Structure/activity relationships of M2 muscarinic allosteric modulators

Allosteric modulation of G protein-coupled receptors has been intensively studied at muscarinic acetylcholine receptors. Findings made with archetypal allosteric agents such as gallamine, alcuronium, and bis(ammonio)alkane-type agents revealed that binding of orthosteric ligands that attach to the acetylcholine site can be allosterically decreased or increased or left unaltered in a subtype-selective fashion. Analyses of structure/activity relationships (SARs) help to elucidate the molecular events underlying the allosteric action and they may pilot the development of new allosteric agents with improved properties and therapeutic perspectives. With a focus on SARs, this review illustrates the principles of muscarinic allosteric interactions, gives an overview of SARs in congeners of archetypal allosteric agents, and considers the topology of M(2) muscarinic allosteric interactions that are characterized by divergent binding modes.     

Impedance analysis applicable to cardiac muscle and smooth musclebundles

An electrical equivalent circuit was constructed to represent a chain of five myocardial cells in a cardiac muscle bundle with various degrees of cell-to-cell coupling, and an impedance analysis was performed. The impedance across the entire network was measured at frequencies ranging from 10(1) to 10(6) Hz. The Bode plots were nearly superimposable for 1, 10, and 100 tunnels; for 10(3), 10(4), and 10(5) tunnels, the absolute zeta at 10 Hz was lower: e.g., 9.82 M omega for 1 tunnel compared to 6.64 M omega for 10(5) tunnels. The delta zeta 1/2 values were shifted to the left in the well-coupled cases: e.g., for 1 tunnel, f1/2 was 37.8 kHz, and for 10(5) tunnels, f1/2 was 1.2 kHz. For high coupling, the Bode plots contained a double component due to the end membranes. When Ro was increased by eight times, zeta increased by 7.47 fold (for 1 tunnel, 10 Hz), and by 3.72 fold (for 10(5) tunnels, 10 Hz). Raising Ro to x 12, x 100, and x 1000 produced a further and further shift to the left of the Bode plots. The total tissue resistivity (Rt) increased as a function Ro. Thus, in low coupling cases, almost all of the applied current passes through the interstitial space; e.g., at 1 tunnel (10 Hz), 1.0% of the current passes through the cell pathway (Rcell). The ratio of impedances at 10 kHz to 10 Hz (zeta 10kHz/zeta 10Hz) decreased with increasing tunnels (for Ro x 1). The ratio of resistivities at Ro x 8 to Ro x 1 (Rt'/Rt) was 7.47 for 1 tunnel. In contrast, the ratio at 10(5) tunnels was 3.73. It is concluded that it is difficult to determine the degree of cell coupling from such impedance analysis, unless the same tissue can be used for its own control, i.e., before and after a large change in cell coupling is introduced.     

M2M在3GPP SA2的研究进展

随着物联网的快速发展,M2M成为各个标准化组织研究和标准制定的工作重点。3GPP作为移动通信技术的主要研究和标准制定者,对M2M的相关研究和标准制定也在加紧进行。本文在介绍3GPP各个工作组的工作情况的基础上,重点介绍了M2M在3GPP在SA2的研究和标准化进展情况。     

Scanning mutagenesis studies of the M1 muscarinic acetylcholine receptor

Following the solution of the structure of bovine rhodopsin by X-ray crystallography, it has been possible to build an improved homology model of the M(1) muscarinic acetylcholine receptor. This has been used to interpret the outcome of an extensive series of scanning and point mutagenesis studies on the transmembrane domain of the receptor. Potential intramolecular interactions enhancing the stability of the protein fold have been identified. The residues contributing to the binding site for the antagonist, N-methylscopolamine, and the agonist, acetylcholine have been mapped. The positively charged headgroups of these ligands appear to bind in a charge-stabilized aromatic cage formed by amino acid side chains in transmembrane (TM) helices 3, 6, and 7, while residues in TM 4 may participate in a peripheral docking site. Closure of the cage around the headgroup of acetylcholine may help to transduce binding energy into receptor activation, possibly disrupting a set of Van der Waals interactions between a set of residues underlying the binding site which help to constrain the receptor to the inactive state, in the absence of agonist. This may trigger the reorganization of a hydrogen bonding network between highly conserved residues in the core of the receptor, whose integrity is crucial for activation.     

M2M应用与3GPP MTC标准化

全面回顾了3GPP在MTC特性方面的标准化进程，系统地梳理了需求、架构和无线接入网方面的重点标准，并提出了未来MTC标准化工作方向建议。     

M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system

A large body of evidence indicates that muscarinic acetylcholine receptors (mAChRs) play critical roles in regulating the activity of many important functions of the central and peripheral nervous systems. However, identification of the physiological and pathophysiological roles of the individual mAChR subtypes (M(1)-M(5)) has proven a difficult task, primarily due to the lack of ligands endowed with a high degree of receptor subtype selectivity and the fact that most tissues and organs express multiple mAChRs. To circumvent these difficulties, we used gene targeting technology to generate mutant mouse lines containing inactivating mutations of the M(1)-M(5) mAChR genes. The different mAChR mutant mice and the corresponding wild-type control animals were subjected to a battery of physiological, pharmacological, behavioral, biochemical, and neurochemical tests. The M(1)-M(5) mAChR mutant mice were viable and reproduced normally. However, each mutant line displayed specific functional deficits, suggesting that each mAChR subtype mediates distinct physiological functions. These results should offer new perspectives for the rational development of novel muscarinic drugs.     

Performance analysis of threshold digital relaying M2M cooperative networks

Exact average bit error probability (BEP) expressions for mobile-to-mobile cooperative networks employing threshold digital relaying over N-Nakagami fading channels are derived. The power allocation problem is formulated for performance optimization. The average BEP performance is evaluated via numerical simulation to verify the accuracy of the analysis with binary phase shift keying (BPSK) modulation. The simulation results showed that the fading coefficient, number of cascaded components, relative geometrical gain, and power-allocation parameter have a significant influence on the performance.     

平滑肌细胞超微结构的共性与异性

平滑肌细胞是机体内分布广泛功能重要的细胞类型之一 ,由于其形态单一、构型简单 ,所以长期以来在科研及教学中一直未列入关注重点。近年来多项观察中相继发现 ,随所在器官不同 ,平滑肌细胞的超微结构也有相应的不同 ,因此认为进一步了解其共性及异性实有必要 ,并做如下报道。样品与方法　本研究采用多年积累的各种动物和临床外科患者的平滑肌样品 ,经常规固定、脱水、包埋后超薄切片 ,利用日立 H- 5 0 0、H- 75 0 0透射电镜进行观察摄影。观察结果　 1平滑肌细胞超微结构共性 :细胞核均呈不同程度扭曲状 ,内外核膜平行 ,核周隙狭小 ,核孔…     

Role of intrinsic muscle properties in producing smooth movements

Human upper limb movement trajectories have been shown to be quite smooth, in that time derivatives of end point position (r), including d ³r/dt³ (i.e., jerk), appear to be minimized during rapid voluntary reaching tasks. Studies have suggested that these movements are implemented by an optimal neural controller which seeks to minimize a cost function, such as average jerk cost, over the course of these motions. While this hypothetical control strategy is widely supported, there are substantial difficulties associated with implementing such a controller, including ambiguities inherent in transformations from Cartesian to joint coordinates, and the lack of appropriate transducers to provide information about higher derivatives of limb motion to the nervous system. Given these limitations, the authors evaluate the possibility that smoothing of movement might be induced primarily by the intrinsic mechanical properties of muscle by recording the trajectories of inertially loaded muscle with the excitatory input held constant. These trajectories are compared with those predicted by a minimum-jerk optimization model, and by a Hill-based muscle model. The authors' results indicate that trajectories produced by inertially loaded muscle alone are smooth (in the minimum-jerk sense), and that muscle properties may suffice to account for much of the observed smoothing of voluntary motion, obviating the need for an optimizing neural strategy     

Modelling and classification of vascular smooth muscle cell images

A technique integrating directional fractals and neural networks for modelling and classification of tissue section images of smooth muscle cells in human resistance arteries is presented. The ability of directional fractals in capturing the orientation and roughness degrees of texture images is shown. This ability entails improved results of tissue classification over the use of isotropic multiresolution fractals     

消化道平滑肌细胞间的机械连接和通讯连接

消化管壁肌层平滑肌细胞均为集束性活动成分 ,且不受意识支配 ,因此 ,其结构和功能既不同于心肌和骨骼肌 ,也与其它系统的平滑肌不尽相同[1,2 ] 。本研究仅就其细胞间机械性连接和通讯性连接的超微结构介绍如下。样品取自正常成年ＳＤ大鼠 ,性别不拘 ,断头处死 ,剖腹切取消化管各段 ,生理盐水冲洗 ,迅速投入 4 %戊二醛固定 ,逐级酒清脱水 ,树脂包埋 ,超薄切片 70ｎｍ ,Ｈ 75 0 0ＴＥＭ观察。作者发现 :1 如常规所见 ,内环行肌及外纵光肌每一肌细胞的梭形端均位于毗邻细胞的中间粗径邻位 ,彼此纵列成束 ,相邻肌细胞以侧—侧面、侧—端面及端…     

Analysis of synaptic quantal depolarizations in smooth muscle using the wavelet transform

The time-frequency characteristics of synaptic potentials contain valuable information about the process of neurotransmission between nerves and their target organs. For example, at the synapse between autonomic nerves and smooth muscle, two central issues of neurophysiology, i.e., 1) the probability of neurotransmitter release and 2) the quantal behavior of transmission can be deduced from analysis of the rising phases of evoked excitatory junction potentials (eEJP's) recorded from smooth muscle. eEJP rising phases are marked by prominent inflexions, which reflect these features of neuronal activity. Since these inflexions contain time-varying frequency information, we have applied recent techniques of time-frequency analysis based upon wavelet transforms to eEJP's recorded from the guinea-pig vas deferens in vitro. We find that these techniques allow accurate and convenient characterization of neuronal release sites, and that their probability of release falls between 0.001-0.004. We have also analyzed eEJP's recorded in the presence of the chemical 1-heptanol, which reveals quantal depolarizations. These results have helped clarify the nature of the quantal depolarizations that underly eEJP's. The present method offers significant advantages over those previously employed for these tasks, and holds promise as a novel approach to the analysis of synaptic potentials.     

M2M风生水起

新闻背景 最近一段时间,M2M受到了空前的关注。2009年8月7日,中共中央政治局常委、国务院总理温家宝在中科院无锡高新微纳传感网工程技术研发中心考察传感网时指出,至少三件事情可以尽快去做：一是把传感系统和3G中的TD—SCDMA技术结合起来;二是在国家重大科技专项中,加快推进传感网发展;二三是尽快建立中国的传感信息中心,即“感知中国”中心。     

基于AF协作的多中继M2M通信系统的SER性能分析

基于移动端对移动端(M2M)信道衰落服从重叠Nakagami-m分布的假设,研究M-PSK调制下移动放大转发(AF)中继对M2M系统的性能影响。利用矩母函数(MGF)方法,推导了多AF中继辅助M2M通信(MAF-M2M)系统的误符号率(SER)性能下界表达式,并结合近似概率密度函数(PDF)方法,给出了更为逼近的近似SER表达式。结果表明,目的端采用最大比合并时,AF中继可以明显改善不同m参数信道下M2M通信系统性能。计算机仿真结果验证了性能界和近似SER的正确性。     

Modeling and performance analysis of unlicensed bands MAC strategy in multi-channel LTE-A networks with M2M/H2H coexistence

With the growing use of the machine-to-machine (M2M) communication and the unlicensed band by advanced long term evolution (LTE-A) networks, known as LTE unlicensed (LTE-U), demand for resource access strategy is rapidly increasing and has recently been attracting considerable attention of mobile operators. The requirement set by 3rd generation partnership project in the release 11 about LTE standards will allow LTE-U and other unlicensed band access technology to peacefully coexist and operate in the same unlicensed band. LTE-U supports not only the human-to-human (H2H) communication but also the M2M communication. In this paper, a new MAC protocol for LTE-U that allow friendly co-existence of H2H with M2M communications working in unlicensed bands is presented. The proposed MAC mechanisms is designed to ensure an efficient and fair channel access as well as enabling better H2H/M2M coexistence. The throughput performance of both H2H and M2M systems is evaluated analytically and by simulation. The impact of H2H/M2M transmissions periods and spectrum sensing time on the throughput performance of H2H and M2M systems are also studied.     

虾夷扇贝(Patinopecten yesonensis)外套膜内平滑肌细胞的微细结构

早在 5 0年代后期 ,国外已有学者对牡蛎等双壳类内收肌内的平滑肌细胞进行了研究 ,并发现这些平滑肌细胞内有一种非常粗的肌丝 (即粗肌丝 )。其横径粗细不一 ,因而可将平滑肌细胞分为几种类型。此后还发现这种粗丝以副肌球蛋白为轴心 ,外围以肌动蛋白[1— 4 ] 。著者在检查虾夷扇贝外套膜 (以下简称套膜 )结构时注意到其中有细而长的平滑肌细胞。其形态特征及微细结构与脊椎动物的有所不同 [5] ,而与上述有关文献报道的双壳类内收肌的平滑肌细胞相同。今就观察所及特整理如下。材料与方法取成体虾夷扇贝套膜组织 ,按常规电镜术固定 ,包埋 ,…     

诱导血红素氧合酶-1及雷帕霉素对PDGF诱导的大鼠平滑肌细胞表型转化的抑制作用

目的观察血红素氧合酶-1(HO-1)与雷帕霉素对血小板源性生长因子-BB(PDGF-BB)诱导的大鼠血管平滑肌细胞(VSMCs)表型转化的作用。方法原代大鼠VSMCs给予PDGF-BB诱导表型转化。同时给予不同剂量的血红素氧合酶诱导剂氯血红素诱导HO-1的表达,和雷帕霉素共培养24h。结果PDGF-BB20nmol/ml作用原代VSMCs24h后,SM-α-actin与PCNA表达减弱,PCNA表达增强。氯血红素诱导HO-1后可以抑制PDGF-BB诱导的VSMCs表型改变,并且随剂量的增加,抑制强度增加。较低剂量的雷帕霉素可以抑制PDGF诱导的VSMCs表型转化。结论PDGF-BB亚型可以促进原代培养的大鼠VSMCs由收缩表型向合成表型转化,给予氯血红素诱导HO-1表达可以对抗PDGF-BB诱导的大鼠VSMCs表型转化,并呈剂量相关。