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Although nonlinear processes are required for autonomous oscillation in clock gene expression, the underlying mechanism remains unclear. Interdependent tandem circadian enhancers on clock genes might cooperatively enhance nonlinearity in transcription, which would lead to limit cycle oscillations in clock gene expression., Limit-cycle oscillations require the presence of nonlinear processes. Although mathematical studies have long suggested that multiple nonlinear processes are required for autonomous circadian oscillation in clock gene expression, the underlying mechanism remains controversial. Here we show experimentally that cell-autonomous circadian transcription of a mammalian clock gene requires a functionally interdependent tandem E-box motif; the lack of either of the two E-boxes results in arrhythmic transcription. Although previous studies indicated the role of the tandem motifs in increasing circadian amplitude, enhancing amplitude does not explain the mechanism for limit-cycle oscillations in transcription. In this study, mathematical analysis suggests that the interdependent behavior of enhancer elements including not only E-boxes but also ROR response elements might contribute to limit-cycle oscillations by increasing transcriptional nonlinearity. As expected, introduction of the interdependence of circadian enhancer elements into mathematical models resulted in autonomous transcriptional oscillation with low Hill coefficients. Together these findings suggest that interdependent tandem enhancer motifs on multiple clock genes might cooperatively enhance nonlinearity in the whole circadian feedback system, which would lead to limit-cycle oscillations in clock gene expression.

Objective To evaluate the safety, efficacy and pharmacokinetics of alemtuzumab in Japanese patients, we conducted a phase I study in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. Methods Six patients received alemtuzumab by intravenous infusion every other day three times a week for 12 weeks. The dose was gradually escalated on daily basis (3, 10 and then 30 mg) until the patient tolerated. The primary objective was to evaluate the safety of alemtuzumab in Japanese patients and the secondary objectives were to evaluate the overall response rate and the pharmacokinetics. Results The major treatment-emergent adverse events were anemia, neutropenia (6/6 patients each) and thrombocytopenia (5/6 patients) in hematologic adverse events, and nausea, vomiting, decreased appetite, cytomegalovirus test positive and pyrexia (4/6 patients) in non-hematologic adverse events. As serious adverse events, cytomegalovirus infection, pulmonary tuberculosis and diffuse large B-cell lymphoma were reported in 1/6 patient each. The overall response rate was 33% (95% confidence interval: 4-78) (1/6 patient each achieved complete response and partial response, respectively) and 3/6 patients had stable disease and 1/6 patient had progressive disease. The median time to response was 2.9 months. After last intravenous dosing (Week 12) of alemtuzumab 30 mg every other day three times a week, Cmax, tmax, AUC0-τ and t1/2 were higher and CL and Vss were lower than the values observed after the first dose. Conclusions The efficacy, safety and pharmacokinetics results observed with alemtuzumab in Japanese patients were generally similar to those reported in overseas clinical studies. Alemtuzumab at 30 mg by intravenous infusion every other day three times a week for 12 weeks should be safe and effective similarly in Japanese B-cell chronic lymphocytic leukemia patients. Clinical trial registration no NCT00923182.

Light is the strongest synchronizer controlling circadian rhythms. The intensity and duration of light change throughout the year, thereby influencing body weight, food preferences, and melatonin secretion in humans and animals. Although the expression of clock genes has been examined using human samples, it currently remains unknown whether bright light during the daytime affects the expression of these genes in humans. Therefore, we herein investigated the effects of bright light exposure during the daytime on clock gene expression in the hair follicular and root cells of the human scalp. Seven healthy men (20.4 ± 2.2 years old; 172.3 ± 5.8 cm; 64.3 ± 8.5 kg; BMI 21.7 ± 3.1 kg/m2, mean ± SD) participated in this study. Subjects completed 3-day experimental sessions twice in 1 month during which they were exposed to bright and dim light conditions. The mRNA expression of Per1–3, Cry1–2, Rev-erb-α (Nr1d1), Rev-erb-β (Nr1d2), and Dec1 was analyzed using branched DNA probes. No significant changes were observed in the expression of Per1, Per2, Per3, Cry1, Cry2, Rev-erb-α (Nr1d1), or Dec1 following exposure to bright light conditions. However, the expression of Rev-erb-β (Nr1d2) tended to be stronger under bright light than dim light conditions. These results suggest that the bright light stimulus did not influence the expression of clock genes in humans. Long-lasting bright light exposure during the daytime may be required to change the expression of clock genes in humans.

SummaryIn the current model of the mammalian circadian clock, PERIOD (PER) represses the activity of the circadian transcription factors BMAL1 and CLOCK, either independently or together with CRYPTOCHROME (CRY). Here, we provide evidence that PER has an entirely different function from that reported previously, namely, that PER inhibits CRY-mediated transcriptional repression through interference with CRY recruitment into the BMAL1-CLOCK complex. This indirect positive function of PER is consistent with previous data from genetic analyses using Per-deficient or mutant mice. Overall, our results support the hypothesis that PER plays different roles in different circadian phases: an early phase in which it suppresses CRY activity, and a later phase in which it acts as a transcriptional repressor with CRY. This buffering effect of PER on CRY might help to prolong the period of rhythmic gene expression. Additional studies are required to carefully examine the promoter- and phase-specific roles of PER.

Secreted Frizzled-related protein 2 (Sfrp2) or Stromal Cell Derived Factor-5 (SDF-5) is highly expressed in the developing limbs. Here we showed the single Sfrp2 inactivation in mice resulted in syndactyly and preaxial synpolydactyly, predominantly in the hindlimbs. Tails were often kinked. A penetrance of the syndactyly was highest in 129/SvJ or CBA/N × 129/SvJ background and the phenotype was haploinsufficient. Preaxial synpolydactyly was seen in homozygous mutants in C57BL/6 × 129/SvJ. Of note, syndactyly showed retarded apoptosis of the second and the third interdigital spaces; concomitantly, mesodermal Msx2 expression was down-regulated. Impaired digital anlagen maturation was also noticeable in the same position. Preaxial synpolydactyly of the Sfrp2 mutants was a non-mirror image type and Shh independent. Although joint formation was not disrupted, chondrocyte maturation was preaxially disturbed. Our results suggest that the Sfrp2 deleted mice can be a useful animal model to study human syndactyly/preaxial synpolydactyly defects. Developmental Dynamics 237:2506–2517, 2008. © 2008 Wiley-Liss, Inc.

The circadian clock is driven by transcriptional oscillation of clock genes in almost all body cells. To investigate the effect of cell type-specific intracellular environment on the circadian machinery, we examined gene expression profiles in five peripheral tissues. As expected, the phase relationship between expression rhythms of nine clock genes was similar in all tissues examined. We also compared relative expression levels of clock genes among tissues and unexpectedly found that quantitative variation remained within an approximately three-fold range, which was substantially smaller than that of metabolic housekeeping genes. Interestingly, circadian gene expression was little affected even when fibroblasts were cultured with different concentrations of serum. Together, these findings support a hypothesis that expression levels of clock genes are quantitatively compensated for the intracellular environment, such as redox potential and metabolite composition. However, more comprehensive studies are required to reach definitive conclusions.

We investigated the influence of grinding as a pretreatment prior to the emitter film formation of single-walled carbon nanotubes (SWNTs) on the field emission and the geometric properties of SWNTs. Field emission from emitter films composed of ground SWNTs was found to be dramatically enhanced as well as to be homogeneous and stable, compared with that from emitter films composed of unground SWNTs. Transmission electron microscopy observations showed that several SWNTs protrude from the ends of ground SWNT bundles. The improved emission current is attributed to the large field enhancement at the sharpened ends of the SWNT bundles.

頸椎症性脊髄症に対して宮崎式脊柱管拡大術を施行し, 術後6か月以上経過を観察した35例 (平均観察期間;1年10か月) の手術成績を検討した。JOAスコアは3～15点, 平均8.7点から11～17点, 平均12.5点に改善した。平均改善率は49%であった。術前のJOAスコアと術後JOAスコアの問には強い相関がみられた (r=0.60, p

A series of A-ring pyrrole derivatives of duocarmycin bearing β-(5′,6′,7′-trimethoxy-2′-indolyl)acryloyl group were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. New Seg-B analogues bearing β-(5′,6′,7′-trimethoxy-2′-indolyl)acryloyl group containing double bond as spacer had lower peripheral blood toxicity than the derivatives bearing 5′,6′,7′-trimethoxyindole-2′-carboxyl group in Seg-B of the natural type. Moreover, most of them exhibited potent antitumor activity against in vivo murine tumor models.

An X-band miniaturized traveling-wave tube (TWT) using a Spindt field emitter array (FEA) cathode was built. The FEA cathode has 542,000 molybdenum tips in an emission area 1.2 mm in diameter. It also has a trench current-limiter that shows low resistance in normal operation. A saturation output power of 28.2 W, a saturation power gain of 40 dB, and a beam transmission ratio of more than 99.3% have been achieved at a frequency of 11.5 GHz under 3% duty ratio.

A series of A-ring pyrrole compounds of duocarmycin bearing 5-membered heteroarylacryloyl groups (thienylacryloyl and pyrrolylacryloyl) and heteroarylcarbonyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the thienylacrylates displayed in vitro anticellular activity equivalent to 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of methoxy-thienylacrylates, compound 11b, having 4'-methoxy-2'-thienylacryloyl as segment-B (Seg-B), showed remarkably potent antitumor activity and low peripheral blood toxicity in vivo, which were equal to those of 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates, compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B. On the other hand, the 2'-pyrrolylacrylates having a double bond as spacer showed 10(2)- to 10(3)-fold stronger anticellular activity than 2'-pyrrolecarboxylates (IC50 < 0.3 nM, 72 h-exposure). The 8-O-acetate and 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 2'-pyrrolylacrylates exhibited an antitumor effect at a lower dose compared with the 8-O-[(N-methylpiperazinyl] derivatives of 4'-methoxycinnamate (1j). Moreover, it was expected that the antitumor activity would be increased by the strength of the extra hydrogen bond formed between the nitrogen of the pyrrole amido group and DNA, owing to the increase of the number of N-methyl-2'-pyrrolecarboxamide units. However, 2'-pyrrolylacrylates having three N-methyl-2'-pyrrolecarboxamide units showed nearly equal antitumor activity to 2'-pyrrolylacrylates having only one N-methyl-2'-pyrrolecarboxamide unit.

Selective-area metalorganic molecular beam epitaxy at low growth temperatures using diethylgallium chloride (DEGaCl) and dimethylgallium chloride (DMGaCl) was investigated and significantly different results from those with metalorganic vapor-phase epitaxy were obtained. In the DEGaClAs4 and DmGaClAs4 systems, growth rates were extremely low or zero because DEGaCl and DMGaCl on the substrate surface decomposed to GaCl, which then desorbed very quickly. Therefore, these precursors and triethylgallium (TEGa) were used simultaneously to obtain a high growth rate and improve the selectivity in the TEGaAs4 system. In both the TEGa/DEGaCl/As4 and TEGa/DMGaCl/As4 systems, high growth rates over 1 μm/h and perfect selectivity were obtained at 500°C. Even at a low temperature of about 400°C, selectivity was perfect when DMGaCl was added: DMGaCl was more effective than DEGaCl. DMGaCl irradiation only prior to growth improves the selectivity in the TEGaAs4 system; therefore, cleaning the mask surface with chlorine-containing species was found to be important in both systems. In the TEGa/DMGaCl/As4 system, moreover, enhanced desorption of TEGa by interaction with methyl radicals supplied by DMGaCl was also found to improve selectivity. This was indicated by the experimental results in which selectivity was improved by adding trimethylgallium or trimethylindium to the TEGaAs4 system.

The cell growth inhibitory activity, antitumor activity and toxicity of M-16 and M-18, the major metabolites of a new mitomycin C (MMC) derivative KW-2149, in mouse and human were compared with those of KW-2149 or MMC in vitro and in vivo. The growth inhibitory activity of M-18, a symmetrical disulfide dimer, against human uterine cervix carcinoma HeLa S3 cells was almost equivalent to that of KW-2149 and their IC50 values were about 10-fold smaller than that of MMC. The activity of M-16, a methyl sulfide form, was almost equivalent to that of MMC. The cell-killing activity of MMC and M-16 was augmented in the hypoxic condition, whereas that of KW-2149 and M-18 was reduced. M-16 also exhibited almost equivalent activities to MMC in vivo in terms of many biological profiles, i.e., antitumor activity against murine P388 leukemia, ascitic or solid B16 melanoma or human lung carcinoma xenograft L-27, and bone marrow toxicity in mice. These in vitro and in vivo results indicate that the antitumor activity and toxicity of KW-2149 might not be mediated by M-16 in mice. On the other hand, M-18 exhibited almost equivalent activities to KW-2149 in these regards, suggesting the involvement of M-18 in the biological activities of KW-2149. However, the small values of the area under the curve of M-18 in mice make this unlikely. Thus the biological activities of KW-2149 in mice are not explained by the M-16 or M-18 concentration in plasma and are postulated to be manifested by KW-2149 itself.

Duocarmycin A (DUMA) and DU‐86, a semisynthetic derivative of duocarmycins (DUMs) and a possible active form of KW‐2189, both showed potent cell growth‐inhibitory and cell‐killing activities against human uterine cervix carcinoma HeLa 83 cells. Both drugs showed similar profiles of inhibition of macromolecular synthesis and influence on cell‐cycle distribution. Namely, they inhibited [3H]thymidine uptake at lower concentrations than [3H]uridine or [3H]Ieucine uptake, suggesting that the inhibition of DNA synthesis is the primary site of their actions. Furthermore, they induced the accumulation of cells in early S phase. However, a significant difference was observed between these drugs in terms of DNA‐fragmentation activity against HeLa S3 cells by using two independent methods, pulse‐field gel electrophoresis and alkaline elution. DNA fragmentation was insignificant in the cells treated with DU‐86, in contrast to the cells treated with DUMA. The analysis of DNA adducts in the cells revealed that DU‐86 alkylated adenine quite selectively, while DUMA alkylated both adenine and guanine. These results suggest that the pyrrolidone ring of DUMA is responsible for its adduct formation with guanine and the subsequent DNA‐fragmentation and inhibition of DNA synthesis, while DU‐86 alkylated adenine and inhibited DNA synthesis through mechanisms other than DNA‐fragmentation.

We have investigated in detail the influence of interlayer structures on nonalloyed ohmic contact resistance (ρc), in terms of the crystalline defects and the potential barrier at the interlayer/GaAs interface. The interlayer structures are a graded‐band‐gap InAs/GaAs strained‐layer superlattice (graded SLS), a graded‐band‐gap InGaAs, and conventional SLSs without graded band gaps. A two‐layer transmission line model indicates that the barrier resistance in the interlayer highly depends on the interlayer structure: ≤5×10−8 Ω cm2 for the graded SLS and graded InGaAs interlayers and 10−5–10−6 Ω cm2 for the conventional SLS interlayers. To explain the large dependence of the interlayer structure, first, the density and distribution of the misfit dislocations and stacking faults caused by the large lattice mismatch between InAs and GaAs have been investigated in detail by high‐resolution transmission electron microscopy. In the graded SLS and conventional SLS interlayers, the influence of the high‐density dep...

A model is proposed for describing the origin of the growth mode transition from two to three dimensions during the molecular‐beam epitaxial growth of InGaAs on GaAs [H. Toyoshima, T. Niwa, J. Yamazaki, and A. Okamoto, Appl. Phys. Lett. 63, 821 (1993)]. In this model the amount of In atoms on the surface arising from surface segregation is crucial in determining the growth mode transition, which provides the upper limit of the In composition and/or the thickness of InGaAs for device applications. The increase of these limited values for a modulation‐doped structure with an InGaAs channel has been implemented on the basis of this model. A lower substrate temperature and a higher As4 pressure during the InGaAs growth greatly suppress the In segregation ratio leading to the decrease of the amount of In on the surface. These growth conditions enable the upper limit of the In composition and/or the critical thickness of the InGaAs channel to be increased, which further verifies the validity of the proposed mod...

In this paper, we give a certain identity between an $\eta$-product of weight 1 and theta series associated with a pair of binary quadratic forms. We also have explicit description of Siegel's theorem by an $\eta$-product. For quadratic forms $Q_1$ and $Q_2$ which are in the same genus, we express the difference $\vartheta_{Q_1}(\tau)-\vartheta_{Q_2}(\tau)$ by an $\eta$-product.

Pulse field gel electrophoresis using a contour-clamped homogeneous electric field was applied for the analysis of DNA-fragmenting activity of antitumor agents towards human uterine cervix carcinoma HeLa S3 cells. Duocarmycins (DUMs), novel antitumor antibiotics with ultrapotent cell growth-inhibitory activities, caused DNA fragmentation at 10 times their IC50 values at 2 h exposure. At 100 times their IC50 values, the size of the smallest fragments was about 245 kilobase pairs (kbp). DUMA, DUMB1 and DUMB2 exhibited similar DNA fragmentation patterns, suggesting similar action mechanisms. DNA fragmentation was also detected in cells treated with radical producers, intercalators and topoisomerase inhibitors. Two bands of about 1800 and 1500 kbp were commonly detected in the cells treated with DUMs and these agents. In addition, fragments of about 900 kbp were detected in the cells treated with a topoisomerase inhibitor, 4'-(9-acridinylamino)methane-sulfon-m-anisidine, and fragments in the broad size range between 700 and 245 kbp in the cells treated with radical producers, bleomycin and neocarzinostatin. DUMs showed a characteristic DNA fragmentation pattern, since both types of fragments induced by the topoisomerase inhibitor and the radical producers were simultaneously detected, suggesting a novel mode of interaction with DNA. DNA-crosslinking agents and mitotic inhibitors did not induce DNA fragmentation under these conditions. The pulse field gel electrophoresis is potentially useful for characterizing DNA-cleaving activity of various antitumor agents at the cellular level.

A series of A-ring pyrrole compounds of duocarmycin bearing 5-membered heteroarylacryloyl groups (thienylacryloyl and pyrrolylacryloyl) and heteroarylcarbonyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the thienylacrylates displayed in vitro anticellular activity equivalent to 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of methoxy-thienylacrylates, compound 11b, having 4'-methoxy-2'-thienylacryloyl as segment-B (Seg-B), showed remarkably potent antitumor activity and low peripheral blood toxicity in vivo, which were equal to those of 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates, compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B. On the other hand, the 2'-pyrrolylacrylates having a double bond as spacer showed 10(2)- to 10(3)-fold stronger anticellular activity than 2'-pyrrolecarboxylates (IC50 < 0.3 nM, 72 h-exposure). The 8-O-acetate and 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 2'-pyrrolylacrylates exhibited an antitumor effect at a lower dose compared with the 8-O-[(N-methylpiperazinyl] derivatives of 4'-methoxycinnamate (1j). Moreover, it was expected that the antitumor activity would be increased by the strength of the extra hydrogen bond formed between the nitrogen of the pyrrole amido group and DNA, owing to the increase of the number of N-methyl-2'-pyrrolecarboxamide units. However, 2'-pyrrolylacrylates having three N-methyl-2'-pyrrolecarboxamide units showed nearly equal antitumor activity to 2'-pyrrolylacrylates having only one N-methyl-2'-pyrrolecarboxamide unit.

Currently, [(3)H]uridine is most often used to monitor rRNA synthesis in cultured cells. We show here that radiolabeled ribonucleoside triphosphates, such as [alpha-(33)P]UTP, in culture medium were also incorporated efficiently not only into cells but also into de novo RNA, particularly rRNA. Using this method, we first revealed that endoplasmic reticulum (ER) stress inducers such as tunicamycin and thapsigargin suppressed de novo rRNA synthesis, and that PERK, but not IRE1alpha or ATF6, mediated the suppression. PERK is known to mediate the suppression of de novo protein synthesis via phosphorylation of eIF2alpha. Consistently, other translational inhibitors such as PSI, proteasomal inhibitor, and cycloheximide suppressed de novo rRNA synthesis. eIF2alpha knockdown also suppressed both de novo protein and rRNA syntheses. Furthermore, ER stress reduced cellular ATP levels, and the suppression of rRNA synthesis apparently mitigated their reduction. These observations provided a close link between ATP levels and suppression of de novo rRNA synthesis at ER stress, and we proposed a novel feedback mechanism, in which ATP levels were maintained via suppression of de novo rRNA synthesis in ATP-demanding stresses, such as ER stress.

The effects of magnesium aluminum silicate (MAS) addition on the sorption of bromhexine HCl to polyethylene film in tablets were studied. The addition of MAS prevented the sorption of bromhexine HCl to polyethylene film. In order to investigate the mechanism, the interaction between bromhexine HCl and MAS was studied by the powder X-ray diffraction method. It was observed that bromhexine HCl was preferentially adsorbed to the surface of MAS rather than to polyethylene film. The adsorption was accelerated at high temperature and reduced pressure conditions. The sorption of bromhexine base and bromhexine HCl to packaging material were compared using tablet dosage forms. The sorption of bromhexine base to polyethylene film was greater than that of bromhexine HCl.

The anticellular and antitumor activities of novel antitumor antibiotics, duocarmycins (DUMs), were examined against human and murine tumor cells. DUMs consist of live compounds, A, B1, B2, C1, and C2, which possess a pharmacophore similar to that of CC‐1065, a previously isolated antibiotic. Among them, DUMA exhibited ultrapotent growth‐inhibitory activity with an IC50 value of 6 pM against human uterine cervix carcinoma HeLa S3 cells. DUMA and DUMB1 also inhibited the growth of adriamycin (ADM)‐resistant lines of human nasopharynx carcinoma KB cells and breast carcinoma MCF‐7 cells as well as their sensitive lines. DUMs inhibited the growth of s.c.‐inoculated murine tumors such as B16 melanoma, sarcoma 180, M5076 sarcoma and colon 26. DUMs were also significantly effective in increasing the lifespan of i.p.‐inoculated B16 melanoma‐bearing mice, although their effect was marginal against other i.p.‐inoculated tumors. As a whole, DUMB1 exhibited superior activity to the other four compounds. DUMB1 rapidly inhibited the incorporation of [3H]‐TdR into macromolecules of HeLa S3 cells as compared with that of [3H]UR or [3H]leucine. DNA strand breaks were detected in DUMB1 ‐treated HeLa S3 cells by agarose gel electrophoresis with a contour‐clamped homogeneous electric field apparatus. These results indicate that DUMs possess interesting biological activities as DNA‐targeting antitumor antibiotics.

GaAs selective growth mechanism was investigated, based on Ga species behavior using trimethyl gallium (TMG) or triethyl gallium (TEG) as the Ga source. Selective growth, using TMG, was obtained at a substrate temperature as low as 400°C. In the case of TEG use, the selective growth temperature was above 600°C. Furthermore, selective Ga deposition on a GaAs substrate with a SiO2 mask was carried out, using only an alkyl Ga source without arsenic. The selective Ga deposition was realized at 350°C for TMG use and above 500°C for TEG use. These results show that the Ga species related to TMG is easier to desorb from a SiO2 surface than that related to TEG, and that the desorption temperature for the Ga species is strongly correlative to the selective growth temperature. Consequently, the difference in selective growth temperature may be caused by the desorption rate for the Ga species, originating from the alkyl Ga source. Moreover, the difference in Ga species desorption rates, between GaAs surface and SiO2 surface, will contribute to the selective growth.

The molecular‐beam epitaxial growth conditions for (InAs)m(GaAs)n short period superlattices (SPSs) on GaAs substrates have been optimized by monitoring reflection high‐energy electron diffraction (RHEED) intensity oscillations. The RHEED oscillation measurements enable understanding InAs growth behavior on a 7% lattice‐mismatch GaAs substrate. Within one monolayer InAs deposition with lower than 560 °C growth temperature can give high SPS crystalline quality. The SPS periodic structure and the monolayer InAs formation, embedded in GaAs layers, have been confirmed by x‐ray diffraction and transmission electron microscopy measurements. The obtained thickness controllability for the SPSs is less than±6% for InAs and ±3% for GaAs. The electron Hall mobilities for modulation‐doped structures having an (InAs)1(GaAs)n SPS as an electron channel, whose layer index of n varied from 3 to 6, have been compared with those with a pseudomorphic InGaAs random alloy channel which has the equivalent In composition. The S...

The interaction between polyethylene containers and bromhexine·HCl solid dosage forms prepared by different methods was studied. It was found that bromhexine·HCl tablets prepared by the wet method (kneading) had more drug remaining than those prepared by the dry method. The sorption of drug to polyethylene was influenced by the kneading solvents used, and the most effective solvent in preventing sorption was methanol, which has high solubility for bromhexine·HCl. A group mixture of bromhexine·HCl with crystalline cellulose was effective inhibiting the sorption of bromhexine to polyethylene. This was explained in terms of the monomolecular dispersion of bromhexine molecules within the network of cellulose molecules in the ground mixture.

(InAs)m(GaAs)m short period superlattices (SPSs) have been grown by molecular‐beam epitaxy on InP substrates with their layer index m value systematically changed from 1 to 3. Their structural and electrical property dependencies on the layer index m value have been examined. During the first growth stage for the SPSs, with layer index m values of 2 and 3, two‐dimensional reflection high‐electron energy diffraction growth patterns were observed. The intended periodic structures without misfit dislocation generation were confirmed by x‐ray diffraction and transmission electron microscopy (TEM) measurements. However, the obtained electrical properties were still poor, indicating the existence of a large amount of disorder in the SPSs. On the other hand, though the thickness of consisting binary compounds was as thin as one monolayer, a high‐quality (InAs)1(GaAs)1 SPS was obtained. The highly ordered monolayer arrangement for InAs and GaAs was first observed by a TEM lattice image as well as x‐ray diffraction measurement. The obtained electron Hall mobilities for the modulation‐doped N‐AlInAs/(InAs)1(GaAs)1 SPS structure were as high as 11 000 cm2/V s at room temperature and 74 000 cm2/V s at 25 K.

High purity GaAs and Al x Ga 1- x As were grown by metalorganic molecular beam epitaxy (MOMBE) using metalorganic sources and arsenic (As 4 ). In GaAs growth using triethylgallium (TEG) and As 4 , carrier concentrations depended on As 4 pressure and substrate temperatures. Below 1.5 x 10 -4 Torr As 4 pressure, the p-type carrier concentrations decreased with an increase in As 4 pressure. Above 1.5 x 10 -4 Torr As 4 pressure, the epilayer converted from p-type to n-type conductivity. Carrier concentrations decreased with a decrease in substrate temperatures. At 500°C and 1.5 x 10 -4 Torr As 4 pressure, the carrier concentration in the p-type GaAs epilayer exhibited 1.5 x 10 14 cm -3 with a room temperature mobility of 400 cm 2 /V.s. Al x Ga 1-x As ( x =0.1-0. .2) was also grown using TEG, three different Al sources (triethylaluminum (TEA), trimethylaluminum (TMA) and dimethylaluminum hydride (DMAH) and As 4 . Using TEG, TEA and As 4 , the Al 0.15 Ga 0.85 As epilayer showed p-type conduction with carrier concentration of 1.2x10 15 cm -3 and mobility of 117 cm 2 /V.s. This carrier concentration is the lowest value ever reported for Al x Ga 1- x As grown by MOMBE.

Cl2 chemical dry etching for GaAs substrates of {111}A, {111}B, {110} and {100} orientations was accomplished under high vacuum conditions. The etch rate for different substrate orientations was {111}B > {110} = {100} > {111}A for temperatures below 450° C, and was nearly equal for temperatures above 450° C. For {111}B, {110} and {100} substrates, the etch rate depends strongly on the substrate temperature above 450° C and below 150° C. Two activation energies for etching (10.0 kcal/mol below 150° C and 16.0 kcal/mol above 450° C) were obtained. Between 150 and 450° C, the etch rate depends weakly on the substrate temperature. However, for {111}A substrate, the etch rate increased monotonically with increasing substrate temperature above 300° C. The activation energy corresponds to that for the other substrates above 450° C. These results are caused by the surface chemical reaction of GaAs/Cl2. By using these etching properties, a vertical side wall was fabricated without ion bombardment.

The interaction between bromhexine HCl and polyethylene containers was studied in solutions and in tablet packaging systems. Various bromhexine HCl aqueous solutions of different pHs were stored in polyethylene containers at 25 degrees C. The remaining amount of bromhexine HCl was determined by high performance liquid chromatography. It was observed that the transition of bromhexine HCl to polyethylene was inhibited by the addition of some surfactants into the solution, and by lowering the solution pH. In the solid dosage forms, influences of the additives were also studied. It was observed that the decrease of the content of bromhexine HCl in the solid dosage form was inhibited by the addition of acids (citric acid, tartaric acid) and surfactant (sodium dodecyl sulfate) and accelerated by the addition of sodium bicarbonate, similarly to those in solutions. The results indicated that the transition to polyethylene films was influenced by the molecular state of bromhexine HCl.

We first built two traveling wave tubes (TWTs) using a Spindt-type field emitter array (FEA) cathode. The first FEA-TWT achieved excellent RF performances. However its beam transmission ratio was only 82%, in contrast with more than 99% of a conventional TWT. To improve the beam transmission ratio and other characteristics, we re-designed the FEA electron gun and fabricated a second experimental FEA-TWT. At the current less than 20 mA, the beam transmission ratio of the second TWT was improved as high as 98%. However, when the current was more than 20 mA, space charge effect became significant and beam transmission ratio was rapidly degraded. The test results indicated that the design criteria for FEA electron guns needed to take into consideration the strong influence of space charge and how a good beam transmission ratio could be obtained.

We have developed highly reliable field emitter arrays with a novel vertical current limiter fabricated with a deep trench forming technology. The vertical current limiter has a local current-control function that automatically prevents fatal arc failure, and it has low resistance when used in the normal operation of a field emitter array. It has demonstrated a breakdown voltage as high as 120 V and a negligible increase in operation voltage, i.e., Vg of 70 V at 1 /spl mu/A/tip with an emitter cone density of more than 5/spl times/10/sup 7/ emitters/cm/sup 2/.

A series of the C7-substituted A-ring pyrrole derivatives of duocarmycin were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. All of the C7-substituted A-ring pyrrole compounds decreased potency in vitro and in vivo. However, some showed strong antitumor activity with T/C values less than 0.3. Among them, the 7-formyl compound 5d Scheme 1. (a) NBS or NCS, CCl4, rt; (b) Ac2O, BF3·Et2O, rt; (c) Cl2CHOMe, TiCl4, CH2Cl2, rt; (d) MeOCH2COCl, AlCl3, CH2Cl2, rt; (e) NaNO2, AcOH, dioxane, −20 °C; (f) 1) NaH, 2) p-nitrophenyl 4-methoxycinnamate, DMF, −20 °C; (g) 1) HCl, 2) 4-methoxycinnamic acid, EDCI, rt; (h) DBU, CH3CN, rt. Figure options Download full-size image Download high-quality image (140 K) Download as PowerPoint slide showed remarkable potent in vivo antitumor activity and low peripheral blood toxicity, which were equal to 2c Figure 1. Structure of duocarmycins and duocarmycin derivatives. Figure options Download full-size image Download high-quality image (106 K) Download as PowerPoint slide .

A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-2189.

A series of 3-substituted A-ring pyrrole compounds of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S 3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among 3-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.

The effects of thermal annealing below 500 °C on Spindt-type molybdenum field emitter arrays were studied through the field emission characteristics and Mo surface analysis. The anode current of the field emitter arrays increases with increasing annealing time and then saturates after a certain period that is shorter for higher-temperature annealing. These phenomena are clearly explained by the molybdenum trioxide (MoO3) desorption revealed by studies using x-ray photoelectron spectroscopy and temperature programmed desorption, and by calculation of MoO3 desorption rates. The MoO3 desorption is the predominant effect for low-temperature annealing and the increase in the anode current is mainly due to lowering of the work function after MoO3 desorption.

To synthesize Au nanorods without the use of seed crystals, we applied gamma-ray irradiation from 60Co radioactive source to reduce aqueous solution containing Au ions. The total dose was fixed to 6.0 kGy with various dose rates from 0.4 to 13.6 kGy/h. After the irradiation, two surface plasmon bands in the range around 530 nm and above 700 nm were observed in UV/vis spectra. We observed by a transmission electron microscopy (TEM) that rod-shaped Au nanoparticles with the length of 20–25 nm, and the width of about 7–15 nm were produced as well as a small amount of spherical particles. The size and the aspect ratio of the Au nanorods are well correlated with gamma-ray irradiation dose rate; with increasing the dose rate, their size decreases and the aspect ratio increases.

We have successfully developed a novel field emitter array (FEA) technology with low leakage current between each emitter and its subhalf-micron diameter gate. The device has two features: (1) a locally oxidized layer and (2) an additional Si3N4 layer as a second insulator layer. In a fabricated FEA with a 0.38-μm-diam gate, the insulator thickness was 0.26 μm, two times thicker than that of the conventional structure, and the creeping distance was ten times longer. Its emission threshold voltage is 32 V, and its leakage current has been reduced to less than a tenth of previous levels.

We developed a fully large-scale integration (LSI)-process-compatible technology with excellent control of emitter shape for the first time. The fabricated emitter tip configuration has two-step-cone shape whose upper and lower cone configurations are controllable independently. While the upper parts determine the emitter tip sharpness and the apex angle, the lower parts determine the emitter height by utilizing two-step thermal oxidation for emitter tip sharpening in addition to anisotropic reactive ion etching for the emitter height control. The stable and uniform thermal oxidation for sharpening emitters produces excellent uniformity, and the process, without liftoff, is matched with Si LSI technology completely. The obtained 1944 tip emitter with 800 nm gate diameter showed low threshold voltage of 35 V.

Extremely uniform epitaxial growth of GaAs and GaAlAs on three-inch wafers was achieved by low pressure metalorganic chemical vapor deposition with substrate rotation. The variations in thickness and doping of GaAs are, respectively, ±2.6% and ±3.5% on the whole wafer except the edge. For GaAlAs, the Al composition changes by less than ±1.0% and the intensity of photoluminescence (PL) is less than ±5%. The growth rate study on a three-inch substrate without rotation shows that the variations of growth rate along the directions parallel and perpendicular to the gas flow compensate each other, and hence the uniform epitaxial growth is realized.

Damage and contamination‐free chemical dry etching of (100)GaAs and (100)InP by Cl2 was demonstrated using a new ultrahigh‐vacuum dry‐etching molecular‐beam‐epitaxy (MBE) system. This system consists of a combined etching chamber, an MBE chamber, and a sample preparation chamber, all at ultrahigh vacuum. A mirrorlike surface was obtained after etching at substrate temperatures ranging from 300 to 400 °C for GaAs, and from 200 to 400 °C for InP. In situ reflection high‐energy electron diffraction observations were accomplished for GaAs, with a mirrorlike surface after etching, and (2×4) surface reconstruction was observed. Results show that a smooth surface was formed at an atomic level.

3,4,5-Triphenylisoxazole was produced by the reaction of the sodium salt of α-aci-nitrotoluene with the 1-cyano-1-methylethyl radical. The reaction was found to proceed via one electron transfer from α-aci-nitrotoluene anion to a 1-cyano-1-methylethyl radical.

The decrease of bromhexine HCl contents in granules and tablets was determined when the preparations were stored in polyethylene film package. Effects of temperature, contact area with film, excipients and moisture contents in the preparation on the remaining amount of bromhexin HCl were studied in order to investigate the interaction mechanism between bromhexine HCl and polyethylene film. It was observed that the decrease of bromhexine HCl was due to the sorption to the polyethylene film. The results indicated that the moisture contents of the dosage forms determined the rate of sorption predominantly, and that removal of adsorbed water from dosage forms was effective to prevent bromhexine HCl content decrease.

3,4,5-Triphenylisoxazole was produced by the reaction of the sodium salt of α-aci-nitrotoluene with the 1-cyano-1-methylethyl radical. The reaction was found to proceed via one electron transfer from α-aci-nitrotoluene anion to a 1-cyano-1-methylethyl radical.

A new resonant tunneling diode has been fabricated by employing an In0.1Ga0.9As strained layer quantum-well, where its conduction band edge is lower than that of emitter and collector regions. The obtained peak-current voltage is reduced to about 150 mV, which is less than half of that for the diode with a GaAs quantum-well. The high peak-to-valley ratio of 13 is observed at 77 K. This suggests that the peak-current voltage for this structure could be controlled by changing indium composition of the In y Ga1-y As quantum-well, while retaining a large peak-to-valley ratio.

InAs was selectively grown on GaAs by conventional molecular beam epitaxy(MBE). No InAs growth was found on SiO2, except small InAs particles, when the substrate temperature was between 550 and 600°C and arsenic pressure was 1×10-5 Torr. The higher the substrate temperature, the better the selectivity. At 650°C, no growth was found on GaAs nor on SiO2. Selective epitaxial growth by MBE has been realized under proper growth conditions, and will be useful for device applications.

The uniform epitaxial growth of a modulation-doped structure on a three-inch substrate was achieved by low-pressure metalorganic chemical vapor deposition. The mobility of the structure at 77 K was between 61,000 and 71,000 cm2/(V.s), and the variation of the sheet carrier concentration was ±6.8% over the whole wafer except in the edge region of 5 mm. Furthermore, adjustment of the growth conditions gave an electron mobility as high as 322,000 cm2/(V.s) at 4.2 K. A horizontal reactor configuration with substrate rotation produces uniform growth with an abrupt interface on a large area.