The unexplored potential of quinone methides in chemical biology

Quinone methides (QMs) are transient reactive species that can be efficiently generated from stable precursors under a variety of biocompatible conditions. Due to their electrophilic nature, QMs have been widely explored as cross-linking agents of DNA and proteins under physiological conditions. However, QMs also have a diene character and can irreversibly react via Diels-Alder reaction with electron-rich dienophiles. This particular reactivity has been recently exploited to label biomolecules with fluorophores in living cells.QMs are characterised by two unique properties that make them ideal candidates for chemical biology applications: i) they can be efficiently generated in situ from very stable precursors by means of bio-orthogonal protocols ii) they are reversible cross-linking agents, making them suitable for “catch and release” target-enrichment experiments. Nevertheless, there are only few examples reported to date that truly take advantage of QMs unique chemistry in the context of chemical-biology assay development. In this review, we will examine the most relevant examples that illustrate the benefit of using QMs for chemical biology purposes and we will anticipate novel approaches to further their applications in biologically relevant contexts.     

基于空间频域滤波高动态光学投影层析的斑马鱼三维成像研究

本文提出了一种基于空间频率滤波的多曝光融合的高动态投影层析三维成像方法,实现了活体斑马鱼（17 mm × 4 mm,最大厚度为2.33 mm,最小厚度为0.29 mm）的三维结构成像. 通过相机采用不同曝光时间记录系列吸收图像,将每张图像取变换到频域去除低频后,将各张滤波后叠加并逆傅里叶变换回空域,对变换后的图像进行归一化处理,最终获得高动态图像. 在每个投影角度获得这种高动态吸收投影图像,进行滤波反投影算法重建,获得高动态的整条斑马鱼三维结构信息. 实验成像结果表明,这种空间频率滤波多曝光融合的高动态光学投影层析三维成像研究,可以获得复杂结构更丰富的空间信息,对斑马鱼等模式生物早期胚胎生长发育进程进行监测和定量评估有一定的应用前景.     

精神药理影像遗传学研究进展及其临床应用前景

精神疾病危害严重,其发病机制复杂难解,临床治疗效果不一,且存在明显的个体差异.近期精准医学研究发现精神药物作用于脑神经的生化过程受到遗传多态性的影响.本文从五羟色胺能、去甲肾上腺素能和多巴胺能三大系统入手,系统综述精神药理影像遗传学的相关研究进展,深入探讨精神药理的神经作用机制以及药物-基因-脑之间的交互作用.我们发现:SLC6A4、BDNF、FKBP5、COMT和多巴胺相关受体等基因多态性与多种精神疾病的发生发展及其治疗效果具有一定的相关性,可能成为相关精神疾病诊断的候选基因.杏仁核、海马、眶额叶、扣带回和前额叶等皮层与皮层下脑结构可能是不同神经递质相关的基因多态性影响精神药物生化作用过程的关键靶点脑区.在建立精神药物-基因-脑影像-行为的因果链中,仍然存在很多相互矛盾的结果和一定的局限性.因此,开展同质性强的临床试验、研究表观遗传作用等可以作为未来的研究发展趋势.     

基于精神影像和人工智能的抑郁症客观生物学标志物研究进展

抑郁症是当今社会上造成首要危害且病因和病理机制最为复杂的精神疾病之一,寻找抑郁症的客观生物学标志物一直是精神医学研究和临床实践的重点和难点,而结合人工智能技术的磁共振影像(magnetic resonance imaging,MRI)技术被认为是目前抑郁症等精神疾病中最有可能率先取得突破进展的客观生物学标志物.然而,当前基于精神影像学的潜在抑郁症客观生物学标志物还未得到一致结论 .本文从精神影像学和以机器学习(machine learning,ML)与深度学习(deep learning, DL)等为代表的人工智能技术相结合的角度,首次从疾病诊断、预防和治疗等三大临床实践环节对抑郁症辅助诊疗的相关研究进行归纳分析,我们发现:a.具有诊断价值的脑区主要集中在楔前叶、扣带回、顶下缘角回、脑岛、丘脑以及海马等;b.具有预防价值的脑区主要集中在楔前叶、中央后回、背外侧前额叶、眶额叶、颞中回等;c.具有预测治疗反应价值的脑区主要集中在楔前叶、扣带回、顶下缘角回、额中回、枕中回、枕下回、舌回等.未来的研究可以通过多中心协作和数据变换提高样本量,同时将多元化的非影像学数据应用于数据挖掘,这将有利于提高人工智能模型的辅助分类能力,为探寻抑郁症的精神影像学客观生物学标志物及其临床应用提供科学证据和参考依据.     

基于双荧光系统的HepG2肝细胞癌原位移植裸鼠模型建立及活体荧光成像动态定量分析

目的:建立一种可以实时、定量、动态监测的肝细胞癌原位移植模型,并利用活体荧光成像系统对裸鼠体内原位肝细胞癌生长进行分析。方法:利用慢病毒包装系统包装pCDH-GFP-Luc质粒,将绿色荧光蛋白(GFP)和萤光素酶(Luc)基因通过病毒感染的方式整合到HepG2肝癌细胞染色体中,利用流式细胞术分选GFP+细胞,扩增培养后,将该细胞注射到裸鼠皮下进行成瘤,成瘤后分离肿瘤组织接种裸鼠肝脏,将造模成功的裸鼠分为对照组和治疗组,分别灌胃给与0.5%羧甲基纤维素钠(CMC-Na)和50 mg/kg索拉非尼,2/d,连续28 d,每7 d利用活体荧光成像系统观察肝癌细胞在对照组和治疗组裸鼠肝脏内的生长情况。实验结束后,分离裸鼠肝脏肿瘤,拍照称重。结果:建立了稳定表达双荧光的人肝癌细胞系HepG2-GFP-Luc,体外发光强度与表达萤光素酶的细胞数量呈正相关(R2=0.9945);建立了肝细胞癌原位移植活体荧光成像模型,对照组和治疗组肝脏内肿瘤细胞荧光强度随时间的延长逐渐增加,治疗组荧光强度明显低于对照组。定量分析结果显示,在第24、31和38 d,治疗组荧光总光子数值显著低于对照组;治疗组平均瘤重显著低于对照组。结论:建立了一种肝细胞癌原位移植荧光成像模型,可通过活体成像系统对肿瘤大小进行动态定量分析,为抗肝癌药物的药效学评价提供了实时定量分析动物模型。     

Single-Molecule Imaging of mRNA Localization and Regulation during the Integrated Stress Response

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Sensitive and Label-Free Detection of DNA by Surface Plasmon Resonance

While an array of technologies based on radioactive labels or luminescent tags are dominant in modern biomedical research on DNA, surface plasmon resonance (SPR) and SPR imaging measurements are sensitive, rapid, and label-free. This review summarizes recent advances in the development of SPR and coupled techniques and their applications in DNA research, including the gene analysis at trace levels and studies of DNA–protein and DNA–drug interactions.     

Molecular and cellular key players in human islet transplantation

Human islet transplantation could represent an attractive alternative to insulin injections for the treatment of diabetes type 1. However, such an approach requires a better understanding of the molecular and cellular switches controlling β-cell function in general as well as after transplantation into the liver. Although much research has been done into the suitability of stem or progenitor cells to generate a limitless supply of human β-cells, a reproducible and efficient protocol for the differentiation of such cells into stably insulin-secreting β-cells suitable for transplantation has yet to be reported. Fueled by recent findings showing that mature β-cells are able to regenerate, many efforts have been undertaken to expand this cell pool. Unfortunately, also these approaches had problems to yield sufficiently differentiated human islet cells. The aim of this review is to summarize recent findings describing some of the molecular and cellular key players of islet biology. A more complete understanding of their orchestration and the use of new methods such as real time confocal imaging for the assessment of islet quality may yield the necessary advancements for more successful human islet transplantation.     

1HMRS在定性诊断乙肝后早期肝硬化中的初步研究

目的:研究慢性乙型肝炎后早期肝硬化患者的氢质子磁共振波谱图像特点,旨在探讨~1HMRS成像技术诊断慢乙肝后早期肝硬化的可行性,为早期肝硬化的定性诊断提供新的方法。方法:首先,筛选出15例健康志愿者及15例慢乙肝后早期肝硬化患者,并将15例患者依据肝穿结果分为S2期、S3期和S4期三组;然后,对15例健康志愿者及15例慢乙肝后肝硬化组患者进行常规MRI扫描,包括三平面定位,横断面T1加权像(T1WI)、T2加权像(T2WI),于T2WI上选取感兴趣区进行单体素氢质子波谱扫描,分别采集各化合物峰,通过GE公司波谱分析软件校正,测量各波峰峰值和峰下面积,分析正常组和病例组各波峰和峰下面积变化特征。结果:正常组均得到谷氨酸和谷氨酰氨复合物(glumatic acid andglutamylamnnia complex,Glx)峰与胆碱/磷酸肌酸(choline/phosphoric creatine acid,Cho/Pcr)峰,病例组除上述两峰外,还得到乳酸(Lacrate,Lac)峰和脂质(Lipid,Lip)峰。经统计学分析正常组与病例组Glx、Cho/Pcr峰值及峰下面积无明显差异(P>0.05),而Lac、Lip峰值及峰下面积有差异统计学意义(P<0.05)。病例组内的S2、S3及S4期三组各自的Glx、Cho/Pcr、Lac、Lip峰值及峰下面积差异无统计学意义(P>0.05)。结论:1H磁共振波谱成像技术是一种非创伤性定性检测慢乙肝后早期肝硬化的方法。     

Improvement of the contrast in cancer detection by autofluorescence bronchoscopy using a narrowband spectral violet excitation: A preliminary study

Autofluorescence (AF) bronchoscopy is a useful tool for early cancer detection. However, the mechanisms involved in this diagnosis procedure are poorly understood. We present a clinical autofluorescence imaging study to assess the depth of the principal contrast mechanisms within the bronchial tissue comparing a narrowband (superficial) and broadband (penetrating) violet excitation. Knowledge of this parameter is crucial for the optimization of the spectral and optical design of clinical diagnostic AF imaging devices. An intensity contrast improvement was observed with the narrowband excitation, suggesting that the heme absorption plays a key role in the AF contrast mechanism.