BACKGROUND & AIMS: In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are highly potent antagonists with inconsistent antiakinetic and strong myorelaxant activity. Other compounds are better tolerated and are capable of relieving immobility and muscular rigidity by themselves (e.g. 1-aminoadamantanes, polyamine site antagonists, kappa agonists, riluzole). Yet others do not restore movements alone (e.g. dextromethorphan, ketamine), but may interact with and strengthen the antiparkinsonian action of L-DOPA (e.g. competitive NMDA and AMPA antagonists, lamotrigine). They may do this by potentiating dopaminergic behaviours mediated by D1 or D2 receptors, or by some other mechanism.

背景与目标： 在帕金森氏症中，基底神经节内的谷氨酸途径变得过度活跃，导致暗示谷氨酸拮抗剂可能具有抗帕金森氏症的特性。本报告研究了特发性帕金森氏病动物模型中NMDA和AMPA型谷氨酸受体拮抗剂以及谷氨酸释放抑制剂的运动特性。高亲和力的NMDA开放通道阻滞剂 (例如MK 801，苯环利定) 是具有不一致的抗肌毒性和强的肌松弛活性的高效拮抗剂。其他化合物具有更好的耐受性，并且能够自行缓解不动和肌肉僵硬 (例如1-氨基金刚烷，多胺位点拮抗剂，κ 激动剂，利鲁唑)。还有其他人不能单独恢复运动 (例如右美沙芬，氯胺酮)，但可能与L-DOPA的抗帕金森病作用相互作用并加强 (例如竞争性NMDA和AMPA拮抗剂，拉莫三嗪)。他们可以通过增强D1或D2受体或其他机制介导的多巴胺能行为来做到这一点。

BACKGROUND & AIMS: :MYC is one of the most commonly overexpressed oncogenes in human cancer. The targeted inactivation of MYC is a possible therapy for neoplasia. Conditional transgenic mouse model systems are tractable methods to precisely dissect how and when the inactivation of MYC might be effective in the treatment for human cancer. From these model systems, several general principles emerge. MYC inactivation stereotypically results in the proliferative arrest, differentiation and/or apoptosis of tumor cells. The specific consequences of MYC inactivation appear to depend both on the type of cancer as well as the constellation of genetic events unique to a given tumor. Tumors can escape from dependence upon MYC by acquiring compensatory genetic events. MYC inactivation can uncover the stem cell properties of tumor cells that differentiate into normal appearing cells. In some cases, these differentiated cells are actually dormant tumor cells that recover their neoplastic properties upon MYC reactivation. In other cases, even brief MYC inactivation is sufficient to induce sustained tumor regression. Insights from conditional transgenic mouse models will be useful in the development of therapies that target MYC for the treatment of cancer.

背景与目标： : MYC是人类癌症中最常见的过度表达的癌基因之一。靶向灭活MYC可能是肿瘤形成的一种治疗方法。条件转基因小鼠模型系统是精确剖析MYC失活如何以及何时有效治疗人类癌症的方法。从这些模型系统中，出现了几个一般原则。MYC失活通常导致肿瘤细胞的增殖停滞，分化和/或凋亡。MYC失活的具体后果似乎既取决于癌症的类型，也取决于给定肿瘤特有的遗传事件的星座。肿瘤可以通过获得代偿性遗传事件来摆脱对MYC的依赖。MYC失活可以揭示肿瘤细胞分化为正常出现细胞的干细胞特性。在某些情况下，这些分化的细胞实际上是休眠的肿瘤细胞，在MYC重新激活后恢复其肿瘤特性。在其他情况下，即使短暂的MYC失活也足以诱导肿瘤持续消退。来自条件转基因小鼠模型的见解将有助于开发靶向MYC治疗癌症的疗法。

BACKGROUND & AIMS: :The aim of this study was to analyse the acting forces and moments induced by a special orthodontic appliance, the Pendulum K, for molar distalization in the transverse and sagittal planes. The purpose-designed test set-up (artificial maxilla with anchorage unit and two electrothermodynamic molars, an electronic measuring unit, a unit with force-moment sensor, an analogue/digital converter, and a data read-out unit) allowed simulation of in vivo conditions on the one hand and precise determination of the force systems on the other. The appliances investigated were three specimens of the Pendulum K. In vitro measurement of the resulting force systems revealed that the forces and moments in the transverse and sagittal planes remained almost constant over a 3 mm measuring increment when the distal screw was continuously activated (10 activations/mm). Without reactivation of the incorporated distal screw, however, a marked decline in the force systems was recorded. The Pendulum K allows translatory distalization of the upper molars and thus dental arch expansion, dispensing with the need for permanent teeth to be extracted, subject to a corresponding indication. This is achieved by continuous adjustment of an incorporated distal screw and by specific pre-activations of the Pendulum springs.

背景与目标： : 这项研究的目的是分析由特殊的正畸矫治器摆K引起的作用力和力矩，以在横向和矢状平面中使磨牙远侧。目的设计的测试装置 (带有锚固单元和两个电热磨牙的人造上颌骨，一个电子测量单元，一个带力-力矩传感器的单元，一个模拟/数字转换器，和数据读出单元) 一方面可以模拟体内条件，另一方面可以精确确定力系统。所研究的器具是摆锤K的三个样本。所得力系统的体外测量表明，当远端螺钉连续激活 (10个激活/mm) 时，在3毫米测量增量内，横向和矢状平面中的力和力矩几乎保持恒定。但是，如果不重新激活合并的远端螺钉，则记录到力系统明显下降。摆锤K允许上磨牙的平移远端化，从而使牙弓扩张，从而无需拔出恒牙，但要有相应的指示。这是通过连续调节结合的远端螺钉和通过摆簧的特定预激活来实现的。

BACKGROUND & AIMS: :The advance of mitral valve repair techniques through tissue engineering is impeded by the lack of information regarding the cellular and extracellular components of the mitral valve. The present study aims to expand our understanding of the mitral valve structure by analysing the synthesis of extracellular matrix (ECM) proteins and the expression of nitric oxide synthase (NOS). Valvular endothelial cells (VECs) and valvular interstitial cells (VICs) were isolated from porcine mitral valves. Immunochemical staining of ECM components, including type I, II, III, IV and V collagen, laminin, fibronectin, elastin and chondroitin sulphate (CS), was performed on both mitral valve tissue and cell cultures. Reverse transcription polymerase chain reaction and immunochemistry were used to analyse NOS expression in native valve and in culture. Both VECs and VICs synthesised the basement membrane components, laminin and type IV collagen both in vivo and in vitro, amongst other fibrous ECM proteins. Synthesis of type I collagen and CS was absent in VEC cultures. Each cell type had a characteristic profile of NOS expression. VECs synthesised endothelial NOS both in vivo and in vitro, with a minority of VICs expressing neuronal NOS in vitro. The present study reports newly recognised aspects of the mitral valve structure and the in vitro behaviour of mitral valve cell populations based on ECM synthesis and NOS expression. The presented profiles can be used as base tools for the generation of data necessary for the selection of ideal cell sources and for the design of appropriate scaffolds for the development of effective tissue-engineered mitral valves.

背景与目标： : 缺乏有关二尖瓣细胞和细胞外成分的信息，阻碍了通过组织工程进行二尖瓣修复技术的发展。本研究旨在通过分析细胞外基质 (ECM) 蛋白的合成和一氧化氮合酶 (NOS) 的表达来扩大我们对二尖瓣结构的理解。从猪二尖瓣分离瓣膜内皮细胞 (VECs) 和瓣膜间质细胞 (VICs)。对二尖瓣组织和细胞培养物进行了ECM成分的免疫化学染色，包括I，II，III，IV和V型胶原蛋白，层粘连蛋白，纤连蛋白，弹性蛋白和硫酸软骨素 (CS)。逆转录聚合酶链反应和免疫化学用于分析天然瓣膜和培养物中NOS的表达。VECs和VICs均在体内和体外合成了基底膜成分，层粘连蛋白和IV型胶原蛋白以及其他纤维ECM蛋白。在VEC培养物中没有I型胶原蛋白和CS的合成。每种细胞类型都有NOS表达的特征。VECs在体内和体外合成了内皮NOS，少数VICs在体外表达神经元NOS。本研究报告了基于ECM合成和NOS表达的二尖瓣结构和二尖瓣细胞群体的体外行为的新认识。所呈现的配置文件可用作基础工具，用于生成选择理想细胞源所需的数据以及设计用于开发有效组织工程二尖瓣的适当支架。

BACKGROUND & AIMS: :Accurate muscle geometry (muscle length and moment arm) is required to estimate muscle function when using musculoskeletal modelling. In shoulder, muscles are often modelled as a collection of independent line segments, leading to non-physiological muscles trajectory, especially for the rotator cuff muscles. To prevent this, a surface mesh model was developed and validated against 7 MRI positions in one participant. Mean moment arm errors was 11.4% for the line vs. 8.8% for the mesh model. While the model with independent lines led to some non-physiological trajectories, the mesh model gave lower misestimations of muscle lengths and moment arms.

背景与目标： : 使用肌肉骨骼模型时，需要准确的肌肉几何形状 (肌肉长度和力矩臂) 来估计肌肉功能。在肩部，肌肉通常被建模为独立线段的集合，从而导致非生理肌肉轨迹，尤其是对于肩袖肌肉。为了防止这种情况，开发了一个表面网格模型，并针对一名参与者的7个MRI位置进行了验证。11.4% 直线的平均力矩臂误差与网格模型的8.8%。虽然具有独立线条的模型导致了一些非生理轨迹，但网格模型对肌肉长度和力矩臂的误判较低。

BACKGROUND & AIMS: :In this editorial, we propose that the association between depression and cardiovascular disease may be conceptualised as a continuous, bidirectional process that originates in youth. The paper byÅberg and colleagues in this issue adds to this literature showing that low cardiovascular fitness at adolescence increases the risk of future depression.

背景与目标： : 在这篇社论中，我们建议抑郁症与心血管疾病之间的关联可以概念化为一个持续的，双向的过程，起源于青年。这期的论文by å berg及其同事补充了这些文献，表明青春期心血管健康水平低会增加未来抑郁症的风险。

BACKGROUND & AIMS: :This study examined the validity of commonly used regression equations for the Actigraph and Actical accelerometers in predicting energy expenditure (EE) in children and adolescents. Sixty healthy (8-16 yrs) participants completed four treadmill (TM) and five self-paced activities of daily living (ADL). Four Actigraph (AG) and three Actical (AC) regression equations were used to estimate EE. Bias (± 95% CI) and root mean squared errors were used to assess the validity of the regression equations compared with indirect calorimetry. For children, the Freedson (AG) model accurately predicted EE for all activities combined and the Treuth (AG) model accurately predicted EE for TM activities. For adolescents, the Freedson model accurately predicted EE for TM activities and the Treuth model accurately predicted EE for all activities and for TM activities. No other equation accurately estimated EE. The percent agreement for the AG and AC equations were better for light and vigorous compared with moderate intensity activities. The Trost (AG) equation most accurately classified all activity intensity categories. Overall, equations yield inconsistent point estimates of EE.

背景与目标： : 这项研究检验了Actigraph和Actical加速度计常用回归方程在预测儿童和青少年能量消耗 (EE) 中的有效性。60名健康 (8-16岁) 的参与者完成了四项跑步机 (TM) 和五项日常生活的自定进度活动 (ADL)。使用四个Actigraph (AG) 和三个Actical (AC) 回归方程来估计EE。与间接量热法相比，使用偏差 (± 95% CI) 和均方根误差来评估回归方程的有效性。对于儿童，Freedson (AG) 模型准确地预测了所有组合活动的EE，而Treuth (AG) 模型准确地预测了TM活动的EE。对于青少年，Freedson模型准确地预测了TM活动的EE，而Treuth模型准确地预测了所有活动和TM活动的EE。没有其他方程准确估计EE。与中等强度的活动相比，AG和AC方程的百分比一致性对于光和活力更好。Trost (AG) 方程最准确地对所有活动强度类别进行了分类。总的来说，方程产生不一致的EE点估计。

BACKGROUND & AIMS: :A kinetic model is proposed for catalysis by an enzyme that has several special characteristics: (i) it catalyses an acyl-transfer bi-substrate reaction between two identical molecules of substrate, (ii) the substrate is an amphiphilic molecule that can be present in two physical forms, namely monomers and micelles, and (iii) the reaction progresses through an acyl-enzyme-based mechanism and the covalent intermediate can react also with water to yield a secondary hydrolytic reaction. The theoretical kinetic equations for both reactions were deduced according to steady-state assumptions and the theoretical plots were predicted. The experimental kinetics of lysophosphatidylcholine:lysophosphatidylcholine acyltransferase from rabbit lung fitted the proposed equations with great accuracy. Also, kinetics of inhibition by products behaved as expected. It was concluded that the competition between two nucleophiles for the covalent acyl-enzyme intermediate, and not a different enzyme action depending on the physical state of the substrate, is responsible for the differences in kinetic pattern for the two activities of the enzyme. This conclusion, together with the fact that the kinetic equation for the transacylation is quadratic, generates a 'hysteretic' pattern that can provide the basis of self-regulatory properties for enzymes to which this model could be applied.

背景与目标： : 提出了一种动力学模型，用于通过具有以下几个特殊特征的酶进行催化 :( i) 它催化两个相同的底物分子之间的酰基转移双底物反应，(ii) 底物是两亲分子，可以以两种物理形式存在，即单体和胶束，(iii) 反应通过基于酰基酶的机理进行，共价中间体也可以与水反应产生二次水解反应。根据稳态假设推导了两个反应的理论动力学方程，并预测了理论曲线。溶血磷脂酰胆碱的实验动力学: 来自兔肺的溶血磷脂酰胆碱酰基转移酶非常准确地拟合了所提出的方程。此外，产品抑制的动力学表现与预期的一样。结论是，两个亲核试剂之间对共价酰基酶中间体的竞争，而不是取决于底物物理状态的不同酶作用，是造成酶两种活性动力学模式差异的原因。该结论以及转酰化的动力学方程是二次的事实，产生了 “滞后” 模式，可以为可以应用该模型的酶提供自我调节特性的基础。

BACKGROUND & AIMS: OBJECTIVE:This pilot study was a comparison of dimensional models assessing personality traits and personality pathology in a clinical sample of adults diagnosed with ADHD and adults diagnosed with borderline personality disorder (BPD), and a nonclinical control sample of healthy adults. METHOD:Personality traits were assessed using the NEO-Personality Inventory-Revised (NEO-PI-R) and dimensional personality pathology with the Dimensional Assessment of Personality Pathology-Basic Questionnaire (DAPP-BQ). RESULTS:Adults with ADHD and BPD produced higher Emotional Dysregulation/Neuroticism and Dissocial Behavior scores than controls. For the Extraversion/Inhibitedness scale, adults with BPD produced significantly lower scores than adults with ADHD and controls. On the Conscientiousness/Compulsivity domains, Conscientiousness scores were lower for both disorders, whereas low Compulsivity values were specific to adult ADHD. CONCLUSION:Our results suggest that patients with adult ADHD and BPD have distinguishable profiles of personality traits and personality pathology.

背景与目标：

BACKGROUND & AIMS: :By regulatory authorities the rat is considered to be a suitable animal model to predict the percutaneous absorption of hazardous substances in humans. In our study, the percutaneous penetration of 2-butoxyethanol (BE) and toluene was compared in different rat models. Intradermal microdialysis and static diffusion cells were used in in vivo and in vitro experiments with haired Wistar and hairless Lewis rats. Microdialysis experiments showed a steady-state penetration for BE and a penetration maximum for toluene in both rat strains at approximately 60 min after beginning of exposure. However, in diffusion cell experiments the penetration of the test compounds in both rat strains increased until the end of exposure (4 h). Additionally, in microdialysis experiments BE penetrated in hairless rats in a higher amount than in haired rats (factor: 1.4; P < 0.01), for toluene it was just the opposite (factor: 1.9; P < 0.001). In diffusion cell experiments, the penetrated amounts of both compounds were higher in hairless rats compared to haired rats. The fluxes for BE were in diffusion cell experiments at a factor of 14.5 (haired rat) and 18.1 (hairless rat) higher than in microdialysis experiments, the difference factor for toluene was 2.6 (haired rat) and 12.9 (hairless rat). The lag times indicate a significantly faster penetration in microdialysis experiments compared with diffusion cell experiments (P < 0.001). There are great differences in percutaneous penetration behaviour between the techniques and the rat strains. The diffusion cell method has difficulties to describe the percutaneous penetration kinetics, whereas microdialysis describes it more reliable. Due to these differences the reliability of a conversion factor for the transfer of percutaneous absorption data from rat to human skin, as proposed in the literature, is questionable.

背景与目标： : 监管机构认为该大鼠是预测人体内有害物质经皮吸收的合适动物模型。在我们的研究中，比较了2-丁氧基乙醇 (BE) 和甲苯在不同大鼠模型中的经皮渗透。皮内微透析和静态扩散细胞用于有毛Wistar和无毛Lewis大鼠的体内和体外实验。微透析实验显示，在暴露开始后约60分钟，两种大鼠菌株中BE的稳态渗透和甲苯的最大渗透。然而，在扩散细胞实验中，测试化合物在两种大鼠品系中的渗透增加，直到暴露结束 (4小时)。此外，在微透析实验中，无毛大鼠的渗透量高于毛发大鼠 (因子: 1.4; P <0.01)，对于甲苯则相反 (因子: 1.9; P <0.001)。在扩散细胞实验中，与无毛大鼠相比，无毛大鼠中两种化合物的渗透量更高。在扩散池实验中，BE的通量为14.5 (毛大鼠) 和18.1 (无毛大鼠) 高于微透析实验中的系数，甲苯的差异系数为2.6 (毛大鼠) 和12.9 (无毛大鼠)。滞后时间表明与扩散池实验相比，微透析实验中的渗透明显更快 (P <0.001)。该技术与大鼠品系之间的经皮穿透行为存在很大差异。扩散池方法难以描述经皮渗透动力学，而微透析则描述其更可靠。由于这些差异，如文献中所述，将经皮吸收数据从大鼠转移到人皮肤的转换因子的可靠性值得怀疑。

BACKGROUND & AIMS: :Bilateral synchronous epileptiform discharges registered in patients with partial epilepsies may be generated by different pathophysiological mechanisms. Differentiation between underlying mechanisms is often crucial for correct diagnosis and adequate treatment in clinical epileptology. The aim of this study was to model in rats two possible mechanisms--secondary bilateral sychrony and interaction between multiple epilepic foci. Furthermore, to describe in detail semiology, laterality and differences in motor phenomena. Secondary bilateral synchrony was modeled by unilateral topical application of bicuculline methiodide (BMI) over the sensorimotor cortex. Bilateral symmetric application of BMI was used as a model of multiple epileptic foci. Electrographic and behavioural phenomena were recorded for 1h following the application of BMI. Electroencephalogram in both groups was characterized by presence of bilateral synchronous discharges. Myoclonic and clonic seizures involving forelimb and head muscles represented the most common motor seizure pattern in both groups. Significant differences were found in the laterality of motor phenomena. Motor seizures in unilateral foci always started in the contralateral limbs whereas symmetrical foci exhibited bilateral independent onset of convulsions. Similar lateralization was observed in interictal motor phenomena (myoclonic jerks). An important influence of posture on epileptic motor phenomena was demonstrated. Active or passive changes in animal posture (verticalization to bipedal posture) caused conversion from unilateral myoclonic jerks or clonic seizures to bilaterally synchronous (generalized) motor phenomena in both groups.

背景与目标： : 部分性癫痫患者的双侧同步癫痫样放电可能是由不同的病理生理机制产生的。潜在机制之间的区分对于临床表皮病的正确诊断和适当治疗通常至关重要。这项研究的目的是在大鼠中建立两种可能的机制-继发性双侧粘连和多个表位灶之间的相互作用。此外，要详细描述符号学，偏侧性和运动现象的差异。次级双侧同步性是通过在感觉运动皮层上单方面局部应用双苏氨酸甲碘化物 (BMI) 来模拟的。双侧对称应用BMI被用作多个癫痫灶的模型。应用BMI后1小时记录了电学和行为现象。两组的脑电图均以双侧同步放电为特征。涉及前肢和头部肌肉的肌阵挛和阵挛性癫痫发作是两组中最常见的运动癫痫发作模式。在运动现象的偏侧性方面发现了显着差异。单侧病灶的运动性癫痫发作总是在对侧肢体开始，而对称性病灶表现出双侧独立的抽搐发作。在发作间运动现象 (肌阵挛抽搐) 中观察到类似的偏侧化。证明了姿势对癫痫运动现象的重要影响。动物姿势的主动或被动变化 (垂直化为两足姿势) 导致两组患者从单侧肌阵挛抽搐或阵挛性癫痫发作转变为双侧同步 (广义) 运动现象。

BACKGROUND & AIMS: :It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals' performance in behavioral tests that often accompany acute and chronic seizure testing.

背景与目标： : 越来越清楚的是，即使在近交品系中，小鼠和大鼠的遗传背景也可能对癫痫发作易感性和癫痫的测量产生深远的影响。这些差异可以通过基因图谱研究来利用，以揭示对癫痫发作和癫痫重要的基因。然而，在菌株的选择以及结果和结论的解释中，需要仔细考虑菌株的背景，尤其是转基因动物的混合遗传背景。例如，根据背景菌株，具有与癫痫有关的基因靶向缺失的小鼠可能具有截然不同的表型。在这篇综述中，我们讨论了与这种遗传异质性如何具有并可以在癫痫领域中使用的发现，以揭示对癫痫发作和癫痫的新见解。此外，我们讨论了在啮齿动物菌株甚至动物供应商的选择方面如何谨慎，以及这如何以意想不到的方式显着影响癫痫发作和癫痫参数。这在决定用于产生具有靶向基因缺失的小鼠的选择菌株方面尤为重要。最后，我们讨论了环境 (在供应商和/或实验室) 和表观遗传因素对菌株间和内差异的作用，以及这些差异如何影响癫痫发作的表达和动物在通常伴随急性和慢性癫痫发作测试的行为测试中的表现。

BACKGROUND & AIMS: :Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease.

背景与目标： : 为什么大脑黑质的含多巴胺神经元在帕金森氏病中死亡一直是一个持久的谜。我们的研究表明，这些神经元对L型Ca(v)1.3 Ca2通道的异常依赖，以驱动其维持的节律性起搏，使其容易受到被认为有助于疾病进展的应激源的影响。对这些通道的依赖随着年龄的增长而增加，因为黑质致密部中含有多巴胺的少年神经元使用了帕金森氏病未受影响的神经元常见的起搏机制。这些机制在成年期仍然是潜在的，并且在成年神经元中阻断Ca(v)1.3 Ca2通道会导致恢复到幼年的起搏形式。这种阻断 (“恢复活力”) 在帕金森氏病的体外和体内模型中保护这些神经元，这表明了一种可以减缓或阻止疾病进展的新策略。

BACKGROUND & AIMS: :Water plays an active role in many fundamental phenomena in cellular systems such as molecular recognition, folding and conformational equilibria, reaction kinetics and phase partitioning. Hence, our ability to account for the energetics of these processes is highly dependent on the models we use for calculating solvation effects. For example, theoretical prediction of protein-ligand binding modes (i.e., docking) and binding affinities (i.e., scoring) requires an accurate description of the change in hydration that accompanies solute binding. In this review, we discuss the challenges of constructing solvation models that capture these effects, with an emphasis on continuum models and on more recent developments in the field. In our discussion of methods, relatively greater attention will be given to boundary element solutions to the Poisson equation and to nonpolar solvation models, two areas that have become increasingly important but are likely to be less familiar to many readers. The other focus will be upon the trending efforts for evaluating solvation models in order to uncover limitations, biases, and potentially attractive directions for their improvement and applicability. The prospective and retrospective performance of a variety of solvation models in the SAMPL blind challenges will be discussed in detail. After just a few years, these benchmarking exercises have already had a tangible effect in guiding the improvement of solvation models.

背景与目标： : 水在细胞系统中的许多基本现象中起着积极作用，例如分子识别，折叠和构象平衡，反应动力学和相分配。因此，我们解释这些过程的能量学的能力在很大程度上取决于我们用于计算溶剂化效应的模型。例如，蛋白质-配体结合模式 (即对接) 和结合亲和力 (即评分) 的理论预测需要准确描述伴随溶质结合的水合变化。在这篇综述中，我们讨论了构建捕获这些影响的溶剂化模型的挑战，重点是连续模型和该领域的最新发展。在我们对方法的讨论中，将相对更多地关注泊松方程的边界元解和非极性溶剂化模型，这两个领域已变得越来越重要，但许多读者可能不太熟悉。另一个重点将放在评估溶剂化模型的趋势上，以发现局限性，偏见以及其改进和适用性的潜在吸引力方向。将详细讨论SAMPL盲挑战中各种溶剂化模型的前瞻性和回顾性表现。短短几年后，这些基准测试工作已经在指导溶剂化模型的改进方面产生了切实的效果。

BACKGROUND & AIMS: :Twenty first century systems toxicology approaches enable the discovery of biological pathways affected in response to active substances. Here, we briefly summarize current network approaches that facilitate the detailed mechanistic understanding of the impact of a given stimulus on a biological system. We also introduce our network-based method with two use cases and show how causal biological network models combined with computational methods provide quantitative mechanistic insights. Our approach provides a robust comparison of the transcriptional responses in different experimental systems and enables the identification of network-based biomarkers modulated in response to exposure. These advances can also be applied to pharmacology, where the understanding of disease mechanisms and adverse drug effects is imperative for the development of efficient and safe treatment options.

背景与目标： : 二十一世纪系统毒理学方法能够发现对活性物质有反应的生物途径。在这里，我们简要总结了当前的网络方法，这些方法有助于对给定刺激对生物系统的影响进行详细的机械理解。我们还通过两个用例介绍了基于网络的方法，并展示了因果生物网络模型与计算方法的结合如何提供定量的机械见解。我们的方法提供了不同实验系统中转录反应的可靠比较，并能够识别响应于暴露而调制的基于网络的生物标志物。这些进展也可以应用于药理学，在药理学中，了解疾病机制和药物不良反应对于开发有效和安全的治疗选择至关重要。