Synthesis and evaluation of 6-(3-[18F]fluoro-2-hydroxypropyl)-substituted 2-pyridylbenzothiophenes and 2-pyridylbenzothiazoles as potential PET tracers for imaging Aβ plaques

3-[¹⁸F]Fluoro-2-hydroxypropyl substituted compounds were synthesized and evaluated as novel ¹⁸F-labeled PET tracers for imaging Aβ plaque in a living brain. All compounds exhibited high binding affinities toward the synthetic Aβ_1–42 aggregate and/or Alzheimer’s disease brain homogenate. In the microPET study with normal mice, the 3-[¹⁸F]fluoro-2-hydroxypropyl substituted compounds resulted in fast brain washout by reducing the lipophilicities of the compounds. Intriguingly, (S)-configured PET tracers, (S)-[¹⁸F]1b and (S)-[¹⁸F]1c, exhibited a 2.8 and 4.0-fold faster brain washout rate at a peak/30 min in the mouse brain than the corresponding (R)-configured PET tracers despite there being no meaningful difference in binding affinities toward Aβ plaque. A further evaluation of (S)-[¹⁸F]1c with healthy rhesus monkeys also revealed excellent clearance from the frontal cortex with ratios of 7.0, 16.0, 30.0 and 49.0 at a peak/30, 60, 90, and 120 min, respectively. These results suggest that (S)-[¹⁸F]1c may be a potential PET tracer for imaging Aβ plaque in a living brain.     

血清sTREM-1、肺功能指数与肺癌患者术后肺部感染的关系及其预测价值研究

目的:探讨血清髓样细胞触发受体-1(sTREM-1)、肺功能指数与肺癌患者术后肺部感染的关系及其预测价值。方法:回顾性分析2016年1月-2019年1月在我院进行手术治疗的115例肺癌患者的临床资料,根据患者术后72 h是否发生肺部感染将其分为感染组(n=28)及未感染组(n=87)。对比两组患者临床资料、术后6 h血清s TREM-1、降钙素原(PCT)水平及术前肺功能指数[第一秒用力呼气量(FEV1)、呼气流量峰值(PEF)]变化,记录感染组患者痰细菌培养结果,采用Logistic分析肺癌患者术后感染的影响因素,并采用受试者工作特征(ROC)曲线分析s TREM-1、FEV1、PEF在肺癌术后感染的预测价值。结果:感染组术后入住ICU比例大于未感染组,感染组TNM分期为IV期的比例大于未感染组(P0.05),感染组术后6 h血清s TREM-1、PCT水平高于未感染组,术前FEV1、PEF水平低于未感染组(P0.05)。感染组痰培养结果提示G-菌为17例,占60.71%;G+菌10例,占35.71%;真菌1例,占3.57%。二元多因素Logistic分析提示术后6 h血清s TREM-1水平升高、术前FEV1下降及PEF下降、术后入住ICU为肺癌患者术后感染的独立影响因素。三者联合预测曲线下面积为0.850(95%CI:1.350～1.745,P=0.000),敏感度与特异性分别为91.3%与80.6%,优于s TREM-1、FEV1、PEF的单独预测效能。结论:s TREM-1水平升高,术前FEV1、PEF水平降低与肺癌患者术后肺部感染密切相关,对s TREM-1、FEV1、PEF三者联合分析对于预测肺癌患者术后肺部感染的发生具有较高的预测价值。     

Genetic background modifies CNS‐mediated sensorimotor decline in the AD‐BXD mouse model of genetic diversity in Alzheimer's disease

Many patients with Alzheimer's dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual's ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer's disease, the AD‐BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD‐BXDs and the relationship to cognitive decline in these mice. We found that age‐ and AD‐related declines in coordination, balance and vestibular function vary significantly across the panel, indicating genetic background strongly influences the expressivity of the familial AD mutations used in the AD‐BXD panel and their impact on motor function. Although young males and females perform comparably regardless of genotype on narrow beam and inclined screen tasks, there were significant sex differences in aging‐ and AD‐related decline, with females exhibiting worse decline than males of the same age and transgene status. Finally, we found that AD motor decline is not correlated with cognitive decline, suggesting that sensorimotor deficits in AD may occur through distinct mechanisms. Overall, our results suggest that AD‐related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease.     

Stable Dynamics Performance and High Efficiency of ABX3‐Type Super‐Alkali Perovskites First Obtained by Introducing H5O2 Cation

Developing new ABX₃‐type perovskites is very important for expanding the family of perovskites and obtaining excellent light absorbing material. One strategy is replacing A site atoms with super‐alkali atoms for the perovskites, but super‐alkali perovskites with stable dynamics performance and high efficiency have not been found until now. Herein, massive super‐alkalis, such as Li₃O, Li₂F, H₅O₂, and so on, are introduced into the cubic CH₃NH₃PbI₃ perovskites, and the perovskites with these super‐alkalis are systematically studied by using ab initio molecular dynamics simulation and density functional theory based first principles calculations. Calculated results indicate that the perovskites with the super‐alkalis including metal atoms show unstable dynamics performance under normal temperature and pressure. On the contrary, the first obtainable super‐alkali perovskites of cubic H₅O₂MBr₃ (M = Ge, Sn, Pb) and H₅O₂PbI₃ show stable dynamics performance. They also show suitable tolerance factors, negative formation energies, tunable direct band gaps, and small effective hole and electron masses. Moreover, the calculated power conversion efficiencies of 23.17% and 22.83% are obtained for the single‐junction solar cells based on the cubic H₅O₂SnBr₃ and H₅O₂PbBr₃ perovskites, respectively.     

Reproductive cycle of the commercially harvested sea urchin (Paracentrotus lividus) along the western coast of Portugal

Harvested populations of the sea urchin (Paracentrotus lividus) from the northwestern (Carreço) and southwestern (Aljezur) coasts of Portugal were surveyed to describe the species reproductive cycle and assess possible relationships with geographical location and seawater temperature. Individuals were sampled monthly to analyze gonad histology, mean gonadal index (GI), and gonadosomatic index (GSI) during 2 consecutive years (November 2010–November 2012). Both populations presented an annual reproductive cycle, with synchronous gonad maturation and gamete release between sexes. Gonad maturation occurred throughout autumn–winter, followed by a single but prolonged spawning season during spring–summer. The duration of the spawning season displayed a latitudinal gradient likely related to the north–south increasing trend in seawater temperature, with the northwestern population (Carreço) exhibiting a shorter spawning period compared to the southwestern population (Aljezur). The timing and duration of the spawning season was compared with several populations throughout the distributional range of P. lividus in the Atlantic Ocean and Mediterranean Sea. In the population from Carreço, the size at first sexual maturity (test diameter = 35.9 mm) was considerably smaller than the minimum conservation reference size (MCRS) of 50 mm test diameter legally established for P. lividus. This study confirms that sustainable exploitation depends on harvesters’ awareness of and compliance with the MCRS and provides useful information for the eventual establishment of a closed season in the harvesting of P. lividus.     

模型膜实验方法在β淀粉样蛋白与细胞膜间相互作用中的应用与改进

β淀粉样蛋白(amyloid β peptide,Aβ)与细胞膜间的相互作用很可能是阿尔茨海默症病(Alzheimer disease, AD)重要的风险因素。模型膜研究方法在该领域的应用和更新持续至今,但仍存在一些问题有待解决,例如,Aβ插膜后聚集状态与Aβ融合到脂质体膜聚集状态的差异,Aβ插膜后形成微通道的时间及与磷脂成分的关系等。本文试图解析这两个问题,同时,系统地总结出常用的和更新的模型膜研究方法,这些方法包括单层膜插膜及电镜样品的制备,脂质体制备方法的改进,脂质体膜上Aβ42经过高盐及酸清洗后的Western 印迹检测,ANTS-DPX研究脂质体泄漏等。研究结果显示：(1)胞外及膜内Aβ42单体与脂质体膜作用后的聚集状态存在差异,Aβ42单体插膜后更容易聚集成纤维,而膜内融合的Aβ42呈现寡聚体形式;(2) Sepharose CL-4B柱过滤比微型挤出器制备的脂质体更加均一分散;(3)Aβ42在膜上形成微通道很可能是一个缓慢的过程,且与脂质体的磷脂种类相关。这些方法为Aβ42与细胞膜的相互作用提供了实用的研究手段,同时也为其他膜蛋白质与细胞膜的相互作用提供了可以借鉴的办法。研究结果使β淀粉样蛋白代谢过程更加清晰。     

Effects of tau phosphorylation on proteasome activity

Dysfunction of proteasome contributes to the accumulation of the abnormally hyperphosphorylated tau in Alzheimer's disease. However, whether tau hyperphosphorylation and accumulation affect the activity of proteasome is elusive. Here we found that a moderate tau phosphorylation activated the trypsin-like activity of proteasome, whereas further phosphorylation of tau inhibited the activity of the protease in HEK293 cells stably expressing tau441. Furthermore, tau hyperphosphorylation could partially reverse lactacystin-induced inhibition of proteasome. These results suggest that phosphorylation of tau plays a dual role in modulating the activity of proteasome.     

营养性缺铁性贫血与注意缺陷多动障碍的临床关系研究——258例病例分析

目的:通过对营养性缺铁性贫血与注意缺陷多动障碍的病例研究,探讨两者之间的关系。方法:对258例NIDA的病因、临床表现和治疗进行临床分析,包括其中的31例中重度ADHD。结果:本组NIDA患儿病因主要为未及时添加富铁辅食、饮食结构不合理、消化道疾病、鼻衄等,临床主要表现为头晕、乏力、注意力不集中、记忆力减退等,对患者进行病因治疗以及服用生血宁片;ADHD的病因不明,临床表现为注意力不集中、活动过度、行为冲动等,通过综合治疗可以改善症状。NIDA的患儿ADHD的发病率较正常儿童为高。结论:NIDA与ADHD的关系密切。     

胆固醇代谢异常与阿尔茨海默氏症

阿尔茨海默氏症(Alzheimer's disease,AD)是一种退行性神经系统疾病。许多已知的AD危险因素都与胆固醇的代谢有关。大量研究发现,胆固醇代谢异常与该病神经变性的机制相关。本文主要综述了近年来关于胆固醇在脑内的代谢过程及其与AD相关因素关系的研究进展。