BACKGROUND & AIMS: :The study was to examine the nature and risk factors associated with road traffic crashes at night in Ghana and identify potential measures to control them. Crash and injury data for the period 2013-2017 were analyzed. The fatality index and fatal crash ratio measures were employed to assess the severity of injuries among traffic participants. Statistical analysis was carried out for the variables using contingency tables and the chi-square (χ2) tests to assess statistical significance. Generally, night-time traffic crashes resulted in severer injury outcomes than crashes in the hours of daylight (χ2(2)=292.7, p < 0.001). The relative risk of death in a night traffic crash was 1.3 times that during the daytime. The risk of death was highest among pedestrians (44%) and motorcyclist (18%) compared to bus/mini-bus occupants (16%) and car occupants (11%) and the observed percentage differences were significant (χ2(14)=2303.2, p < 0.001). Most of the collisions (67%) occurred at the early hours of the night, between 18:00 and 22:00 hours. Poor night visibility coupled with poor visual guidance on roads are the key contributory risk factors associated with night travels. Policies must be geared towards provision of functioning street lights in built-up areas, road line markings, delineators and signage for the highways and arterial roads.

背景与目标： : 这项研究旨在研究与加纳夜间道路交通事故相关的性质和风险因素，并确定控制它们的潜在措施。分析了2013-2017年期间的碰撞和伤害数据。使用死亡指数和致命撞击率测量来评估交通参与者受伤的严重程度。使用列联表和卡方 (χ2) 检验对变量进行统计分析，以评估统计意义。通常，夜间交通事故导致的伤害后果比白天的事故严重 (χ2(2)= 292.7，p  <  0.001)。夜间交通事故的相对死亡风险是白天的1.3倍。与公共汽车/小型公共汽车乘员 (16%) 和汽车乘员 (11%) 相比，行人 (44%) 和摩托车骑士 (18%) 的死亡风险最高，观察到的百分比差异显着 (χ2(14)= 2303.2，p  <  0.001)。大多数碰撞 (67%) 发生在深夜18:00至22:00小时之间。夜间能见度差加上道路上的视觉引导差是与夜间旅行相关的主要危险因素。政策必须针对在建成区提供有效的路灯，道路线标记，公路和主干道的轮廓和标志。

BACKGROUND & AIMS: :BALB/c-H-2dm2 mice (H-2KdI-AdI-EdDd), a congenic strain of BALB/c mice, have a deletion of the class I MHC Ag, H-2Ld. This gene encodes the exclusive class I MHC-restricting gene product for vesicular stomatitis virus-specific cytolytic T lymphocytes. When dm2 mice were immunized with infectious vesicular stomatitis virus, a specific CTL response was generated. These CTL lysed VSV-infected targets that expressed Iad gene products, but not VSV-infected Iad- targets. The CTL were used initially as long term cytolytic lines; 13 CTL clones were derived by limit dilution. All of the clones expressed the phenotype CD3+, CD4+, CD8-; some clones expressed TCR that are members of the V beta 8 family, others did not. The clones were restricted by class II MHC Ag, both I-Ad and I-Ed serving as restricting elements for individual clones of the panel. All of the clones derived from dm2 mice were specific for the immunizing serotype, Indiana, of VSV and did not lyse syngeneic cells infected with VSV of the New Jersey serotype. Studies using defective interfering virus particles, UV light-inactivated virus, and purified micelles of the viral glycoprotein indicated that infectious virus was not required for sensitization of target cells for immune recognition by the class II MHC-restricted CTL clones. Additional studies using recombinant vaccinia virus vectors to sensitize targets confirmed the specificity of the clones for the viral glycoprotein. These studies also demonstrated a cryptic population of class II-restricted CTL in BALB/c lines specific for VSV G. Naturally occurring variant viruses and mutant viruses, selected for escape from neutralization by mAb, were used in an effort to map the determinant(s) recognized; on the basis of patterns of target cell lysis, three groups of epitopes recognized by the clones were defined. Therefore, in the absence of the class I MHC Ag required for a CTL response to VSV, dm2 mice generated CTL with the CD4+ phenotype that recognized different epitopes on the viral glycoprotein, and lysed cells in a class II-MHC restricted, Ag-specific manner.

背景与目标： : BALB/c-H-2dm2小鼠 (H-2KdI-AdI-EdDd) 是BALB/c小鼠的同系菌株，H-2Ld具有I类MHC Ag的缺失。该基因编码水泡性口炎病毒特异性溶细胞T淋巴细胞的唯一I类MHC限制基因产物。当用传染性水泡性口炎病毒免疫dm2小鼠时，会产生特定的CTL反应。这些CTL裂解了表达Iad基因产物的VSV感染的靶标，但不表达VSV感染的Iad靶标。CTL最初用作长期溶细胞系; 通过极限稀释获得13个CTL克隆。所有克隆均表达表型CD3，CD4，CD8-; 一些克隆表达了vβ8家族成员的TCR，而其他克隆则没有。克隆受到II类MHC Ag的限制，i-ad和i-ed均作为面板各个克隆的限制元素。来自dm2小鼠的所有克隆均对VSV的免疫血清型印第安纳州具有特异性，并且不会裂解被新泽西州血清型VSV感染的同系细胞。使用有缺陷的干扰病毒颗粒，紫外线灭活病毒和病毒糖蛋白的纯化胶束进行的研究表明，感染性病毒不需要II类MHC限制性CTL克隆对靶细胞进行免疫识别的敏化。使用重组痘苗病毒载体对靶标敏感的其他研究证实了克隆对病毒糖蛋白的特异性。这些研究还表明，在针对VSV G的BALB/c品系中，具有II类限制性CTL的隐秘群体。天然存在的变异病毒和突变病毒被选择用于逃避mAb的中和，以试图绘制确定的决定因素; 根据靶细胞裂解的模式，定义了克隆识别的三组表位。因此，在缺乏对VSV的CTL应答所需的I类mhcag的情况下，dm2小鼠产生了具有CD4表型的CTL，该表型识别了病毒糖蛋白上的不同表位，并以II类MHC受限的Ag-特异性方式裂解了细胞。

BACKGROUND & AIMS: :Rapid information processing in our nervous system relies on high-frequency fusion of transmitter-filled vesicles at chemical synapses. Some sensory synapses possess prominent electron-dense ribbon structures that provide a scaffold for tethering synaptic vesicles at the active zone (AZ), enabling sustained vesicular release. Here, we review functional data indicating that some central and neuromuscular synapses can also sustain vesicle-fusion rates that are comparable to those of ribbon-type sensory synapses. Comparison of the ultrastructure across these different types of synapses, together with recent work showing that cytomatrix proteins can tether vesicles and speed vesicle reloading, suggests that filamentous structures may play a key role in vesicle supply. We discuss potential mechanisms by which vesicle tethering could contribute to sustained high rates of vesicle fusion across ribbon-type, central, and neuromuscular synapses.

背景与目标： : 我们神经系统中的快速信息处理依赖于化学突触中充满递质的囊泡的高频融合。一些感觉突触具有突出的电子致密带状结构，为在活动区 (AZ) 的突触囊泡提供了束缚的支架，从而实现了持续的囊泡释放。在这里，我们回顾了功能数据，这些数据表明某些中枢和神经肌肉突触也可以维持与带状感觉突触相当的囊泡融合速率。比较这些不同类型的突触的超微结构，以及最近的研究表明，细胞基质蛋白可以束缚囊泡并加快囊泡的重新加载，表明丝状结构可能在囊泡供应中起关键作用。我们讨论了囊泡束缚可能有助于跨带状，中枢和神经肌肉突触持续高速囊泡融合的潜在机制。

BACKGROUND & AIMS: OBJECTIVE:The purpose of this study is to detail the natural coping strategies used by children involved in everyday road traffic accidents (RTAs). The relationship between coping strategies, post-traumatic stress disorder (PTSD), gender and age was investigated. DESIGN:Children aged 7-18 who attended an accident and emergency department following involvement in a RTA were assessed, 6 weeks after their accident (N = 97). A subgroup of 36 children were re-assessed approximately 8 months after the trauma. METHODS:The presence of PTSD was determined via a semi-structured interview incorporating the Clinician Administered Post-traumatic Scale for Children (CAPS-C). Self-completed psychometric assessments were undertaken to assess the presence of clinically significant levels of depression (Birleson Depression Inventory), anxiety (Revised Manifest Anxiety Scale) and coping style (Kidcope). RESULTS:Children involved in RTAs used between 5 and 7 different coping strategies. Younger children and those with PTSD used more strategies than older children and those not suffering from PTSD. Children with PTSD were more likely to use the strategies of distraction, social withdrawal, emotional regulation and blaming others. CONCLUSION:The limitations of Kidcope are discussed and the need to develop more complex ways of assessing childhood coping within a developmental framework highlighted.

背景与目标：

BACKGROUND & AIMS: :The primary objective of this study is the development and application of a 3D road traffic noise attenuation calculation algorithm. First, the traditional empirical method does not address problems caused by non-direct occlusion by buildings and the different building heights. In contrast, this study considers the volume ratio of the buildings and the area ratio of the projection of buildings adjacent to the road. The influence of the ground affection is analyzed. The insertion loss due to barriers (infinite length and finite barriers) is also synthesized in the algorithm. Second, the impact of different road segmentation is analyzed. Through the case of Pearl River New Town, it is recommended that 5° is the most appropriate scanning angle as the computational time is acceptable and the average error is approximately 3.1 dB. In addition, the algorithm requires only 1/17 of the time that the beam tracking method requires at the cost of more imprecise calculation results. Finally, the noise calculation for a large urban area with a high density of buildings shows the feasibility of the 3D noise attenuation calculation algorithm. The algorithm is expected to be applied in projects requiring large area noise simulations.

背景与目标： : 本研究的主要目的是开发和应用3D道路交通噪声衰减计算算法。首先，传统的经验方法没有解决由建筑物的非直接遮挡和建筑物高度不同引起的问题。相比之下，本研究考虑了建筑物的体积比和与道路相邻的建筑物的投影的面积比。分析了地面影响的影响。由于势垒 (无限长度和有限势垒) 导致的插入损耗也在算法中被合成。其次，分析了不同道路分割的影响。通过珠江新城的案例，建议在计算时间可接受且平均误差约为3.1 dB时，以5 ° 为最合适的扫描角度。此外，该算法只需要波束跟踪方法所需的1/17时间，代价是计算结果更加不精确。最后，对具有高密度建筑物的大型城市区域进行噪声计算，表明了3D噪声衰减计算算法的可行性。该算法有望应用于需要大面积噪声模拟的项目中。

BACKGROUND & AIMS: Introduction:With the development of transportation system and the economy, the rapidly increasing number of automobiles brings the associated problem of road traffic noise, especially in metropolitan and densely populated high-rise cities like Hong Kong. In Hong Kong, approximately one million people are affected by severe road traffic noise. Excessive noise exposure is hazardous to the health and wellbeing of people and therefore has drawn progressively more attention in Hong Kong. The Calculation of Road Traffic Noise (CRTN) has been adopted as the sole tool to evaluate road traffic noise in the form of descriptor LA10. The accuracy and suitability of the CRTN method for predicting road traffic noise in Hong Kong were evaluated in this study by comparing the prediction results and measured traffic noise levels. The results show that the CRTN method was able to provide adequate predictions with correlation coefficients of 0.8032 and 0.7626 between the predicted and measured LA10 for 2007 and 2017 respectively. The predicted traffic noise levels on different floors of seven selected residential buildings in 2017 were compared with those predictions for the same buildings in 2007. The worsening traffic noise exposure in these residential buildings was analysed and some suggestions and counter-measures to alleviate the traffic noise problems are put forward. Since the situation of Hong Kong is an example of what may happen in other cities, the present longitudinal study of the road traffic noise in Hong Kong hopes to contribute to a better urban acoustic environment worldwide. Context:Excessive noise exposure is hazardous to the health and wellbeing of people and therefore has drawn progressively more attention in Hong Kong. The urban road traffic noise exposure of residential buildings in Hong Kong over the past decade has been analysed. Aims:This study aims to assess the road traffic noise exposure of residential buildings over the past decade. Settings and Design:Measurements of traffic noise levels at some selected residential buildings were first conducted in 2007, and then repeated at the same buildings in 2017. Material and Methods:The CRTN was adopted to predict the traffic noise levels based on the recorded traffic flow data. Results:The exposure of these buildings to road traffic noise is higher in 2017 than in 2007. The study illustrates that the deterioration of the urban acoustic environment may not be caused by an increased total number of vehicles, but that heavy vehicles are dominantly responsible for the increased traffic noise levels. Restriction of vehicle velocity for urban street canyons is useless for road traffic noise control. Conclusions:This study shows the deterioration of traffic noise levels is mainly due to the increased heavy vehicles instead of the increased total number of vehicles. The alleviation of traffic noise levels by velocity restriction may not be obvious for urban street canyons and may only work with a certain velocity range.

背景与目标：

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。