most common cause of dementia and loss of memory in old adults. Inactive cholinergic neurotransmission is responsible for cognitive deficits in Alzheimer’s disease patients. Deficiency or deprivation of retinoic acid in mice is associated with loss of spatial learning and memory. Retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer’s disease. Stimulation of retinoic acid receptors and retinoid X receptors slows down accumulation of amyloids, reduces neurodegeneration, and thereby prevents pathogenesis of Alzheimer’s disease in mice. In this review, we described chemistry and biochemistry of some natural and synthetic retinoids and potentials of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease.

Toxic tau: structural origins of tau aggregation in Alzheimer’s disease

Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.

Tibolone modulates neuronal plasticity through regulating Tau, GSK3β/Akt/PI3K pathway and CDK5 p35/p25 complexes in the hippocampus of aged male mice

Aging is a key risk factor for cognitive decline and age-related neurodegenerative disorders. Also, an age-related decrease in sex steroid hormones may have a negative impact on the formation of neurofibrillary tangles （NFTs）; these hormones can regulate Tau phosphorylation and the principal kinase GSK3β involved in this process. Hormone replacement therapy decreases NFTs, but it increases the risk of some types of cancer. However, other synthetic hormones such as tibolone （TIB） have been used for hormone replacement therapy. The aim of this work was to evaluate the long-term effects of TIB （0.01 mg/kg and 1mg/kg, intragastrically for 12 weeks） on the content of total and hyperphosphorylated Tau （PHF-1） proteins and the regulation of GSK3β/Akt/PI3K pathway and CDK5/p35/p25 complexes in the hippocampus of aged male mice. We observed that the content of PHF-1 decreased with TIB administration. In contrast, no changes were observed in the active form of GSK3β or PI3K. TIB decreased the expression of the total and phosphorylated form of Akt while increased that of p110 and p85. The content of CDK5 was differentially modified with TIB： it was increased at low doses and decreased at high doses. When we analyzed the content of CDK5 activators, an increase was found on p35; however, the content of p25 decreased with administration of low dose of TIB. Our results suggest a possible mechanism of action of TIB in the hippocampus of aged male mice. Through the regulation of Tau and GSK3β/Akt/PI3K pathway, and CDK5/p35/p25 complexes, TIB may modulate neuronal plasticity and regulate learning and memory processes.

Hydrogen-rich water ameliorates neuropathological impairments in a mouse model of Alzheimer's disease through reducing neuroinflammation and modulating intestinal microbiota

Hydrogen exhibits the potential to treat Alzheimer's disease. Stereotactic injection has been previously used as an invasive method of administering active hydrogen, but this method has limitations in clinical practice. In this study, triple transgenic(3×Tg) Alzheimer's disease mice were treated with hydrogen-rich water for 7 months. The results showed that hydrogen-rich water prevented synaptic loss and neuronal death, inhibited senile plaques, and reduced hyperphosphorylated tau and neurofibrillary tangles in 3×Tg Alzheimer's disease mice. In addition, hydrogen-rich water improved brain energy metabolism disorders and intestinal flora imbalances and reduced inflammatory reactions. These findings suggest that hydrogen-rich water is an effective hydrogen donor that can treat Alzheimer's disease. This study was approved by the Animal Ethics and Welfare Committee of Shenzhen University, China(approval No. AEWC-20140615-002) on June 15, 2014.

MicroRNA and mRNA profiling of cerebral cortex in a transgenic mouse model of Alzheimer’s disease by RNA sequencing

In a previous study,we found that long non-coding genes in Alzheimer’s disease(AD)are a result of endogenous gene disorders caused by the recruitment of microRNA(miRNA)and mRNA,and that miR-200a-3p and other representative miRNAs can mediate cognitive impairment and thus serve as new biomarkers for AD.In this study,we investigated the abnormal expression of miRNA and mRNA and the pathogenesis of AD at the epigenetic level.To this aim,we performed RNA sequencing and an integrative analysis of the cerebral cortex of the widely used amyloid precursor protein and presenilin-1 double transgenic mouse model of AD.Overall,129 mRNAs and 68 miRNAs were aberrantly expressed.Among these,eight down-regulated miRNAs and seven up-regulated miRNAs appeared as promising noninvasive biomarkers and therapeutic targets.The main enriched signaling pathways involved mitogen-activated kinase protein,phosphatidylinositol 3-kinase-protein kinase B,mechanistic target of rapamycin kinase,forkhead box O,and autophagy.An miRNA-mRNA network between dysregulated miRNAs and corresponding target genes connected with AD progression was also constructed.These miRNAs and mRNAs are potential biomarkers and therapeutic targets for new treatment strategies,early diagnosis,and prevention of AD.The present results provide a novel perspective on the role of miRNAs and mRNAs in AD.This study was approved by the Experimental Animal Care and Use Committee of Institute of Medicinal Biotechnology of Beijing,China(approval No.IMB-201909-D6)on September 6,2019.

任意维数两体量子态的Tangle

利用任意维数两体量子态密度矩阵的concurrence判据、著名的Peres-Horodecki判据及重排判据之间的重要联系,来获得纠缠量tangle(即I-concurrence)的两个解析下界.

Neurofibrillary tangles in Alzheimer＇s disease： elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics

As a key contributor to memory storage, the synapse is one of the earliest affected neuronal components in Alzheimer＇s disease （AD）. Under physiological conditions, the synaptic con- nections between neurons undergo activity-dependent func- tional and morphological re-organisation. This dynamic, ＇plastic＇ neural ability critically depends on the structural integrity of the synapse. Thus, proteins that are implicated in preserving the organisation and dynamics of synaptic connections, including microtubules of the cytoskeleton and associated proteins, have attracted much focus for their involvement in the malfunction- ing AD synapse.

Therapeutic targets and delivery challenges for Alzheimer's disease

Dementia, including Alzheimer’s disease, the 21^st Century epidemic, is one of the most signifcant social and health crises which has currently afficted nearly 44 million patients worldwide and about new 7.7 million cases are reported every year. This portrays the unmet need towards better understanding of Alzheimer’s disease pathomechanisms and related research towards more effective treatment strategies. The review thus comprehensively addresses Alzheimer’s disease pathophysiology with an insight of underlying multicascade pathway and elaborates possible therapeutic targets- particularly anti-amyloid approaches, anti-tau approaches, acetylcholinesterase inhibitors, glutamatergic system modifiers, immunotherapy, anti-nflammatory targets, antioxidants, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors and insulin. In spite of extensive research leading to identification of newer targets and potent drugs, complete cure of Alzheimer’s disease appears to be an unreached holy grail. This can be attributed to their ineffective delivery across blood brain barrier and ultimately to the brain. With this understanding, researchers are now focusing on development of drug delivery systems to be delivered via suitable route that can circumvent blood brain barrier effectively with enhanced patient compliance. In this context, we have summarized current drug delivery strategies by oral, transdermal, intravenous, intranasal and other miscellaneous routes and have accentuated the future standpoint towards promising therapy ultimately eading to Alzheimer’s disease cure.

This Tangled Web

OH! What a tangled web we weave when fir st practise to deceive!" So said Sir Walter Scott in his epic poem Marmion, published in 1808. Of course, he could never have imagined the

Monogamous nature of symmetric N-qubit states of the W class: Concurrence and negativity tangle

Using Majorana representation of symmetric N-qubit pure states, we have examined the monogamous nature of the family of states with two-distinct spinors, the W class of states. We have evaluated the N-concurrence tangle and showed that all the states in this family have vanishing concurrence tangle. The negativity tangle for the W class of states is shown to be non-zero, illustrating the fact that the concurrence tangle is always lesser than or equal to the negativity tangle in a pure N-qubit state.

Role of glycogen synathese kinase-3β in Alzheimer-like neurodegeneration

Hyperphosphorylated tau in the form of paired helical filament is the major protein component of neurofibrillary tangle,which is positively correlated with the degree of dementia in patients with Alzheimer disease(AD),the most common cause of dementia in the elderly.Activation of protein kinases or/and inhibition of protein phosphatases is responsible for tau hyperphosphorylation.Among various kinases,glycogen

A Unified Model of All Generalizations from the Jones Polynomial

From the basic properties of skein systems, we build a generalized tangle algebra (GTA). The elements of GTA are four basic tangles. There are three operations, which are connection, splicing and scalar multiplication. From GTA we derive two generalized recursion formulae (GRF) and prove the existence of a generalized skein relation which satisfies GRF. The obtained generalized skein relation epitomizes all generalizations from the Jones polynomial and thus forms a unified model. Two important topological parameters, twisting measure and loop values, appear explicitly in the expressions of the unified model, and this fact greatly simplifies the operations.

Plastic Deformation in Quench-and 650℃ Tempered Steel

The variations of the dislocation structures in the quench and 650℃ tempered steel with increase of elongations have been investigated by using transmission electron microscopy. In the small elongation stage, the boundaries between ferrite and carbide in this steel can release dislocations. As the elongations increase, the moving dislocations in the ferrite slip onto the carbides. Then, the interaction between moving dislocations and dislocations released from this boundaries, and the interaction between the dislocations moving to the carbides in every slip plane occurs. Thereby, the dislocation tangles around the carbides can be formed. In the large elongation stage, the dislocation tangles with high dislocation density and the developed dislocation cells are formed.

Forensic Pathological Expertise of Medical Tangle Analysis of 139 Autopsy Cases

In this article , we report 139 autopsy cases of medical tangle , which were examined by the Department of Forensic Pathology, Faculty of Medicine, Tongji Medical University from Jan. 1972 to Dec. 1992.The emphasis is put on analyses of the status of medical tangle autopsy in forensic pathology, involved medical departments , distribution of victim's age and sex , differences between clinical diagnosis and autoptical conclusion, the composition and causes of medical tangle. The associated problems in forensic pathological autopsy are also discussed.

The fractal structure in the ionization dynamics of Rydberg lithium atoms in a static electric field

The ionization rate of Rydberg lithium atoms in a static electric field is examined within semiclassical theory which involves scattering effects off the core. By semiclassical analysis, this ionization process can be considered as the promoted valence electrons escaping through the Stark saddle point into the ionization channels. The resulting escape spectrum of the ejected electrons demonstrates a remarkable irregular electron pulse train in time-dependence and a complicated nesting structure with respect to the initial launching angles. Based on the Poincaré} map and homoclinic tangle approach, the chaotic behaviour along with its corresponding fractal self-similar structure of the ionization spectra are analysed in detail. Our work is significant for understanding the quantum-classical correspondence.