BACKGROUND & AIMS: :Using single and multiunit recordings in the striate cortex of alert macaque monkeys, we find that gamma-band (20-70 Hz) oscillations in neuronal firing are a prominent feature of V1 neuronal activity. The properties of this rhythmic activity are very similar to those previously observed in the cat. Gamma-band activity is strongly dependent on visual stimulation, largely absent during spontaneous activity and, under the conditions of our experiment, not time-locked to the vertical refresh of the computer monitor (80 Hz) used to present the stimuli. In our sample, 61% of multiunit activity (MUA) and 46% of single-unit activity (SUA) was significantly oscillatory, with mean frequencies of 48+/-9 and 42+/-13 Hz, respectively. Gamma-band activity was most likely to occur when cells were activated by their optimal stimuli, but still occurred, although less often and with lower amplitude, in response to nonoptimal stimuli. The frequency of gamma-band activity also reflected stimulus properties, with drifting gratings evoking higher-frequency oscillations than stationary gratings. As in the cat, the spike trains of single cells showing gamma-band oscillations often displayed a pattern of repetitive burst firing, with intraburst firing rates of 300-800 Hz. The overall similarity of rhythmic neuronal activity in the primary visual cortex of cats and monkeys suggests that the phenomenon is not species-specific. The stimulus-dependence of the rhythmic activity is consistent with a functional role in visual perception.

背景与目标： ：在警觉猕猴的纹状皮层中使用单单位和多单位记录，我们发现神经元放电中的伽马波段（20-70 Hz）振荡是V1神经元活动的突出特征。有节奏的活动的性质与以前在猫中观察到的性质非常相似。伽玛带活动强烈依赖于视觉刺激，在自发活动过程中基本上不存在，在我们的实验条件下，γ波段活动没有时间锁定到用于呈现刺激的计算机监视器的垂直刷新（80 Hz）上。在我们的样本中，61％的多单位活性（MUA）和46％的单单位活性（SUA）具有明显的振荡性，平均频率分别为48 / -9和42 / -13 Hz。当细胞被其最佳刺激激活时，伽马带活动最有可能发生，但仍会发生，尽管频率较低且幅度较小，但响应非最佳刺激仍会发生。 γ波段活动的频率也反映出刺激特性，与固定光栅相比，漂移光栅引起更高的频率振荡。像猫一样，显示伽马波段振荡的单个细胞的尖峰序列通常显示出重复的爆发式发射模式，爆发内发射频率为300-800 Hz。在猫和猴的初级视觉皮层中，节律性神经元活动的总体相似性表明，这种现象不是特定于物种的。节律活动的刺激依赖性与视觉感知中的功能作用一致。

BACKGROUND & AIMS: :Combining the measurement of bone mineral density (BMD) and the classification of the trabecular structure in cancellous bone improves the estimation of the degree of osteoporosis. A fractal method for the automatic quantitative classification of the trabecular structure in midvertebral slices of lumbar vertebrae is introduced. This method is based on the computation of the fractal dimension (box counting method) for varying binarization thresholds. Radiographic images from 30 lumbar vertebrae and CT images from an additional 16 lumbar vertebrae were analysed by calculating the dimension D in dependency of the threshold value T. The function D(T) was normalized by the average image grey value, eliminating the bone mineral density from the computations. The results show that the images of the lumbar vertebrae have fractal properties, and the function D(T) has a typical behaviour that allows the discrimination of the degree of osteoporosis. With two parameters extracted from the function D(T) the correlation coefficients with BMD were both -79% for the radiographic images, and -93% and -91% for the CT data, respectively.

背景与目标： ：结合骨矿物质密度（BMD）的测量和松质骨中小梁结构的分类，可以改善对骨质疏松程度的估计。介绍了一种用于腰椎中段椎骨小梁结构自动定量分类的分形方法。此方法基于变化的二值化阈值的分形维数（盒计数法）的计算。通过根据阈值T计算尺寸D来分析30个腰椎的放射线图像和其他16个腰椎的CT图像。函数D（T）通过平均图像灰度值归一化，消除了骨矿物质密度从计算。结果表明，腰椎图像具有分形特性，并且函数D（T）具有典型的行为，可以区分骨质疏松程度。从函数D（T）中提取两个参数后，对于放射线图像，与BMD的相关系数分别为-79％和CT数据分别为-93％和-91％。

BACKGROUND & AIMS: Objectives:This study investigated the role of locus coeruleus (LC) nucleus TRPV1 receptors (TRPV1r) in the expression and development of morphine physical dependence by intra-LC administration of AMG9810 (selective TRPV1r antagonist) in male Wistar rats. Materials and Methods:For assessing the development of morphine dependence, AMG9810 (0.03 and 0.3 mM in 10% DMSO, 0.2 µl; intra-LC microinjection) was administered before each morphine administration for seven continues days (once daily; 6, 16, 26, 36, 46, 56, and 66 mg/kg; sc). Furthermore, for evaluating the expression of morphine dependence, a single dose of AMG9810 (0.03 and 0.3 mM in 10% DMSO, 0.2 µl; intra-LC microinjection) was administered to morphine-dependent rats on day 8 of the experiment. Results:Obtained data demonstrated that co-administration of TRPV1r antagonist with morphine reduced the development of morphine withdrawal syndrome somatic signs induced by naloxone. Moreover, single intra-LC administration of TRPV1r antagonist on the final day of the examination period significantly decreased the expression of some signs of morphine withdrawal in rats. Conclusion:The results showed that LC TRPV1r might be participating in the expression and development of morphine dependence.

背景与目标： 目的：本研究通过LC内注射AMG9810（选择性TRPV1r拮抗剂）在雄性Wistar大鼠中研究了蓝斑核（TR）核TRPV1受体（TRPV1r）在吗啡物理依赖性表达和发育中的作用。
材料和方法：为了评估吗啡依赖性的发展，在每次连续7天（每天一次；每天一次； 6、16、26）连续施用吗啡之前，先施用AMG9810（0.03和0.3 mM，在10％DMSO中，0.2 µl； LC内注射）。 ，36、46、56和66 mg / kg； sc）。此外，为了评估吗啡依赖性的表达，在实验的第8天，向吗啡依赖性大鼠单剂量给予AMG9810（0.03和0.3 mM，在10％DMSO中，0.2 µl； LC内注射）。
结果：获得的数据表明，TRPV1r拮抗剂与吗啡并用可减少纳洛酮诱导的吗啡戒断综合征体征的发生。此外，在检查期的最后一天单次LC-内给予TRPV1r拮抗剂可显着降低大鼠吗啡戒断症状的表达。
结论：结果表明，LC TRPV1r可能参与了吗啡依赖的表达和发展。

BACKGROUND & AIMS: :Ferumoxytol is an ultrasmall super paramagnetic particles of iron oxide (USPIO) agent recently used for magnetic resonance (MR) vascular imaging. Other USPIOs have been previously used for assessing inflammation within atheroma. We aim to assess feasibility of ferumoxytol in imaging carotid atheroma (with histological assessment); and the optimum MR imaging time to detect maximum quantitative signal change post-ferumoxytol infusion. Ten patients with carotid artery disease underwent high-resolution MR imaging of their carotid arteries on a 1.5 T MR system. MR imaging was performed before and at 24, 48, 72 and 96 hrs post ferumoxytol infusion. Optimal ferumoxytol uptake time was evaluated by quantitative relaxometry maps indicating the difference in T2* (ΔT2*) and T2 (ΔT2) between baseline and post-Ferumoxytol MR imaging using 3D DANTE MEFGRE qT2*w and iMSDE black-blood qT2w sequences respectively. 20 patients in total (10 symptomatic and 10 with asymptomatic carotid artery disease) had ferumoxytol-enhanced MR imaging at the optimal imaging window. 69 carotid MR imaging studies were completed. Ferumoxytol uptake (determined by a decrease in ΔT2* and ΔT2) was identified in all carotid plaques (symptomatic and asymptomatic). Maximum quantitative decrease in ΔT2* (10.4 [3.5-16.2] ms, p < 0.001) and ΔT2 (13.4 [6.2-18.9] ms; p = 0.001) was found on carotid MR imaging at 48 hrs following the ferumoxytol infusion. Ferumoxytol uptake by carotid plaques was assessed by histopathological analysis of excised atheroma. Ferumoxytol-enhanced MR imaging using quantitative 3D MR pulse sequences allows assessment of inflammation within carotid atheroma in symptomatic and asymptomatic patients. The optimum MR imaging time for carotid atheroma is 48 hrs after its administration.

背景与目标： ：Ferumoxytol是一种超小型超顺磁性氧化铁（USPIO）剂，最近用于磁共振（MR）血管成像。其他USPIO以前已用于评估动脉粥样硬化内的炎症。我们旨在评估阿魏酸在颈动脉粥样硬化成像中的可行性（通过组织学评估）；以及最佳的MR成像时间，以检测在输精铁输注后最大的定量信号变化。十名颈动脉疾病患者在1.5 T MR系统上对其颈动脉进行了高分辨率MR成像。 MR成像是在输注阿魏酸之前和之后24、48、72和96小时进行的。通过定量弛豫测定图评估最佳阿魏木醇的摄取时间，该图显示了分别使用3D DANTE MEFGRE qT2 * w和iMSDE黑血qT2w序列在基线和富罗莫斯托尔MR成像之间的T2 *（ΔT2*）和T2（ΔT2）的差异。共有20例患者（10例有症状的患者和10例无症状的颈动脉疾病的患者）在最佳成像窗口进行了铁氧嘧啶增强的MR成像。完成69例颈动脉MR成像研究。在所有颈动脉斑块（有症状和无症状）中均发现了阿魏酸的摄取（由ΔT2*和ΔT2的降低确定）。在注入阿魏美土醇后48小时的颈动脉MR成像中，发现ΔT2*（10.4 [3.5-16.2] ms，p <0.001）和ΔT2（13.4 [6.2-18.9] ms； p = 0.001）的最大定量下降。通过切除的动脉粥样硬化的组织病理学分析评估颈动脉斑块对阿魏酸的摄取。使用定量3D MR脉冲序列增强阿魏酸的MR成像可以评估有症状和无症状患者的颈动脉粥样硬化内的炎症。颈动脉粥样硬化的最佳MR成像时间为给药后48小时。

BACKGROUND & AIMS: :The influence of perfusate flow rate on the two-dimensional (2-D) temperature distributions induced by hyperthermia in the canine kidney was evaluated. Localized hyperthermia was induced by ultrasound (frequency 2.040 MHz, transducer diameter 6.7 cm) in the ex-vivo perfused kidney. Temperatures were mapped using shielded copper/constantan thermocouple sensors. The 2-D temperature distribution of the kidney was obtained by pulling these sensors through a planar array of eight stainless-steel trocars inserted along its longitudinal axis. The perfusion system allowed for the control of internal/external organ temperature and type of perfusate, and it simulated vasodilation and vasoconstriction by changing the arterial volume flow rate. The temperature data obtained at flow rates ranging from 0 to 570 ml/min and power levels from 0 to 150 W showed that acoustic power densities in excess of 1.5 W/cm2 were required to maintain therapeutic temperatures in this system. Contour maps for characterizing the 2-D temperature distributions induced in this system were analysed with the introduction of a quantitative measure based on the area within a given isotherm. They show the effects of tissue heterogeneity, flow rate, and non-uniform power deposition. Time constants computed from the exponentially decaying temperatures measured following power off ranged from 5 to 555 s. These findings provide a basis for comparison with temperature measurements being acquired in the in-vivo kidney system. Information acquired from this system may facilitate the process of developing tissue-equivalent dynamic phantoms for ultrasound-induced hyperthermia. The ex-vivo model presented in this paper might be used to study the performance of alternative heating applicators, the effect of haematocrit, blood viscosity, and the use of vasoactive drugs.

背景与目标： ：评估了灌注液流速对犬肾脏中热疗引起的二维（2-D）温度分布的影响。超声（频率2.040 MHz，换能器直径6.7 cm）在离体灌注肾脏中引起局部热疗。使用屏蔽的铜/常数热电偶传感器绘制温度图。肾脏的二维温度分布是通过将这些传感器拉过沿其纵轴插入的八个不锈钢套管针的平面阵列而获得的。灌注系统可以控制内部/外部器官的温度和灌注液的类型，并且它通过改变动脉体积流量来模拟血管舒张和血管收缩。在0到570 ml / min的流速和0到150 W的功率水平下获得的温度数据表明，在该系统中维持治疗温度需要超过1.5 W / cm2的声功率密度。通过引入基于给定等温线内面积的定量测量，分析了表征该系统中感应的二维温度分布的轮廓图。它们显示了组织异质性，流速和功率沉积不均匀的影响。根据断电后测得的指数衰减温度计算的时间常数范围为5到555 s。这些发现为与体内肾脏系统中获得的温度测量值进行比较提供了基础。从该系统获取的信息可能有助于开发用于超声诱发的体温过高的组织等效动态体模的过程。本文介绍的体外模型可用于研究替代供热器的性能，止血药的作用，血液粘度和使用血管活性药物。

BACKGROUND & AIMS: :Polysaccharide lyases (PLs) are enzymes that cleave glycosidic linkages in hexuronate polysaccharides, such as homogalacturonan (HG), using a β-elimination mechanism. Traditionally, PL activities on HG have been associated with catalytic calcium cofactors, unusually high pH optima, and arginine Brønstead bases. Recently, however, PL families that harness transition metal cofactors, utilize lysine and histidine Brønstead bases, and display more neutral pH optima have been described. One such family is PL2, which has members found primarily in phytopathogenic (e.g., Dickeya spp. and Pectobacterium spp.) or enteropathogenic (e.g., Yersinia spp.) bacterial species. PL2 is divided into two major subfamilies that are correlated with either an endolytic or exolytic activity. This study has focused on the activity of a PL2 member, which is not classified within either subfamily and helps to illuminate the origin of enzyme activities within the family. In addition, the role of Mg(2+) as a preferential catalytic metal for an intracellular PL2 (PaePL2) is described. The implications for the relationship between catalytic metal selectivity and the cellular location of pectate lyase-mediated catalysis are discussed.

背景与目标： ：多糖裂解酶（PLs）是使用β-消除机制裂解己糖酸酯多糖（如高半乳糖醛酸聚糖（HG））中糖苷键的酶。传统上，PL对HG的活性与催化性钙辅因子，异常高的pH最适值和精氨酸Brønstead碱有关。然而，最近已经描述了利用过渡金属辅因子，利用赖氨酸和组氨酸布朗斯台德碱并显示出更中性的pH最佳值的PL系列。一个这样的家族是PL2，其成员主要存在于植物致病性（例如Dickeya spp。和Pectobacterium spp。）或肠致病性（例如Yersinia spp。）细菌物种中。 PL2分为两个主要的亚科，它们与内切或外切活性相关。这项研究的重点是PL2成员的活性，该成员在任何一个亚科中均未分类，有助于阐明该家族中酶活性的起源。另外，描述了Mg（2）作为细胞内PL2（PaePL2）的优先催化金属的作用。讨论了催化金属选择性与果胶酸裂合酶介导的催化作用在细胞中的位置之间的关系。

BACKGROUND & AIMS: BACKGROUND:The Dutch multi-ethnic Healthy Life in an Urban Setting study recently showed that alcohol consumption was lower in ethnic minority groups than those of Dutch origin, but that binge drinking in drinkers of Turkish and Moroccan origin was relatively high. The aim of the current study is to examine factors that may contribute to the differences in drinking patterns and how they relate to the relationship between drinking patterns and alcohol dependence (AD) across ethnic groups. METHODS:The rate of last year alcohol use, alcohol use patterns and AD was assessed in 4,635 Dutch, 4,317 Moroccan, 4,036 Turkish, 2,459 Ghanaian, 4,426 African Surinamese and 3,357 South-Asian Surinamese participants (both men and women) born in Amsterdam, the Netherlands. RESULTS:Compared to the Dutch, the prevalence of (regular) drinking is substantially lower in all ethnic minority groups and regular drinkers among most ethnic minority groups have a lower adjusted risk to develop binge drinking and AD than the Dutch. For the prevalence of regular drinking, the ethnic differences are bigger than for the prevalence of current drinking. However, regular drinkers of Moroccan origin have a risk similar to the Dutch to develop binge drinking and AD; a finding that could not be explained by group differences in age, sex, religiosity, perceived discrimination, depression or guilt feelings about drinking. DISCUSSION:The prevalence data show that current drinking is lower and that regular drinking is much lower in ethnic minorities and - with the exception of those of Moroccan origin - ethnic minority regular drinkers also have a significant lower risk to develop binge drinking or AD than regular drinkers of Dutch origin. This implies that the magnitude of problematic alcohol use is substantially smaller in ethnic minorities than in the ethnic Dutch population of Amsterdam. Unfortunately, no explanation was found for the special risk situation of regular drinkers of Moroccan origin.

背景与目标： 背景：荷兰城市环境中的多种族健康生活研究​​显示，少数民族人群的酒精消费量低于荷兰人群，但土耳其和摩洛哥裔饮酒者的酗酒相对较高。当前研究的目的是研究可能导致饮酒方式差异的因素，以及它们如何与跨族裔的饮酒方式与酒精依赖（AD）之间的关系相关。
方法：评估了在阿姆斯特丹出生的4,635荷兰人，4,317摩洛哥人，4,036土耳其人，2,459加纳人，4,426非洲苏里南人和3,357南亚苏里南人（男性和女性）的去年酒精使用率，酒精使用方式和AD的发生率，荷兰人。
结果：与荷兰人相比，在所有少数族裔人群中，（正常）饮酒的患病率要低得多，并且大多数少数民族人群中的经常饮酒者与荷兰人相比，发生暴饮和AD的调整后风险较低。就经常饮酒的患病率而言，种族差异要大于目前饮酒的患病率。但是，经常饮用摩洛哥起源的饮酒者与荷兰人有类似的发展狂饮和AD的风险。这一发现无法通过年龄，性别，宗教信仰，感知的歧视，沮丧或内drinking的饮酒感的群体差异来解释。
讨论：患病率数据显示，少数民族中目前的饮酒量较低，而经常饮酒的比例要低得多-除了摩洛哥血统的少数民族以外，少数民族经常饮酒的人患暴饮或AD的风险也比正常人低得多荷兰裔饮酒者。这意味着在少数民族中，有问题的酒精消费量要比在阿姆斯特丹的荷兰族裔人口要小得多。不幸的是，没有找到关于摩洛哥普通饮酒者特殊危险情况的解释。

BACKGROUND & AIMS: BACKGROUND:In several countries, especially in Africa, the dominant method of heroin intake is smoking a joint of cannabis laced with heroin. There is no data exploring the impact of smoking heroin with cannabis on treatment outcomes. AIM:To compare treatment outcomes between people who inject heroin and people who smoke heroin with cannabis. METHODOLOGY:Three hundred heroin users were assessed on admission to inpatient rehabilitation and after treatment. We compared drug use, psychopathology, criminality, social functioning and general health between heroin injectors and heroin-cannabis smokers at treatment entry, and at 3 and 9 months after rehabilitation. RESULTS:The sample comprised 211 (70.3%) heroin-cannabis smokers and 89 (29.7%) heroin injectors. Eighty-four percent were followed up at 3 months and 75% at 9 months. At 9 months, heroin-cannabis smokers had a higher proportion of those who relapsed to heroin use compared with intravenous (IV) users (p = 0.036). The median number of heroin use episodes per day was lower for IV users than heroin-cannabis smokers at both follow-up points (p = 0.013 and 0.0019). A higher proportion of IV users was HIV positive (p = 0.002). There were no significant differences in psychopathology, general health, criminality and social functioning between IV users and heroin-cannabis smokers at all three time points. CONCLUSIONS:Heroin users who do not inject drugs but use other routes of administration may have increased risk for relapse to heroin use after inpatient rehabilitation and should therefore have equal access to harm reduction treatment services. Advocating a transition from injecting to smoking heroin in an African context may pose unique challenges.

背景与目标： 背景：在一些国家，特别是在非洲，海洛因摄入的主要方法是吸烟与海洛因绑在一起的大麻。没有数据探讨使用大麻吸食海洛因对治疗效果的影响。
目的：比较注射海洛因的人和吸食海洛因的人与大麻之间的治疗效果。
方法：对入院康复后和治疗后的300名海洛因使用者进行了评估。我们比较了进入治疗时以及康复后3个月和9个月时海洛因注射者与海洛因大麻吸烟者之间的药物使用，心理病理学，犯罪，犯罪行为，社会功能和一般健康状况。
结果：该样本包括211名（70.3％）海洛因大麻吸烟者和89名（29.7％）海洛因注射者。在3个月时随访了84％，在9个月时随访了75％。在9个月的时间里，与静脉注射（IV）的使用者相比，吸食海洛因和大麻的吸烟者复发海洛因的比例更高（p = 0.036）。在两个随访点上，静脉吸毒者每天使用海洛因的中位数均低于海洛因大麻吸烟者（p = 0.013和0.0019）。静脉吸毒者中艾滋病毒呈阳性的比例更高（p = 0.002）。在所有三个时间点，静脉吸毒者和海洛因大麻吸烟者之间的心理病理学，总体健康，犯罪和社交功能均无显着差异。
结论：未注射毒品但使用其他给药途径的海洛因使用者在住院康复后可能会增加海洛因使用的复发风险，因此应平等获得减害治疗服务。在非洲背景下倡导从注射海洛因向吸烟海洛因的过渡可能会带来独特的挑战。

BACKGROUND & AIMS: :We used the Heaviness of Smoking Index, a subset of the Fagerstrom Test for Nicotine Dependence, to classify 608 cigarette smokers planning a cessation attempt as low or high in nicotine dependence. Subjects within each level of dependence were then randomly assigned to placebo, 2-mg, or 4-mg nicotine gum treatment. Subjects were also provided brief (5-10 min per visit) behavioral counseling during a 1-year period of follow-up. At 1 year post-cessation, quit rates were 11.2, 19.5, and 18.4% for low-dependence smokers receiving placebo, 2-mg, and 4-mg gum, respectively (plinear trend = 0.20). For high-dependence smokers, quit rates at 1 year were 6.1, 15.7, and 20.7% for the placebo, 2-mg, and 4-mg gum conditions, respectively (plinear trend = 0.002). The interaction of nicotine-gum dose and dependence group was not significant (p = 0.42), nor did the 2-mg and 4-mg doses differ significantly in effectiveness, though both 2-mg and 4-mg gum were significantly more effective than placebo gum. We also found a significant dose-related effect for nicotine gum to moderate post-cessation heart-rate decline. Other variables related to abstinence at 1 year post-cessation were a longer period of abstinence on a prior quit attempt, being married, higher education level, and having a non-smoking spouse or significant other. Results indicate that nicotine gum is a significant aid to smoking cessation, more than doubling the odds of successful cessation compared to the odds for placebo-gum users. The 4-mg dose provided a non-significant increase in cessation rates for high-dependence smokers. Smoking history and demographic variables also have a significant impact on the outcome of a quit-smoking attempt.

背景与目标： ：我们使用烟瘾重度指数（法格斯特罗姆烟碱依赖性测试的一个子集）对计划戒烟尝试的608名吸烟者分类为低烟碱依赖性或高烟碱依赖性。然后将每个依赖性水平内的受试者随机分配给安慰剂，2 mg或4 mg尼古丁胶治疗。在一年的随访期内，还向受试者提供了简短的行为咨询（每次访问5-10分钟）。戒烟后1年，接受安慰剂，2 mg和4 mg牙龈的低依赖性吸烟者的戒烟率分别为11.2％，19.5％和18.4％（线性趋势= 0.20）。对于高依赖性吸烟者，安慰剂，2 mg和4 mg牙龈疾病在1年时的戒烟率分别为6.1、15.7和20.7％（线性趋势= 0.002）。尼古丁-口香糖剂量与依赖性组之间的相互作用不显着（p = 0.42），尽管2-mg和4-mg口香糖的疗效显着高于2-mg和4-mg口香糖，但两者的疗效也无显着差异。安慰剂胶。我们还发现尼古丁胶对中度戒烟后心率下降具有显着的剂量相关作用。与戒酒后1年的禁欲有关的其他变量包括戒烟前的戒酒时间较长，已婚，受过高等教育，配偶不吸烟或其他重要。结果表明，尼古丁口香糖是戒烟的重要辅助手段，与安慰剂口香糖使用者的戒烟几率相比，成功戒烟的几率要高出一倍以上。 4毫克剂量对高依赖性吸烟者的戒烟率没有显着增加。吸烟史和人口统计学变量也对尝试戒烟的结果产生重大影响。

BACKGROUND & AIMS: :The transport of preproteins into or across the mitochondrial inner membrane requires the membrane potential Deltapsi across this membrane. Two roles of Deltapsi in the import of cleavable preproteins have been described: an electrophoretic effect on the positively charged matrix-targeting sequences and the activation of the translocase subunit Tim23. We report the unexpected finding that deletion of a segment within the sorting sequence of cytochrome b(2), which is located behind the matrix-targeting sequence, strongly influenced the Deltapsi-dependence of import. The differential Deltapsi-dependence was independent of the submitochondrial destination of the preprotein and was not attributable to the requirement for mitochondrial Hsp70 or Tim23. With a series of preprotein constructs, the net charge of the sorting sequence was altered, but the Deltapsi-dependence of import was not affected. These results suggested that the sorting sequence contributed to the import driving mechanism in a manner distinct from the two known roles of Deltapsi. Indeed, a charge-neutral amino acid exchange in the hydrophobic segment of the sorting sequence generated a preprotein with an even better import, i.e. one with lower Deltapsi-dependence than the wild-type preprotein. The sorting sequence functioned early in the import pathway since it strongly influenced the efficiency of translocation of the matrix-targeting sequence across the inner membrane. These results suggest a model whereby an electrophoretic effect of Deltapsi on the matrix-targeting sequence is complemented by an import-stimulating activity of the sorting sequence.

背景与目标： ：前蛋白进入或穿过线粒体内膜的运输需要跨该膜的膜电位Δpsi。已经描述了Deltapsi在可裂解的前蛋白的导入中的两个作用：对带正电的基质靶向序列的电泳作用和对转位酶亚基Tim23的激活。我们报告出乎意料的发现，删除细胞色素b（2）的排序序列中位于矩阵目标序列后面的一个段，强烈影响了进口的Deltapsi依赖性。差异Deltapsi依赖性与前蛋白的线粒体目的地无关，并且不依赖于线粒体Hsp70或Tim23的需求。使用一系列前蛋白构建体，分选序列的净电荷发生了变化，但导入的Deltapsi依赖性不受影响。这些结果表明，分拣顺序以不同于Deltapsi的两个已知角色的方式对进口驱动机制做出了贡献。实际上，在分选序列的疏水区段中的电荷中性氨基酸交换产生了具有甚至更好的进口的前蛋白，即，其具有比野生型前蛋白更低的Δpsi依赖性。分选序列在导入途径的早期起作用，因为它强烈影响基质靶向序列跨内膜的转运效率。这些结果提出了一种模型，其中Deltapsi对基质靶向序列的电泳作用被分选序列的导入刺激活性所补充。

BACKGROUND & AIMS: :We compared three unstructured mathematical models, the master reaction, the square root, and the damage/repair models, for describing the relationship between temperature and the specific growth rates of bacteria. The models were evaluated on the basis of several criteria: applicability, ease of use, simple interpretation of model parameters, problem-free determination of model parameters, statistical evaluation of goodness of fit (chi 2 test), and biological relevance. Best-fit parameters for the master reaction model could be obtained by using two consecutive nonlinear least-square fits. The damage/repair model proved to be unsuited for the data sets considered and was judged markedly overparameterized. The square root model allowed nonproblematical parameter estimation by a nonlinear least-square procedure and, together with the master reaction model, was able to describe the temperature dependence of the specific growth rates of Klebsiella pneumoniae NCIB 418, Escherichia coli NC3, Bacillus sp. strain NCIB 12522, and the thermotolerant coccobacillus strain NA17. The square root and master reaction models were judged to be equally valid and superior to the damage/repair model, even though the square root model is devoid of a conceptual basis.

背景与目标： ：我们比较了三种非结构化数学模型，即主反应，平方根和损伤/修复模型，用于描述温度与细菌特定生长速率之间的关系。根据几个标准对模型进行了评估：适用性，易用性，模型参数的简单解释，模型参数的确定无问题，拟合优度的统计评估（χ2检验）和生物学相关性。主反应模型的最佳拟合参数可以通过使用两个连续的非线性最小二乘拟合获得。损坏/修复模型被证明不适合所考虑的数据集，并被判断为参数过大。平方根模型允许通过非线性最小二乘法进行非问题参数估计，并且与主反应模型一起，能够描述肺炎克雷伯菌NCIB 418，大肠杆菌NC3，芽孢杆菌属（Bacillus sp。）特定生长速率的温度依赖性。菌株NCIB 12522和耐热球菌NA17。即使平方根模型没有概念基础，也可以认为平方根模型和主反应模型是同等有效的，并且优于损坏/修复模型。

BACKGROUND & AIMS: :Cancer cells acquire disruptions in normal signal transduction pathways and homeostatic mechanisms that would trigger apoptosis in normal cells. These abnormalities include genomic instability, oncogene activation, and growth factor independent proliferation. Therefore, cancer cells likely require a block in apoptosis in order to survive. Overexpression of the antiapoptotic protein BCL-2 provides a block in apoptosis that is frequently observed in cancer cells. We have developed methods for the detection and analysis of BCL-2 dependence and here apply them to acute lymphoblastic leukemia (ALL). BH3 profiling, a mitochondrial assay that classifies blocks in the intrinsic apoptotic pathway, indicated a dependence on BCL-2 of both ALL cell lines and primary samples. This dependence predicted that BCL-2 would be complexed with select pro-death BH3 family proteins, a prediction confirmed by the isolation of BCL-2 complexes with BIM. Furthermore, the BH3 profiling and protein analysis predicted that ALL cell lines and primary cells would be sensitive to ABT-737 as a single agent. Finally, BH3 profiling and protein studies accurately predicted a relative degree of sensitivity to BCL-2 antagonism in cell lines. The ALL cells studied exhibit BCL-2 dependence, supporting clinical trials of BCL-2 antagonists in ALL as single agents or combination therapies.

背景与目标： 癌细胞会破坏正常信号传导途径和体内稳态机制，从而触发正常细胞的凋亡。这些异常包括基因组不稳定，致癌基因激活和生长因子非依赖性增殖。因此，癌细胞可能需要阻断凋亡才能生存。抗凋亡蛋白BCL-2的过表达提供了在癌细胞中经常观察到的凋亡阻滞作用。我们已经开发出用于检测和分析BCL-2依赖性的方法，并将其应用于急性淋巴细胞白血病（ALL）。 BH3分析，一种线粒体分析，可对内在凋亡途径中的区域进行分类，表明所有细胞系和原代样品均依赖于BCL-2。这种依赖性预示着BCL-2将与选择的死亡前BH3家族蛋白复合，这一预言通过与BIM分离BCL-2复合物得到了证实。此外，BH3分析和蛋白质分析预测，ALL细胞系和原代细胞对ABT-737作为单一试剂会敏感。最后，BH3分析和蛋白质研究准确地预测了细胞系中对BCL-2拮抗作用的相对敏感性。研究的ALL细胞表现出BCL-2依赖性，支持BCL-2拮抗剂在ALL中作为单一药物或联合疗法的临床试验。

BACKGROUND & AIMS: :Risk assessment of environmental contaminants is usually based on experiments on well-fed individuals held at low population densities. However, field populations are often subject to resource limitation. Individuals who are already stressed by crowding or food limitation may show greater susceptibility to toxicants. But density dependence could also reduce population-level impacts as toxicant-related mortalities may reduce competition for resources. This study examines the joint effects of toxicants and food availability on populations of Drosophila melanogaster. The interactions between the effects of food limitation and toxicant stress were dose dependent and strongly influenced by toxicity mechanisms. In food-limited conditions, a compensatory effect often occurred, with toxicant exposure having a lower proportional impact than at higher food levels. This provides further evidence that density-dependent population processes can produce an assimilative capacity for the effects of toxicants. But synergistic food-toxicant effects were also common and the interaction often switched between synergistic and compensatory at different toxicant concentrations and food supplies. There is no simple "less-than-additive", "additive" or "more-than-additive" relationship between density and toxicant effects, even for a single toxicant.

背景与目标： ：对环境污染物的风险评估通常是基于对人口密度低的饮食条件良好的个体进行的实验。但是，野外种群经常受到资源的限制。已经因拥挤或食物不足而承受压力的个人可能对毒物表现出更大的敏感性。但是依赖密度还可以减少对人口水平的影响，因为与毒物有关的死亡率可能会减少对资源的竞争。这项研究检查了有毒物质和食物供应对果蝇果蝇的联合影响。食物限制和毒性应激之间的相互作用是剂量依赖性的，并且受毒性机制的强烈影响。在食物限制的情况下，经常会发生补偿作用，与较高食物水平相比，接触毒物的比例影响要小。这提供了进一步的证据，表明依赖密度的种群过程可以产生有毒物质的同化能力。但是，协同作用的食物毒性作用也很普遍，并且在不同的毒性物质浓度和食物供应下，相互作用经常在协同作用和补偿作用之间切换。即使对于单一毒物，在密度和毒物作用之间也没有简单的“小于添加剂”，“添加剂”或“大于添加剂”关系。

BACKGROUND & AIMS: :When an antipsychotic drug is given repeatedly and intermittently, there is often a long-term increase in its behavioral efficacy, termed antipsychotic sensitization. With the passage of time, the magnitude of antipsychotic sensitization may increase or decrease based on the principle of time-dependent sensitization (TDS) or memory decay, respectively. In the present study, we examined the time-dependent feature and possible dopamine D2 receptor mechanism of sensitization induced by risperidone and asenapine in the conditioned avoidance response test. Well-trained male adult Sprague-Dawley rats were first repeatedly treated with risperidone (1.0mg/kg) or asenapine (0.2mg/kg) and tested for avoidance response daily for 5 consecutive days. Eight, 18 or 38 days after the 5th drug treatment, all rats were retested drug-free to assess the long-term impact of prior risperidone or asenapine treatment. Drug-pretreated rats had significantly lower avoidance than vehicle-pretreated ones on this test, and the group differences increased with the passage of time. In the subsequent drug challenge test at 10, 20 or 40 days after the 5th drug treatment, all rats were injected with a low dose of risperidone (0.3mg/kg) or asenapine (0.1mg/kg). Drug-pretreated rats again made significantly fewer avoidances than controls, confirming the antipsychotic sensitization effect. Finally, in the quinpirole (a D2/3 receptor agonist, 1.0mg/kg, sc)-induced hyperlocomotion test, risperidone-pretreated rats exhibited a significantly higher level of motor activity than the vehicle-pretreated ones. These findings suggest that risperidone and asenapine sensitization is long-lasting, follows the TDS principle, and is likely mediated by D2 receptor supersensitivity.

背景与目标： ：反复或间断使用抗精神病药时，其行为功效通常会长期增加，这被称为抗精神病药致敏作用。随着时间的流逝，基于时间依赖性敏化（TDS）或记忆衰退的原理，抗精神病药敏化的幅度可能会增加或降低。在本研究中，我们在条件回避反应测试中研究了利培酮和阿塞那平致敏的时间依赖性特征和可能的多巴胺D2受体致敏机制。训练有素的雄性成年Sprague-Dawley大鼠首先反复使用利培酮（1.0mg / kg）或阿塞那平（0.2mg / kg）反复治疗，并连续5天每天测试其回避反应。第5次药物治疗后第8、18或38天，所有大鼠均重新进行了无药物测试，以评估先前使用利培酮或阿塞那平治疗的长期影响。在该试验中，药物预处理的大鼠回避率明显低于媒介物预处理的大鼠，且随着时间的流逝，组间差异有所增加。在第5次药物治疗后第10、20或40天进行的随后的药物激发试验中，所有大鼠均注射了低剂量的利培酮（0.3mg / kg）或阿塞那平（0.1mg / kg）。药物预处理的大鼠回避率也大大低于对照组，证实了抗精神病药的致敏作用。最后，在喹吡罗（D2 / 3受体激动剂，1.0mg / kg，皮下注射）诱发的超运动试验中，用利培酮治疗的大鼠的运动活动水平明显高于用载体治疗的大鼠。这些发现表明，利培酮和阿塞那平的致敏作用是持久的，遵循TDS原理，并且可能由D2受体超敏作用介导。

BACKGROUND & AIMS: OBJECTIVE:Native Americans have high rates of drug use and dependence yet little is known concerning its etiology or clinical course. These analyses were conducted to describe the heritability of the use of a variety of illicit drugs, as well as the conditional probability of transitioning from use to dependence for each drug class in a community sample of Native American men and women. METHODS:The sample included 460 participants (190 men and 270 women), recruited through community effort, from eight contiguous Indian reservations in Southern California. Participants were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. The Semi-Structured Assessment for the Genetics of Alcoholism interview retrospectively asks about the initial use and drug dependence of the following illicit drug classes: marijuana, cocaine, stimulants, sedatives, opiates, hallucinogens, and solvents. Heritability of initial use was determined using SOLAR (http://www.sfbr.org/solar/). RESULTS:Ninety-one percent of this select Indian population had tried at least one of the illicit drug classes. The most commonly tried substance was marijuana (88%), followed by stimulants (60%), cocaine (44%), hallucinogens (34%), and solvents (20%). The heritability of initiation of drug use ranged from 0.14 for cocaine to 0.59 for marijuana. The conditional probability of transition from initiation to drug dependence ranged from 0.66 for stimulants to 0.06 for hallucinogens. CONCLUSIONS:These findings suggest that heritability of the initiation of substance use, in Southwest California Indians, may be similar to other population samples. In this population, however, high rates of dependence on marijuana, opiates, and stimulants are seen once initiation of the use of the substance has occurred.

背景与目标： 目的：美国原住民吸毒和依赖程度很高，但对其病因或临床病程知之甚少。进行了这些分析，以描述各种非法药物使用的遗传性，以及在美洲原住民男女社区样本中每种药物类别从使用转变为依赖的条件概率。
方法：样本包括460名参与者（190名男性和270名女性），这些参与者是通过社区努力从南加利福尼亚州的八个连续印第安保留区中招募而来的。使用酒精中毒遗传学的半结构评估法对参与者进行评估。酒精中毒遗传学的半结构评估访谈回顾性询问了以下非法药物类别的初始用途和药物依赖性：大麻，可卡因，兴奋剂，镇静剂，鸦片，致幻剂和溶剂。使用SOLAR（http://www.sfbr.org/solar/）确定了初次使用的遗传力。
结果：在这些选定的印度人口中，有91％曾尝试过至少一种非法药物。最常用的物质是大麻（88％），其次是兴奋剂（60％），可卡因（44％），致幻剂（34％）和溶剂（20％）。吸毒开始的可遗传性范围从可卡因的0.14到大麻的0.59。从引发到药物依赖的条件转移概率从兴奋剂的0.66到致幻剂的0.06不等。
结论：这些发现表明，在西南加州印第安人中，开始使用毒品的遗传力可能与其他人群样本相似。但是，在该人群中，一旦开始使用该物质，对大麻，阿片和兴奋剂的依赖性就很高。