Nuclear reprogramming and pluripotency

The cloning of mammals from differentiated donor cells has refuted the old dogma that development is an irreversible process. It has demonstrated that the oocyte can reprogramme an adult nucleus into an embryonic state that can direct development of a new organism. The prospect of deriving patient-specific embryonic stem cells by nuclear transfer underscores the potential use of this technology in regenerative medicine. The future challenge will be to study alternatives to nuclear transfer in order to recapitulate reprogramming in a Petri dish without the use of oocytes.     

Substrate-targeting gamma-secretase modulators

Selective lowering of Abeta42 levels (the 42-residue isoform of the amyloid-beta peptide) with small-molecule gamma-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the gamma-secretase complex, but instead labelled the beta-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-beta peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP gamma-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-beta act as GSMs, and some GSMs alter the production of cell-derived amyloid-beta oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Abeta42 production and inhibition of amyloid-beta aggregation, which may synergistically reduce amyloid-beta deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets.     

Arachidonic acid metabolites as intracellular modulators of the G protein-gated cardiac K+ channel

Arachidonic acid is released from cell membranes in response to receptor-dependent as well as receptor-independent stimulation in various cells, including cardiac myocytes. Arachidonic acid is converted to prostaglandins by cyclooxygenase and to leukotrienes by 5-lipoxygenase, metabolites which are very biologically active and modulate cellular functions such as platelet aggregation, smooth muscle contraction and neural excitation. The molecular mechanisms underlying their modulations are, however, still badly understood. Here, we report that the 5-lipoxygenase metabolites of arachidonic acid activate the pertussis toxin-sensitive G protein-gated muscarinic K+ channel (IK.ACh): arachidonic acid activation of IK.ACh was prevented by the lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861; leukotriene A4 and C4 activated IK.ACh. The activation occurred in pertussis toxin-treated atrial cells and ceased when inside-out patches were formed but the patches were still susceptible to stimulation by GTP and to inhibition by GDP-beta-S. These results indicate that arachidonic acid metabolites may stimulate the G-protein in a receptor-independent way.     

Epigenetic reprogramming in mammalian nuclear transfer

Somatic cloning has been succeeded in some species, but the cloning efficiency is very low, which limits the application of the technique in many areas of research and biotechnology. The cloning of mammals by somatic cell nuclear transfer (NT) requires epigenetic reprogramming of the differentiated state of donor cell to a totipotent, embryonic ground state. Accumulating evidence indicates that incomplete or inappropriate epigenetic reprogramming of donor nuclei is likely to be the primary cause of failures in nuclear transfer. This review summarizes the roles of various epigenetic mechanisms, including DNA methylation, histone acetylation, imprinting, X-chromosome inactivation, telomere maintenance and expressions of development-related genes on somatic nuclear transfer.     

Delta Sigma调制器非理想因素建模

提出并构建了开关电容积分器Delta Sigma调制器非理想因素行为级模型,该模型基于Matlab中的Simulink工具,包含开关非线性、时钟抖动、量化器非线件和积分器非线性等调制器非理想囚素,能为电路模块的设计提供精确的设计指标.重点研究并实现一种运放非线性直流增益模型,仿真结果表明它能更有效反映奇次谐波失真.同时综合考虑调制器其他非理想因素,例如采样噪声、开关非线性电阻以及运放参数(色化噪声.增益带宽,摆率,饱和电压),仿真得到其对调制器性能的影响.     

不确定Sigma-Delta调制器的鲁棒滤波

研究级联Sigma-Delta调制器在非理想性电路中的鲁棒校正滤波器设计问题.基于MARKOV区间算法和线性区间系统的等价描述,将扰动抑制问题转化为增广系统的鲁棒稳定问题.给出以线性矩阵不等式描述的鲁棒滤波器存在的充分条件,该条件保证所设计的校正滤波器能有效抑制电路不确定性对调制器性能的影响.仿真结果表明,与传统校正滤波器相比,该调制器获得了更好的信号噪声比.方案降低了电路实现过程中器件精确度的要求,从而达到低应用成本的目的.     

传感器网络中一种轻量级的安全重编程方法

针对无线传感器网络中无率码重编程协议现有安全方案开销过大的问题,提出一种分层Hash树(HHT)的认证方法,该方法由两层Merkle树组成,底层基于代码映像页构建多个小Hash树,并把这些树的树根聚合成根指纹以减小通信开销,然后以根指纹为叶子节点构造顶层Hash树以减小认证开销.对HHT方法的安全性进行证明,并应用该方法实现SReluge协议的页认证.实验结果表明:与Merkle树相比,HHT的认证开销有明显下降,同时降低了通信开销、构建开销和分发完成时间.     

基于分层网络和反馈机制的细胞重编程

在多潜能细胞分化并最终形成相应的谱系结构的过程中, 多潜能细胞可能发生重编程.主要研究细胞分化过程中由双重负反馈回路的层级网络如何产生细胞重编程. 通过建立数学模型对整个系统的分叉进行分析, 揭示分层网络以及反馈机制产生细胞重编程的机理.     

In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes

The reprogramming of adult cells into pluripotent cells or directly into alternative adult cell types holds great promise for regenerative medicine. We reported previously that cardiac fibroblasts,which represent 50%of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT). Here we use genetic lineage tracing to show that resident non-myocytes in the murine heart can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of GMT after coronary ligation. Induced cardiomyocytes became binucleate, assembled sarcomeres and had cardiomyocyte-like gene expression. Analysis of single cells revealed ventricular cardiomyocyte-like action potentials, beating upon electrical stimulation, and evidence of electrical coupling. In vivo delivery of GMT decreased infarct size and modestly attenuated cardiac dysfunction up to 3 months after coronary ligation. Delivery of the pro-angiogenic and fibroblast-activating peptide, thymosin b4, along with GMT, resulted in further improvements in scar area and cardiac function. These findings demonstrate that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in their native environment for potential regenerative purposes.     

近红外波段硅基石墨烯电光调制器研究进展

 近红外波段的电光调制器是未来光信号处理和计算系统中的关键功能元器件,硅基石墨烯电光调制器在结构尺寸、调制速率、调制带宽及大规模片上集成等方面具有诸多潜在优点而引起人们的广泛关注和重视。本文介绍了石墨烯的光电特性及光调制机理,结合石墨烯在近红外波段电光调制器中的研究及应用,综述了国内外近红外波段硅基石墨烯电光调制器的研究进展,重点叙述了条形波导结构、谐振结构、纳米梁结构的电光调制器的工作原理及各器件的特性,展望了硅基石墨烯电光调制器的研究方向。     

应用于连续时间∑Δ调制器的时钟抖动建模方法

提出了一种能够快速而精确地模拟时钟抖动的建模方法,可应用于连续时间Sigma-Delta调制器(continuous-time sigma-delta-modulator,CT-SDM)等系统的仿真与验证。相较于传统的基于离散时间的建模方法,所提出的一种基于连续时间的模型,可以灵活地应用于各种连续时间电路中,且可在保证精度的情况下,快速完成仿真。给出了关于时钟抖动的理论分析和该模型的数学理论推导,并通过搭建一个完整的连续时间Sigma-Delta调制器,验证了所提时钟抖动方法的正确性与可行性,仿真时间在数十秒内。