李于：SIRT1 Regulation of Energy Metabolism: Attenuation of Hepatic Steatosis and ObesITy
Fibroblast growth factor 21 (FGF21) is the hepatocyte-derived hormone that regulates fatty acid metabolism and has potential to treat obesITy and diabetes. We recently indicate that hepatic overexpression of SIRT1 in diabetic mice attenuates hepatic steatosis and insulin resistance. However, the in vivo long-term consequence of hepatic SIRT1 ablation in liver physiology remains unknown.
We showed that hepatocyte-specific SIRT1 knockout (SIRT1 LKO) mice wITh the albumin Cre-loxP system exhibITed a striking phenotype wITh greater propensITy for obesITy on a chow diet, characterized by increased whole body mass and fat mass, reduced energy expendITure, and unaltered food intake and physical activITy. The obese phenotypes of SIRT1 LKO mice were associated wITh reduced hepatic and circulating levels of fasting FGF21.
Hepatic impairment of FGF21 repressed expression of key enzymes involving fatty acid oxidation such as CPT1α and MCAD, and inhibITed expression of ketogenic enzymes including ACAT1, HMGCS2, HMGCL, and BDH1, thereby reducing plasma β–hydroxybutyrate levels in SIRT1 LKO mice. Moreover, transcriptional activITy of a FGF21 promoter-driven luciferase reporter was stimulated by SIRT1 activators, resveratrol and SRT1720, in SIRT1+/+ MEFs, but not in SIRT1-/- MEFs.
The abilITy of resveratrol and SRT1720 to stimulate FGF21 protein was abolished by SIRT1 H335A inactive mutant or by nicotinamide and splITomicin in HepG2 cells. Induction of FGF21 by SIRT1 activators enhanced expression of key enzymes for fatty acid oxidation and ketogenesis.
These in vivo and in vITro findings characterize 1) hepatic SIRT1 as a master regulator of FGF21; 2) SIRT1-dependent activation of FGF21 in liver as a component for adaptive fasting response; and 3) defective hepatic SIRT1 and FGF21 signaling as a key pathological determinant of energy metabolic abnormalITy and obesITy susceptibilITy.
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).
KeITh Barry的大脑魔术表演
这是第一次, KeITh Barry告诉我们的大脑如何愚弄我们的身体.KeITh Barry邀请了观众参与令人瞠目结舌(甚至有点危险)的大脑魔术表演.
Western Blot Using The invITrogen NuPAGE Novex Bis-Tris MiniGel System(Aubin Penna.Ph.D)
Western Blot Using The invITrogen NuPAGE Novex Bis-Tris MiniGel System(Aubin Penna.Ph.D)
GE：Dharmacon EdIT-R基因编辑平台——即开即用，任性编辑！
CRISPR-Cas9基因编辑系统正以前所未有的速度席卷科研界。自从GE Dharmacon推出EdIT-R CRISPR-Cas9系统以来，其"无需克隆，任性编辑"的特点广受好评。在此基础上，GE Dharmacon进一步扩充并更新了EdIT-R基因编辑系统，以业界领先的guide RNA设计技术提供各种即开即用的预制产品，同时提供全基因组文库和各信号通路亚文库，满足不同实验者的实验需求。
StabilITy of Morphogen Gradients & Movement of Molecules
In my second lecture I describe experiments using EGFP tagged Bicoid to follow Bcd gradient establishment in living embryos, and to test various aspects of the simple model. DespITe continuous synthesis of new Bcd protein at the anterior end of the egg, we find that the concentration of Bcd in nuclei at any given point along the anterior posterior axis is constant over time and is reproducible from embryo to the next. This reproducibilITy means that the gradient is sufficiently robust to provide posITional information and thus can accurately direct gene activITies. One the other hand, quantITative imaging experiments point to several features of the gradient that are hard to explain - how target genes activated by Bcd distinguish relatively subtle differences in low concentrations, and how Bcd molecules move from the anterior sITe of their synthesis to the sITe of their transcriptional activITy. See more at http://www.ibioseminars.org
Protein synthesis: a high fidelITy molecular event
Rachel Green (Johns Hopkins U., HHMI) 1: Protein synthesis: a high fidelITy molecular event
Talk Overview:
In her first talk, Green provides a detailed look at protein synthesis, or translation. Translation is the process by which nucleotides, the “language” of DNA and RNA, are translated into amino acids, the “language” of proteins. Green begins by describing the components needed for translation; mRNA, tRNA, ribosomes, and the inITiation, elongation, and termination factors. She then explains the roles of these players in ensuring accuracy during the inITiation, elongation, termination and recycling steps of the translation process. By comparing translation in bacteria and eukaryotes, Green explains that IT is possible to determine which components and steps are highly conserved and predate the divergence of different kingdoms on the tree of life, and which are more recent adaptations.
Green’s second talk focuses on work from her lab investigating how ribosomes detect defective mRNAs and trigger events leading to the degradation of the bad RNA and the incompletely translated protein product and to the recycling of the ribosome components. Working in yeast and using a number of biochemical and genetic techniques, Green’s lab showed that the protein Dom34 is crITical for facilITating ribosome release from the short mRNAs that result from mRNA cleavage. Experiments showed that Dom34-mediated rescue of ribosomes from short mRNAs is an essential process for cell survival in higher eukaryotes.
Speaker Biography:
Rachel Green received her BS in chemistry from the UniversITy of Michigan. She then moved to Harvard to pursue her PhD in the lab of Jack Szostak where she worked on designing catalytic RNA molecules and investigating their implications for the evolution of life. As a post-doctoral fellow at the UniversITy of California, Santa Cruz, Green began to study how the ribosome translates mRNA to protein wITh such accuracy.
Currently, Green is a Professor of Molecular Biology and Genetics at the Johns Hopkins School of Medicine and an Investigator of the Howard Hughes Medical InstITute. Research in her lab continues to focus on the ribosome and factors involved in the fidelITy of eukaryotic and prokaryotic translation.
Green is the recipient of a Johns Hopkins UniversITy School of Medicine Graduate Teaching Award as well as the recipient for numerous awards for her research. She was elected to the National Academy of Sciences in 2012.
Connectomics: Seeking neural circuIT motifs
人类的大脑是非常复杂的，更大的结构和功能的多样性比其他器官和这种复杂性是确定的按某人的经验和某人的基因。 在报告1部分，Lichtman解释了如何映射的关系在大脑（神经连接）可能会导致一个更好的理解大脑的功能。
Clock Genes,Clock Cells and Clock CircuITs
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。在第1部分，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。
Clock Genes,Clock Cells and Clock CircuITs
在第2部分，Takahashi介绍了如何穿越不同遗传B许多老鼠背景允许他的实验室识别几个基因通过不同的机制影响时钟基因系统的输出。与晶体结构Takahashi开始他的演讲的最后一部分的Bmal和时钟，时钟基因的转录激活因子的两个中心。他继续描述他的实验室展示的是怎样的Bmal /时钟控件的转录调控的DNA结合活性调节不仅循环基因，而且基本的细胞功能如RNA聚合酶2占用和组蛋白修饰。