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The injection pulling of oscillators in phase-locked loop (PLL) circuits is analyzed by the linear approximation of nonlinear differential equations in terms of the oscillator phase. Applying this analysis to injection pulling in an injection-locked PLL (IL-PLL) and mutual injection between oscillators in a cascaded PLL, it is shown that the feedback loop becomes unstable due to the injection and the transfer function exhibits a large peak gain at the edge of the PLL bandwidth. These observations are confirmed by simulations based on linear model. It is also found that coupling from the second stage to the first stage can control the peak gain of transfer characteristics. Measurements on the test circuits of IL-PLL and cascaded PLL validate the proposed linear model. In particular, it reveals the dependence of jitter generation on the timing difference between the injection and oscillator. Additionally, in the cascaded PLL, it is shown that a properly controlled injection pulse mitigates the jitter generation caused by mutual injection pulling. This study presents important viewpoints on self and mutual interference in stand-alone and individual PLLs.

Homogeneous Sc(OTf)3 used in nitromethane showed excellent catalytic activity for the direct allylation reactions of general alcohols including benzylic, propargylic, allylic, and some aliphatic alcohols with allyltrimethylsilane under mild and neutral reaction conditions. Metal-free β-silyl-substituted carbocations are intermediates generated by the highly oxophilic Sc(OTf)3-assisted rapid removal of a hydroxyl group in alcohols, which is supported by the result that allylation of (R)-1-(naphthalen-2-yl)ethan-1-ol with allytrimethylsilanes using the Sc(OTf)3 catalyst combined with (R)- or (S)-[1,1′-binaphthalene]-2,2′-diol ligands gave only racemic 2-(pent-4-en-2-yl)naphthalene in quantitative yield. The present study resolves the argument about the uncertain catalytic activity of Sc(OTf)3.

A time-interleaved analog-to-digital converter (TI-ADC) with voltage controlled oscillators (VCOs) is one promising candidate for ADCs in direct-RF sampling receivers. The VCO-based ADC, however, produces many harmonics due to the nonlinearity of the VCO gain, degrading the signal-to-noise-and-distortion ratio. We present a digital correction method for the third-order nonlinearity of TI-ADCs with VCOs in direct-RF sampling receivers dealing input signals centered at a quarter of the sampling frequency. Our method first estimates the nonlinearity with the cross-correlation function and adaptive signal processing of a third-order harmonic distortion (HD 3 ) tone for a continuous wave (CW) signal. Then, it generates HD 3 and third-order intermodulation products for modulated signals to subtract them from the output of the receiver. This approach using the CW wave makes the correction circuit much simpler; it requires no lookup tables and auxiliary ADCs (VCOs). MATLAB/Simulink simulations show that the proposed method reduces an HD 3 tone from −49.8 dBc to −78 9 dBc for a CW signal and improves an error vector magnitude from 2.48% to 0.87% for a 16-QAM signal.

Decimation filters in direct-RF sampling receivers are implemented with the polyphase decompositions of cascaded integrator-comb (CIC) filters to decrease gigasamples per second (GS/s) rates to low ones. First delays and decimators of the first decimation filter in the receiver can be eliminated in a time-interleaved ADC (TI-ADC) with the same number of channels as a decimation factor of the filter. However, the remaining adders need to operate at the same rate as each ADC samples (>1 GS/s), limiting the maximum operating speed of the receiver. We present a polyphase filter with a decimation factor of twice the channel number. This enables decimators to be inserted before the adders, reducing their operating frequencies to a half of the sampling frequency of each ADC. We synthesize a 7-bit polyphase filter based on a 2nd-order CIC filter with a decimation factor of 8 for a 4-channel TI-ADC by using a 65-nm CMOS process. Simulations show that the filter combined with I/Q mixers operates at twice the operating frequency (1.67 GS/s) of the conventional one with 2.0 mW, while consuming twice or more the chip area.

Analog-to-digital converters (ADCs) using voltage-controlled oscillators (VCOs) digitize analog signals in the phase domain, requiring no analog comparators and resistor ladders. This VCO-based ADC can be implemented with only digital standard cells provided by process vendors to maximize the advantages of technology scaling and design automation. A conventional VCO-based ADC consisting of the standard cells consumes additional power consumption and operates at the limited sampling frequencies due to buffers or sense amplifiers, keeping the output amplitude of the VCO constant, and a phase detector based on counters, respectively. We present an ADC with a back-gate VCO and a phase detector consisting of NAND gates and a fat tree encoder. The VCO produces rail-to-rail output signals not depending on the input signals, requiring no buffers and amplifiers. The phase detector can operate at higher sampling frequencies than the ones based on counters. The proposed VCO-based ADC, designed in a 65-nm digital CMOS process, achieves an SNR of 57.9 dB, excluding harmonics, in 20-MHz bandwidth with a sampling frequency of 800 MHz and a power consumption of 2.7 mW on simulation. This results in the best FoM (105 fJ/step) among the previously reported VCO-based ADCs consisting of standard cells.

In this paper, we analyze the mechanism of the phase noise generation caused by the mutual interference of two oscillators and investigate the control method of this issue. At first, in the cascaded phase-locked loop (PLL) circuit, we show the interference noise model between oscillators based on the linear model. From the simulation results, we present the possibility of the phase noise generation within the PLL bandwidth caused by this interference. In our analysis, the timing adjustment between the first-stage PLL and the second-stage PLL is shown to be effective for the control of noise generation. In addition, our simulation results show that the internal injection loops between the first and the second PLL’s oscillators would degrade the influence of the interference between oscillators. Next, we designed and fabricated the testchip for the verification of our analysis on the 0.18-μm standard CMOS process. The oscillation phases of two oscillators in the cascaded PLL can be changed externally by the variable delay line between the first and the second PLLs. From the measurement result, we confirmed that the jitter generation caused by the mutual interference between oscillators was controlled by the timing adjustment of oscillators.

Time-interleaving analog-to-digital converters (ADCs) decreases the required sampling rate for one ADC to achieve gigasamples per second (GS/s) rates. The gain and timing mismatches among the ADCs generate aliasing signals, degrading the spurious-free dynamic range of the time-interleaved ADC (TI-ADC). The conventional digital correction methods for TI-ADCs have not considered application to direct-RF sampling receivers. We present a digital correction method for M-channel TI-ADCs in the receivers. The proposed method employs in-phase/quadrature-phase (I/Q) downconversion mixers and cascaded integrator-comb (CIC) filters in the receiver. This allows the correction circuit (except for mismatch estimation) to have fewer building blocks than the conventional methods: one adder, one multiplier, and no filter. Simulations and measurements show that the proposed method completely reduces the aliasing signals below the noise floor of 4- and 2-channel 12-bit TI-ADCs, respectively.

In this study, the influence of external-voltage noise on voltage-controlled oscillators (VCOs) is investigated. The phase error is derived using the extended phase domain response of the oscillators based on the impulse sensitivity function. We found that the frequency properties of the noise sensitivity strongly depend on the circuit configuration of the VCO. We applied these results to the linear model of a phase-locked loop (PLL) and conducted a numerical simulation. The simulation result showed that the generation of the phase error depends on the timing of impulse noise and the bandwidth of the PLL. The test chip for verification is designed and fabricated with a standard CMOS process.

A voltage-controlled ring oscillator (VCO), consisting of delay cells, changes its oscillation frequency with the amplitude of an input signal in an analog-to-digital converter (ADC). The previously reported methods to control the frequency reduce the input range of the ADC because of voltage headroom required for the delay cells. This limits the achievable signal-to-noise ratio (SNR) under low supply voltages (

Cascaded integrator-comb (CIC) filters in a direct-RF sampling receiver reduce the quantization noise of an analog-to-digital converter (ADC) and out-of-band blockers being folded into the signal band. A higher order provides more attenuation for them but proportionally increases the power consumption and chip area. We present the procedure to determine the orders of a multistage CIC filter by using the analytical expressions of its output signal-to-noise ratio (SNR) and rejection in the signal band. The derived expressions first show a lower limit for the order to achieve the required SNR and then provide orders to satisfy the rejection requirements. A two-stage CIC filter consisting of 2nd- and 3rd-order CIC filters with a total decimation factor of 1024 is designed for a direct-RF sampling receiver complying with Bluetooth Low Energy (BLE) in MATLAB/Simulink. Simulations show that the CIC filter completely removes the folded quantization noise of a 2nd-order bandpass delta-sigma modulator and has a rejection of 63 dB for out-of-band blockers. The proposed procedure provides the lowest order of each CIC filter to enable the receiver to satisfy the SNR and out-of-band blocking requirements of BLE.

Energy storage technology is becoming more and more important in today's environmentally conscious society. In the conventional method of directly charging a capacitor under a constant power supply voltage, the amount of energy dissipation is the same as the energy stored in the capacitor. In this paper, we propose the stepwise charging of a capacitor by consecutively changing the duty ratio of the DC-DC down converter. In $ {\rm N} $ step charging, the energy dissipation is reduced to one Nth when compared with the conventional direct charging. The reduction of the dissipated energy is verified by SPICE simulations and by breadboard experiments, through which an energy reduction of one fourth and one eighth is confirmed from the measured power supply currents in four and eight step charging, respectively.

Lenvatinib is a multityrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors, and is being developed as an anticancer drug. P450s are involved in one of the elimination pathways of lenvatinib, and mono-oxidized metabolites, such as N-oxide (M3) and desmethylated metabolite (M2), form in rats, dogs, monkeys, and humans. Meanwhile, two other oxidative metabolites are produced only in monkey and human liver S9 fractions, and their structures have been identified using high-resolution mass spectrometry as a quinolinone form of lenvatinib (M3') and a quinolinone form of desmethylated lenvatinib (M2'). The formation of M3' from lenvatinib occurred independently of NADPH and was effectively inhibited by typical inhibitors of aldehyde oxidase, indicating the involvement of aldehyde oxidase, but not P450s, in this pathway. M2' was a dioxidized metabolite arising from a combination of mono-oxidation and desmethylation and could only be produced from M2 in a NADPH-independent manner; M2' could not be generated from M3 or M3'. These results suggested that M2' is formed from lenvatinib by a unique two-step pathway through M2. Although both lenvatinib and M2 were substrates for aldehyde oxidase, an enzyme kinetic study indicated that M2 was a much more favorable substrate than lenvatinib. No inhibitory activities of lenvatinib, M2', or M3' and no significant inhibitory activities of M2 or M3 on aldehyde oxidase were observed, suggesting a low possibility of drug-drug interactions in combination therapy with substrates of aldehyde oxidase.

Organic anion transporting polypeptide (OATP) 1B1 plays an important role in the hepatic uptake of many drugs, and the evaluation of OATP1B1-mediated drug-drug interactions (DDIs) is emphasized in the latest DDI (draft) guidance documents from U.S. and E.U. regulatory agencies. It has been suggested that some OATP1B1 inhibitors show a discrepancy in their inhibitory potential, depending on the substrates used in the cell-based assay. In this study, inhibitory effects of 14 compounds on the OATP1B1-mediated uptake of the prototypical substrates [³H]estradiol-17β-glucuronide (E₂G), [³H]estrone-3-sulfate (E₁S), and [³H]sulfobromophthalein (BSP) were studied in OATP1B1-transfected cells. Inhibitory potencies of tested compounds varied depending on the substrates. Ritonavir, gemfibrozil, and erythromycin caused remarkable substrate-dependent inhibition with up to 117-, 14-, and 13-fold difference in their IC₅₀ values, respectively. Also, the clinically relevant OATP inhibitors rifampin and cyclosporin A exhibited up to 12- and 6-fold variation in their IC₅₀ values, respectively. Regardless of the inhibitors tested, the most potent OATP1B1 inhibition was observed when [³H]E₂G was used as a substrate. Mutual inhibition studies of OATP1B1 indicated that E₂G and E₁S competitively inhibited each other, whereas BSP noncompetitively inhibited E₂G uptake. In addition, BSP inhibited E₁S in a competitive manner, but E₁S caused an atypical kinetics on BSP uptake. This study showed substrate-dependent inhibition of OATP1B1 and demonstrated that E₂G was the most sensitive in vitro OATP1B1 probe substrate among three substrates tested. This will give us an insight into the assessment of clinically relevant OATP1B1-mediated DDI in vitro with minimum potential of false-negative prediction.

New chemical entities often exhibit nonlinear pharmacokinetics (PK) profiles in experimental animals. However, the number of studies that have focused on species differences in nonlinear PK is very limited; thus, the aim of this study was to clarify the mechanism of the nonlinear PK of E2074 (2-[(2R)-2-fluoro-3-{(3r)-[(3-fluorobenzyl)oxy]-8-azabicyclo[3.2.1]oct-8-yl}propyl]-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one), a novel sodium channel inhibitor, in rats, dogs, and monkeys. Nonlinear PK profiles with more than dose-proportional increases of Cmax and area under the plasma concentration curve were observed in all species after oral administration. The Michaelis-Menten constant (Km) values of hepatic microsomal metabolism were 7.23 and 0.41 μM in rats and dogs in vitro, respectively, which were lower than the unbound maximum plasma concentrations after oral administration in vivo, indicating that the nonlinear PK in rats and dogs was attributable to the saturation of hepatic metabolism. However, we do not believe that the saturation of hepatic metabolism was the mechanism of nonlinearity in monkeys because of the high Km value (42.44 μM) observed in liver microsomes. Intestinal metabolism was observed in monkey intestinal microsomes but not in rats and dogs, and the nonlinear PK in monkeys was diminished by inhibition of intestinal metabolism with a concomitant oral dose of ketoconazole. These results suggest that saturation of the intestinal metabolism is the potential mechanism of nonlinearity in monkeys. P-glycoprotein was not involved in the nonlinear PK profiles in any species. In conclusion, the mechanism of the nonlinear PK of E2074 is species dependent, with the saturation of hepatic metabolism in rats and dogs and that of intestinal metabolism in monkeys being the primary cause.

An on-chip transformer, with two inductors magnetically coupled, provides input single-to-differential conversion (passive balun) for a differential low-noise amplifier (LNA), but significantly influences its input impedance and noise performance. We derive the analytical expressions for the performances of differential inductively-degenerated common-source (CS) LNA and cross-coupled common-gate (CG) LNA with on-chip transformers to present their design considerations. The derived expressions provide the minimum requirement for the quality factor of the inductor and the optimum inductance for the minimum noise figure (NF) of the LNA. Both the LNAs with inter-winding symmetric octagonal transformers are designed for Bluetooth Low Energy (BLE) receivers with a 65-nm CMOS process. Simulations show that the differential CS and CG LNAs achieve |S 21 | of 20.4 dB and 20.9 dB, and NF of 5.18 dB and 4.55 dB at 2.45 GHz, respectively, with a power consumption of 2.8 mW from a 0.7-V supply. The CG LNA can achieve a higher gain and lower NF than the CS one. The presented analysis and design considerations significantly reduce the design efforts to differential LNAs with on-chip transformers.

This paper investigates low-phase-noise and low-spur subharmonically injection-locked phase-locked loop (IL-PLL) circuits. Here the multiple injection is applied for the effective injection locking. In order to reduce the spur, a high-pass filter is inserted into the signal path of the injection for decreasing the subharmonic elements of injections. The testchip is designed and fabricated in the 0.18µm standard CMOS process. The rms jitter was 3.2ps in the 2.6GHz IL-PLL. By adding the injection-locked control into the phase-locked control, we achieved the 26% jitter reduction.

An accelerated evaluation method for the SRAM cell write margin is proposed using the conventional Write Noise Margin (WNM) definition based on the “butterfly curve”. The WNM is measured under a lower word line voltage than the power supply voltage VDD. A lower word line voltage is chosen in order to make the access transistor operate in the saturation mode over a wide range of threshold voltage variation. The final WNM at the VDD word line voltage, the Accelerated Write Noise Margin (AWNM), is obtained by shifting the measured WNM at the lower word line voltage. The WNM shift amount is determined from the measured WNM dependence on the word line voltage. As a result, the cumulative frequency of the AWNM displays a normal distribution. Together with the maximum likelihood method, a normal distribution of the AWNM drastically improves development efficiency because the write failure probability can be estimated from a small number of samples. The effectiveness of the proposed method is verified using the Monte Carlo simulation.

Lenvatinib, a potent inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptors 2 and 3, generated unique metabolites after oral administration of [(14)C]lenvatinib (30 mg/kg) to a male cynomolgus monkey. Lenvatinib was found to be transformed to a GSH conjugate, through displacement of an O-aryl moiety, at the quinoline part of the molecule in the liver and kidneys. The GSH conjugate underwent further hydrolysis by γ-glutamyltranspeptidase and dipeptidases, followed by intramolecular rearrangement, to form N-cysteinyl quinoline derivatives, which were dimerized to form disulfide dimers and also formed an N,S-cysteinyl diquinoline derivative. In urine, a thioacetic acid conjugate of the quinoline was also observed as one of the major metabolites of lenvatinib. Lenvatinib is a 4-O-aryl quinoline derivative, and such compounds have been known to undergo conjugation with GSH, accompanied by release of the O-aryl moiety. Because of intramolecular rearrangement in the case of lenvatinib, hydrolysis of the GSH conjugate yielded N-cysteinylglycine and N-cysteine conjugates instead of the corresponding S-conjugates. Because the N-substituted derivatives possess free sulfhydryl groups, dimerization through disulfide bonds and another nucleophilic substitution reaction with lenvatinib resulted in the formation of disulfanyl dimers and an N,S-cysteinyl diquinoline derivative, respectively. Characteristic product ions at m/z 235 and m/z 244, which were associated with thioquinoline and N-ethylquinoline derivatives, respectively, were used to differentiate S- and N-derivatives in this study. On the basis of accurate mass and NMR measurements, a unique metabolic pathway for lenvatinib in monkey and the proposed formation mechanism have been elucidated.

Rufinamide was evaluated in vitro to determine which enzyme(s) are responsible for rufinamide hydrolysis and whether valproate, one of its metabolites (valproyl-CoA), and/or the rufinamide hydrolysis product (CGP 47292) could inhibit hydrolysis. Rufinamide hydrolysis was mediated primarily by human carboxylesterase (hCE) 1 and was nonsaturable up to 500 μM. Two-thirds of rufinamide hydrolysis was estimated to occur in human microsomes and one-third in cytosol. Valproate was a selective inhibitor for hCE1 compared to hCE2 and inhibition had a greater impact on rufinamide hydrolysis in microsomes than in cytosol. Valproyl-CoA caused similar inhibition of rufinamide hydrolysis in both microsomes and cytosol. Carboxylesterases were not significantly inhibited by CGP 47292. Inhibition of in vitro rufinamide hydrolysis by valproate could offer an explanation for the observed in vivo drug-drug interaction between the two antiepileptic drugs.

An accelerated evaluation method for the SRAM cell write margin is proposed based on the conventional Write Noise Margin (WNM) definition. The WNM is measured under a lower word line voltage than the power supply voltage VDD. A lower word line voltage is used because the access transistor operates in the saturation mode over a wide range of threshold voltage variation. The final WNM at the VDD word line voltage, the Accelerated Write Noise Margin (AWNM), is obtained by shifting the measured WNM at the lower word line voltage. The amount of WNM shift is determined from the WNM dependence on the word line voltage. As a result, the cumulative frequency of the AWNM displays a normal distribution. A normal distribution of the AWNM drastically improves development efficiency, because the write failure probability can be estimated by a small number of samples. Effectiveness of the proposed method is verified using the Monte Carlo simulation. © 2011 IEEE.

Human tumors grown as xenografts in immunodeficient nude mice are widely used to investigate the pharmacological activities of anticancer drugs. Drug-metabolizing enzymes and transporters are expressed in tumor cell lines and changes in drug metabolism and pharmacokinetics (DMPK)-related gene expression after inoculation of the tumor cell may affect the pharmacological activity of the drug under consideration. The aims of the current study were to characterize DMPK-related gene expression profiles and responses to typical cytochrome P450 inducers in monolayer carcinoma cells grown in tissue culture versus those inoculated into a xenograft model. We used the human hepatocellular carcinoma cell line PLC/PRF/5 for this study and comprehensively assessed changes in DMPK-related gene expression by reverse transcription-polymerase chain reaction quantitation. CYP3A4 and UDP-glucuronosyltransferase 1A protein amounts were also analyzed by immunoprecipitation followed by immunoblotting. We found that the expression of many DMPK-related genes was elevated in the inoculated tumor compared with the monolayer carcinoma cells, indicating changes in their gene regulation pathways, presumably due to modulation of the nuclear receptor family of transcription factors. In addition, monolayer carcinoma versus inoculated tumor cells showed different responses to rifampicin, but similar responses to dexamethasone or 3-methylcholanthrene. These results suggest that inoculation of tumor cells results in the activation of drug metabolism and transport function, leading to changes in the responses to pregnane X receptor ligands and consequent discrepancies in the pharmacological activities between in vitro monolayer carcinoma cells and in vivo xenograft models.

The athymic nude mouse is often used to grow tumors for in vivo oncology research, including the identification of anticancer drugs, whereas wild-type mice are usually used to assess the pharmacokinetics (PK) of new chemical entities. The relationship between PK and pharmacodynamics (PD) provides useful mechanistic information and helps guide of the clinical regimen. The aim of this study was to assess whether the inoculation of human hepatocellular carcinoma cells (PLC/PRF/5) into athymic nude mice alters the expression of genes encoding the drug-metabolizing enzymes and transporters in host liver. The livers from nontumor- and tumor-bearing mice were initially subjected to drug metabolism gene microarray analysis. Microarray analysis indicated that tumor inoculation had little effect on drug metabolism-related genes, including several cytochrome P450s: Cyp1a, Cyp2b, and Cyp3a. This result was further confirmed by reverse transcription-polymerase chain reaction (RT-PCR). However, immunoreactive proteins of Cyp1a, Cyp2b, and Cyp3a were suppressed by tumor inoculation. RT-PCR and Western immunoblotting analysis showed that the inducibility of Cyp1a, Cyp2b, and Cyp3a by 3-methylcholanthrene, phenobarbital, and dexamethasone, respectively, was similar between nontumor- and tumor-bearing mice. These results suggest that inoculation of human tumor cells into athymic nude mice suppresses the expression of certain drug-metabolizing enzymes, which may alter the PK and PD of antitumor drugs.

Omeprazole induces human CYP1A1 and CYP1A2 in human hepatoma cells and human liver. Aryl hydrocarbon receptor (AHR) is shown to be involved in this induction. However, its precise molecular mechanism remains unknown because the chemical activates AHR without its direct binding in contrast to typical AHR ligands such as 3-methylcholanthrene (3MC) and beta-naphthoflavone (BNF). Human CYP1A1 and CYP1A2 genes are located in a head-to-head orientation sharing about 23 kb 5'-flanking region. Recently, we succeeded to measure CYP1A1 and CYP1A2 transcriptional activities simultaneously using dual reporter gene constructs containing the 23 kb sequence. In this study, transient transfection assays have been performed using numbers of single and dual reporter constructs to identify omeprazole-responsive region for CYP1A1 and CYP1A2 induction. Reporter assays with deletion constructs have demonstrated that the omeprazole-induced expression of both CYP1A1 and CYP1A2 is mediated via the common regulatory region containing multiple AHR-binding motifs (the nucleotides from -464 to -1829 of human CYP1A1), which is identical with the region for BNF and 3MC induction. Interestingly, omeprazole activated the transcription of CYP1A1 and CYP1A2 to similar extents while BNF and 3MC preferred CYP1A1 expression. We have also found that primaquine is an omeprazole-like CYP1A inducer, while lansoprazole and albendazole are 3MC/BNF-like in terms of the CYP1A1/CYP1A2 preference. The present results suggest that omeprazole as well as BNF and 3MC activates both human CYP1A1 and CYP1A2 expression through the common regulatory region despite that omeprazole may involve a different cellular signal(s) from BNF and 3MC.

The rubber materials are used for various appliations such as tires, belts, seals, gaskets, and O-rings.We call rubbers used for parts that are required to resist to oils and fuel special-purpose rubber. Special-purpose rubber is mainly used for automotive applications.Recently, the environment and the energy problems, which will become the most important in the future, have been closed up as big problems.These problems affect automotive rubber parts.As a result, the demand of HNBR, ACM and FKM increses, and this tendency will expand further in the future.In this paper, the latest technical improvements are reported on HNBR and ACM.

A light-inducible sigma factor of RNA polymerase, SigD, can contributes to the light-induced transcription of psbA in the cyanobacterium Synechocystis sp. PCC 6803. Here, another light-induced sigma factor, SigE, was characterized together with SigD. Results indicated that SigE also contributes to light-induced transcription on the cpcBACD, psbA, petBD and psaAB promoters whose potential sequences are of the Escherichia coli sigma(70)-type. SigD and SigE interfere with each other's expression. A rhythmic expression, in which the periodic peak of SigE exhibits a 24-h interval according to the upcoming night, was observed at the protein level. The cooperation of group 2 sigma factors, SigD and SigE, for light-induced transcription was discussed.

Trapping reagents are powerful tools to detect unstable reactive metabolites. There are a variety of trapping reagents based on chemical reactivity to electrophiles, and we investigated the reactivity of thiol and amine trapping reagents to metabolically generated electrophiles and commercially available electrophilic compounds. Glutathione (GSH) and N-acetylcysteine (Nac) trapped soft electrophiles, and amine derivatives such as semicarbazide (SC) and methoxyamine (MeA) reacted as hard nucleophiles to trap aldehydes as imine derivatives. Cysteine (Cys) and homocysteine (HCys) captured both soft electrophiles and hard electrophilic aldehydes. There were no qualitative differences in trapping soft electrophiles among Cys, HCys, GSH, and Nac, although quantitative reactivity to trap soft electrophiles varied likely depending on the pKa values of their thiol group. In the reactivity with aldehydes, Cys and HCys showed relatively lower reactivity as compared with SC and MeA. Nonetheless, they can trap aldehydes, and the resulting conjugates were stable and detected easily because their amino group formed imines after reaction with aldehydes, which are successively attacked by the intramolecular thiol group to form stable ring structures. This report demonstrated that Cys and HCys are advantageous to evaluate the formations of both soft electrophiles and aldehyde-type derivatives from a lot of drug candidates at early drug discovery by their unique structural characteristics.

The human CYP1A1 and CYP1A2 genes on chromosome 15 are orientated head-to-head and are separated by a 23-kilobase (kb) intergenic spacer region. Thus, the possibility exists for sharing common regulatory elements contained in the spacer region responsible for transcriptional activation and regulation of the CYP1A1 and CYP1A2 genes. In the present study, a reporter gene construct containing -22.4 kb of the 5'-flanking region of the CYP1A2 gene was found to support beta-naphthoflavone (BNF) and 3-methylchoranthrene (3-MC)-mediated transcriptional activation. The responsive region was also functional in directing activation of the CYP1A1 promoter, indicating that the region works bidirectionally to govern transcriptional activation of both CYP1A1 and CYP1A2. To simultaneously evaluate transcriptional activation of both genes, a dual reporter vector was developed in which the spacer region was inserted between two different reporter genes, firefly luciferase and secreted alkaline phosphatase. Transient transfection of the dual reporter vector in HepG2 cells revealed increases in both reporter activities after exposure of the cells to BNF and 3-MC. Deletion studies of the spacer region indicated that a region from -464 to -1829 of the CYP1A1 gene works bidirectionally to enhance the transcriptional activation of not only CYP1A1 but also CYP1A2. In addition, a negative bidirectional regulatory region was found to exist from -18,989 to -21,992 of the CYP1A1 gene. These data established that induction of human CYP1A1 and CYP1A2 is simultaneously controlled through bidirectional and common regulatory elements.

In this paper, the influence of the external voltage noise on VCOs (voltage-controlled oscillators) is studied. The phase error is derived by using the impulse response of the oscillators. We found that the frequency properties of the noise sensitivity strongly depend on the circuit configuration of the VCO. We applied these results to the linear model of a PLL (phase-locked loop) and carried out a numerical simulation. The simulation result shows that the generation of the phase error depends on the timing of the impulse noise and the bandwidth of the PLL. The test chip for the verification is designed and fabricated in a standard CMOS process.