Human cytosolic NADP-1DH （IDH1） has recently been found to be involved in tumorigenesis. Notably, the tumorderived IDH1 mutations identified so far mainly occur at Arg132, and mutation R132H is the most prevalent on...Human cytosolic NADP-1DH （IDH1） has recently been found to be involved in tumorigenesis. Notably, the tumorderived IDH1 mutations identified so far mainly occur at Arg132, and mutation R132H is the most prevalent one. This mutation impairs the oxidative IDH activity of the enzyme, but renders a new reduction function of converting a-ketoglutarate （aKG） to 2-hydroxyglutarate. Here, we report the structures of the R132H mutant IDH1 with and without isocitrate OCT） bound. The structural data together with mutagenesis and biochemical data reveal a previ- ously undefined initial ICT-binding state and demonstrate that IDH activity requires a conformational change to a closed pre-transition state. Arg132 plays multiple functional roles in the catalytic reaction; in particular, the R132H mutation hinders the conformational changes from the initial ICT-binding state to the pre-transition state, leading to the impairment of the IDH activity. Our results describe for the first time that there is an intermediate conformation that corresponds to an initial ICT-binding state and that the R132H mutation can trap the enzyme in this conforma- tion, therefore shedding fight on the molecular mechanism of the ＂off switch＂ of the potentially tumor-suppressive IDH activity. Furthermore, we proved the necessity of Tyr139 for the gained aKG reduction activity and propose that Tyr139 may play a vital role by compensating the increased negative charge on the C2 atom of aKG during the trans- fer of a hydride anion from NADPH to aKG, which provides new insights into the mechanism of the ＂on switch＂ of the hypothetically oncogenic reduction activity of IDH1 by this mutation.展开更多
This paper presents an innovative switched-mode auto gain control （AGC） circuit with internally created reset module for DC-10Mb/s burst-mode unbalanced （BMU） optical data transmission. Conventional AGC circuit is...This paper presents an innovative switched-mode auto gain control （AGC） circuit with internally created reset module for DC-10Mb/s burst-mode unbalanced （BMU） optical data transmission. Conventional AGC circuit is inappropriate for BMU data transmission because it is based on average level detection and requires considerable time to settle on a predefined gain. Therefore, we adopt a fast switched-mode AGC based on peak level detection. After the gain is adjusted, the peak level detectors need to re-detect the peak level of the input signal. Thus, we develop an internally created reset module. This AGC with reset module exhibits a fast operation and achieves an adjusted stable gain within one-bit, avoiding any bit loss up to 10Mb/s data rate. During power-up, the peak level detectors possibly hold an uncertain level resulting in the bit-errors. We propose a power-up reset circuit to solve this problem. Designed in a 0.5μm CMOS technology, the circuit achieves an optical sensitivity of better than -30dBm and a wide dynamic range of over 30dB with a power dissipation of only 30 mW from a 5V supply.展开更多
文摘Human cytosolic NADP-1DH （IDH1） has recently been found to be involved in tumorigenesis. Notably, the tumorderived IDH1 mutations identified so far mainly occur at Arg132, and mutation R132H is the most prevalent one. This mutation impairs the oxidative IDH activity of the enzyme, but renders a new reduction function of converting a-ketoglutarate （aKG） to 2-hydroxyglutarate. Here, we report the structures of the R132H mutant IDH1 with and without isocitrate OCT） bound. The structural data together with mutagenesis and biochemical data reveal a previ- ously undefined initial ICT-binding state and demonstrate that IDH activity requires a conformational change to a closed pre-transition state. Arg132 plays multiple functional roles in the catalytic reaction; in particular, the R132H mutation hinders the conformational changes from the initial ICT-binding state to the pre-transition state, leading to the impairment of the IDH activity. Our results describe for the first time that there is an intermediate conformation that corresponds to an initial ICT-binding state and that the R132H mutation can trap the enzyme in this conforma- tion, therefore shedding fight on the molecular mechanism of the ＂off switch＂ of the potentially tumor-suppressive IDH activity. Furthermore, we proved the necessity of Tyr139 for the gained aKG reduction activity and propose that Tyr139 may play a vital role by compensating the increased negative charge on the C2 atom of aKG during the trans- fer of a hydride anion from NADPH to aKG, which provides new insights into the mechanism of the ＂on switch＂ of the hypothetically oncogenic reduction activity of IDH1 by this mutation.
基金Supported by the Natural Science Foundation of Jiangsu Province （ BK2010411 ） and the National International Cooperation Project of China-Korea （2011DFA11310）.
文摘This paper presents an innovative switched-mode auto gain control （AGC） circuit with internally created reset module for DC-10Mb/s burst-mode unbalanced （BMU） optical data transmission. Conventional AGC circuit is inappropriate for BMU data transmission because it is based on average level detection and requires considerable time to settle on a predefined gain. Therefore, we adopt a fast switched-mode AGC based on peak level detection. After the gain is adjusted, the peak level detectors need to re-detect the peak level of the input signal. Thus, we develop an internally created reset module. This AGC with reset module exhibits a fast operation and achieves an adjusted stable gain within one-bit, avoiding any bit loss up to 10Mb/s data rate. During power-up, the peak level detectors possibly hold an uncertain level resulting in the bit-errors. We propose a power-up reset circuit to solve this problem. Designed in a 0.5μm CMOS technology, the circuit achieves an optical sensitivity of better than -30dBm and a wide dynamic range of over 30dB with a power dissipation of only 30 mW from a 5V supply.
