BACKGROUND & AIMS: :In September 2003, Mexico City introduced "Conduce sin Alcohol" (CSA)-drive without alcohol-a program that monitors breath alcohol concentration limits among drivers to reduce road traffic crashes. To our knowledge, no study has evaluated the impact of this program on mortality. We estimated the effect of CSA on the monthly rate of traffic-related deaths (deaths per one million people) in Mexico City. We applied interrupted time series analyses (ITSA) using monthly data from 1998 to 2016, adjusting for number of people covered by a public health insurance, monthly number of public health care facilities in the city, monthly average rain precipitation in milliliters, and number of vehicles registered. Our results show a statistically significant average reduction in the monthly trend of traffic-related deaths of 0.08 per 1 million people/per month after the program was implemented relative to the pre-intervention trend. The relative difference comparing pre- and post-intervention predicted values from the ITSA model shows that there was a 23.2% reduction in the fatality rate. Findings from this study can be used to scale up programs to monitor alcohol concentration limits among drivers in cities with high alcohol-related crashes and deaths where the program has not been implemented.

背景与目标： : 在2003年9月，墨西哥城推出了 “Conduce sin Alcohol” (CSA)-无酒精驾驶-该程序可监视驾驶员之间的呼吸酒精浓度限制，以减少道路交通事故。据我们所知，没有研究评估该计划对死亡率的影响。我们估计了CSA对墨西哥城交通相关死亡率 (每100万人死亡) 的影响。我们使用每月数据1998年2016年应用中断时间序列分析 (ITSA)，并根据公共健康保险覆盖的人数，城市中公共医疗保健设施的每月数量，每月平均降雨量 (以毫升为标准) 和登记的车辆数量进行调整。我们的结果显示，相对于干预前的趋势，实施该计划后，与交通相关的死亡每月趋势平均减少了0.08/100万人/月。比较ITSA模型的干预前后预测值的相对差异表明，死亡率23.2% 降低。这项研究的结果可用于扩大计划的规模，以监测与酒精有关的撞车事故和死亡人数较高的城市中驾驶员的酒精浓度限值，而该计划尚未实施。

BACKGROUND & AIMS: Effects of exogenous cytokines on replication of vesicular stomatitis virus (VSV) in amniotic membrane and placental organ cultures (OC) were studied. We compared the effects observed in OC and established human carcinoma cell linesA549 and HEp-2. Recombinant human tumor necrosis factor alpha (rHuTNF-alpha), added to amniotic membrane, villous, or decidual OC at concentrations of 30 to 3000 U/ml, potentiated VSV replication by 10-1000 fold. Addition of 5 to 10000 U/ml of recombinant human interleukin 6 (rHuIL-6) to OC from 5 placentas was without effect on VSV growth, except one culture in which enhanced VSV replication has been observed. rHuTNF-alpha was found to have no effect on VSV growth in HEp-2 and A549 cell cultures.

In contrast, the placental OC were sensitive to antiviral activity of natural interferons (IFNs)alpha, beta and recombinant IFN-gamma, although A549 cells were 5 to 10 fold more responsive to the cytokines.

背景与目标： 研究了外源性细胞因子对羊膜和胎盘器官培养物 (OC) 中水泡性口炎病毒 (VSV) 复制的影响。我们比较了在OC和建立的人癌细胞线a549和HEp-2中观察到的效果。以30至3000 U/ml的浓度添加到羊膜，绒毛或蜕膜OC中的重组人肿瘤坏死因子 α (rHuTNF-α) 可使VSV复制增强10-1000倍。从5个胎盘向OC中添加5至10000 U/ml的重组人白细胞介素6 (rHuIL-6) 对VSV生长没有影响，除了一个已经观察到增强的VSV复制的培养物。发现rHuTNF-α 对HEp-2和A549细胞培养物中的VSV生长没有影响。
相反，胎盘OC对天然干扰素 (IFN) α，β 和重组IFN-γ 的抗病毒活性敏感，尽管A549细胞对细胞因子的反应要高5到10倍。

BACKGROUND & AIMS: :The small GTPase Rab6 regulates retrograde membrane traffic from endosomes to the Golgi apparatus and from the Golgi to the endoplasmic reticulum (ER). We examined the role of a Rab6-binding protein, TMF/ARA160 (TATA element modulatory factor/androgen receptor-coactivator of 160 kDa), in this process. High-resolution immunofluorescence imaging revealed that TMF signal surrounded Rab6-positive Golgi structures and immunoelectron microscopy revealed that TMF is concentrated at the budding structures localized at the tips of cisternae. The knockdown of either TMF or Rab6 by RNA interference blocked retrograde transport of endocytosed Shiga toxin from early/recycling endosomes to the trans-Golgi network, causing missorting of the toxin to late endosomes/lysosomes. However, the TMF knockdown caused Rab6-dependent displacement of N-acetylgalactosaminyltransferase-2 (GalNAc-T2), but not beta1,4-galactosyltransferase (GalT), from the Golgi. Analyses using chimeric proteins, in which the cytoplasmic regions of GalNAc-T2 and GalT were exchanged, revealed that the cytoplasmic region of GalNAc-T2 plays a crucial role in its TMF-dependent Golgi retention. These observations suggest critical roles for TMF in two Rab6-dependent retrograde transport processes: one from endosomes to the Golgi and the other from the Golgi to the ER.

背景与目标： : 小GTPase Rab6调节从内体到高尔基体以及从高尔基体到内质网 (ER) 的逆行膜运输。我们检查了Rab6-binding蛋白TMF/ARA160 (160 kDa的TATA元件调节因子/雄激素受体共激活因子) 在此过程中的作用。高分辨率免疫荧光成像显示TMF信号包围Rab6-positive高尔基体结构，免疫电子显微镜显示TMF集中在位于水箱尖端的萌芽结构上。RNA干扰对TMF或Rab6的敲除阻止了内吞志贺毒素从早期/循环内体到反式高尔基体网络的逆行运输，导致毒素向晚期内体/溶酶体的分类错误。然而，TMF敲低引起了N-acetylgalactosaminyltransferase-2 (GalNAc-T2) 的Rab6-dependent移位，但没有引起 β1，4-半乳糖基转移酶 (GalT) 的移位。使用嵌合蛋白进行的分析 (其中交换了GalNAc-T2和GalT的细胞质区域) 表明，GalNAc-T2的细胞质区域在其TMF依赖性高尔基体保留中起着至关重要的作用。这些观察结果表明，TMF在两个Rab6-dependent的逆行转运过程中起着关键作用: 一个从内体到高尔基体，另一个从高尔基体到ER。

BACKGROUND & AIMS: :In Saccharomyces cerevisiae, endocytic material is transported through different membrane-bound compartments before it reaches the vacuole. In a screen for mutants that affect membrane trafficking along the endocytic pathway, we have identified a novel mutant disrupted for the gene YJL204c that we have renamed RCY1 (recycling 1). Deletion of RCY1 leads to an early block in the endocytic pathway before the intersection with the vacuolar protein sorting pathway. Mutation of RCY1 leads to the accumulation of an enlarged compartment that contains the t-SNARE Tlg1p and lies close to areas of cell expansion. In addition, endocytic markers such as Ste2p and the fluorescent dyes, Lucifer yellow and FM4-64, were found in a similar enlarged compartment after their internalization. To determine whether rcy1Delta is defective for recycling, we have developed an assay that measures the recycling of previously internalized FM4-64. This method enables us to follow the recycling pathway in yeast in real time. Using this assay, it could be demonstrated that recycling of membranes is rapid in S. cerevisiae and that a major fraction of internalized FM4-64 is secreted back into the medium within a few minutes. The rcy1Delta mutant is strongly defective in recycling.

背景与目标： : 在酿酒酵母中，内吞物质在到达液泡之前通过不同的膜结合区室运输。在筛选影响沿内吞途径的膜运输的突变体中，我们发现了一个新的突变体，该突变体被破坏了YJL204c基因，我们将其重命名为RCY1 (回收1)。RCY1的缺失导致内吞途径的早期阻滞，然后与液泡蛋白分选途径相交。RCY1的突变导致一个扩大的区室的积累，该区室包含t-snan Tlg1p并位于细胞扩增区域附近。此外，内在化后，在类似的扩大的隔室中发现了诸如Ste2p和荧光染料Lucifer yellow和FM4-64的内吞标记。为了确定rcy1Delta是否有回收缺陷，我们开发了一种测定先前内在化FM4-64的回收的方法。这种方法使我们能够实时跟踪酵母中的回收途径。使用该测定法，可以证明在酿酒酵母中膜的再循环是快速的，并且内化的FM4-64的大部分在几分钟内被分泌回培养基中。rcy1Delta突变体在回收方面存在强烈缺陷。

BACKGROUND & AIMS: :gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in insects and is widely distributed in the central nervous system (CNS). GABA acts on ion channel receptors (GABA(A)R) for fast inhibitory transmission and on G-protein-coupled ones (GABA(B)R) for slow and modulatory action. We used immunocytochemistry to map GABA(B)R sites in the Drosophila CNS and compared the distribution with that of the GABA(A)R subunit RDL. To identify GABAergic synapses, we raised an antiserum to the vesicular GABA transporter (vGAT). For general GABA distribution, we utilized an antiserum to glutamic acid decarboxylase (GAD1) and a gad1-GAL4 to drive green fluorescent protein. GABA(B)R-immunoreactive (IR) punctates were seen in specific patterns in all major neuropils of the brain. Most abundant labeling was seen in the mushroom body calyces, ellipsoid body, optic lobe neuropils, and antennal lobes. The RDL distribution is very similar to that of GABA(B)R-IR punctates. However, the mushroom body lobes displayed RDL-IR but not GABA(B)R-IR material, and there were subtle differences in other areas. The vGAT antiserum labeled punctates in the same areas as the GABA(B)R and appeared to display presynaptic sites of GABAergic neurons. Various GAL4 drivers were used to analyze the relation between GABA(B)R distribution and identified neurons in adults and larvae. Our findings suggest that slow GABA transmission is very widespread in the Drosophila CNS and that fast RDL-mediated transmission generally occurs at the same sites.

背景与目标： Γ-氨基丁酸 (GABA) 是昆虫中主要的抑制性神经递质，广泛分布于中枢神经系统 (CNS)。GABA作用于离子通道受体 (GABA(A)R) 以实现快速抑制传递，而作用于g蛋白偶联受体 (GABA(B)R) 以实现缓慢和调节作用。我们使用免疫细胞化学对果蝇CNS中的GABA(B)R位点进行了定位，并将其分布与GABA(A)R亚基RDL的分布进行了比较。为了鉴定GABA能突触，我们培养了对囊泡GABA转运蛋白 (vGAT) 的抗血清。对于一般的GABA分布，我们使用抗谷氨酸脱羧酶 (GAD1) 的抗血清和gad1-GAL4来驱动绿色荧光蛋白。GABA(B)R-免疫反应性 (IR) 点状物在大脑的所有主要神经pil中以特定模式可见。在蘑菇体的花萼，椭球体，视神经叶和触角叶中观察到最丰富的标记。RDL分布与GABA(B) r-ir点状物的分布非常相似。但是，蘑菇体裂片显示rdl-ir，但不显示GABA(B) r-ir材料，并且在其他区域存在细微差异。vGAT抗血清标记在与GABA(B)R相同的区域点出，并似乎显示出GABA能神经元的突触前位点。使用各种GAL4驱动程序来分析成年和幼虫中GABA(B)R分布与鉴定的神经元之间的关系。我们的发现表明，缓慢的GABA传播在果蝇CNS中非常普遍，并且快速的RDL介导的传播通常发生在相同的位点。

BACKGROUND & AIMS: :Outdoor air pollution has been associated with decrements in lung function and growth of lung function in school-age children. Lung function effects have not been examined in preschoolers, with the exception of one study on minute ventilation in newborns. Our goal was to assess the relationship between long- and short-term exposure to traffic-related air pollution and interrupter resistance in 4-year-old children. Lung function was measured using the interrupter resistance method in children participating in a Dutch birth cohort study. Long-term average air pollution concentrations of fine particulate matter, nitrogen dioxide and soot at the residential address at birth were assessed using land-use regression models. Daily average air pollution concentrations on the day of clinical examination were obtained from the Dutch National Air Quality Monitoring Network. Significant associations were found between long-term average air pollution concentrations and interrupter resistance. Interrupter resistance increased by 0.04 kPa·s·L(-1) (95% CI 0.01-0.07) per interquartile range increase (3.3 μg·m(-3)) in fine particle concentration. Short-term exposure was not associated with interrupter resistance. Long-term exposure to traffic-related air pollution was associated with increased interrupter resistance in 4-year-old children, supporting previous birth cohort studies reporting effects of air pollution on subjectively reported respiratory symptoms in preschool children.

背景与目标： : 室外空气污染与学龄儿童肺功能下降和肺功能增长有关。除了一项关于新生儿分钟通气量的研究外，尚未在学龄前儿童中检查肺功能的影响。我们的目标是评估4岁儿童长期和短期暴露于与交通相关的空气污染与中断器抵抗力之间的关系。在参加荷兰出生队列研究的儿童中，使用中断阻力法测量了肺功能。使用土地利用回归模型评估出生时居住地址的细颗粒物，二氧化氮和烟灰的长期平均空气污染浓度。临床检查当天的每日平均空气污染浓度是从荷兰国家空气质量监测网络获得的。发现长期平均空气污染浓度与中断器阻力之间存在显着关联。在细颗粒浓度下，每四分位数范围增加 (3.3 μ g·m(-3))，中断器电阻增加0.04 kPa·s·L(-1) (95% CI 0.01-0.07)。短期暴露与中断器电阻无关。长期暴露于交通相关的空气污染与4岁儿童的中断阻力增加有关，支持先前的出生队列研究，该研究报告了空气污染对学龄前儿童主观报告的呼吸道症状的影响。

BACKGROUND & AIMS: :The insides of cells can be viewed as a treasure trove of targets for therapeutic intervention of diseases or as deposits for contrasting agents. Increasingly the molecules that need to be delivered to the inside of cells for these purposes are macromolecular and membrane impermeable. Cell penetrating peptides (CPPs) have proven abilities to deliver a range of macromolecular cargo into cells thus raising their profile as potential delivery vectors for wide-ranging applications. There is evidence to suggest that CPPs first enter cells through endocytosis and that cytosolic delivery is mediated across endolysosomal membranes. Their capacity to do this, over direct plasma membrane translocation, is likely to depend on the nature and size of the cargo. Cells use a range of endocytic routes to facilitate entry from well characterised pathways regulated by clathrin to more recently discovered and less characterised pathways regulated by clathrin independent mechanisms. These are likely to determine the intracellular fate of cell delivery vectors including those based on cell penetrating peptides. Thus gaining accurate knowledge of their endocytic uptake and traffic is an important characterisation criteria for progress in this field. This review describes the different endocytic pathways that have been identified in mammalian cells and specific reports that have studied the uptake mechanisms and endocytic traffic of cell penetrating peptides and their associated cargo. These cargoes range from short peptides to an increasing library of nanoparticles such as quantum dots, liposomes and polymeric dendrimers. The studies highlight the effectiveness of cell penetrating peptides for delivering these entities into a diverse array of cell types using different endocytic pathways. This is shown using microscopy based colocalisation analysis with the few specific endocytic probes available, and chemical inhibitors of endocytosis that suffer from lack of specificity. Overall, more specific probes, inhibitors and novel technologies are required for accurate characterisation of cellular dynamics of cell penetrating peptide conjugates thus allowing them to reach their full potential as vectors for therapeutics and other payloads.

背景与目标： : 细胞内部可以被视为疾病治疗干预靶标的宝库或对比剂的沉积物。为了这些目的，需要递送到细胞内部的分子越来越多地是大分子和膜不可渗透的。细胞穿透肽 (cpp) 已被证明具有将一系列大分子货物递送到细胞中的能力，从而提高了它们作为广泛应用的潜在递送载体的特性。有证据表明，CPPs首先通过胞吞作用进入细胞，并且胞质递送是跨内溶酶体膜介导的。通过直接质膜移位，它们的能力可能取决于货物的性质和大小。细胞使用一系列内吞途径来促进从网格蛋白调节的特征良好的途径进入到最近发现的，由网格蛋白独立机制调节的特征较少的途径。这些可能会确定细胞递送载体 (包括基于细胞穿透肽的载体) 的细胞内命运。因此，获得有关其内吞吸收和流量的准确知识是该领域进展的重要表征标准。这篇综述描述了在哺乳动物细胞中发现的不同的内吞途径，以及研究了细胞穿透肽及其相关货物的摄取机制和内吞运输的具体报道。这些货物的范围从短肽到越来越多的纳米颗粒库，例如量子点，脂质体和聚合物树状大分子。研究强调了细胞穿透肽使用不同的内吞途径将这些实体递送到各种细胞类型的有效性。这是使用基于显微镜的共定位分析和少数可用的特定内吞探针以及缺乏特异性的内吞作用化学抑制剂来显示的。总的来说，需要更具体的探针、抑制剂和新技术来准确表征细胞穿透肽缀合物的细胞动力学，从而使它们能够作为治疗和其他有效载荷的载体达到其全部潜力。

BACKGROUND & AIMS: :How the occupied KDEL receptor ERD2 is sorted into COPI vesicles for Golgi-to-ER transport is largely unknown. Here, interactions between proteins of the COPI transport machinery occurring during a "wave" of transport of a KDEL ligand were studied in living cells. FRET between CFP and YFP fusion proteins was measured by multifocal multiphoton microscopy and bulk-cell spectrofluorimetry. Ligand binding induces oligomerization of ERD2 and recruitment of ARFGAP to the Golgi, where the (ERD2)n/ARFGAP complex interacts with membrane-bound ARF1. During KDEL ligand transport, interactions of ERD2 with beta-COP and p23 decrease and the proteins segregate. Both p24a and p23 interact with ARF1, but only p24 interacts with ARFGAP. These findings suggest a model for how cargo-induced oligomerization of ERD2 regulates its sorting into COPI-coated buds.

背景与目标： : 如何将占据的KDEL受体ERD2分类为COPI囊泡以进行高尔基体到ER运输，目前尚不清楚。在这里，在活细胞中研究了KDEL配体转运 “波” 过程中发生的COPI转运机制蛋白质之间的相互作用。CFP和YFP融合蛋白之间的FRET通过多焦点多光子显微镜和体细胞荧光光谱法测量。配体结合诱导ERD2的低聚和ARFGAP向高尔基体的募集，其中 (ERD2)n/ARFGAP复合物与膜结合的arf1相互作用。在KDEL配体转运过程中，ERD2与 β-COP和p23的相互作用降低，蛋白质分离。p24a和p23都与ARF1相互作用，但只有p24与ARFGAP相互作用。这些发现为cargo诱导的ERD2寡聚化如何调节其分选为COPI包被的芽提供了一个模型。

BACKGROUND & AIMS: :Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 h in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine.

背景与目标： 拉西地平是一种有效的二氢吡啶类钙通道阻滞剂，用于治疗高血压和动脉粥样硬化。由于其广泛的肝首过代谢和降低的水溶性，该药物的口服生物利用度较低且波动。因此，这项工作旨在通过鼻内纳米拉西地平甘油体的配制来克服上述挑战。Box-Behnken已成功用于甘油体的配方和体外优化。统计分析表明，胆固醇浓度对囊泡大小有显着影响，而磷脂®90g和甘油浓度对包封效率和变形性指数均显示出显着影响。与拉西地平悬浮液相比，优化的配方显示出球形形状，良好的可变形性，220.25 nm的囊泡尺寸，61.97% 的包封效率以及3.65倍的离体渗透增强。共聚焦激光散射显微镜显示，与罗达明染料溶液 (26 µ m) 相比，罗丹明标记的甘油体通过鼻粘膜的穿透深度更高 (最高60 µ m)。此外，与口服药物悬浮液相比，优化的拉西地平甘油小体可显着降低醋酸甲基泼尼松龙诱导的大鼠高血压长达24小时。组织病理学评估显示完整的鼻粘膜上皮衬里，没有炎症或坏死的迹象，证实了所提出的甘油体的安全性和耐受性。声明的结果突显了利用拟议的甘油体作为鼻内递送拉西地平的安全有效平台的潜力。

BACKGROUND & AIMS: :Congenital anomalies are a leading cause of infant mortality and are important contributors to subsequent morbidity. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. We aimed to investigate whether ambient air pollutant and traffic exposures in early gestation contribute to the risk of selected congenital anomalies in the San Joaquin Valley of California, 1997-2006. Seven exposures and 5 outcomes were included for a total of 35 investigated associations. We observed increased odds of neural tube defects when comparing the highest with the lowest quartile of exposure for several pollutants after adjusting for maternal race/ethnicity, education, and multivitamin use. The adjusted odds ratio for neural tube defects among those with the highest carbon monoxide exposure was 1.9 (95% confidence interval: 1.1, 3.2) compared with those with the lowest exposure, and there was a monotonic exposure-response across quartiles. The highest quartile of nitrogen oxide exposure was associated with neural tube defects (adjusted odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). The adjusted odds ratio for the highest quartile of nitrogen dioxide exposure was 1.7 (95% confidence interval: 1.1, 2.7). Ozone was associated with decreased odds of neural tube defects. Our results extend the limited body of evidence regarding air pollution exposure and adverse birth outcomes.

背景与目标： : 先天性异常是婴儿死亡的主要原因，也是导致随后发病的重要因素。研究表明，环境污染物与某些异常之间存在关联，尽管证据有限。我们旨在调查1997-2006年加利福尼亚州圣华金河谷的环境空气污染物和交通暴露是否会导致某些先天性异常的风险。共纳入35个调查关联的7个暴露和5个结果。在调整了母亲的种族/民族，教育程度和多种维生素的使用后，比较几种污染物的最高和最低四分位数暴露时，我们观察到神经管缺陷的几率增加。与最低一氧化碳暴露的神经管相比，一氧化碳暴露最高的神经管缺陷的校正比值比为1.9 (95% 置信区间: 1.1，3.2)，并且在四分位数之间存在单调暴露响应。氮氧化物暴露的最高四分位数与神经管缺陷相关 (调整后的比值比 = 1.8，95% 置信区间: 1.1，2.8)。二氧化氮暴露的最高四分位数的调整比值比为1.7 (95% 置信区间: 1.1，2.7)。臭氧与神经管缺陷的几率降低有关。我们的结果扩展了有关空气污染暴露和不良出生结局的有限证据。

BACKGROUND & AIMS: OBJECTIVES:Associations between cardiovascular mortality and air pollution and noise together were investigated. METHODS:Data from the ongoing Netherlands Cohort Study on Diet and Cancer (120,852 subjects; follow-up 1987-1996) were used. Cox proportional hazard analyses were conducted for the association between cardiovascular mortality and exposure to black smoke, traffic intensity on the nearest road and road traffic noise at the home address. RESULTS:The correlations between traffic noise and background black smoke, and traffic intensity on the nearest road were moderate at 0.24 and 0.30, respectively. Traffic intensity was associated with cardiovascular mortality, with highest relative risk (95% confidence interval) for ischaemic heart disease (IHD) mortality being 1.11 (1.03 to 1.20) (increment 10,000 motor vehicles/24 h). Relative risks for black smoke concentrations were elevated for cerebrovascular (1.39 (0.99 to 1.94)) and heart failure mortality (1.75 (1.00 to 3.05)) (increment 10 microg/m(3)). These associations were insensitive to adjustment for traffic noise. There was an excess of cardiovascular mortality in the highest noise category (>65 dB(A)), with elevated risks for IHD (1.15 (0.86 to 1.53)) and heart failure mortality (1.99 (1.05 to 3.79)). After adjustment for black smoke and traffic intensity, noise risk reduced to unity for IHD mortality and was slightly reduced for heart failure mortality. CONCLUSIONS:Associations between black smoke concentrations and traffic intensity on the nearest road with specific cardiovascular causes of death were not explained by traffic noise in this study.

背景与目标：

BACKGROUND & AIMS: :Latency and eye movement measures were used to examine the effects of aging, clutter, and luminance on visual search for traffic signs embedded in digitized images of driving scenes. Initially 14 older and 14 younger observers classified daytime and nighttime traffic scenes as containing low or high amounts of clutter. Next, an independent sample of 14 younger and 14 older participants searched for traffic signs contained within these scenes. Errors were more common among the elderly. Search efficiency declined with increased clutter and with aging. However, relative to the young, older adults did not suffer disproportionately as a result of increased clutter. The methods developed might be profitably employed to assess sign conspicuity and sign acquisition during driving.

背景与目标： : 使用潜伏期和眼球运动措施来检查老化，混乱和亮度对视觉搜索嵌入驾驶场景数字化图像中的交通标志的影响。最初，有14位年龄较大的观察者和14位年龄较小的观察者将白天和夜间的交通场景归类为包含少量或大量的杂物。接下来，由14名年轻人和14名年龄较大的参与者组成的独立样本搜索了这些场景中包含的交通标志。错误在老年人中更为常见。搜索效率随着混乱和老化而下降。然而，相对于年轻人，老年人并没有因为杂乱增加而遭受不成比例的痛苦。开发的方法可用于评估驾驶过程中的标志显着性和标志获取。

BACKGROUND & AIMS: :Exposures to ambient diesel exhaust particles have been associated with respiratory symptoms and asthma exacerbations in children; however, epidemiologic evidence linking short-term exposure to ambient diesel exhaust particles with airway inflammation is limited. We conducted a panel study with asthmatic and nonasthmatic adolescents to characterize associations between ambient diesel exhaust particle exposures and exhaled biological markers of airway inflammation and oxidative stress. Over four weeks, exhaled breath condensate was collected twice a week from 18 asthmatics and 18 nonasthmatics (ages 14-19 years) attending two New York City schools and analyzed for pH and 8-isoprostane as indicators of airway inflammation and oxidative stress, respectively. Air concentrations of black carbon, a diesel exhaust particle indicator, were measured outside schools. Air measurements of nitrogen dioxide, ozone, and fine particulate matter were obtained for the closest central monitoring sites. Relationships between ambient pollutants and exhaled biomarkers were characterized using mixed effects models. Among all subjects, increases in 1- to 5-day averages of black carbon were associated with decreases in exhaled breath condensate pH, indicating increased airway inflammation, and increases in 8-isoprostane, indicating increased oxidative stress. Increases in 1- to 5-day averages of nitrogen dioxide were associated with increases in 8-isoprostane. Ozone and fine particulate matter were inconsistently associated with exhaled biomarkers. Associations did not differ between asthmatics and nonasthmatics. The findings indicate that short-term exposure to traffic-related air pollutants may increase airway inflammation and/or oxidative stress in urban youth and provide mechanistic support for associations documented between traffic-related pollutant exposures and respiratory morbidity.

背景与目标： : 暴露于环境柴油废气颗粒与儿童的呼吸道症状和哮喘发作有关; 然而，流行病学证据将短期暴露于环境柴油废气颗粒与气道炎症联系在一起是有限的。我们对哮喘和非哮喘青少年进行了一项小组研究，以表征周围柴油废气颗粒暴露与呼出的气道炎症和氧化应激生物标志物之间的关联。在四个星期内，每周两次从纽约市两所学校的18名哮喘患者和18名非哮喘患者 (年龄在14-19岁之间) 收集呼出气冷凝液，并分析pH和8-异前列腺素作为气道炎症和氧化应激的指标，分别。在学校外测量了柴油排气颗粒指示器黑碳的空气浓度。在最近的中央监测点获得了二氧化氮，臭氧和细颗粒物的空气测量值。使用混合效应模型表征了环境污染物与呼出生物标志物之间的关系。在所有受试者中，黑碳的1至5天平均值的增加与呼出气冷凝物pH的降低有关，这表明气道炎症增加，而8-异前列腺素的增加表明氧化应激增加。二氧化氮1至5天平均值的增加与8-异前列腺素的增加有关。臭氧和细颗粒物与呼出的生物标志物不一致。哮喘和非哮喘患者之间的关联没有差异。研究结果表明，短期暴露于与交通有关的空气污染物可能会增加城市青年的气道炎症和/或氧化应激，并为记录与交通有关的污染物暴露与呼吸道发病率之间的关联提供机械支持。

BACKGROUND & AIMS: :Fluorescent protein markers are widely used to report plant membrane traffic; however, effective protocols to quantify fluorescence or marker expression are lacking. Here the 20 residue self-cleaving 2A peptide from Foot and Mouth Disease Virus was used to construct polyproteins that expressed a trafficked marker in fixed stoichiometry with a reference protein in a different cellular compartment. Various pairs of compartments were simultaneously targeted. Together with a bespoke image analysis tool, these constructs allowed biosynthetic membrane traffic to be assayed with markedly improved sensitivity, dynamic range and statistical significance using protocols compatible with the common plant transfection and transgenic systems. As marker and effector expression could be monitored in populations or individual cells, saturation phenomena could be avoided and stochastic or epigenetic influences could be controlled. Surprisingly, mutational analysis of the ratiometric assay constructs revealed that the 2A peptide was dispensable for efficient cleavage of polyproteins carrying a single internal signal peptide, whereas the signal peptide was essential. In contrast, a construct bearing two signal peptide/anchors required 2A for efficient separation and stability, but 2A caused the amino-terminal moiety of such fusions to be mis-sorted to the vacuole. A model to account for the behaviour of 2A in these and other studies in plants is proposed.

背景与目标： : 荧光蛋白标记被广泛用于报告植物膜运输; 然而，缺乏定量荧光或标记表达的有效方案。在这里，来自口蹄疫病毒的20个残基自切割2A肽被用于构建多蛋白，该多蛋白以固定的化学计量与参考蛋白在不同的细胞区室中表达了被贩运的标记。同时针对各种隔室。与定制的图像分析工具一起，这些构建体可以使用与普通植物转染和转基因系统兼容的协议，以显着提高的灵敏度，动态范围和统计意义来分析生物合成膜的流量。由于可以在群体或单个细胞中监测标记物和效应子的表达，因此可以避免饱和现象，并且可以控制随机或表观遗传影响。令人惊讶的是，对比率测定构建体的突变分析表明，2A肽对于有效切割携带单个内部信号肽的多蛋白是必不可少的，而信号肽是必不可少的。相反，带有两个信号肽/锚的构建体需要2A才能有效分离和稳定性，但是2A导致这种融合物的氨基末端部分被错误分选到液泡中。提出了一个模型来说明植物在这些研究和其他研究中的2A行为。

BACKGROUND & AIMS: :We developed a web-based route planning tool for cyclists in Montreal, Canada, using spatial monitoring data for ambient nitrogen dioxide (NO2). With this tool, we estimated exposures to NO2 along shortest routes and lower exposure alternatives using origin-destination survey data. On average, exposures were estimated to be lower by 0.76 ppb (95% CI: 0.72, 0.80) relative to the shortest route, with decreases of up to 6.1 ppb for a single trip. Cumulative exposure levels (ppb km) decreased by approximately 4%. In general, the benefits of decreased exposure could be achieved with little increase (less than 1 km) in the overall route length.

背景与目标： : 我们使用环境二氧化氮 (NO2) 的空间监测数据，为加拿大蒙特利尔的骑自行车者开发了基于网络的路线规划工具。使用此工具，我们使用起点-目的地调查数据估算了最短路线和较低暴露替代方案对NO2的暴露。平均而言，相对于最短路线，暴露量估计降低了0.76 ppb (95% CI: 0.72，0.80)，单次旅行最多减少6.1 ppb。累积暴露水平 (ppbkm) 降低约4%。通常，减少暴露的好处可以在总路线长度几乎不增加 (小于1千米) 的情况下实现。