符合美国CLia标准的高通量测序临床试验研发案例分享
孙洪业博士现场分享了归国后在药明康德基因中心组建的努力。包括该中心如何利用高效、整合地运用基因组学最新技术，推动药物研发、临床试验以及个性化治疗事业进步。
孙博士就进行中的3个临床相关项目做了分享。
符合美国CLia标准的高通量测序临床试验研发案例分享
视频内容主要包括：药明康德基因中心的使命，基因中心的成就和服务范畴，基因组学能力建设：顶级平台，进行中的临床相关项目等。
Targets-based therapy for leukemia: opportunity and challenge
优点主要为：能增强患者的免疫力，防止肿瘤的转移和复发，对病人机体的损伤小。 在我国，现在普遍开展的树突状细胞（DC）和细胞因子诱导的杀伤细胞（CIK）的生物疗法被广泛应用。
Erich Gnaiger：Life Style and Mitochondrial Competence – Modern Drugs for T2 Diabetes in Aging and Degenerative Diseases.
D. Swarovski Research Laboratory (Mitochondrial Physiology), Dept. General, Visceral and Transplant Surgery, Innsbruck Medical University; and OROBOROS INSTRUMENTS, Innsbruck, Austria. - Email: erich.gnaiger@oroboros.at
The contribution of mitochondrial dysfunction to the etiology of T2 diabetes and a range of preventable metabolic diseases is the subject of intensive current research with world-wide health implications.
Recently these investigations gained depth and scope by technological advances for diagnosis of mitochondrial function by comprehensive OXPHOS analysis using high-resolution respirometry [1,2]. Fundamental questions of a causal relationship, however, between compromised mitochondrial function and development of T2 diabetes remain to be resolved [3,4] to optimize prevention and treatment of insulin resistance.
For preventable diseases such as T2 diabetes, the evolutionary background of mitochondrial competence provides a solid basis for improved and broad application of a well established modern drug, mtLSD.
Post-industrial societies are characterized by a high-energy input lifestyle with diminished physical activity and high incidence of non-transmittable diseases, in comparison to human populations where physical work is essentially important for sustaining life and in which degenerative diseases (T2 diabetes, various cancers, Alzheimer's) are essentially absent [5]. The capacity of oxidative phosphorylation (OXPHOS) is increased or maintained high by a life style involving endurance exercise and strength training [6].
Life style changes from the age of 20-30 years to the elderly, but is subject to change and intervention. Depending on group selection in cross-sectional studies, OXPHOS capacity declines from the age of 20-30 years [7,8], or is independent of age up to 80 years [9,10].
Independent of age, there is a strong decline of OXPHOS capacity in human vastus lateralis from BMI of 20 to 30 [1]. At a BMI >30, a threshold OXPHOS capacity is reached in human v. lateralis that may be characteristic of a low-grade inflammatory state (‘mitochondrial fever’).
Onset of degenerative diseases (T2 diabetes, neuromuscular degeneration, various cancers) and mitochondrial dysfunction interact in an amplification loop progressing slowly with age, such that cause and effect of mitochondrial dysfunction cannot be distinguished. Diminished antioxidant capacity at low mitochondrial density is an important mechanistic candidate in the state of mitochondrial fever.
For implementing a life style supporting mitochondrial competence and preventing degenerative diseases in modern societies, we need (1) extended research programmes focused on the causative link between mitochondrial competence and effective prevention of degenerative diseases, (2) educational programmes on mitochondrial physiology targeted at general practitioners, teachers and the society at large, (3) cooperation of health care and insurance organizations to support preventive life style activities, and (4) do not miss any opportunity in taking the lead in living the mtLife Style Drug (mtLSD).
金颖：Fox3 suppresses NFAT-mediated differentiation to maintain self-renewal of embryonic stem cells
金颖教授为分子发育生物学研究室主任，健康科学中心研究员。金教授介绍了Fox3通过抑制NFAT介导的分化维持了胚胎干细胞的自我更新的机制等前沿发现。
Pluripotency-associated transcription factor Foxd3 is required for maintaining pluripotent cells. However, molecular mechanisms underlying its function are largely unknown.
Here, we report that Foxd3 suppresses differentiation induced by Calcineurin-NFAT signaling to maintain the ESC identity. Mechanistically, Foxd3 interacts with NFAT proteins and recruits co-repressor Tle4, a member of the Tle suppressor family highly expressed in undifferentiated ESCs, to repress NFATc3’s transcriptional activities.
Furthermore, global transcriptome analysis shows that Foxd3 and NFATc3 co-regulate a set of differentiation-associated genes in ESCs. Collectively, our study establishes a molecular and functional link between a pluripotency-associated factor and an important ESC differentiation-inducing pathway.
秦正红：DRAM1 regulates autophagy flux and Bid-mediated cell death via lysosomes
秦正红，博士，教授，神经药理专业博士生导师。1994年在美国宾州医学院研究生院获博士学位，先后在美国国家卫生研究院(NIH)及麻省总医院和哈佛大学医学院从事研究工作。2003年从哈佛大学引进，现为苏州大学医学部基础医学与生物科学学院科研中心实验室主任，中国药理学会生化药理学专业委员会委员，中国药理学会神经药理学专业委员会委员，美国神经科学学会会员。
Damage-regulated autophagy modulator1 (DRAM1), a novel TP53 target gene, is an evolutionarily conserved lysosomal protein and plays an essential role in TP53-dependent autophagy activation and apoptosis (Crighton et al, 2006). However, the mechanisms by which DRAM1 promotes autophagy and apoptosis are not clear.
3-Nitropropionic acid (3-NP) is an inhibitor of mitochondrial respiratory complex II. Intrastriatal administration of 3-NP produces neuropathology resemble to Huntington disease. 3-NP-induced neuronal death was involved in autophagy and apoptosis. In vitro studies with 3-NP in TP53 wt and null cells, 3-NP or CCCP increased the protein levels of DRAM1 in a TP53-dependent or independent manner. DRAM1 induction contributed to 3-NP-induced autophagy activation. Knock-down of DRAM1 with siRNA inhibited the activity of V-ATPase, acidification of lysosomes and activation of lysosomal proteases. Knock-down of DRAM1 reduced the clearance of autophagososmes.
3-NP also induced a transcription independent upregulation of BAX protein levels. Knock-down of DRAM1 suppressed the increase in BAX levels. Co-immunoprecipitation and pull-down studies revealed an interaction of DRAM1 and BAX protein. Stably expression of exogenous DRAM1 increased the half-life of BAX. Upregulation of DRAM1 recruited BAX to lysosomes and induced cathepsin B-dependent cleavage of Bid and cytochrome c release. Knockdown of DRAM1, BAX or inhibition of lysosomal enzymes reduced 3-NP-induced cytochrome c release and cell death.
These data suggest that DRAM1 plays important roles in regulating autophagy flux and apoptosis. DRAM1 promotes autophagy flux through a mechanism involves activation of V-ATPase and enhances the acidification of lysosomes. DRAM1 promotes apoptosis via a mechanism involving recruitment of BAX to lysosomes to trigger cathepsin B-mediated Bid cleavage.
控制老化的基因 - Cynthia Kenyon P1
本视频由科普中国和生物医学大讲堂出品
Cynthia Kenyon (UCSF) Part 1: Genes that Control Aging
Once it was thought that aging was just a random and haphazard process. Instead, the rate of aging turns out to be subject to regulation by transcription factors that respond to hormones and other signals. In the nematode C. elegans, in which many key discoveries about aging were first made, the aging process is subject to regulation by food intake, sensory perception, and signals from the reproductive system. Changing genes and cells that affect aging can lengthen lifespan by six fold, and can also delay age-related disease, such as the growth of tumors.
来自生殖系统的信号显示衰老的规律 - Cynthia Kenyon P2
本视频由科普中国和生物医学大讲堂出品
Cynthia Kenyon (UCSF) Part 2: The Regulation of Aging by Signals from the Reproductive System
Once it was thought that aging was just a random and haphazard process. Instead, the rate of aging turns out to be subject to regulation by transcription factors that respond to hormones and other signals. In the nematode C. elegans, in which many key discoveries about aging were first made, the aging process is subject to regulation by food intake, sensory perception, and signals from the reproductive system. Changing genes and cells that affect aging can lengthen lifespan by six fold, and can also delay age-related disease, such as the growth of tumors.
Inermediate Filaments中间丝
中间丝的基本构建块是二聚体，它在细胞质和细胞核中形成复杂的网络，它是灵活的，可扩展的，很难打破的，在活细胞中有动态的性质，它的拆卸和组装是受激酶和磷酸酶参与信号转导。西北大学费因伯格医学和海洋生物学院的鲍勃戈德曼从中间丝的命名到中间丝蛋白家族，为我们讲解细胞骨架中间丝的作用及细胞骨架的相互对话与稳定性、细胞的机械完整性、细胞形状的测定与维护； 波形蛋白迅速诱导上皮细胞改变形状，增加上皮细胞的活力......
Genetic Analysis of Mammalian Cricadian Clocks
昼夜节律是一个适应的24小时的一天，我们的经验。一个历史性的概述，Takahashi开始他的演讲如何控制生物钟的基因在drosophi首次发现和克隆旅游所需的力量，以确定在小鼠时钟基因。他还介绍了实验，导致实现人体内的所有细胞都有一个生物钟，而不仅仅是在大脑中的细胞。在这部分讲座中，Takahashi解释说，视交叉上核（SCN）在大脑中产生一种昼夜节律的体温波动的体温反过来，信号到外周组织。热休克因子1是负责的信号分子之一通信温度信息和复位外周时钟。