BACKGROUND & AIMS: :Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder. Despite intensive research efforts, the aetiology of ADHD remains unknown. Current evidence suggests that the aetiology of ADHD is heterogeneous, comprising of multiple factors. Recently, it has been proposed that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be implicated in the pathogenesis of ADHD. This hypothesis is supported by recent genetic studies in ADHD. Drawing on findings from studies into the drugs for ADHD relating to central BDNF expression, hyperactivity in BDNF knockout mice, BDNF effects in midbrain dopaminergic function and the close association between BDNF and the dopamine transporter (an important molecule for ADHD pathogenesis), it is proposed here that decreased central BDNF, particularly in the midbrain region, may play an important role in the pathogenesis ADHD. This hypothesis may have some implications for clinical findings in ADHD (for example, the co-morbidity between ADHD and major depression), and provide a new direction for the development of medication for ADHD treatment.

背景与目标： : 注意力缺陷多动障碍 (ADHD) 是一种常见的儿童精神疾病。尽管进行了大量研究，但ADHD的病因仍然未知。目前的证据表明，ADHD的病因是异质的，由多种因素组成。最近，有人提出，神经营养因子家族的成员脑源性神经营养因子 (BDNF) 可能与ADHD的发病机理有关。该假设得到了ADHD最近的遗传研究的支持。根据对ADHD药物的研究结果，该药物与中枢BDNF表达，BDNF基因敲除小鼠的活动过度，BDNF在中脑多巴胺能功能中的作用以及BDNF与多巴胺转运蛋白 (ADHD发病机理的重要分子) 之间的密切联系有关，在这里提出降低中枢BDNF，特别是在中脑区域，可能在ADHD的发病机理中起重要作用。该假设可能对ADHD的临床发现 (例如，ADHD与重度抑郁症之间的合并症) 具有一定的意义，并为ADHD治疗药物的发展提供了新的方向。

BACKGROUND & AIMS: :Chronic pain may result from hyperexcitability following activation of spinal NMDA receptors. A naturally-derived mammalian peptide, histogranin, may possess NMDA antagonist activity. This study explored the possibility that stable analog [Ser1]Histogranin (SHG) could reduce chronic pain. Neuropathic pain was induced using the chronic constriction injury model (CCI). Intrathecal injection of SHG markedly attenuated the hyperalgesia and allodynia resulting from CCI, nearly normalizing responses. These results suggest that the natural peptide histogranin may be a novel adjunct in neuropathic pain management.

背景与目标： : 脊髓NMDA受体激活后过度兴奋可能导致慢性疼痛。天然衍生的哺乳动物肽组织蛋白可能具有NMDA拮抗剂活性。这项研究探讨了稳定的类似物 [Ser1] 组织蛋白 (SHG) 可以减轻慢性疼痛的可能性。使用慢性收缩损伤模型 (CCI) 诱发神经病理性疼痛。鞘内注射SHG可显着减轻由CCI引起的痛觉过敏和异常性疼痛，几乎使反应正常化。这些结果表明，天然肽组织粒蛋白可能是神经性疼痛管理的新型辅助手段。

BACKGROUND & AIMS: :In monocytes, the fimbriae of the oral pathogen Porphyromonas gingivalis activate cross talk signaling from Toll-like receptor 2 (TLR2) to the beta2 integrin CD11b/CD18, leading to the induction of the high-affinity state of the latter receptor. CD14 plays an important role in this "inside-out" proadhesive pathway by binding fimbriae and facilitating the activation of TLR2 and phosphatidylinositol 3-kinase signaling. In its high-affinity state, CD11b/CD18 mediates monocyte adhesion to endothelial cells and transmigration to sites of infection. We have now shown that P. gingivalis fimbriae function as both an activator and a ligand of CD11b/CD18; thus, fimbriae proactively promote their own binding to monocytes. Indeed, treatments that interfered with fimbria-induced activation of CD11b/CD18 (i.e., blockade of CD14, TLR2, or phosphatidylinositol 3-kinase signaling) also suppressed the cell binding activity of fimbriae, which was largely inducible and CD11b/CD18 dependent. Development of a recombinant inside-out signaling system in Chinese hamster ovary cells confirmed the ability of fimbriae to activate CD14/TLR2 signaling and induce their own CD11b/CD18-dependent binding. Induction of this proadhesive pathway by P. gingivalis fimbriae appeared to take place in lipid rafts. Indeed, methyl-beta-cyclodextrin, a cholesterol-sequestering agent that disrupts lipid raft organization, was found to inhibit the fimbria-induced assembly of CD14/TLR2 signaling complexes and the activation of the high-affinity state of CD11b/CD18. Experiments using macrophages from mice deficient in various pattern recognition receptors indicated that the receptors involved in the inside-out proadhesive pathway (CD14, TLR2, and CD11b/CD18) are important for mediating P. gingivalis internalization within macrophages. It therefore appears that P. gingivalis proactively modulates beta2 integrin adhesive activity for intracellular uptake.

背景与目标： : 在单核细胞中，口腔病原体牙龈卟啉单胞菌的菌毛激活从Toll样受体2 (TLR2) 到 β2整合素CD11b/CD18的串扰信号，导致诱导后者受体的高亲和力状态。CD14通过结合菌毛并促进TLR2和磷脂酰肌醇3-激酶信号的激活，在这种 “由内而外” 的前粘附途径中起重要作用。在其高亲和力状态下，CD11b/CD18介导单核细胞与内皮细胞的粘附并转移到感染部位。我们现在已经证明，牙龈卟啉单胞菌菌毛既是CD11b/CD18的激活剂又是配体。因此，菌毛会主动促进其自身与单核细胞的结合。实际上，干扰菌毛诱导的CD11b/CD18激活 (即CD14，TLR2或磷脂酰肌醇3-激酶信号传导的阻断) 的治疗也抑制了菌毛的细胞结合活性，这在很大程度上是可诱导的并且CD11b/CD18依赖性。在中国仓鼠卵巢细胞中开发了重组的由内而外信号系统，证实了菌毛激活CD14/TLR2信号并诱导其自身CD11b/CD18-dependent结合的能力。牙龈卟啉单胞菌诱导这种前粘附途径似乎发生在脂质筏中。实际上，发现甲基-β-环糊精是一种破坏脂质筏组织的胆固醇螯合剂，可抑制菌毛诱导的CD14/TLR2信号复合物的组装以及CD11b/cd18高亲和力状态的激活。使用缺乏各种模式识别受体的小鼠的巨噬细胞进行的实验表明，参与由内而外的前粘附途径 (CD14，TLR2和CD11b/CD18) 的受体对于介导巨噬细胞内牙龈卟啉单胞菌内化很重要。因此，似乎牙龈卟啉单胞菌主动调节 β2整合素粘附活性以促进细胞内摄取。

BACKGROUND & AIMS: :The sodium iodide symporter (NIS) mediates iodide (I(-)) transport in the thyroid gland and other tissues and is of increasing importance as a therapeutic target and nuclear imaging reporter. NIS activity in vitro is currently measured with radiotracers and electrophysiological techniques. We report on the development of a novel live cell imaging assay of NIS activity using the I(-)-sensitive and genetically encodable yellow fluorescent protein (YFP) variant YFP-H148Q/I152L. In FRTL-5 thyrocytes stably expressing YFP-H148Q/I152L, I(-) induced a rapid and reversible decrease in cellular fluorescence characterized by 1) high affinity for extracellular I(-) (35 muM), 2) inhibition by the NIS inhibitor perchlorate, 3) extracellular Na(+) dependence, and 4) TSH dependence, suggesting that fluorescence changes are due to I(-) influx via NIS. Individual cells within a population of FRTL-5 cells exhibited a 3.5-fold variation in the rate of NIS-mediated I(-) influx, illustrating the utility of YFP-H148Q/I152L to detect cell-to-cell difference in NIS activity. I(-) also caused a perchlorate-sensitive decrease in YFP-H148Q/I152L fluorescence in COS-7 cells expressing NIS but not in cells lacking NIS. These results demonstrate that YFP-H148Q/I152L is a sensitive biosensor of NIS-mediated I(-) uptake in thyroid cells and in nonthyroidal cells following gene transfer and suggest that fluorescence detection of cellular I(-) may be a useful tool by which to study the pathophysiology and pharmacology of NIS.

背景与目标： : 碘化钠同向转运体 (NIS) 介导碘 (I(-)) 在甲状腺和其他组织中的转运，作为治疗靶标和核成像报告基因的重要性日益提高。目前使用放射性示踪剂和电生理技术测量体外的NIS活性。我们报告了使用I(-) 敏感且可遗传编码的黄色荧光蛋白 (YFP) 变体YFP-H148Q/I152L对NIS活性进行新型活细胞成像测定的开发。在稳定表达YFP-H148Q/I152L的FRTL-5甲状腺细胞中，I(-) 诱导细胞荧光的快速和可逆降低，其特征是1) 对细胞外I(-) (35 muM) 的高亲和力，2) NIS抑制剂高氯酸盐的抑制，3) 细胞外Na(+) 依赖性，和4) TSH依赖性，表明荧光变化是由于I(-) 通过NIS流入所致。FRTL-5细胞群内的单个细胞表现出NIS介导的I(-) 流入速率的3.5倍变化，说明YFP-H148Q/I152L用于检测NIS活性的细胞间差异。I(-) 还导致表达NIS的COS-7细胞中YFP-H148Q/I152L荧光的高氯酸盐敏感降低，但在缺乏NIS的细胞中不引起。这些结果表明，YFP-H148Q/I152L是基因转移后甲状腺细胞和非甲状腺细胞中NIS介导的I(-) 摄取的敏感生物传感器，并表明细胞I(-) 的荧光检测可能是研究的有用工具。NIS的病理生理学和药理学。

BACKGROUND & AIMS: BACKGROUND:Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (uPA) are involved in colorectal cancer invasion and metastasis. There is still debate whether the activity of MMP-2 and MMP-9 differs between tumors located in the colon and rectum. We designed this study to determine any differences in the expression of MMP-2, MMP-9 and uPA system between colon and rectal cancer tissues. METHODS:Cancer tissue samples were obtained from colon carcinoma (n = 12) and rectal carcinomas (n = 10). MMP-2 and MMP-9 levels were examined using gelatin zymography and Western blotting; their endogenous inhibitors, tissue inhibitor of metalloproteinase-2 (TIMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), were assessed by Western blotting. uPA, uPAR and PAI-1 were examined using enzyme-linked immunosorbent assay (ELISA). The activity of uPA was assessed by casein-plasminogen zymography. RESULTS:In both colon and rectal tumors, MMP-2, MMP-9 and TIMP-1 protein levels were higher than in corresponding paired normal mucosa, while TIMP-2 level in tumors was significantly lower than in normal mucosa. The enzyme activities or protein levels of MMP-2, MMP-9 and their endogenous inhibitors did not reach a statistically significant difference between colon and rectal cancer compared with their normal mucosa. In rectal tumors, there was an increased activity of uPA compared with the activity in colon tumors (P = 0.0266), however urokinase-type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) showed no significant difference between colon and rectal cancer tissues. CONCLUSION:These findings suggest that uPA may be expressed differentially in colon and rectal cancers, however, the activities or protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, PAI-1 and uPAR are not affected by tumor location in the colon or the rectum.

背景与目标：

BACKGROUND & AIMS: :Malfunction of the SLC26A4 protein leads to Pendred syndrome, characterized by sensorineural hearing loss, often associated with mild thyroid dysfunction and goiter. It is generally assumed that SLC26A4 acts as a chloride/anion exchanger, which in the thyroid gland transports iodide, and in the inner ear contributes to the conditioning of the endolymphatic fluid. Here we describe a fast fluorometric method able to be used to functionally scrutinize SLC26A4 and its mutants described in Pendred syndrome. The validation of the method was done by functionally characterizing the chloride/iodide transport of SLC26A4, and a mutant, i.e. SLC26A4(S28R), which we previously described in a patient with sensorineural hearing loss, hypothyroidism and goiter. Using the fluorometric method we describe here we can continuously monitor and quantify the iodide or chloride amounts transported by the cells, and we found that the transport capability of the SLC26A4(S28R) mutant protein is markedly reduced if compared to wild-type SLC26A4.

背景与目标： : SLC26A4蛋白的故障导致Pendred综合征，其特征是感音神经性听力损失，通常与轻度甲状腺功能障碍和甲状腺肿有关。通常认为SLC26A4充当氯化物/阴离子交换剂，在甲状腺中转运碘化物，在内耳中有助于调节内淋巴液。在这里，我们描述了一种快速荧光测量方法，该方法能够用于功能检查SLC26A4及其在Pendred综合征中描述的突变体。该方法的验证是通过功能表征SLC26A4的氯化物/碘化物转运和突变体即SLC26A4(S28R) 来完成的，我们先前在患有感音神经性听力损失，甲状腺功能减退和甲状腺肿的患者中进行了描述。使用我们在这里描述的荧光法，我们可以连续监测和定量细胞转运的碘化物或氯化物量，并且我们发现与野生型SLC26A4相比，SLC26A4(S28R) 突变蛋白的转运能力显着降低。

BACKGROUND & AIMS: We describe a new principle for assessment of the activity of proteolytic enzymes of all classes and show the application of this principle for the quantitative assay of bacterial collagenase and human matrix metalloproteinases (MMPs). Central to this new principle is the presence of a proenzyme that can be activated into an active enzyme by a single proteolytic event. The regular activation sequence in the proenzyme is replaced using protein engineering by an artificial sequence recognized by the proteinase to be determined. The latter can act as an activator for the newly engineered proenzyme. In the present paper a simple colorimetric assay for the determination for MMPs is described based on this principle. With the aid of protein engineering, a modified pro-urokinase has been prepared in which the activation sequence normally recognized by plasmin (Pro-Arg-Phe-Lys upward arrowIle-Ile-Gly-Gly) has been replaced by a sequence expected to be recognized and hydrolysed by many MMPs (Arg-Pro-Leu-Gly upward arrowIle-Ile-Gly-Gly). The active urokinase resulting from activation of the modified pro-urokinase by a MMP could be measured either directly, using a specific chromogenic peptide substrate for urokinase, or indirectly via urokinase-catalysed plasminogen activation. The response of the assay to equal molar quantities of active MMPs decreases in the order MMP-2>MMP-9>MMP-1>MMP-3>MMP-7. The detection limit for MMP-9 was below 15 pM, corresponding to 3. 75x10(-15) mol per assay. Using the assay, increased MMP activity was detected in synovial tissue extracts from rheumatoid arthritis patients compared with those from osteoarthritis patients, and in stomach tumour extracts as compared with normal stomach tissue extracts.

背景与目标： 我们描述了一种评估所有类别蛋白水解酶活性的新原理，并展示了该原理在细菌胶原酶和人类基质金属蛋白酶 (MMPs) 定量测定中的应用。这一新原理的核心是存在一种原酶，该原酶可以通过一次蛋白水解事件被激活为活性酶。使用蛋白质工程技术将原酶中的常规激活序列替换为待确定的蛋白酶识别的人工序列。后者可以作为新改造的原酶的激活剂。在本文中，基于此原理描述了一种用于确定MMPs的简单比色测定法。借助蛋白质工程，已经制备了一种改良的尿激酶原，其中通常由纤溶酶识别的激活序列 (pro-Arg-Phe-Lys向上arrowIle-Ile-Gly) 已被预期被许多MMPs识别和水解的序列所取代 (Arg-Pro-Leu-Gly向上arrowIle-ile-Gly)。通过MMP激活修饰的尿激酶原而产生的活性尿激酶可以直接，使用尿激酶的特定显色肽底物进行测量，也可以通过尿激酶催化的纤溶酶原活化间接测量。测定对相等摩尔量的活性mmp的响应以MMP-2>MMP-9>MMP-1>MMP-3>MMP-7的顺序降低。MMP-9的检测限低于15μm，对应于3。每项测定75x10(-15) 摩尔。使用该测定法，类风湿关节炎患者的滑膜组织提取物与骨关节炎患者的滑膜组织提取物相比，以及与正常胃组织提取物相比，胃肿瘤提取物中的MMP活性增加。

BACKGROUND & AIMS: :A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 +/- 0.5 microM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC50 = 0.9 +/- 0.2 microM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 +/- 0.02 microM). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [3H]IP accumulation in CHO cells expressing or not expressing the CaSR.

背景与目标： : 主要在N1-arylsulfonyl-N2-[1-(1-萘基) 乙基]-trans-1，2-二氨基环己烷的N1位置进行了构效关系 (SAR) 研究，作用于钙感应受体 (CaSR) 的新的钙离子家族。该系列中最具活性的化合物是4-(三氟甲氧基) 苯磺酰基衍生物7e，在表达CaSR的中国仓鼠卵巢 (CHO) 细胞中，对钙诱导的tri化肌醇磷酸 ([3H]IP) 积累的抑制作用显示出5.4/- 0.5微米的IC50。用甲酰胺代替该化合物的磺酰胺键导致6倍活动增加 (7m，IC50 = 0.9 +/- 0.2微米)。在合成的甲酰胺中，最具活性的化合物之一是4-氯苯基甲酰胺 (1S，2S，1'R)-7n (Calhex 231，IC50 = 0.33 +/- 0.02微米)。(1S，2S，1'R)-7n是根据对化合物7d的非对映异构体之一的x射线晶体学研究得出的。(1S，2S，1'R)-异构体可以在CaSR的煅烧结合袋的三维模型的基础上合理化。C-1甲基的去除或2-萘基或联苯部分取代1-萘基导致煅烧活性的明显损失。化合物7e，7m，并且Calhex 231不刺激表达或不表达CaSR的CHO细胞中的 [3H]IP积累。

BACKGROUND & AIMS: :Long-term cold exposure (5-7 days) is known to induce concomitant increases in the levels of adrenomedullary tyrosine hydroxylase (TH) RNA, protein, and enzyme activity. In this report, we compare the time courses of these changes and investigate the effects of cold exposure on the levels of biopterin, the cofactor required for tyrosine hydroxylation. After only 1 h of cold exposure, TH mRNA abundance increased 71% compared with nonstressed controls. Increases in total cellular TH RNA levels were maximal (threefold over control values) within 3-6 h of cold exposure and remained elevated throughout the duration of the experiment (72 h). TH protein levels increased rapidly after 24 h of cold exposure and reached a maximal value threefold above that of controls at 48-72 h. Despite the relatively rapid and large elevations in TH RNA and protein content, only modest increases in TH activity were detected during the initial 48 h of cold exposure. Adrenomedullary biopterin increased rapidly after the onset of cold exposure, rising to a level approximately twofold that of the nonstressed controls at 24 h, and remained at this level throughout the duration of the stress period. Taken together, the results of this time course study indicate that cold-induced alterations in adrenal TH activity are mediated by multiple cellular control mechanisms, which may include pre- and posttranslational regulation. Our findings also suggest that cold stress-induced increases in the levels of the TH cofactor may represent another key event in the sympathoadrenal system's response to cold stress.

背景与目标： : 已知长期冷暴露 (5-7天) 会引起肾上腺髓质酪氨酸羟化酶 (TH) RNA，蛋白质和酶活性的同时增加。在本报告中，我们比较了这些变化的时间过程，并研究了冷暴露对酪氨酸羟基化所需的辅因子生物蝶呤水平的影响。冷暴露仅1小时后，与无应激对照相比，TH mRNA丰度71% 增加。在冷暴露的3-6小时内，总细胞TH RNA水平的增加最大 (是对照值的三倍)，并且在整个实验期间 (72小时) 保持升高。冷暴露24小时后，TH蛋白水平迅速增加，并在48-72小时达到对照组的三倍的最大值。尽管TH RNA和蛋白质含量的升高相对较快且较大，但在冷暴露的最初48小时内仅检测到TH活性的适度增加。冷暴露开始后，肾上腺髓质生物蝶呤迅速增加，在24小时时升至非应激对照的大约两倍，并在整个应激期内保持在该水平。总之，该时间过程研究的结果表明，冷诱导的肾上腺TH活性的改变是由多种细胞控制机制介导的，其中可能包括翻译前和翻译后的调节。我们的发现还表明，冷应激引起的TH辅因子水平的增加可能是交感肾上腺系统对冷应激反应的另一个关键事件。

BACKGROUND & AIMS: INTRODUCTION:Although the health benefits of walking for physical activity have received increasing research attention, barriers specific to walking are not well understood. In this study, questions to measure barriers to walking for physical activity were developed and tested among college students. The factor structure, test-retest and internal consistency reliability, and discriminant and criterion validity of the perceived barriers were evaluated. METHODS:A total of 305 undergraduate students participated. Participants had a mean age (+/- SD) of 20.6 (+/- 3.02) years, and 70.3% were female. Participants responded to a questionnaire assessing barriers specific to walking for physical activity. Perceived barriers to vigorous exercise, walking for transportation and recreation, and participation in lifestyle activities (such as taking the stairs instead of the elevator) were also assessed. Subsamples completed the walking barriers instrument a second time after 5 days in order to determine test-retest reliability (n = 104) and wore an accelerometer to measure moderate-intensity physical activity (n = 85). RESULTS:Factor analyses confirmed the existence of three factors underlying the perceived barriers to walking questions: appearance (four items), footwear (three items), and situation (three items). Appearance and situational barriers demonstrated acceptable reliability, discriminant validity, and relations with physical activity criteria. After we controlled for barriers to vigorous exercise, appearance and situational barriers to walking explained additional variation in objectively-measured moderate physical activity. CONCLUSION:The prediction of walking for physical activity, especially walking that is unstructured and spontaneous, may be improved by considering appearance and situational barriers. Assessing barriers specific to walking may have important implications for interventions targeting walking as means for engaging in physical activity.

背景与目标：

BACKGROUND & AIMS: :Methyl-β-cyclodextrin (MβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MβCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MβCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MβCDs. Our data revealed varied mass spectrum profiles and pharmacological activities on the reduction of lysosomal cholesterol accumulation in NPC1 fibroblasts for these three preparations of MβCDs obtained from different batches and different sources. Furthermore, a proteomic analysis showed the differences of these three MβCD preparations on amelioration of dysregulated protein expression levels in NPC1 cells. The results demonstrate the importance of prescreening of different cyclodextrin preparations before use as a therapeutic agent. A combination of mass spectrum analysis, measurement of pharmacological activity, and proteomic profiling provides an effective analytical procedure for characterization of cyclodextrins for therapeutic applications.

背景与目标： : 甲基-β-环糊精 (m β cd) 减少Niemann-Pick病C1 (NPC1) 患者成纤维细胞中的溶酶体胆固醇积累。但是，不同实验室报道的m β cd的药理活性有所不同。为了确定这种变异的潜在原因，我们分析了三种m β cds制剂的质谱特征，药理活性以及用不同来源的m β cds处理后NPC1患者成纤维细胞的蛋白表达谱。我们的数据揭示了从不同批次和不同来源获得的这三种m β cds制剂在NPC1成纤维细胞中减少溶酶体胆固醇积累的不同质谱谱和药理活性。此外，蛋白质组学分析表明，这三种m β cd制剂在改善NPC1细胞中蛋白表达水平失调方面存在差异。结果表明，在用作治疗剂之前，对不同的环糊精制剂进行预检查的重要性。质谱分析，药理活性测量和蛋白质组学分析相结合，为表征用于治疗应用的环糊精提供了有效的分析程序。

BACKGROUND & AIMS: :Submitochondrial particles prepared from rat liver during hepatic regeneration exhibit a depressed ATPase activity which is correlated with a decrease in F1 subunit content as shown by SDS-PAGE. Use of an antibody directed against the F1 portion of the H+-ATPase complex demonstrated that there is a definite decrease in the amount of beta-subunit of F1 in both submitochondrial particles and mitochondria from rat liver 24 h after partial hepatectomy.

背景与目标： : 在肝再生过程中从大鼠肝脏制备的亚线粒体颗粒表现出降低的ATPase活性，这与F1亚基含量的降低有关，如sdds-PAGE所示。使用针对H-ATPase复合物的F1部分的抗体表明，部分肝切除术后24小时，大鼠肝脏的线粒体颗粒和线粒体中F1的 β 亚基数量均明显减少。

BACKGROUND & AIMS: :Mitochondrial dysfunction is the most prominent source of oxidative stress in acute and chronic kidney disease. NLRX1 is a receptor of the innate immune system that is ubiquitously expressed and localized in mitochondria. We investigated whether NLRX1 may act at the interface of metabolism and innate immunity in a model of oxidative stress. Using a chimeric mouse model for renal ischemia-reperfusion injury, we found that NLRX1 protects against mortality, mitochondrial damage, and epithelial cell apoptosis in an oxidative stress-dependent fashion. We found that NLRX1 regulates oxidative phosphorylation and cell integrity, whereas loss of NLRX1 results in increased oxygen consumption, oxidative stress, and subsequently apoptosis in epithelial cells during ischemia-reperfusion injury. In line, we found that NLRX1 expression in human kidneys decreased during acute renal ischemic injury and acute cellular rejection. Although first implicated in immune regulation, we propose that NLRX1 function extends to the control of mitochondrial activity and prevention of oxidative stress and apoptosis in tissue injury.

背景与目标： : 线粒体功能障碍是急性和慢性肾脏疾病中氧化应激的最突出来源。NLRX1是先天免疫系统的受体，广泛表达并定位在线粒体中。我们研究了NLRX1是否可能在氧化应激模型中作用于代谢和先天免疫的界面。使用嵌合小鼠肾缺血再灌注损伤模型，我们发现NLRX1以氧化应激依赖性方式保护死亡率，线粒体损伤和上皮细胞凋亡。我们发现NLRX1调节氧化磷酸化和细胞完整性，而NLRX1的丢失会导致缺血再灌注损伤期间的耗氧量增加，氧化应激以及上皮细胞的凋亡。我们发现，在急性肾缺血损伤和急性细胞排斥反应期间，人肾脏中NLRX1的表达降低。尽管首先涉及免疫调节，但我们建议NLRX1功能扩展到控制线粒体活性以及预防组织损伤中的氧化应激和凋亡。

BACKGROUND & AIMS: :A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

背景与目标： : 已经确定了一系列新型的有效且有效的Xa因子抑制剂，该抑制剂在邻氨基苯甲酰胺化学型中具有磺胺嘧啶部分作为新型的S4结合元件。在这种新型P4组中进行铅优化可导致许多有效的Xa因子抑制剂在人血浆中具有出色的抗凝活性。将选定的化合物口服给大鼠，并检查其离体凝血酶原时间延长活性，结果鉴定了化合物5-氯-N-(5-氯吡啶-2-基)-2-(4-(N-(2-二乙基氨基) 乙酰基)-S-甲基磺酰亚胺基) 苯甲酰胺 (18f)。18f的详细药代动力学评估和随后的代谢研究表明存在活性代谢物。该化合物18f及其活性代谢物18b在大鼠动脉和静脉血栓形成模型中均表现出出色的体内功效，并被发现对相关丝氨酸蛋白酶具有高度选择性。基于这一前景，选择化合物18f进行进一步评估。

BACKGROUND & AIMS: :Studies show that both low physical activity (PA) and adiposity are associated with a higher risk of hypertension. However, the relationship between PA and blood pressure in adolescents is controversial and other studies have reported that no association was observed. Of particular interest is the evaluation of whether the association between PA and high blood pressure is independent of adiposity. A sample of 3764 Brazilian adolescents who attend high schools was selected using random cluster sampling. Data were collected using the Global School-based Student Health Survey, anthropometry, and blood pressure readings. The prevalence of high blood pressure was 14.6% (95% Confidence Interval (CI) 13.5-15.7), higher amongst males (20.0%; 95%CI 18.0-22.1) compared with females (10.9%; 95%CI 9.7-12.3). Sixty-six per cent of the adolescents were reported to be insufficiently active. The prevalence of high blood pressure was 12.8% (95%CI 11.0-14.7) amongst active compared with 15.4% (95%CI 14.0-16.9) amongst insufficiently active adolescents. The association between PA and high blood pressure was observed only amongst females after adjusting for waist circumference (odds ratio (OR) 1.67; 95%CI 1.21-2.31) and body mass index (OR 1.71; 95%CI 1.23-2.37). Notwithstanding levels of adiposity, higher PA levels are associated with a lower prevalence of high blood pressure amongst females, although not amongst males.

背景与目标： : 研究表明，低体力活动 (PA) 和肥胖都与高血压的高风险相关。然而，PA与青少年血压之间的关系存在争议，其他研究报告未观察到关联。特别令人感兴趣的是评估PA与高血压之间的关联是否独立于肥胖。采用随机整群抽样的方法，选取了3764名就读高中的巴西青少年样本。数据是使用全球学校学生健康调查，人体测量学和血压读数收集的。高血压的患病率为14.6% (95% 置信区间 (CI) 13.5-15.7)，男性 (20.0%; 95% CI 18.0-22.1) 高于女性 (10.9%; 95% CI 9.7-12.3)。据报告，66% 的青少年活动不足。在活跃的青少年中，高血压的患病率12.8% (95% CI 11.0-14.7)，而在不活跃的青少年中，高血压的患病率为15.4% (95% CI 14.0-16.9)。仅在调整腰围 (比值比 (OR) 1.67; 95% CI 1.21-2.31) 和体重指数 (OR 1.71; 95% CI 1.23-2.37) 后，在女性中观察到PA与高血压之间的关联。尽管肥胖程度较高，但女性中PA水平较高与高血压患病率较低有关，尽管男性中并非如此。