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行为测试中的表现，通常伴随急性和慢性癫痫发作测试。

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。

BACKGROUND & AIMS: :Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10µg/50µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1mg/50µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats.

背景与目标： : 将功能成像技术应用于动物模型对于了解疼痛机制至关重要，但通常由于需要限制麻醉的运动伪影，并且关注诱发反应而不是临床相关的自发性疼痛和相关的痛觉过敏而感到困惑。本研究的目的是研究锰增强磁共振成像 (MEMRI) 在持续疼痛期间测量神经反应的潜力，这种疼痛是伤害感受的临床前模型中痛觉过敏的基础。为了证明MEMRI对自发的间歇性行为的神经活动敏感，我们研究了一个单独的阳性对照组，并进行了自愿的跑步轮实验。在疼痛模型中，在基线和关节内注射神经生长因子 (NGF，10 µ g/50 µ l; 急性疼痛模型，每组n = 4只大鼠) 后测量疼痛行为 (负重不对称和后爪戒断阈值 (PWTs))，或软骨细胞毒素碘乙酸单钠 (MIA，1mg/50 µ l; 慢性模型，每组n = 8只大鼠) 或对照注射。不同组的大鼠接受了自愿轮跑方案 (每组n = 8只大鼠)。在7天内 (皮下渗透泵) 给大鼠以顺磁性离子Mn2作为可溶性MnCl2，以允许在疼痛模型中或在一段时间内累积活动依赖性神经积累。在异氟醚麻醉下，使用仅接收的大鼠头线圈和72毫米体积线圈进行激发，在7t下进行T1-weighted MR成像。疼痛模型导致负重不对称 (NGF: 20.0 ± 5.2%，MIA: 15 ± 3%)，并且在进行MR成像之前的评估的最后一天，MIA模型中的PWT降低 (8.3 ± 1.5g)。对MEMRI数据进行的体素分析和基于区域的分析未识别T1信号的组差异。然而，VTA，右Ce杏仁核和左扣带回中的MnCl2积累与疼痛反应呈负相关 (负重差异更大)，类似地，VTA中的MnCl2积累与痛觉过敏 (较低的PWTs) 相一致，这表明由于MnCl2暴露7天期间经历的疼痛强度和持续时间导致区域激活减少。在车轮运行研究中，运动皮层T1-weighted信号的增加与行驶距离有关，而组之间没有差异。我们的数据表明，使用MEMRI识别出的与疼痛相关的持续信号变化为研究大鼠自发性疼痛的神经基础提供了新的窗口。

BACKGROUND & AIMS: :Drug concentrations in one-compartment systems are frequently modeled using a single exponential function. Two methods of estimation are commonly used for determining the parameters of such a model. In the first method, non-linear least-squares regression is used to calculate the parameters. In the second method, the data are first transformed by a logarithmic function, and then the log-concentration data are fit using linear least-squares regression. The assumptions for fitting these models are discussed with special emphasis on which data points are most influential in determining parameter values. The similarities between fitting a linear regression model to the log-concentration data and fitting a weighted regression model to the original data are noted. An example is presented that illustrates the differences in fitting a model to the log-transformed data versus fitting unweighted and weighted models to the original-scale data.

背景与目标： : 单室系统中的药物浓度通常使用单个指数函数进行建模。通常使用两种估计方法来确定此类模型的参数。在第一种方法中，使用非线性最小二乘回归来计算参数。在第二种方法中，首先通过对数函数对数据进行变换，然后使用线性最小二乘回归对对数浓度数据进行拟合。讨论了拟合这些模型的假设，并特别强调了哪些数据点对确定参数值最有影响。注意将线性回归模型拟合到对数浓度数据与将加权回归模型拟合到原始数据之间的相似性。给出了一个示例，该示例说明了将模型拟合到对数转换数据与将未加权和加权模型拟合到原始比例数据的差异。

BACKGROUND & AIMS: :We propose Bayesian case influence diagnostics for complex survival models. We develop case deletion influence diagnostics for both the joint and marginal posterior distributions based on the Kullback-Leibler divergence (K-L divergence). We present a simplified expression for computing the K-L divergence between the posterior with the full data and the posterior based on single case deletion, as well as investigate its relationships to the conditional predictive ordinate. All the computations for the proposed diagnostic measures can be easily done using Markov chain Monte Carlo samples from the full data posterior distribution. We consider the Cox model with a gamma process prior on the cumulative baseline hazard. We also present a theoretical relationship between our case-deletion diagnostics and diagnostics based on Cox's partial likelihood. A simulated data example and two real data examples are given to demonstrate the methodology.

背景与目标： : 我们提出了复杂生存模型的贝叶斯案例影响诊断。我们基于Kullback-Leibler散度 (k-l散度) 开发了关节和边缘后验分布的病例缺失影响诊断。我们提供了一个简化的表达式，用于基于单个病例删除来计算具有完整数据的后验与后验之间的k-l差异，并研究其与条件预测坐标的关系。使用来自完整数据后验分布的马尔可夫链蒙特卡洛样本，可以轻松完成建议的诊断措施的所有计算。我们考虑在累积基线风险上具有伽马过程的Cox模型。我们还提出了基于Cox部分可能性的病例删除诊断与诊断之间的理论关系。给出了一个模拟数据示例和两个真实数据示例来演示该方法。

BACKGROUND & AIMS: :Repressor element-1 silencing transcription factor (REST) is a candidate modulator of gene expression during status epilepticus in the rodent. In such models, full-length REST and the truncated REST4 variant are induced and can potentially direct differential gene expression patterns. We have addressed the regulation of these REST variants in rodent hippocampal seizure models and correlated this with expression of the proconvulsant, substance P encoding, PPT-A gene. REST and REST4 were differentially regulated following kainic acid stimulus both in in vitro and in vivo models. REST4 was more tightly regulated than REST in both models and its transient expression correlated with that of the differential regulation of PPT-A. Consistent with this, overexpression of a truncated REST protein (HZ4, lacking the C-terminal repression domain) increased expression of the endogenous PPT-A gene. Similarly the proximal PPT-A promoter reporter gene construct was differentially regulated by the distinct REST isoforms in hippocampal cells with HZ4 being the major inducer of increased reporter expression. Furthermore, REST and REST4 proteins were differentially expressed and compartmentalized within rat hippocampal cells in vitro following noxious stimuli. This differential localization of the REST isoforms was confirmed in the CA1 region following perforant path and kainic acid induction of status epilepticus in vivo. We propose that the interplay between REST and REST4 alter the expression of proconvulsant genes, as exemplified by the PPT-A gene, and may therefore regulate the progression of epileptogenesis.

背景与目标： : 阻遏元件-1沉默转录因子 (REST) 是啮齿动物癫痫持续状态期间基因表达的候选调节剂。在这样的模型中，全长REST和截短的REST4变体被诱导，并可能指导差异基因表达模式。我们已经解决了啮齿动物海马癫痫发作模型中这些REST变体的调节，并将其与前惊厥，p物质编码，ppt-a基因的表达相关联。在体外和体内模型中，海藻酸刺激后，REST和REST4均受到差异调节。在两个模型中，REST4的调控都比REST更为严格，其瞬态表达与ppt-a的差异调控相关。与此一致，截短的REST蛋白 (HZ4，缺乏C末端抑制结构域) 的过表达增加了内源性ppt-a基因的表达。同样，近端ppt-a启动子报告基因构建体受海马细胞中不同的REST亚型的差异调节，其中HZ4是报告基因表达增加的主要诱导剂。此外，在有害刺激后，REST和REST4蛋白在体外大鼠海马细胞内差异表达和分隔。在体内癫痫持续状态的穿孔路径和海藻酸诱导后，在CA1区域证实了其余同工型的这种差异定位。我们建议REST和REST4之间的相互作用会改变惊厥前基因的表达，例如ppt-a基因，因此可能会调节癫痫发生的进展。

BACKGROUND & AIMS: :Regression methods for the analysis of paired measurements produced by two fallible assay methods are described and their advantages and pitfalls discussed. The difficulties for the analysis, as in any errors-in-variables problem lies in the lack of identifiability of the model and the need to introduce questionable and often naïve assumptions in order to gain identifiability. Although not a panacea, the use of instrumental variables and associated instrumental variable (IV) regression methods in this area of application has great potential to improve the situation. Large samples are frequently needed and two-phase sampling methods are introduced to improve the efficiency of the IV estimators.

背景与目标： : 描述了用于分析由两种易出错的测定方法产生的成对测量的回归方法，并讨论了它们的优点和陷阱。与任何变量错误问题一样，分析的困难在于模型缺乏可识别性，并且需要引入可疑且通常是幼稚的假设以获得可识别性。虽然不是灵丹妙药，但在这一应用领域中使用工具变量和相关工具变量 (IV) 回归方法具有很大的改善潜力。经常需要大样本，并引入了两阶段采样方法以提高IV估计量的效率。

BACKGROUND & AIMS: :An important stabilizing mechanism in most diversity stability models is the insurance hypothesis, which involves correlation/covariance relationships among species. These models require that species do not fluctuate synchronously over time: that is, the correlation between pairs of species does not equal 1.0. However, the strength of this stabilizing mechanism increases as correlations decline away from 1.0, especially as they become more negative and also as the summed covariance across all species pairs becomes more negative. We evaluated the importance of the insurance hypothesis as a stabilizing mechanism by examining a variety of terrestrial assemblages using long-term data from the Global Population Dynamics Database, the Breeding Bird Survey, and a long-term site in southeastern Arizona, USA. We identified co-occurring assemblages of species and calculated the Spearman rank correlations of all pairs of species and the summed covariance of the entire assemblage. We found that, in most assemblages, positive correlations were two to three times more common than negative and that the magnitude of the positive correlations tended to be stronger than the negative correlations. For all but three assemblages, the summed covariance was positive. Data from larger spatial scales tended to exhibit more positive correlations, but even at the smallest spatial scales, positive correlations outnumbered negative. We suggest that species often covary positively because coexisting species respond similarly to fluctuations in their resource base driven by climatic fluctuations. As such, our review suggests that the insurance hypothesis may not be a strong mechanism stabilizing fluctuations in natural terrestrial communities.

背景与目标： : 在大多数多样性稳定性模型中，一个重要的稳定机制是保险假说，它涉及物种之间的相关性/协方差关系。这些模型要求物种不会随时间同步波动: 也就是说，成对物种之间的相关性不等于1.0。然而，这种稳定机制的强度随着相关性远离1.0的下降而增加，尤其是当它们变得更负并且所有物种对的总协方差变得更负时。我们使用全球人口动态数据库，繁殖鸟类调查和美国亚利桑那州东南部的长期站点的长期数据，通过检查各种陆生组合，评估了保险假说作为稳定机制的重要性。我们确定了同时发生的物种组合，并计算了所有物种对的Spearman等级相关性以及整个组合的总协方差。我们发现，在大多数组合中，正相关是负相关的两到三倍，正相关的幅度往往强于负相关。对于除三个组合外的所有组合，总协方差均为正值。来自较大空间尺度的数据往往表现出更多的正相关性，但是即使在最小的空间尺度上，正相关性也超过了负相关性。我们建议物种通常呈正相关，因为共存物种对气候波动驱动的资源基础波动的反应相似。因此，我们的评论表明，保险假说可能不是稳定自然陆地社区波动的强大机制。

BACKGROUND & AIMS: :The malonyl coenzyme A (CoA)-acyl carrier protein (ACP) transacylase (MCAT) plays a key role in cell wall biosynthesis in Mycobacterium tuberculosis and other bacteria. The M. tuberculosis MCAT (MtMCAT) is encoded by the FabD gene and catalyzes the transacylation of malonate from malonyl-CoA to holo-ACP. Malonyl-ACP is the substrate in fatty acid biosynthesis and is a by-product of the transacylation reaction. This ability for fatty acid biosynthesis enables M. tuberculosis to survive in hostile environments, and thus understanding the mechanism of biosynthesis is important for the design of new anti-tuberculosis drugs. The 2.3 A crystal structure of MtMCAT reported here shows that its catalytic mechanism differs from those of ScMCAT and EcMCAT, whose structures have previously been determined. In MtMCAT, the C(beta)-O(gamma) bond of Ser91 turns upwards, resulting in a different orientation and thus an overall change of the active pocket compared to other known MCAT enzymes. We identify three new nucleophilic attack chains from the MtMCAT structure: His90-Ser91, Asn155-Wat6-Ser91 and Asn155-His90-Ser91. Enzyme activity assays show that His90A, Asn155A and His90A-Asn155A mutants all have substantially reduced MCAT activity, indicating that M. tuberculosis MCAT supports a unique means of proton transfer. Furthermore, His194 cannot form part of a His-Ser catalytic dyad and only stabilizes the substrate. This new discovery should provide a deeper insight into the catalytic mechanisms of MCATs.

背景与目标： : 丙二酰辅酶a (CoA)-酰基载体蛋白 (ACP) 转酰基酶 (MCAT) 在结核分枝杆菌和其他细菌的细胞壁生物合成中起关键作用。结核分枝杆菌MCAT (MtMCAT) 由FabD基因编码，可催化丙二酸从丙二酰辅酶a转酰化为holo-ACP。丙二酰-ACP是脂肪酸生物合成中的底物，是转酰化反应的副产物。这种脂肪酸生物合成的能力使结核分枝杆菌能够在恶劣的环境中生存，因此了解生物合成的机理对于设计新的抗结核药物很重要。本文报道的MtMCAT的2.3 A晶体结构表明其催化机理不同于ScMCAT和EcMCAT的催化机理，ScMCAT和EcMCAT的结构先前已经确定。在MtMCAT中，与其他已知的MCAT酶相比，Ser91的C (β)-O (γ) 键向上旋转，导致不同的方向，从而导致活性口袋的整体变化。我们从MtMCAT结构中识别出三个新的亲核攻击链: His90-Ser91，Asn155-Wat6-Ser91和Asn155-His90-Ser91。酶活性测定表明His90A，Asn155A和His90A-Asn155A突变体均具有显着降低的MCAT活性，表明结核分枝杆菌MCAT支持质子转移的独特手段。此外，His194不能形成His-Ser催化二元体的一部分，只能稳定底物。这一新发现将为MCATs的催化机制提供更深入的了解。

BACKGROUND & AIMS: :Aberrations in the p53 tumor suppressor pathway are associated with hematologic malignancies. p53-dependent cell cycle control, senescence, and apoptosis functions are actively involved in maintaining hematopoietic homeostasis under normal and stress conditions. Whereas loss of p53 function promotes leukemia and lymphoma development in humans and mice, increased p53 activity inhibits hematopoietic stem cell function and results in myelodysplasia. Thus, exquisite regulation of p53 activity is critical for homeostasis. Most of our understanding of p53 function in hematopoiesis is derived from genetically engineered mice. Here we summarize some of these models, the various mechanisms that disrupt the regulation of p53 activity, and their relevance to human disease.

背景与目标： : p53肿瘤抑制途径的畸变与血液系统恶性肿瘤有关。p53-dependent细胞周期控制，衰老和凋亡功能积极参与维持正常和应激条件下的造血稳态。p53功能的丧失会促进人和小鼠的白血病和淋巴瘤的发展，而p53活性的增加会抑制造血干细胞功能并导致骨髓增生异常。因此，p53活性的精细调节对于稳态至关重要。我们对造血过程中p53功能的大多数理解都来自基因工程小鼠。在这里，我们总结了其中的一些模型，破坏p53活性调节的各种机制，以及它们与人类疾病的相关性。

BACKGROUND & AIMS: :An important challenge for conservation is a quantitative understanding of how multiple human stressors will interact to mitigate or exacerbate global environmental change at a community or ecosystem level. We explored the interaction effects of fishing, ocean warming, and ocean acidification over time on 60 functional groups of species in the southeastern Australian marine ecosystem. We tracked changes in relative biomass within a coupled dynamic whole-ecosystem modeling framework that included the biophysical system, human effects, socioeconomics, and management evaluation. We estimated the individual, additive, and interactive effects on the ecosystem and for five community groups (top predators, fishes, benthic invertebrates, plankton, and primary producers). We calculated the size and direction of interaction effects with an additive null model and interpreted results as synergistic (amplified stress), additive (no additional stress), or antagonistic (reduced stress). Individually, only ocean acidification had a negative effect on total biomass. Fishing and ocean warming and ocean warming with ocean acidification had an additive effect on biomass. Adding fishing to ocean warming and ocean acidification significantly changed the direction and magnitude of the interaction effect to a synergistic response on biomass. The interaction effect depended on the response level examined (ecosystem vs. community). For communities, the size, direction, and type of interaction effect varied depending on the combination of stressors. Top predator and fish biomass had a synergistic response to the interaction of all three stressors, whereas biomass of benthic invertebrates responded antagonistically. With our approach, we were able to identify the regional effects of fishing on the size and direction of the interacting effects of ocean warming and ocean acidification.

背景与目标： : 保护的一个重要挑战是对多种人类压力源将如何相互作用以减轻或加剧社区或生态系统层面的全球环境变化的定量理解。我们探索了随着时间的推移捕鱼，海洋变暖和海洋酸化对澳大利亚东南部海洋生态系统中60种功能物种的相互作用。我们在耦合的动态全生态系统建模框架内跟踪了相对生物量的变化，该框架包括生物物理系统，人类影响，社会经济学和管理评估。我们估计了对生态系统和五个社区群体 (顶级捕食者，鱼类，底栖无脊椎动物，浮游生物和初级生产者) 的个体，累加和交互影响。我们用加性零模型计算了相互作用效应的大小和方向，并将结果解释为协同作用 (放大应力)，加性 (无附加应力) 或拮抗作用 (降低应力)。单独地，只有海洋酸化对总生物量有负面影响。捕鱼和海洋变暖以及海洋酸化对生物量有累加作用。将捕鱼添加到海洋变暖和海洋酸化中，显着改变了相互作用的方向和大小，从而对生物量产生了协同响应。交互效应取决于所检查的响应水平 (生态系统与社区)。对于社区，交互作用的大小，方向和类型取决于压力源的组合。顶级捕食者和鱼类生物量对所有三种应激源的相互作用具有协同反应，而底栖无脊椎动物的生物量具有拮抗反应。通过我们的方法，我们能够确定捕鱼对海洋变暖和海洋酸化相互作用的大小和方向的区域影响。