Apoptosis in health and disease and modulation of apoptosis for therapy: An overview

Apoptosis a physiological mechanism that eliminates excessive, damaged or unwanted cells, is a highly regulated pathway important for maintaining homeostasis in multicellular organisms. It can be initiated through various signals via the extrinsic pathway which involves death receptors, or via the intrinsic pathway which is initiated by intracellular damage and involves the mitochondria and release of cytochrome c from it to further activate caspases. The Bcl-2 family of proteins is situated upstream to the irreversible damage of cellular constituents and is an important checkpoint in the fate of a cell. The pro-apoptotic members, BH3 only members include BID, BAD and BIM. They directly or indirectly activate multidomain BAX/BAK that constitute the requisite gateway to the intrinsic pathway which operates at the mitochondrial surface and endoplasmic reticulum. In contrast, antiapoptotic members such as Bcl-2, Bcl-XL bind and sequester activation. Downstream of mitochondria, the apoptosome involvement is seen to generate caspase activity. Post mitochondria regulation involves IAPs, and their inhibitors. The pathogenesis of several diseases such as cancer, neurodegenerative disorders, autoimmune disorders, heart disease, infectious diseases including AIDS is closely related to aberrant apoptosis. Consequently interest has emerged in employing various the rapeutic approaches such as gene therapy, antisense therapy, recombinant biologicals, organic and combinatorial chemistry, to specifically target apoptosis signaling pathways such as death receptors FAS/TRAIL, Bcl-2, p53, IAPs, SMAC and caspases, etc. and are now advancing from preclinical to clinical phase.     

Adenosine and its role in asthma

Endogenous adenosine formed from ADP and AMP by the action of ATPase and 5′-nucleotidase is known to cause bronchoconstriction and asthma in humans. It has been suggested that this action of adenosine is due to its binding to specific purino receptors in the mast cells in the lungs and consequent release of mediators which elicit bronchoconstriction and asthma. The release of these mediators leading to asthma was also believed to be due to vagal stimulation by adenosine. Though the role of adenosine in causing bronchoconstriction leading to asthma is well confirmed the actual mode of action and details of the mechanisms involved in the clinical manifestation of asthma remain unclear.     

Protective effect of CD73 inhibitor α, β-methylene ADP against amyloid-β-induced cognitive impairment by inhibiting adenosine production in hippocampus

BackgroundAlzheimer's disease (AD) is a chronic, progressive neurodegenerative disease. Recent studies have reported the close association between cognitive function in AD and purinergic receptors in the central nervous system. In the current study, we investigated the effect of CD73 inhibitor α, β-methylene ADP (APCP) on cognitive impairment of AD in mice, and to explore the potential underlying mechanisms.ResultsWe found that acute administration of Aβ_1–42 (i.c.v.) resulted in a significant increase in adenosine release by using microdialysis study. Chronic administration of APCP (10, 30 mg/kg) for 20 d obviously mitigated the spatial working memory impairment of Aβ_1–42-treated mice in both Morris water maze (MWM) test and Y-maze test. In addition, the extracellular adenosine production in the hippocampus was inhibited by APCP in Aβ-treated mice. Further analyses indicated expression of acetyltransferase (ChAT) in hippocampus of mice of was significantly reduced, while acetylcholinesterase (AChE) expression increased, which compared to model group. We observed that APCP did not significantly alter the NLRP3 inflammasome activity in hippocampus, indicating that anti-central inflammation seems not to be involved in APCP effect.ConclusionsIn conclusion, we report for the first time that inhibition of CD73 by APCP was able to protect against memory loss induced by Aβ_1–42 in mice, which may be due to the decrease of CD73-driven adenosine production in hippocampus. Enhancement of central cholinergic function of the central nervous system may also be involved in the effects of APCP.How to cite: Song W, Tang Y, Wei L, et al. Protective effect of CD73 inhibitor α, β-methylene ADP against amyloid-β-Induced cognitive impairment by inhibiting adenosine production in hippocampus. Electron J Biotechnol 2020;48. https://doi.org/10.1016/j.ejbt.2020.09.002     

Adenosine deaminase and protein tyrosine phosphatase activities in liver and peritoneal macrophages of streptozotocin induced diabetic mice

Adenosine deaminase and protein tyrosine phosphatase activities in liver and peritoneal macrophages were estimated in control, streptozotocin induced diabetes and insulin treated diabetic groups of Swiss albino mice. Both the enzyme levels were elevated while glycogen content decreased in the liver of diabetic group of animals as compared to controls, while in insulin treated group, they were comparable to control levels. In macrophages also, both adenosine deaminase which plays an important role in their maturation and protein tyrosine phosphatase enzyme involved in their activation were high in diabetic group, whereas in insulin treated diabetic group, the values were comparable to control levels. *** DIRECT SUPPORT *** A00FN011 00003     

Convexity of the Energy Domain

A basic theorem describing the convexity of the energy domain for the general family of linear time-invariant (active or passive, reciprocal or non-reciprocal, lumped or distributed, single variable or multivariable) physical system {T} is proved.Theorem: Let F = P + jQ represent the complex energy associated with any linear physical system T (n-port). For any specified excitation of frequency s and the family of constant energy content input signals {i:∥i∥= constant}, the point F describes a convex domain in the {P;Q} plane.Part I contains a mathematical and a network theoretic proof of the foregoing theorem. In Part II the geometric nature of the energy loci for the two-ports is examined. It is shown that for all two-ports with double eigenvalves the energy domain is circular. For two-ports with distinct eigenvalves, the convex energy domain is an ellipse. The geometric characterization of this elliptic domain is examined and examples verified by computer.The concept of convexity is frequently exploited in optimization of energy in electric power system and quadratic cost functions in control theory. In this respect the central theorem of this paper, its proof and geometric ramifications should prove to be of basic interest for all linear systems.     

Neuroses of the stomach: eating, gender, and psychopathology in French medicine, 1800-1870

In the period 1800-1870, French physicians approached psychic illness (Philippe Pinel's "neurosis") within competing "cerebralist" and "visceralist" frameworks. Cerebralism, which dominated the specialty of mental medicine, sought the origins of psychic illness in lesions of the brain and central nervous system. "Visceralism," upheld by generalists, clung to the view of the ancients that psychic disorder was seated in the abdominal viscera. The distinction enjoyed credibility thanks to widespread acceptance of Xavier Bichat's "two lives" doctrine, which demarcated functions of the central and the "vegetative" nervous systems. Once the "two lives" conception was undercut after midcentury, cerebralists sought to draw disturbances of appetite, digestion, and eating within the domain of the central nervous system. This essay suggests that historical study of "hysterical anorexia" and related disease entities that displaced "neuroses of the stomach" has overemphasized sociocultural determinants to the neglect of the internal dynamics of biomedical science.     

Interaction of LDL and platelets in ischaemic and ischaemic risk subjects

Platelets play a vital role in the progression of atherosclerosis and thrombosis, a major cause of death worldwide. Platelets are activated by many triggers like elevated LDL in blood resulting in aggregation and formation of plaque. The purpose of this study was to investigate the effect of LDL and signal transduction inhibitor on the activation of platelets in Ischaemic risk subjects. Platelets from IHD and hyperlipidemic subjects were hypersensitive to ADP, as higher levels of platelet aggregation were observed in these groups. LDL from IHD hyperlipidemic subjects was more effective in activating platelets from any other group. Ox-LDL was more effective in activating platelets than native-LDL as monitored by level of platelet aggregation induced by PAF and thrombin. Calcium channel blocker, nifedipine and verapamil inhibited platelet aggregation at micromolar level. Protein kinase inhibitor, staurosporine was effective in inhibiting ADP induced aggregation at nanomolar level.     

Sequential Profiling of Anti-SARS CoV-2 IgG Antibody in Post COVID-19 Patients

Upon SARS CoV-2 infection, humoral immune system triggers production of anti-SARS CoV-2 IgM and IgG antibodies. Currently, antibodies against SARS CoV-2 spike protein receptor binding domain play a central role in disease protection, making them potential target for in vitro diagnostics applications. This study determines the expression level and sustainability of anti-receptor binding domain (RBD) SARS CoV-2 IgG in post COVID-19 patients. Anti-RBD SARS CoV-2 IgG antibodies in patient serum were analysed by standardised indirect ELISA using SARS CoV-2 spike receptor binding domain protein and HRP conjugated anti-human IgG antibody (anti-h IgG). The study was conducted using 35 adult patient samples with confirmed SARS CoV-2 infection. Additionally, correlation between antibody response after each stage and disease symptoms in post COVID-19 patients were studied. Maximum antibody titre was seen at Day 40 and decreased relatively to Day 180 in antibody positive samples when compared with controls. Overall, more IgG antibody expression is observed in patients who suffered from loss of smell and taste at Day 40. 71% of the positive subjects in this study showed high SARS CoV-2 IgG antibody concentration of above 10 ng/mL and 37% showed strong antibody concentration above 20 ng/mL at the peak of seroconversion.     

A generic construct based workload model for web search

Benchmarks are vital tools in the performance measurement, evaluation, and comparison of computer hardware and software systems. Standard benchmarks such as the TREC, TPC, SPEC, SAP, Oracle, Microsoft, IBM, Wisconsin, AS³AP, OO1, OO7, XOO7 benchmarks have been used to assess the system performance. These benchmarks are domain-specific and domain-dependent in that they model typical applications and tie to a problem domain. Test results from these benchmarks are estimates of possible system performance for certain pre-determined problem types. When the user domain differs from the standard problem domain or when the application workload is divergent from the standard workload, they do not provide an accurate way to measure the system performance of the user problem domain. System performance of the actual problem domain in terms of data and transactions may vary significantly from the standard benchmarks.In this research, we address the issue of generalization and precision of benchmark workload model for web search technology. The current performance measurement and evaluation method suffers from the rough estimate of system performance which varies widely when the problem domain changes. The performance results provided by the vendors cannot be reproduced nor reused in the real users’ environment. Hence, in this research, we tackle the issue of domain boundness and workload boundness which represents the root of the problem of imprecise, ir-representative, and ir-reproducible performance results. We address the issue by presenting a domain-independent and workload-independent workload model benchmark method which is developed from the perspective of the user requirements and generic constructs. We present a user-driven workload model to develop a benchmark in a process of workload requirements representation, transformation, and generation via the common carrier of generic constructs. We aim to create a more generalized and precise evaluation method which derives test suites from the actual user domain and application setting.The workload model benchmark method comprises three main components. They are a high-level workload specification scheme, a translator of the scheme, and a set of generators to generate the test database and the test suite. They are based on the generic constructs. The specification scheme is used to formalize the workload requirements. The translator is used to transform the specification. The generator is used to produce the test database and the test workload. We determine the generic constructs via the analysis of search methods. The generic constructs form a page model, a query model, and a control model in the workload model development. The page model describes the web page structure. The query model defines the logics to query the web. The control model defines the control variables to set up the experiments.In this study, we have conducted ten baseline research experiments to validate the feasibility and validity of the benchmark method. An experimental prototype is built to execute these experiments. Experimental results demonstrate that the method based on generic constructs and driven by the perspective of user requirements is capable of modeling the standard benchmarks as well as more general benchmark requirements.     

超嗜热菌Aquifex aeolicus 亮氨酰-tRNA 合成酶和tRNALeu的相互作用（英文）

超嗜热菌Aquifex aeolicus 亮氨酰-tRNA 合成酶(αβ-LeuRS) 是已知的唯一的双肽链LeuRS。通过αβ-LeuRS和大肠杆菌LeuRS相应肽段的重组和重组酶性质的研究发现，αβ-LeuRS的α亚基C末端36个氨基酸对于αβ-LeuRS的氨基酰化活力至关重要。αβ-LeuRS的两个亚基人为融合得到的单亚基酶SLeuRS-αβ，具有完全的野生型双亚基酶活力，其热稳定性显著增强。同时，通过亚基重组揭示了LeuRS 对于不同种属的tRNALeu的识别元件位于α亚基内，而其中的CP1 结构域不仅是LeuRS 行使编校功能的结构基础，对于LeuRS识别不同种属来源的tRNALeu 也是十分重要的。通过不同来源的LeuRS一级结构比较，克隆了单独的CP1结构域组成的肽(CP1),发现唯有A. aeolicus　αβ-LeuRS 的CP1对错误的氨基酰化产物具有体外编校功能。它与其它3种来源于细菌LeuRS的CP1都能够编校误氨基酰化的古老形式的亮氨酸小螺旋 (minihelixLeu)。通过同源序列比较发现，在αβ-LeuRS的CP1内存在一个由20个氨基酸组成的特异的结构模体，它对CP1发挥体外编校功能必不可少，引入原本不具有体外编校功能的E. coli的CP1 后则可使其获得编校功能，但是该模体不影响全酶的编校功能。αβ-LeuRS中与tRNA结合有关的亚基－β亚基也可以赋予E. coli CP1编校功能。这些研究结果充分表明，来源于古老的超嗜热菌A. aeolicus 的αβ-LeuRS 保留了进化的遗迹－具有编校活力的CP1和与其编校功能密切相关的由20个氨基酸组成的特异的结构模体，它们在进化过程中随着其它结构域招募进合成酶中而逐渐失去了对全酶编校功能的作用。这一发现有力地支持了aaRS通过纳入新的结构域以加速进化过程的理论，并且也从不同角度为aaRS/tRNA共进化理论提供了可靠的依据。     

Spacecraft output feedback attitude control based on extended state observer and adaptive dynamic programming

This paper investigates spacecraft output feedback attitude control problem based on extended state observer (ESO) and adaptive dynamic programming (ADP) approach. For the plant described by the unit quaternion, an ESO is first presented in view of the property of the attitude motion, and the norm constraint on the unit quaternion can be satisfied theoretically. The practical convergence proof of the developed ESO is illustrated by change of coordinates. Then, the controller is designed with an involvement of two parts: the basic part and the supplementary part. For the basic part, a proportional-derivative control law is designed. For the supplementary part, an ADP method called action-dependent heuristic dynamic programming (ADHDP) is adopted, which provides a supplementary control action according to the differences between the actual and the desired system signals. Simulation studies validate the effectiveness of the proposed scheme.     

Data-driven optimal tracking control for discrete-time systems with delays using adaptive dynamic programming

In this paper, the data-driven adaptive dynamic programming (ADP) algorithm is proposed to deal with the optimal tracking problem for the general discrete-time (DT) systems with delays for the first time. The model-free ADP algorithm is presented by using only the system’s input, output and the reference trajectory of the finite steps of historical data. First, the augmented state equation is constructed based on the time-delay system and the reference system. Second, a novel data-driven state equation is derived by virtue of the history data composed of input, output and reference trajectory, which is considered as a state estimator.Then, a novel data-driven Bellman equation for the linear quadratic tracking (LQT) problem with delays is deduced. Finally, the data-driven ADP algorithm is designed to solve the LQT problem with delays and does not require any system dynamics. The simulation result demonstrates the validity of the proposed data-driven ADP algorithm in this paper for the LQT problem with delays.     

高效液相色谱法检测细胞能量代谢物质的方法建立与应用

建立高效液相色谱法(HPLC)测定细胞中ATP、ADP和AMP含量的方法,以比较高糖培养的MRC-5细胞和D-半乳糖诱导的拟衰老MRC-5细胞能量代谢水平。体外培养的细胞经高氯酸裂解后,用反向HPLC法检测两组细胞ATP、ADP和AMP的含量。HPLC系统采用Ecosil C18反相柱(4.6*250mm 5μm pH 2～8),流动相为15mM磷酸二氢钾缓冲液和10%甲醇,流速0.5mL/min,紫外检测波长为254nm;检测温度为25℃,进样量20μL。以标准曲线法计算ATP、ADP和AMP含量,并计算腺苷酸能荷(EC)。结果显示拟衰老细胞的ATP含量及EC较对照组显著降低,而AMP含量明显升高,差异具有统计学意义(p<0.05),但两组之间的ADP含量没有明显差别。结果表明高效液相色谱法可检测出不同状态细胞能量物质的差异,其具有操作简便、快速、重现性好等特点,可以作为线粒体能量代谢功能的评估方法之一。     

Data-driven adaptive optimal control of linear uncertain systems with unknown jumping dynamics

This paper focuses on the optimal control of a DC torque motor servo system which represents a class of continuous-time linear uncertain systems with unknown jumping internal dynamics. A data-driven adaptive optimal control strategy based on the integration of adaptive dynamic programming (ADP) and switching control is presented to minimize a predefined cost function. This takes the first step to develop switching ADP methods and extend the application of ADP to time-varying systems. Moreover, an analytical method to give the initial stabilizing controller for policy iteration ADP is proposed. It is shown that under the proposed adaptive optimal control law, the closed-loop switched system is asymptotically stable at the origin. The effectiveness of the strategy is validated via simulations on the DC motor system model.     

Backstepping-based adaptive dynamic programming for missile-target guidance systems with state and input constraints

In this paper, a novel backstepping-based adaptive dynamic programming (ADP) method is developed to solve the problem of intercepting a maneuver target in the presence of full-state and input constraints. To address state constraints, a barrier Lyapunov function is introduced to every backstepping procedure. An auxiliary design system is employed to compensate the input constraints. Then, an adaptive backstepping feedforward control strategy is designed, by which the tracking problem for strict-feedback systems can be reduced to an equivalence optimal regulation problem for affine nonlinear systems. Secondly, an adaptive optimal controller is developed by using ADP technique, in which a critic network is constructed to approximate the solution of the associated Hamilton–Jacobi–Bellman (HJB) equation. Therefore, the whole control scheme consists of an adaptive feedforward controller and an optimal feedback controller. By utilizing Lyapunov's direct method, all signals in the closed-loop system are guaranteed to be uniformly ultimately bounded (UUB). Finally, the effectiveness of the proposed strategy is demonstrated by using a simple nonlinear system and a nonlinear two-dimensional missile-target interception system.     

Disturbance observer-based repetitive control with application to optoelectronic precision positioning system

Rejection of periodic disturbance and/or tracking of periodic reference is of importance in high-precision control systems. Conventional repetitive control is often used to solve the problem, but it cannot precisely set effective frequency points and adversely amplify the non-periodic component disturbance. Therefore, it is not applicable in actual systems where external disturbances exist in the whole frequency domain. In this paper, we propose an improved discrete-time repetitive control method based on the disturbance observer to correct the undesired deviation at repetitive frequencies and mitigate the amplification of the non-components. Moreover, in the observer structure, an intuitive and flexible Q-filter design is presented to suppress low-frequency broadband and intermediate-frequency narrowband disturbances. The conditions of closed-loop stability, performance analysis, and the implementation of the proposed scheme are provided in detail. Finally, the effectiveness of the method is verified by simulation and experimentation on an optoelectronic precision positioning system under the condition of disturbances, and the disturbance suppression and tracking error attenuation are improved.     

Dynamic event-triggered optimal tracking control for constrained nonlinear stochastic systems

This paper investigates the optimal tracking control problem (OTCP) for nonlinear stochastic systems with input constraints under the dynamic event-triggered mechanism (DETM). Firstly, the OTCP is converted into the stabilizing optimization control problem by constructing a novel stochastic augmented system. The discounted performance index with nonquadratic utility function is formulated such that the input constraint can be encoded into the optimization problem. Then the adaptive dynamic programming (ADP) method of the critic-only architecture is employed to approximate the solutions of the OTCP. Unlike the conventional ADP methods based on time-driven mechanism or static event-triggered mechanism (SETM), the proposed adaptive control scheme integrates the DETM to further lighten the computing and communication loads. Furthermore, the uniform ultimately boundedness (UUB) of the critic weights and the tracking error are analysed with the Lyapunov theory. Finally, the simulation results are provided to validate the effectiveness of the proposed approach.     

Ethical requirements for reconfigurable sensor technology: a challenge for value sensitive design

Information technology is widely used to fulfill societal goals such as safety and security. These application areas put ever changing demands on the functionality of the technology. Designing technological appliances to be reconfigurable, thereby keeping them open to functionalities yet to be determined, will possibly allow the technology to fulfill these changing demands in an efficient way. In this paper we present a first exploration of potential societal and moral issues of reconfigurable sensors developed for application in the safety and security domain, in the context of a large scale R&D-project in the Netherlands. We discuss the subtle distinction between the relevant notions of reconfigurability, function creep, and unrestricted or unforeseen technological affordances. We argue that the feature of reconfigurability makes context of use the central issue in the assessment of the societal and moral impact of the technology. It follows that the design of good policies for new application contexts has to be central in a value sensitive design approach to reconfigurable technology.     

Rob Kling In Search of One Good Theory

Rob Kling's legacy is a corpus of work that exemplifies the craft of inquiry and the social enterprise of science. This article examines his contribution to social informatics through an analysis of the multiple theories, methods, and sources of evidence he relied on to make his arguments about the social life of computing and the consequences of computerization. His citation identity demonstrates that he transcended disciplinary boundaries but grounded his analysis of the political and social order in interpretive theory and critique. Kling created a working vocabulary for theorizing about computerization and social life. His sustained inquiry and critique, a very public record of his work, enthusiasm, and charisma, contributed to the penetration of his ideas and the fostering of a world-wide community of interest for a domain of study called social informatics.     

The complex nature of regional knowledge production: Evidence on European regions

Knowledge creation is widely considered as the central driver for innovation, and accordingly, for creating competitive advantage. However, most measurement approaches have so far mainly focused on the quantitative dimension of knowledge creation, neglecting that not all knowledge has the same value (Balland and Rigby, 2017). The notion of knowledge complexity has come into use in this context just recently as an attempt to measure the quality of knowledge in terms of its uniqueness and its replicability. The central underlying assumption is that more complex knowledge is more difficult to be replicated, and therefore provides a higher competitive advantage for firms, or at an aggregated level, regions and countries. The objective of this study is to advance and apply measures for regional knowledge complexity to a set of European regions, and to highlight its potential in a regional policy context. This is done by, first, characterising the spatial distribution of complex knowledge in Europe and its dynamics in recent years, second, establishing that knowledge complexity is associated with future regional economic growth, and third, illustrating the usefulness of the measures by means of some policy relevant example applications. We proxy the production of complex knowledge with a regional knowledge complexity index (KCI) that is based on regional patent data of European metropolitan regions from current EU and EFTA member countries. The results are promising as the regional KCI unveils knowledge creation patterns not observed by conventional measures. Moreover, regional complexity measures can be easily combined with relatedness metrics to support policy makers in a smart specialisation context.