BACKGROUND & AIMS: :The secretory pathway Ca(2+) ATPase (SPCA) provides the Golgi apparatus with a Ca(2+) supply essential for Ca(2+)-dependent enzymes involved in the post-translational modification of proteins in transit through the secretory pathway. Ca(2+) in the Golgi apparatus is also agonist-releasable and plays a role in hormone-induced Ca(2+) transients. Although the Ca(2+) ATPase inhibitors thapsigargin is more selective for the sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase (SERCA) than for SPCA, no inhibitor has been characterised that selectively inhibits SPCA. A number of inhibitors were assessed for their selectivity to the human SPCA1d compared to the more ubiquitous human SERCA2b. Each isoform was over-expressed in COS-7 cells and the Ca(2+)-dependent ATPase activity measured in their microsomal membranes. Both bis(2-hydroxy-3-tert-butyl-5-methyl-phenyl)methane(bis-phenol) and 2-aminoethoxydiphenylborate (2-APB) selectively inhibited SPCA1d (with IC(50) values of 0.13 μM and 0.18 mM, respectively), which were of 62- and 8.3-fold greater potency than the values for hSERCA2b (IC(50) values; 8.1 μM and 1.5mM, respectively). Other inhibitors tested such as bis-phenol-A, tetrabromobisphenol-A and trifluoperazine inhibited both Ca(2+) ATPases similarly. Furthermore, bis-phenol was able to mobilize Ca(2+) in cells that had been pre-treated with thapsigargin. Therefore we conclude that given the potency and selectivity of bis-phenol it may prove a valuable tool in further understanding the role of SPCA in cellular processes.

背景与目标： ：分泌途径Ca（2）ATPase（SPCA）为高尔基体提供了Ca（2）供应，这对于参与通过分泌途径转运的蛋白质的翻译后修饰的Ca（2）依赖性酶必不可少。高尔基体中的Ca（2）也是激动剂可释放的，并在激素诱导的Ca（2）瞬变中起作用。尽管Ca（2）ATPase抑制剂thapsigargin对肌浆网-内质网Ca（2）ATPase（SERCA）的选择性比对SPCA的选择性更高，但尚无抑制剂选择性抑制SPCA的特征。与更普遍的人SERCA2b相比，评估了许多抑制剂对人SPCA1d的选择性。每个同工型在COS-7细胞中过表达，并在其微粒体膜中测量Ca（2）依赖的ATPase活性。双（2-羟基-3-叔丁基-5-甲基-苯基）甲烷（双酚）和2-氨基乙氧基二苯基硼酸酯（2-APB）选择性抑制SPCA1d（IC（50）值为0.13μM和0.18 mM分别比hSERCA2b的值高62倍和8.3倍（IC（50）值；分别为8.1μM和1.5mM）。测试的其他抑制剂，如双酚A，四溴双酚A和三氟哌嗪类似地抑制了两个Ca（2）ATPases。此外，双酚能够动员已经用毒胡萝卜素预处理的细胞中的Ca（2）。因此，我们得出结论，鉴于双酚的效力和选择性，它可能被证明是进一步了解SPCA在细胞过程中的作用的有价值的工具。

BACKGROUND & AIMS: :Intestinal secretion was evoked in periarterially denervated jejunal segments of anesthetized rats and cats by exposing the intestines to the heat stable (ST) toxins from a strain of Escherichia coli producing both STa and STb toxins. The secretion was significantly inhibited and to about the same relative extent by the addition of each one of the three following drugs: hexamethonium (i.v., rats), lidocaine (applied on the serosal surface, rats) and tetrodotoxin (intra-arterial, cats). Atropine inhibited fluid secretion in some experiments. It is proposed that a nervous mechanism is mediating part of the secretory response to Escherichia coli heat stable toxins, since three different drugs, which influence nervous activity in different ways, significantly diminished the secretory response. A model for the secretory nervous reflex(es) within the enteric nervous system is proposed; Escherichia coli heat stable toxins activate a "receptor cell" in the epithelium, which then stimulates surrounding dendritic nerve endings via the release of unknown substance(s). A nicotinic receptor is involved but further characteristics of the nervous reflex(es) remain to be elucidated.

背景与目标： ：通过将肠暴露于产生STa和STb毒素的大肠杆菌菌株的热稳定（ST）毒素，在麻醉的大鼠和猫的动脉周围神经支配的空肠段中引起肠道分泌。通过添加以下三种药物中的每一种，分泌被显着抑制，并且相对抑制程度大致相同：六甲铵（静脉注射，大鼠），利多卡因（应用于浆膜表面，大鼠）和河豚毒素（动脉内，猫） 。在某些实验中，阿托品抑制体液分泌。提出神经机制介导了对大肠杆菌热稳定毒素的分泌反应的一部分，因为以不同方式影响神经活动的三种不同药物显着降低了分泌反应。提出了肠道神经系统内分泌神经反射的模型。大肠杆菌的热稳定毒素会激活上皮细胞中的“受体细胞”，然后通过释放未知物质刺激周围的树突神经末梢。涉及烟碱样受体，但神经反射的进一步特征尚待阐明。

BACKGROUND & AIMS: :Chronic administration of a high tolbutamide dose to rats induces islet hypertrophy associated with a decreased insulin content per islet and with a diminished insulin release in response to a glucose or leucine stimulus. These changes are reversible after discontinuation of tolbutamide. Chronic administration of a low tolbutamide dose (effective on islet size, on insulin content per islet, or on leucine-induced insulin release is normal in the presence of glucagon (5 mug/ml) or theophylline (5 mM). Since islet hypertrophy occurs following administration of high tolbutamide doses only and is associated with hypofunction rather than with hyperfunction, it seems hardly conceivable that the therapeutic principle of tolbutamide is based on a beta-cytotrophic effect. B-cell hypofunction seems to be due to at least three factors: the decrease in the insulin content per islet, an impairement in secretory signal recognition, and an interference with the process of signal transmission.

背景与目标： ：对大鼠长期给予高剂量的甲苯磺丁酰胺会诱发胰岛肥大，这与每个胰岛的胰岛素含量降低以及对葡萄糖或亮氨酸刺激的胰岛素释放减少有关。停用甲苯磺丁酰胺后，这些变化是可逆的。在存在胰高血糖素（5杯/毫升）或茶碱（5毫米）的情况下，长期给予低剂量的甲苯磺丁酰胺（对胰岛大小，每个胰岛胰岛素含量或亮氨酸诱导的胰岛素释放有效）是正常的。仅在服用高剂量的甲苯磺丁酰胺后，它与功能减退而不是功能亢进有关，因此很难想象甲苯磺丁酰胺的治疗原理是基于β-细胞营养作用，而B细胞功能减退似乎是由于至少三个因素引起的：每个胰岛中胰岛素含量的减少，分泌信号识别的障碍以及对信号传输过程的干扰。

BACKGROUND & AIMS: :The dynamic activities of mitochondria and lysosomes, which play important roles in maintaining cellular homeostasis, were observed without labeling by using highly sensitive photothermal (PT) microscopy. This imaging modality allows for the direct observation of cellular organelles that contain endogenous chromophores, with high temporal and spatial resolution. We identified mitochondria and lysosomes inside living mammalian cells via simultaneous dual-color imaging. Moreover, dynamic imaging revealed that the lysosomes make contact with mitochondria and move between sites within the dynamic mitochondrial network. Since mitochondrial and lysosomal functions are intricately connected, PT microscopy should provide in-depth understanding of cellular functions associated with mitochondria-lysosome communication as well as insights into various human diseases caused by dysfunction of these organelles.

背景与目标： ：通过使用高灵敏度的光热（PT）显微镜，无需标记即可观察到线粒体和溶酶体的动态活动，它们在维持细胞稳态中起着重要作用。这种成像方式可以以高的时间和空间分辨率直接观察包含内生发色团的细胞器。我们通过同步双色成像鉴定了活的哺乳动物细胞内的线粒体和溶酶体。此外，动态成像显示溶酶体与线粒体接触并在动态线粒体网络内的位点之间移动。由于线粒体功能和溶酶体功能错综复杂地联系在一起，因此，PT显微镜应能深入了解与线粒体-溶酶体通讯相关的细胞功能，并深入了解由这些细胞器功能障碍引起的各种人类疾病。

BACKGROUND & AIMS: :Carcinomas develop in complex environments that include a diverse spectrum of cell types that influence tumor cell behavior. These microenvironments represent dynamic systems that contribute to pathologic processes. Damage to DNA is a notable inducer of both transient and permanent alterations in cellular phenotypes. Induction of a DNA damage secretory program is known to promote adverse tumor cell behaviors such as proliferation, invasion, metastasis, and treatment resistance. However, prior studies designed to identify genotoxic stress-induced factors evaluated actively proliferating in vitro cultures of cells such as fibroblasts as experimental models. Conversely, the vast majority of benign cells in a typical tumor microenvironment (TME) are not proliferating but rather exist in quiescent (i.e., G0) or in terminally differentiated states. In this study, the diversity and magnitude of transcriptional responses to genotoxic damage in quiescent prostate fibroblasts were assessed using gene expression profiling. The secretory damage response in quiescent cells was highly concordant with that of actively dividing cells. Quiescent human prostate stroma exposed to genotoxic agents (e.g., mitoxantrone) in vivo resulted in significant upregulation (2.7- to 5.7-fold; P ≤ 0.01) of growth factors and cytokines including IL1β, MMP3, IL6, and IL8. The paracrine effects of damaged quiescent cells consistently increased the proliferation and invasion of prostate cancer cells and promoted cell survival and resistance to apoptosis following exposure to chemotherapy.Implications: Benign quiescent cells in the TME respond to genotoxic stress by inducing a secretory program capable of promoting therapy resistance. Developing approaches to suppress the secretory program may improve treatment responses. Mol Cancer Res; 15(7); 842-51. ©2017 AACR.

背景与目标： 癌在复杂的环境中发展，其中包括影响肿瘤细胞行为的多种细胞类型。这些微环境代表了有助于病理过程的动态系统。 DNA损伤是细胞表型瞬时和永久性变化的明显诱因。已知DNA损伤分泌程序的诱导可促进不良的肿瘤细胞行为，例如增殖，侵袭，转移和治疗抗性。然而，旨在鉴定遗传毒性应激诱导因素的先前研究评估了诸如成纤维细胞等细胞的体外培养中活跃增殖的实验模型。相反，在典型的肿瘤微环境（TME）中，绝大多数良性细胞并未增殖，而是以静止状态（即G0）或终末分化状态存在。在这项研究中，使用基因表达谱评估了静态前列腺成纤维细胞中对遗传毒性损伤的转录反应的多样性和强度。静止细胞的分泌损伤反应与主动分裂细胞的分泌损伤反应高度一致。体内暴露于遗传毒性剂（例如米托蒽醌）的静态人前列腺基质导致生长因子和包括IL1β，MMP3，IL6和IL8在内的细胞因子显着上调（2.7-至5.7倍; P≤0.01）。受损的静态细胞的旁分泌作用持续增加前列腺癌细胞的增殖和侵袭，并促进化疗后的细胞存活和对凋亡的抗性。意义：TME中的良性静态细胞通过诱导能够促进分泌的分泌程序来对遗传毒性应激作出反应。治疗抵抗力。开发抑制分泌程序的方法可以改善治疗反应。分子癌症研究； 15（7）； 842-51。 ©2017 AACR。

BACKGROUND & AIMS: :Specialization of many cells, including the acinar cells of the salivary glands and pancreas, milk-producing cells of mammary glands, mucus-secreting goblet cells, antibody-producing plasma cells, and cells that generate the dense extracellular matrices of bone and cartilage, requires scaling up both secretory machinery and cell-type specific secretory cargo. Using tissue-specific genome-scale analyses, we determine how increases in secretory capacity are coordinated with increases in secretory load in the Drosophila salivary gland (SG), an ideal model for gaining mechanistic insight into the functional specialization of secretory organs. Our findings show that CrebA, a bZIP transcription factor, directly binds genes encoding the core secretory machinery, including protein components of the signal recognition particle and receptor, ER cargo translocators, Cop I and Cop II vesicles, as well as the structural proteins and enzymes of these organelles. CrebA directly binds a subset of SG cargo genes and CrebA binds and boosts expression of Sage, a SG-specific transcription factor essential for cargo expression. To further enhance secretory output, CrebA binds and activates Xbp1 and Tudor-SN. Thus, CrebA directly upregulates the machinery of secretion and additional factors to increase overall secretory capacity in professional secretory cells; concomitant increases in cargo are achieved both directly and indirectly.

背景与目标： ：许多细胞的专业化，包括唾液腺和胰腺的腺泡细胞，乳腺产生乳汁的细胞，粘液分泌的杯状细胞，产生抗体的浆细胞以及产生密集的骨和软骨细胞外基质的细胞，需要扩大分泌机器和特定于细胞类型的分泌货物的规模。使用组织特异性基因组规模的分析，我们确定果蝇唾液腺（SG）中分泌能力的增加如何与分泌负荷的增加协调起来，果蝇唾液腺（SG）是获得有关分泌器官功能专业化的机制的理想模型。我们的发现表明，bZIP转录因子CrebA直接结合编码核心分泌机制的基因，包括信号识别颗粒和受体的蛋白质成分，ER货物转运子，Cop I和Cop II囊泡以及结构蛋白和酶。这些细胞器。 CrebA直接结合SG货物基因的一个子集，而CrebA结合并增强Sage的表达，Sage是货物表达必不可少的SG特异性转录因子。为了进一步增强分泌输出，CrebA结合并激活Xbp1和Tudor-SN。因此，CrebA直接上调分泌机制和其他因素，以增加专业分泌细胞的总体分泌能力。直接和间接实现了货运量的同时增加。

BACKGROUND & AIMS: :Rapid actions of T3 on TSH synthesis in posttranscriptional steps, such as polyadenylation and translation rate, have already been described. The focus of this paper was to characterize rapid actions of T3 on TSH secretion and the involvement of actin and microtubule cytoskeleton in this process. For that, sham-operated (SO) and thyroidectomized (Tx) rats were subjected to acute or chronic treatment with T3. We observed a disarrangement in microtubule and actin cytoskeletons and an increase in Tshb mRNA levels in Tx rats, whereas the total TSH protein content was reduced in the pituitary gland as a whole, but increased in the secretory granules close to the plasma membrane of thyrotrophs, as well as in the extracellular space. The acute T3 dose promoted a rapid increase and redistribution of TSH secretory granules throughout the cytoplasm, as well as a rearrangement in actin and microtubule cytoskeletons. The T3 chronic treatment outcome reinforces the acute effects observed and, additionally, evinces an increase in the α-tubulin content and a rearrangement in microtubule cytoskeleton. Thus, T3 is able to rapidly suppress TSH secretion and, in parallel, to promote a rearrangement in actin and microtubules assembly throughout the pituitary gland, effects that seem to be independent from each other.

背景与目标： ：已经描述了T3在转录后步骤中对TSH合成的快速作用，例如聚腺苷酸化和翻译速率。本文的重点是表征T3对TSH分泌的快速作用以及肌动蛋白和微管细胞骨架在此过程中的参与。为此，对假手术（SO）和甲状腺切除（Tx）大鼠进行T3急性或慢性治疗。我们在Tx大鼠中观察到微管和肌动蛋白细胞骨架的紊乱以及Tshb mRNA水平的增加，而垂体的总TSH蛋白含量总体上减少了，但在靠近甲状腺营养细胞质膜的分泌颗粒中增加了，以及在细胞外空间急性T3剂量促进了TSH分泌颗粒在整个细胞质中的快速增加和重新分布，以及肌动蛋白和微管细胞骨架的重排。 T3慢性治疗的结果可增强观察到的急性作用，此外，还需要增加α-微管蛋白含量和微管细胞骨架的重排。因此，T3能够迅速抑制TSH分泌，并同时促进整个垂体的肌动蛋白和微管装配的重排，效果似乎彼此独立。

BACKGROUND & AIMS: :We report here the interesting case of a 76-year-old man with severe proteinuria who was diagnosed with systemic mastocytosis accompanied by a clonal non-mast-cell lineage haematological disorder (a non-secretory plasma cell dyscrasia). This is a unique report of systemic mastocytosis with a non-secretory plasma cell dyscrasia and nephrotic syndrome. The pathophysiological relevance between these entities along with the probability of occult amyloidosis is discussed.

背景与目标： ：我们在这里报告了一个有趣的案例，该例是一名患有严重蛋白尿的76岁男性，他被诊断患有系统性肥大细胞增多症，并伴有克隆性非肥大细胞系血液系统疾病（非分泌性浆细胞分泌异常）。这是系统性肥大细胞增多伴非分泌性浆细胞分泌异常和肾病综合征的独特报道。讨论了这些实体之间的病理生理相关性以及隐性淀粉样变性的可能性。

BACKGROUND & AIMS: :The secretome of a parasite in its definitive host can be considered to be its genome in trans, to the extent that secreted products encoded by the parasite fulfill their function in the host milieu. The 'extended phenotype' of the filarial parasite, Brugia malayi, is of particular interest because of the evidence that infection results in potent down-modulation of the host immune response. We collected B. malayi 'excretory-secretory' (BES) proteins from adult parasites and using a combination of shotgun LC-MS/MS and 2D gel electrophoresis, identified 80 B. malayi and two host proteins in BES, of which 31 (38%) were detectable in whole worm extract (BmA). Products which were enriched in BES relative to BmA included phosphatidylethanolamine-binding protein (PEB), leucyl aminopeptidase (LAP, homologue of ES-62 from the related filaria Acanthocheilonema viteae), N-acetylglucosaminyltransferase (GlcNAcT) and galectin-1, in addition to the previously described major surface glycoprotein, glutathione peroxidase (gp29, GPX-1) and the cytokine homologue macrophage migration inhibitory factor (MIF-1). One of the most abundant released proteins was triose phosphate isomerase (TPI), yet many other glycolytic enzymes (such as aldolase and GAPDH) were found only in the somatic extract. Among the more prominent novel products identified in BES were a set of 11 small transthyretin-like proteins, and three glutamine-rich-repeat mucin-like proteins. Notably, no evidence was found of any secreted protein corresponding to the genome of the Wolbachia endosymbiont present in B. malayi. Western blotting with anti-phosphorylcholine (PC) monoclonal antibody identified that GlcNAcT, and not the ES-62 homologue, is the major PC-bearing protein in BES, while probing with human filariasis sera showed preferential reactivity to galectin-1 and to processed forms of myotactin. Overall, this analysis demonstrates selective release of a suite of newly identified proteins not previously suspected to be involved at the host-parasite interface, and provides important new perspectives on the biology of the filarial parasite.

背景与目标： ：在寄生虫编码的分泌产物在宿主环境中发挥其功能的范围内，其最终宿主中的寄生虫的分泌组可以认为是其反基因组。丝状寄生虫马来氏布鲁氏菌的“扩展表型”特别受关注，因为有证据表明感染会导致宿主免疫反应强烈下调。我们从成虫体内收集了马来芽孢杆菌的“排泄分泌物”（BES）蛋白，并使用of弹枪LC-MS / MS和2D凝胶电泳的组合，在BES中鉴定出80个马来芽孢杆菌和两种宿主蛋白​​，其中31（38 ％）在整个蠕虫提取物（BmA）中均可检测到。相对于BmA而言，富含BES的产品还包括磷脂酰乙醇胺结合蛋白（PEB），亮氨酰肽酶（LAP，来自相关丝虫棘皮动物丝虫的ES-62的同源物），N-乙酰氨基葡萄糖基转移酶（GlcNAcT）和半乳糖凝集素-1。先前描述的主要表面糖蛋白，谷胱甘肽过氧化物酶（gp29，GPX-1）和细胞因子同源物巨噬细胞迁移抑制因子（MIF-1）。释放最丰富的蛋白质之一是磷酸丙糖异构酶（TPI），但仅在体提取物中发现了许多其他糖酵解酶（如醛缩酶和GAPDH）。在BES中鉴定出的最杰出的新产品中，有11种小运甲状腺素蛋白样蛋白和3种富含谷氨酰胺的重复粘蛋白样蛋白。值得注意的是，没有证据表明存在任何与马来芽孢杆菌中Wolbachia内共生体的基因组相对应的分泌蛋白。用抗磷酸胆碱（PC）单克隆抗体进行的Western印迹鉴定出Blc中主要的PC携带蛋白是GlcNAcT，而不是ES-62同源物，而用人丝虫病血清进行的检测显示出对galectin-1和加工形式的优先反应性肌动蛋白。总的来说，该分析表明选择性释放了一组新鉴定的蛋白质，这些蛋白质以前不怀疑与宿主-寄生虫的界面有关，并为丝虫的生物学提供了重要的新观点。

BACKGROUND & AIMS: :To investigate mechanisms of apical sorting in the secretory pathway of epithelial cells, we expressed varying amounts of the 165 amino acid isoform of vascular endothelial growth factor (VEGF(165)) and transforming growth factor beta1 (TGF-beta1) via replication defective adenoviruses. Apical sorting of both proteins was efficient at low expression levels but saturated or was reversed at high expression levels. High expression levels of TGF-beta1 were effective at competing VEGF(165) out of the apical pathway; however, VEGF(165) did not compete out TGF-beta1. Tunicamycin inhibition experiments showed that the apical polarity of VEGF(165) was independent of N-glycosylation. We conclude that the apical sorting of these two molecules is a saturable, signal-mediated process, involving competition for apical sorting receptors. The sorting of the two proteins does not appear to involve N-glycans as sorting signals, or lectin sorters. The observations are particularly relevant to gene therapy because they demonstrate that overexpression of a transgene can result in undesirable missorting of the encoded protein.

背景与目标： ：为了研究上皮细胞分泌途径中根尖分选的机制，我们通过复制缺陷型腺病毒表达了不同数量的血管内皮生长因子（VEGF（165））的165个氨基酸同工型和转化生长因子beta1（TGF-beta1） 。两种蛋白质的顶端分选在低表达水平下均有效，但在高表达水平下饱和或逆转。 TGF-beta1的高表达水平可以有效地将VEGF（165）竞争出根尖通路。但是，VEGF（165）不能与TGF-beta1竞争。衣霉素抑制实验表明，VEGF（165）的顶端极性与N-糖基化无关。我们得出结论，这两个分子的根尖分选是一个可饱和的，信号介导的过程，涉及到对根尖分选受体的竞争。两种蛋白质的分选似乎不涉及N-聚糖作为分选信号或凝集素分选仪。这些发现与基因治疗特别相关，因为它们证明了转基因的过表达会导致所编码蛋白的错误缺失。

BACKGROUND & AIMS: :Recent seroepidemiological and immunohistochemical studies have demonstrated an association between microbial infections and atherosclerosis. However, the mechanisms underlying this association are widely unknown. In the present study, arterial specimens obtained at autopsy after sudden death were analyzed concerning (1) the presence of Chlamydia pneumoniae, cytomegalovirus, herpes simplex virus, and Helicobacter pylori; (2) the expression of secretory group IIA phospholipase A(2) (sPLA(2)-IIA) and of proinflammatory cytokines; and (3) the stage of atherosclerosis. Genomic DNA of microbial pathogens was determined by the polymerase chain reaction technique. The expression of sPLA(2)-IIA was studied immunohistochemically by using monoclonal antibodies against human sPLA(2)-IIA. Transcripts specific for sPLA(2)-IIA, interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma were identified by reverse transcription-polymerase chain reaction. In 18 of 102 analyzed specimens, DNA of microbial pathogens was found. Thirteen sections were positive for C pneumoniae, whereas 2 specimens were positive either for cytomegalovirus or for herpes simplex virus. One section contained genomic DNA of all 3 pathogens simultaneously. None of the analyzed tissues exhibited nucleic acids specific for H pylori. In addition to macrophage infiltrates, the presence of microbial DNA was closely associated with the occurrence of transcripts specific for proinflammatory cytokines and sPLA(2)-IIA. Pathogens as well as sPLA(2)-IIA and cytokines were found to be present not only in advanced but also in early stages of atherosclerosis. In tissues negative for sPLA(2)-IIA and cytokine expression, none of the pathogens could be identified. Because macrophages exposed to phospholipase A(2)-treated lipoproteins are transformed into foam cells in vitro, the results of this study suggest an alternative mechanism by which microbial infections may act in a proatherogenic fashion in vessel walls.

背景与目标： ：最近的血清流行病学和免疫组化研究表明，微生物感染与动脉粥样硬化之间存在关联。但是，这种关联的基础机制是广泛未知的。在本研究中，分析了在突然死亡后尸体解剖获得的动脉标本，其中涉及：（1）肺炎衣原体，巨细胞病毒，单纯疱疹病毒和幽门螺杆菌的存在； （2）分泌型IIA磷脂酶A（2）（sPLA（2）-IIA）和促炎细胞因子的表达； （3）动脉粥样硬化的阶段。通过聚合酶链反应技术确定了微生物病原体的基因组DNA。 sPLA（2）-IIA的表达是通过使用抗人sPLA（2）-IIA的单克隆抗体进行免疫组织化学研究的。通过逆转录聚合酶链反应鉴定了对sPLA（2）-IIA，白介素-1β，肿瘤坏死因子-α和干扰素-γ特异的转录本。在102个分析标本中的18个中，发现了微生物病原体的DNA。肺炎衣原体阳性的13个切片，而巨细胞病毒或单纯疱疹病毒的2个标本均为阳性。一块包含了所有三种病原体的基因组DNA。所分析的组织均未显示出对幽门螺杆菌具有特异性的核酸。除了巨噬细胞浸润，微生物DNA的存在与促炎细胞因子和sPLA（2）-IIA特异的转录物的出现密切相关。发现病原体以及sPLA（2）-IIA和细胞因子不仅存在于动脉粥样硬化的晚期，而且也存在于动脉粥样硬化的早期。在sPLA（2）-IIA和细胞因子表达阴性的组织中，没有发现任何病原体。由于暴露于磷脂酶A（2）处理的脂蛋白的巨噬细胞在体外转化为泡沫细胞，因此本研究的结果提出了一种微生物感染可能以血管生成方式在血管壁上起作用的替代机制。

BACKGROUND & AIMS: :The present study was conducted to examine the effect of organochlorine (Heptachlor, Benzene hexachloride (BHC)), organophosphorus (Malathion, Monitor) and pyrethroid (Karate, Talstar) insecticides on the thyroid secretory function in rats. Heptachlor (0.5 mg per rat), BHC (0.66 mg per rat) Malathion (0.06 mg per rat), Monitor (0.2 mg per rat), Karate (0.2 mg per rat), Talstar (0.5 mg per rat) were orally administered to young adult rats for 21 days. Serum concentrations of triiodothyronine (T3), thyroxine (T4) and thyrotrophin (TSH) were determined by using specific radioimmunoassays. Body weight was not affected by treatment with any insecticide except Talstar (P < 0.01). Among organochlorine and organophosphorus insecticides, treatment with BHC and Malathion, respectively, led to a significant decrease (P < 0.01) in serum concentration of T3 and T4. Administration of BHC and Malathion also increased (P < 0.01) TSH secretion. Treatment with both of the pyrethroid insecticides similarly induced significant suppression (P < 0.01) of serum T3 and T4 levels, and concomitant stimulation (P < 0.01) of TSH concentrations. The T4/T3 ratio was decreased (P < 0.05) in rats treated with Karate but not with any other insecticide. These data indicate that immense care is warranted in the use of insecticides, because they not only affect the liver, kidney and other organs but also may alter the activity of the endocrine glands.

背景与目标： ：本研究旨在检查有机氯（七氯，六氯化苯（BHC）），有机磷（马拉硫磷，监控器）和拟除虫菊酯（空手道，Talstar）杀虫剂对大鼠甲状腺分泌功能的影响。口服给予七氯（0.5 mg每只大鼠），BHC（0.66 mg每只大鼠）马拉硫磷（0.06 mg每只大鼠），监测器（0.2 mg每只大鼠），空手道（0.2 mg每只大鼠），Talstar（0.5 mg每只大鼠）口服年轻的成年大鼠21天。使用特定的放射免疫分析法测定血清三碘甲状腺素（T3），甲状腺素（T4）和促甲状腺素（TSH）的浓度。体重不受除Talstar以外的任何杀虫剂治疗的影响（P <0.01）。在有机氯和有机磷杀虫剂中，分别用BHC和马拉硫磷处理可导致T3和T4血清浓度显着降低（P <0.01）。施用BHC和马拉硫磷也可增加（P <0.01）TSH分泌。两种拟除虫菊酯类杀虫剂的处理均相似地引起血清T3和T4水平的显着抑制（P <0.01），并同时刺激TSH浓度（P <0.01）。用空手道但未使用任何其他杀虫剂治疗的大鼠，T4 / T3比降低（P <0.05）。这些数据表明，在使用杀虫剂时必须格外小心，因为它们不仅影响肝脏，肾脏和其他器官，而且还可能改变内分泌腺的活性。

BACKGROUND & AIMS: :Secretory immunoglobulin A (sIgA) in saliva and cardiovascular activity were measured at rest and in response to three film extracts varying in affective content. Subjective ratings of film impact confirmed a priori assumptions; the humorous film was rated as funnier than the other two films, the didactic film as more boring than the other two films, and the exciting film as more exciting and more stressful than the other two films. The films elicited distinct patterns of cardiovascular autonomic activity. The exciting film provoked changes characteristic of beta-adrenergic activation: increased systolic blood pressure (SBP); heart rate (HR); cardiac output (CO); and shortened pre-ejection period (PEP). The didactic film had little impact on cardiovascular activity. While an increase in total peripheral resistance (TPR) occurred, the humorous film was largely notable for a reduction in beta-adrenergic drive, as evidenced by reduced CO and a lengthening of PEP. In contrast to previous research reporting a rise in sIgA particular to humorous exposures, the sIgA secretion rate, although enhanced by exposure to the films, did not vary with film content.

背景与目标： ：静息时和响应情感含量变化的三种薄膜提取物时，测量唾液和心血管活动中的分泌型免疫球蛋白A（sIgA）。电影冲击力的主观评价证实了先验的假设；幽默影片被认为比其他两部电影更有趣，教actic电影比其他两部电影更无聊，激动人心的电影比其他两部电影更令人兴奋和压力更大。影片引起了心血管自主活动的不同模式。激动人心的影片激起了β-肾上腺素激活特征的改变：收缩压升高（SBP）；收缩压升高。心率（HR）;心输出量（CO）；并缩短了射血前期（PEP）。放映膜对心血管活动影响很小。虽然总外周阻力（TPR）升高，但幽默片在很大程度上显着降低了β-肾上腺素驱动，这可通过降低CO和PEP的延长来证明。与以前的研究报道的sIgA升高（尤其是体液暴露）相反，尽管sIgA分泌速率虽然通过暴露于薄膜而增加，但并未随薄膜含量而变化。

BACKGROUND & AIMS: :The processing of the amyloid precursor protein (APP) has become a major focus of research into Alzheimer's disease (AD). Recently, repeated doses of testosterone have been shown to enhance the secretion of the product of the alpha-cleavage pathway of APP (sAPPalpha) over a period of days. Here, the time course of secretion of sAPPalpha after a single physiological dose of testosterone using an immortalized rat hypothalamic cell line (GT1-7) and the signalling pathways involved was analyzed. Testosterone was found to increase the amount of APP secretion rapidly after treatment without effecting the overall amount of cellular APP. The species of APP secreted was found to be predominantly the product of the non-amyloidogenic alpha-secretory pathway. Further, this event is regulated via aromatase-mediated conversion of testosterone to estrogen and the mitogen-activated protein kinase (MAP kinase) signalling pathway. Taken together these data partially elucidates the cellular cascade by which testosterone stimulates sAPP secretion.

背景与目标： ：淀粉样蛋白前体蛋白（APP）的加工已成为阿尔茨海默氏病（AD）研究的主要重点。最近，已显示重复剂量的睾丸激素可在几天内增强APP（sAPPalpha）的alpha裂解途径的产物的分泌。在这里，分析了使用永生化的大鼠下丘脑细胞系（GT1-7）进行单次生理剂量的睾丸激素分泌后sAPPalpha分泌的时程和涉及的信号通路。发现睾丸激素可在治疗后迅速增加APP分泌​​量，而不会影响细胞APP的总量。发现分泌的APP种类主要是非淀粉样生成的α分泌途径的产物。此外，该事件是通过芳香酶介导的睾丸激素向雌激素的转化以及有丝分裂原激活的蛋白激酶（MAP激酶）信号传导途径来调节的。这些数据加在一起，部分阐明了睾丸激素刺激sAPP分泌​​的细胞级联反应。

BACKGROUND & AIMS: BACKGROUND:To maintain organelle integrity, resident proteins must segregate from itinerant cargo during secretory transport. However, Golgi resident enzymes must have intimate access to secretory cargo in order to carry out glycosylation reactions. The amount of cargo and associated membrane may be significant compared to the amount of Golgi membrane and resident protein, but upon Golgi exit, cargo and resident are efficiently sorted. How this occurs in live cells is not known. RESULTS:We observed partitioning of the fluorescent Golgi resident T2-CFP and fluorescent cargo proteins VSVG3-YFP or VSVG3-SP-YFP upon Golgi exit after a synchronous pulse of cargo was released from the ER. Golgi elements remained stable in overall size, shape and relative position as cargo emptied. Cargo segregated from resident rapidly by blebbing into micron-sized domains that contained little or no detectable resident protein and that appeared to be continuous with the parent Golgi element. Post-Golgi transport carriers (TCs) exited repeatedly from these domains. Alternatively, entire cargo domains exited Golgi elements, forming large TCs that fused directly with the plasma membrane. However, domain formation did not appear to be an absolute prerequisite for TC exit, since TCs also exited directly from Golgi elements in the absence of large domains. Quantitative cargo-specific photobleaching experiments revealed transfer of cargo between Golgi regions, but no discrete intra-Golgi TCs were observed. CONCLUSIONS:Our results establish domain formation via rapid lateral partitioning as a general cellular strategy for segregating different transmembrane proteins along the secretory pathway and provide a framework for consideration of molecular mechanisms of secretory transport.

背景与目标： 背景：为保持细胞器的完整性，在分泌运输过程中，驻留蛋白必须与流动的货物分离。但是，高尔基驻地酶必须密切接触分泌物才能进行糖基化反应。与高尔基膜和驻留蛋白的数量相比，货物和相关膜的数量可能很重要，但是在高尔基体退出后，货物和驻留的有效分类。在活细胞中如何发生这种情况尚不清楚。
结果：我们观察到从ER释放同步脉冲后，高尔基体退出时，荧光高尔基体驻留的T2-CFP和荧光体货物蛋白VSVG3-YFP或VSVG3-SP-YFP之间的分配。清空货物后，高尔基体的整体尺寸，形状和相对位置保持稳定。货物通过起泡迅速进入微米级的区域，从居民中快速分离出来，该域中几乎没有或没有可检测的居民蛋白，并且似乎与母高尔基体元素是连续的。高尔基后运输承运人（TC）反复从这些域中退出。或者，整个货物区域都离开高尔基体，形成直接与质膜融合的大TC。但是，域形成似乎不是TC退出的绝对先决条件，因为在没有大域的情况下TC也直接从高尔基体中退出。特定于货物的定量光漂白实验表明，货物在高尔基体区域之间转移，但未观察到离散的高尔基体内部TC。
结论：我们的研究结果建立了通过快速横向分区形成结构域的方法，将其作为沿着分泌途径分离不同跨膜蛋白的一般细胞策略，并为考虑分泌转运的分子机制提供了框架。