Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles

The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains.This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals.Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin.Recently,we showed that the PINK1 kinase is selectively expressed as a truncated form(PINK1–55)in the primate brain.In the present study,we used multiple antibodies,including our recently developed monoclonal anti-PINK1,to validate the selective expression of PINK1 in the primate brain.We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages,which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains.PINK1 was enriched in the membrane-bound fractionations,whereas Parkin was soluble with a distinguishable distribution.Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes,though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress.These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.

Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

胃癌高发区武威市人群幽门螺杆菌抗生素耐药性分子诊断研究

目的:本研究旨在通过分析幽门螺杆菌(Helicobacter pylori,HP)抗生素耐药性的分子特征,为临床根除HP合理用药提供分子生物学依据。方法:收集2019年2月至2023年11月在甘肃省武威肿瘤医院检查^(14)C呼气试验阳性的1 144例患者的临床资料。采用扩散法药敏实验、耐药基因检测实验、一代测序法进行CYP2C19基因多态性检测,分析HP抗生素耐药性及相关分子生物学特性。结果:在6种抗生素中,甲硝唑的耐药率和耐药基因(rdxA)突变率最高,分别为92.00%和86.12%,阿莫西林的耐药率和耐药基因(Pbp1)突变率最低,分别为11.78%和37.11%;CYP2C19等位基因出现频率快代谢型占46.77%,中等代谢型占44.58%,慢代谢型占8.65%;免疫组织化学发生球形变148例(18.55%)。常规治疗方案用药的HP根除率低于个性化诊疗方案根除率(χ^(2)=8.627,P=0.003);首次接受耐药分子诊断结果治疗方案的根除者根除率要高于复治患者(χ^(2)=6.242,P=0.012)。结论:胃癌高发区武威市人群对阿莫西林抗生素耐药率较低;通过耐药分子生物学诊断结果,可有效提高HP根除率,并为临床合理用药提供参考依据。

Recurrent Neural Network Inspired Finite-Time Control Design

Dear Editor,This letter is concerned with the role of recurrent neural networks(RNNs)on the controller design for a class of nonlinear systems.Inspired by the architectures of RNNs,the system states are stacked according to the dynamic along with time while the controller is represented as the neural network output.To build the bridge between RNNs and finite-time controller,a novel activation function is imposed on RNNs to drive the convergence of states at finite-time and propel the overall control process smoother.Rigorous stability proof is briefly provided for the convergence of the proposed finite-time controller.At last,a numerical simulation example is presented to illustrate the efficiency of the proposed strategy.Neural networks can be classified as static(feedforward)and dynamic(recurrent)nets[1].The former nets do not perform well in dealing with training data and using any information of the local data structure[2].In contrast to the feedforward neural networks,RNNs are constituted by high dimensional hidden states with dynamics.

Composite Nonlinear Bilateral Control for Teleoperation Systems With External Disturbances

This paper presents a new composite nonlinear bilateral control method based on the nonlinear disturbance observer(NDOB) for teleoperation systems with external disturbances. By introducing the estimations of NDOB and systems' nominal nonlinear dynamics into controller design, a NDOB based composite nonlinear bilateral controller is constructed to attenuate the influence of disturbance and uncertain nonlinearities. As compared with the existing bilateral control methods which usually achieve force haptic(i.e., contact force tracking)through a passive way, the newly proposed method has two major merits: 1) asymptotical convergence of both position and force tracking errors is guaranteed;2) disturbance influence on force tracking error dynamics is rejected through the direct feedforward compensation of disturbance estimation. Simulations on a nonlinear teleoperation system are carried out and the results validate the effectiveness of the proposed controller.

Finite-time Feedback Stabilization of a Class of Input-delay Systems With Saturating Actuators via Digital Control

In this paper, the problem of making an input-delay system with saturating actuators finite-time stable by virtue of digital control is investigated. A digital state feedback controller and digital observer-controller compensator are designed for two cases: when the state of the input-delay system are available or when it is unavailable. Sufficient conditions which guarantee finite-time stability of a closed-loop input-delay system are given and the proof procedure is presented in a heuristic way by constructing appropriate comparison functions. The condition can be transformed into the intersection of two curves satisfying some constraints, which reveals the relationship between designed parameters clearly. Finally, simulation results are presented to validate the method proposed in this paper.

Reduced-Order GPIO Based Dynamic Event-Triggered Tracking Control of a Networked One-DOF Link Manipulator Without Velocity Measurement

In networked robot manipulators that deeply integrate control, communication and computation, the controller design needs to take into consideration the limited or costly system resources and the presence of disturbances/uncertainties. To cope with these requirements, this paper proposes a novel dynamic event-triggered robust tracking control method for a onedegree of freedom(DOF) link manipulator with external disturbance and system uncertainties via a reduced-order generalized proportional-integral observer(GPIO). By only using the sampled-data position signal, a new sampled-data robust output feedback tracking controller is proposed based on a reduced-order GPIO to attenuate the undesirable influence of the external disturbance and the system uncertainties. To save the communication resources, we propose a discrete-time dynamic event-triggering mechanism(DETM), where the estimates and the control signal are transmitted and computed only when the proposed discrete-time DETM is violated. It is shown that with the proposed control method, both tracking control properties and communication properties can be significantly improved. Finally, simulation results are shown to demonstrate the feasibility and efficacy of the proposed control approach.

Study on Ecological Compensation Policy among the Micro Subjects on Water Energy Resources Development

The subjects of ecological compensation involve the nation, society, development enterprises of wa-ter-energy resources, as well as the location of resource itself. This paper systematically studies on how to make “water energy sources market compensation policy”, “the economic compensation policy for relevant interest subjects” and “the ecological compensation policy of basin ecological water.” So, it is necessary to exert the complementary function between market compensation and government compensation by the means of economic compensation and to establish the ecological compensation policy of basin ecological water, which is beneficial to coordinating the stakeholders’ interests of cross-region or inter-basin. And it is important and significant to establish constantly perfected ecological compensation policy among the micro subjects on water energy resources development, so as to coordinate interest relationships among various subjects and finally reach the aim of sustainable use of water energy resources and environmental protection as possible.

Actuation Spaces Synthesis of Lower-Mobility Parallel Mechanisms Based on Screw Theory

The lower-mobility parallel mechanism has been widely used in the engineering field due to its numerous excellent characteristics.However,little work has been devoted to the actuator selection and placement that best satisfy the system's functional requirements during concept design.In this study,a unified approach for synthesizing the actuation spaces of both rigid and flexure parallel mechanisms has been presented,and all possible combinations of inputs could be obtained,laying a theoretical foundation for the subsequent optimization of inputs.According to the linear independence of actuation space and constraint space of the lower-mobility parallel mechanism,a general expression of actuation spaces in the format of screw systems is deduced,a unified synthesis process for the lower-mobility parallel mechanism is derived,and the efficiency of the method is validated with two selective examples based on screw theory.This study presents a theoretical framework for the input selection problems of parallel mechanisms,aiming to help designers select and place actuators in a correct and even optimal way after the configuration design.

Type Synthesis of Fully Decoupled Three Translational Parallel Mechanism with Closed-Loop Units and High Stifness

In order to solve the problem of weak stifness of the existing fully decoupled parallel mechanism, a new synthesis method of fully decoupled three translational (3T) parallel mechanisms (PMs) with closed-loop units and high stifness is proposed based on screw theory. Firstly, a new criterion for the full decoupled of PMs is presented that the reciprocal product of the transmission wrench screw matrix and the output twist screw matrix of PMs is a diagonal matrix, and all elements on the main diagonal are nonzero constants. The forms of the transmission wrench screws are determined by the criterion. Secondly, the forms of the actuated and unactuated screws can be obtained according to their relationships with the transmission wrench screws. The basic decoupled limbs are generated by combination of the above actuated and unactuated screws. Finally, a closed-loop units construction method is investigated to apply the decoupled mechanisms in a better way on the high stifness occasion. The closed-loop units are constructed in the basic decoupled limbs to generate a high-stifness fully decoupled 3T PM. Kinematic and stifness analyses show that the Jacobian matrix is a diagonal matrix, and the stifness is obviously higher than that of the coupling mechanisms, which verifes the correctness of the proposed synthesis method. The mechanism synthesized by this method has a good application prospect in vehicle durability test platform.

Adaptive fault-tolerant controller design for airbreathing hypersonic vehicle with input saturation

The problem of fault-tolerant control is discussed for the longitudinal model of an airbreathing hypersonic vehicle （AHV） with actuator faults and external disturbances. Firstly, a fault-tolerant control strategy is presented for the longitudinal model of an AHV, which guarantees that velocity and altitude track their reference trajectories at an exponential convergence rate. However, this method needs to know the minimum value of the actuator efficiency factor and the upper bound of the external disturbances, which makes it not easy to implement. Then an improved adaptive fault-tolerant control scheme is proposed, where two adaptive laws are employed to estimate the upper bound of the external disturbances and the minimum value of the actuator efficiency factor, respectively. Secondly, the problem of designing a control scheme with control constraints is further considered, and a new adaptive fault-tolerant control strategy with input saturation is designed to guarantee that velocity and altitude track their reference trajectories. Finally, simulation results are given to show the effectiveness of the proposed methods.

A Model-Based Unmatched Disturbance Rejection Control Approach for Speed Regulation of a Converter-Driven DC Motor Using Output-Feedback

The speed regulation problem with only speed measurement is investigated in this paper for a permanent magnet direct current(DC)motor driven by a buck converter.By lumping all unknown matched/unmatched disturbances and uncertainties together,the traditional active disturbance rejection control(ADRC)approach provides an intuitive solution for the problem under consideration.However,for such a higher-order disturbed system,the increase of poles for the extended state observer(ESO)therein will lead to drastically growth of observer gains,which causes severe noise amplification.This paper aims to propose a new model-based disturbance rejection controller for the converter-driven DC motor system using output-feedback.Instead of estimating lumped disturbances directly,a new observer is constructed to estimate the desired steady state of control signal as well as errors between the real states and their desired steady-state responses.Thereafter,a controller with only speed measurement is proposed by utilizing the estimates.The performance of the proposed method is tested through experiments on dSPACE.It is further shown via numerical calculations and experimental results that the poles of the observer within the proposed control approach can be largely increased without significantly increasing magnitude of the observer gains.

Pathological insights from amyotrophic lateral sclerosis animal models:comparisons,limitations,and challenges

In order to dissect amyotrophic lateral sclerosis(ALS),a multigenic,multifactorial,and progressive neurodegenerative disease with heterogeneous clinical presentations,researchers have generated numerous animal models to mimic the genetic defects.Concurrent and comparative analysis of these various models allows identification of the causes and mechanisms of ALS in order to finally obtain effective therapeutics.However,most genetically modified rodent models lack overt pathological features,imposing challenges and limitations in utilizing them to rigorously test the potential mechanisms.Recent studies using large animals,including pigs and non-human primates,have uncovered important events that resemble neurodegeneration in patients’brains but could not be produced in small animals.Here we describe common features as well as discrepancies among these models,highlighting new insights from these models.Furthermore,we will discuss how to make rodent models more capable of recapitulating important pathological features based on the important pathogenic insights from large animal models.

ADAPTIVE SET STABILIZATION OF THE ATTITUDE OF A RIGID SPACECRAFT WITHOUT ANGULAR VELOCITY MEASUREMENTS

The global adaptive set stabilization problem of the attitude of a rigid spacecraft is addressed in this paper. Two different cases are considered. First, by using adaptive backstepping method, the authors design a global adaptive control law for the attitude control system with unknown inertia matrix such that the attitude and the angular velocities can be globally asymptotically stabilized to a set consisting of two equilibria. And then, based on the obtained backstepping adaptive law, the authors consider the case that the angular velocities are not measurable. By introducing an auxiliary state, a semi-global adaptive set stabilization law without angular velocity measurements is also designed. It is rigorously proved that, for the two cases, both of the closed loop systems satisfy the set stability. The effectiveness of the proposed methods is verified by simulation results.

A neutralizing-protective supersite of human monoclonal antibodies for yellow fever virus

The yellow fever virus(YFV)is a life-threatening human pathogen.Owing to the lack of available therapeutics,non-vaccinated individuals are at risk.Here,we isolated eight human monoclonal antibodies that neutralize YFV infection.Five recognized overlapping epitopes and exhibited potent neutralizing activity.Two(YD6 and YD73)were ultra-potent and conferred complete protection against the lethal challenge of YFV as both prophylactics and therapeutics in a mouse model.Crystal structures revealed that YD6 engaged the YFV envelope protein in both pre-and post-fusion states,suggesting viral inhibition by a“double-lock”mechanism.The recognition determinants for YD6 and YD73 are clustered at the premembrane(prM)-binding site.Notably,antibodies targeting this site were present in minute traces in YFV-infected individuals but contributed significantly to neutralization,suggesting a vulnerable supersite of YFV.We provide two promising candidates for immunotherapy against YFV,and the supersite represents an ideal target for epitope-based vaccine design.

Development of a reverse transcription quantitative polymerase chain reaction-based assay for broad coverage detection of African and Asian Zika virus lineages

The Zika virus(ZIKV) is an arbovirus that has spread rapidly worldwide within recent times. There is accumulating evidence that associates ZIKV infections with Guillain-Barré Syndrome(GBS) and microcephaly in humans. The ZIKV is genetically diverse and can be separated into Asian and African lineages. A rapid, sensitive, and specific assay is needed for the detection of ZIKV across various pandemic regions. So far, the available primers and probes do not cover the genetic diversity and geographic distribution of all ZIKV strains. To this end, we have developed a one-step quantitative reverse transcription polymerase chain reaction(qRT-PCR) assay based on conserved sequences in the ZIKV envelope(E) gene. The detection limit of the assay was determined to be five RNA transcript copies and 2.94 × 10^(–3) 50% tissue culture infectious doses(TCID50) of live ZIKV per reaction. The assay was highly specific and able to detect five different ZIKV strains covering the Asian and African lineages without nonspecific amplification, when tested against other flaviviruses. The assay was also successful in testing for ZIKV in clinical samples. Our assay represents an improvement over the current methods available for the detection ZIKV and would be valuable as a diagnostic tool in various pandemic regions.

Emerging NIR-Ⅱ Luminescent Gold Nanoclusters for In Vivo Bioimaging

Gold nanoclusters(AuNCs)with near-infraredⅡ(NIR-Ⅱ)photoluminescence(PL)have emerged as novel bioimaging probes for in vivo disease diagnosis.So far,it still lacks a systematic review focusing on the synthesis,PL tuning,and in vivo imaging of NIR-Ⅱluminescent AuNCs.In this review,we briefly introduce the synthesis of NIR-Ⅱluminescent AuNCs using various surface ligands.We discuss the origins and properties of NIR-ⅡPL in AuNCs,and summarize the strategies for improving and/or tuning NIR-ⅡPL emissions.We also provide an overview of the recent progress in the application of AuNCs in tumor-targeted imaging,molecular imaging,and other areas(such as the sensitive imaging of bones,vessels,lymph nodes,etc.).Finally,we present the prospects and challenges in the field of NIR-Ⅱluminescent AuNCs and related imaging applications,expecting to offer comprehensive understanding of this field,and thereby deepening and broadening the biological application of AuNCs.

Infection of SARS-CoV-2 causes severe pathological changes in mouse testis

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),has affected more than 600 million people worldwide.Several organs including lung,intestine,and brain are infected by SARS-CoV-2.It has been reported that SARS-CoV-2 receptor angiotensin-converting enzyme-2(ACE2)is expressed in human testis.However,whether testis is also affected by SARS-CoV-2 is still unclear.In this study,we generate a human ACE2(hACE2)transgenic mouse model in which the expression of hACE2 gene is regulated by hACE2 promoter.Sertoli and Leydig cells from hACE2 transgenic mice can be infected by SARS-CoV-2 pseudovirus in vitro,and severe pathological changes are observed after injecting the SARS-CoV-2 pseudovirus into the seminiferous tubules.Further studies reveal that Sertoli and Leydig cells from hACE2 transgenic mice are also infected by authentic SARS-CoV-2 virus in vitro.After testis interstitium injection,authentic SARS-CoV-2 viruses are first disseminated to the interstitial cells,and then detected inside the seminiferous tubules which in turn cause germ cell loss and disruption of seminiferous tubules.Our study demonstrates that testis is most likely a target of SARS-CoV-2 virus.Attention should be paid to the reproductive function in SARS-CoV-2 patients.

高效X射线紫外发光稀土纳米闪烁体及其活体X射线激活肿瘤治疗应用

基于X射线纳米闪烁体的光响应疗法是一种新兴的有良好应用前景的活体肿瘤治疗策略,迫切需要开发具有高效X射线激发紫外发光性能的纳米闪烁体.然而,由于当前纳米闪烁体的X射线紫外发光性能仍较弱,实现高效的X射线激活肿瘤治疗仍然是一个巨大的挑战.为此,我们发展了一种新型的具有良好X射线紫外发光性能的Gd^(3+)/Ce^(3+)共掺杂的LiLuF4纳米闪烁体,并将其应用于活体肿瘤治疗.通过优化基质材料、掺杂剂和能量传递设计合成的纳米闪烁体,其X射线紫外发光强度比传统的Ce^(3+)单掺杂材料增强了约18倍.我们进一步将纳米闪烁体与一氧化氮(NO)前体结合以概念验证研究纳米闪烁体的应用.在X射线照射下,该纳米复合物能够可控地产生NO,并在X射线诱导的NO和放射治疗协同作用下实现了优异的抗肿瘤效果.此外,X射线激活的NO治疗可以抑制肿瘤向肝脏转移,抑制肿瘤再生,延长小鼠存活率.这项工作有望推动纳米闪烁体的发展及其在活体深层组织疾病治疗中的应用.