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Antisense oligonucleotides (ASOs) containing bridged nucleic acids (BNAs) have been proven to be very powerful. However, ensuring a reliable discovery and translational development scheme for this class of ASOs with wider therapeutic windows remains a fundamental challenge. We here demonstrate the robustness of our scheme in the context of the selection of ASOs having two different BNA chemistries (2,′4′-BNA/locked nucleic acid [LNA] and amido-bridged nucleic acid [AmNA]) targeting human proprotein convertase subtilisin/kexin type 9 (PCSK9). The scheme features a two-step process, including (1) a unique and sensitive in vitro screening approach, called Ca2+ enrichment of medium (CEM) transfection, and (2) a ligand-targeted drug delivery approach to better reach target tissues, averting unintended accumulation of ASOs. Using CEM screening, we identified a candidate ASO that shows >70% cholesterol-lowering action in monkeys. An N-acetylgalactosamine (GalNAc) ligand then was appended to the candidate ASO to further broaden the therapeutic margin by altering the molecule’s pharmacokinetics. The GalNAc conjugate, HsPCSK9-1811-LNA, was found to be at least ten times more potent in non-human primates (compared with the unconjugated counterpart), with reduced nephrotoxicity in rats. Overall, we successfully showed that our drug development scheme is better suited for selecting clinically relevant BNA-based ASOs, especially for the treatment of liver-associated diseases., Graphical abstract, A robust discovery and translational development scheme for selection of clinically relevant BNA-based gapmer ASOs was developed. The scheme features a two-step process, including (1) a unique and sensitive in vitro screening approach called CEM and (2) a ligand-targeted drug delivery approach to better reach target tissues, averting unintended side effects.

Background Treatment for acute abdomen during chemotherapy is frequently difficult because of the complicated status of the patients, and there have been only a few case series summarizing the outcomes of emergent surgery during chemotherapy. The aim of this study was to clarify the clinical outcomes of emergency surgery for acute abdomen during chemotherapy and identify predictive factors associated with mortality. Methods We retrospectively analyzed the records of patients who underwent emergency surgery for acute abdomen within 30-days after anti-cancer drugs administration between 2009 and 2020. Results Thirty patients were identified. The primary malignancies were hematological (n = 7), colorectal (n = 4), lung (n = 4), stomach (n = 2), breast (n = 2), prostate (n = 2) and others (n = 5). Fifteen patients were treated with the regimen, including molecular-targeted anti-cancer drugs (Bevacizumab: 8 cases, Rituximab: 4, Ramucirumab: 2, and Gefitinib: 1). Indications for emergency surgery were perforation of the gastrointestinal tract (n = 24), appendicitis (n = 3), bowel obstruction (n = 2), and gallbladder perforation (n = 1). Severe morbidity (Clavien-Dindo IIIa or more) occurred in 8 cases (27%), and there were 6 in-hospital deaths (20%). Significant factors related to in-hospital death were age >70 years old (P = 0.029), poor performance status (ECOG score 1 or 2) (P = 0.0088), and serum albumin level, Highlights • Thirty patients underwent emergency surgery for acute abdomen after anti-cancer drugs administration. • Mortality rate was 20%. Significant factors related to mortality were high age, poor PS, and low albumin level. • The incidence of acute abdomen was significantly higher in the patients receiving anti-VEGF drugs.

Primary extramammary Paget’s disease (EMPD) is a rare intraepithelial adenocarcinoma. Lymph node metastasis from noninvasive EMPD originating in the anorectal region is extremely rare, and the recurrence of noninvasive EMPD is commonly associated with local recurrence mainly due to an insufficient resection margin. We herein report a case of inguinal and para-aortic lymph node recurrence without local recurrence after complete margin-free surgical resection of noninvasive perianal EMPD. The patient was a man in his 40s who presented with an erythematous plaque of 7 × 5 cm in the perianal region, which had been present for 1 year. Biopsy from the perianal skin suggested EMPD; it was positive for cytokeratin (CK)7 and negative for CK20. Underlying malignancy was ruled out based on whole-body enhanced computed tomography (CT) and total colonoscopy. Surgery including complete wide resection of the lesion with preservation of the rectum was performed, and VY-advancement flap reconstruction and flap-rectum anastomosis were performed. A histological examination of the whole specimen with 5-mm slices confirmed noninvasive EMPD resected with all-negative surgical margins. At 2 years and 6 months after surgery, however, enlargement of the inguinal and para-aortic lymph nodes was detected by follow-up enhanced CT, and the recurrence of EMPD was diagnosed based on left inguinal lymph node biopsy. The patient underwent chemotherapy without a remarkable response. He died of the disease 53 months after the first surgery. This is the first case report of lymph node metastasis without local recurrence after complete margin-free resection of noninvasive perianal EMPD.

Peroxisome proliferator–activated receptor α (PPARα) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPARα is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPARα activators are often used to treat patients with dyslipidemia. To discover additional PPARα activators as potential compounds for use in hypolipidemic drugs, here we established human hepatoblastoma cell lines with luciferase reporter expression from the promoters containing peroxisome proliferator–responsive elements (PPREs) and tetracycline-regulated expression of full-length human PPARα to quantify the effects of chemical ligands on PPARα activity. Using the established cell-based PPARα-activator screening system to screen a library of >12,000 chemical compounds, we identified several hit compounds with basic chemical skeletons different from those of known PPARα agonists. One of the hit compounds, a 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivative we termed compound 3, selectively up-regulated PPARα transcriptional activity, leading to PPARα target gene expression both in vitro and in vivo. Of note, the half-maximal effective concentrations of the hit compounds were lower than that of the known PPARα ligand fenofibrate. Finally, fenofibrate or compound 3 treatment of high fructose–fed rats having elevated plasma triglyceride levels for 14 days indicated that compound 3 reduces plasma triglyceride levels with similar efficiency as fenofibrate. These observations raise the possibility that 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives might be effective drug candidates for selective targeting of PPARα to manage dyslipidemia.

We previously reported that 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivative 6 is an agonist of human peroxisome proliferator-activated receptor alpha (hPPARα). Here, we prepared a series of 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivatives in order to examine the structure-activity relationships (SAR). SAR studies clearly indicated that the steric bulkiness of the substituent on 1H-pyrazolo-[3,4-b]pyridine ring, the position of the distal hydrophobic tail part, and the distance between the distal hydrophobic tail part and the acidic head part are critical for hPPARα agonistic activity. These SAR results are somewhat different from those reported for fibrate-class hPPARα agonists. A representative compound (10f) was as effective as fenofibrate in reducing the elevated plasma triglyceride levels in a high-fructose-fed rat model.

Introduction The σ 1 ligands are considered to be a new class of potential therapeutic agents for several types of central nervous system disorder. Carbon-11-labeled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([ 11 C]SA4503) was shown to be a promising PET ligand for mapping σ 1 receptors, and was applied to measure receptor occupancy with several therapeutic drugs in the living human brain. In this study, we applied this technique for preclinical in vivo screening of novel σ 1 selective agonists. Methods Six newly synthesized piperazine derivatives containing arylalkylamine groups and cyclohexylamine derivatives containing phenyl groups were selected and tested for their in vivo σ 1 receptor binding with [ 11 C]SA4503. The test compounds were administered by intravenous co-injection or oral administration. The in vivo receptor binding of [ 11 C]SA4503 was evaluated by a tissue dissection method at a single time point. Results Our in vivo screen identified the most promising candidate of novel σ 1 agonist in the piperazine derivatives. Some correlations between in vitro affinity and in vivo receptor blocking rate were observed when considering oral bioavailability. In vivo receptor blocking of piperazine derivatives after oral administration may be predictable by simple co-injection study. Conclusion Ligand selection with [ 11 C]SA4503 by the in vivo receptor binding assay was performed successfully. This technique is a practical and high-throughput method that can directly evaluate blood–brain barrier permeability, receptor binding, and bioavailability of drug candidates at the same time.

For establishing a new generation of ac voltage standards, digital-to-analog converters (DACs) based on rapid single flux quantum (RSFQ) technology, which enable synthesis of arbitrary waveforms with fundamental accuracy, are developed. An RSFQ-DAC consists of three main subsystems: a pulse-number multiplier (PNM), a pulse distributor (PD) and voltage multipliers (VMs). Conventional RSFQ-DACs generate arbitrary voltages by switching a binary array of the VM cells. In this paper, we propose a Variable-PNM for a new RSFQ-DAC based on frequency modulation. The output voltage is determined by the multiplication factor m of the Variable-PNM that consists of a ring oscillator, an n -bit counter and a decoder. We designed a 2-bit Variable-PNM using the CONNECT cell library. The circuit was fabricated using the ISTEC Nb standard process (STP2). We have confirmed the correct functionalities for 2-, 4-, 6- and 8-fold multiplication in functional testing at low speed.

We propose a detailed model of a single-electron turnstile device in which each island electrode has a finite self-capacitance. The Coulomb blockade (CB) regions are obtained by calculating the free energy of the system, and are graphically presented in the gate-charge versus bias-voltage plane. We confirm the CB regions obtained to be octagonal, instead of the quadrilateral CB regions obtained in the conventional model.

Charge tunneling events in an ac-voltage-driven asymmetric single-electron transistor (aSET) under appropriate gate charge are rectified due to the tilted Coulomb blockade (CB) diagram, which induces a finite dc electric current even under zero dc biasing. We demonstrate dependence of the dc current upon the gate charge and the amplitude of the ac voltage by means of numerical simulation based on the Monte Carlo method. Device parameters of the aSET optimized for generation of the ac-induced dc current are derived by both analytical and numerical methods.

We evaluated mutual inductances between two superconducting striplines coupled through a superconducting intermediate layer in Nb Josephson IC.In order to measure the mutual inductances we designed eight test circuits based on a superconducting quantum interference device (SQUID), which included intermediate layers of two different thicknesses and four different widths. The inductance extraction program FastHenry with superconductor support was used for numerical calculation. The experimental results agreed with the calculated results, both of which confirmed that a thicker and wider intermediate layer reduced the mutual coupling more efficiently.

Sigma receptors are expressed in a wide variety of tumor cell lines, and are expressed in proliferating cells. A radioligand for the visualization of sigma receptors could be useful for selective detection of primary tumors and their metastases, and for non-invasive assessment of tumor proliferative status. To this end we evaluated two sigma receptor ligands, [11C]SA5845 and [11C]SA4503. In an in vitro study, AH109A hepatoma showed moderate densities of sigma1 and sigma2 receptors, and VX-2 carcinoma showed a high density of sigma2 receptors: Bmax (fmol/mg protein) for sigma1 vs. sigma2, 1,700 vs. 1,200 for AH109A hepatoma and 800 vs. 10,000 for VX-2 carcinoma. In a cell growth assay in vitro, neither SA5845 nor SA4503 (

To determine whether positron emission tomography (PET) can be used for imaging of neuroreceptors in eyes of rabbits. PET imaging of dopamine D2 receptor, dopamine transporter, serotonin1A receptor and sigma1 receptor in the eyes and brain was performed using corresponding positron-emitting ligands in baseline, pretreatment and displacement conditions. The 4 radioligands outlined the eyes and brain in the baseline. Pretreatment resulted in a slight reduction (26–28%) in the uptake in the anterior segments of eyes. The binding of each radioligand in the iris-ciliary body and retina was confirmed by ex vivo autoradiography. However, the PET signal in the eyes was unexpectedly higher than the autoradiography signal. The identification of radioligand-neuroreceptor binding by PET in the rabbit eyes is not specific enough.

PET-imaging of the sigma receptors is very helpful to understand processes, e.g., several central nervous system (CNS)-diseases in which the sigma receptors are involved. The [F-18]fluoroethylated analogs of SA4503 and SA5845 ([F-18]FE-SA4503 and [F-18]FE-SA5845) were evaluated in conscious monkeys to estimate its suitability for human application for PET. Conscious monkeys (Macaca Mulatta) were either scanned with [F-18]FE-SA4503 or [F-18]FE-SA5845 (n = 3 for both groups, 220 - 802 MBq). After a dynamic study of 120 min, radioactivity was displaced by intravenous (i.v.) injection of haloperidol (1 mg/kg). One month later the same set of three monkeys were scanned with [F-18]FE-SA4503 for 120 min and "cold" SA4503 (1 mg/kg) was infused to displace the radioactivity, and the other three monkeys were pretreated with haloperidol (1 mg/kg) before the 120-min PET-scan with [F-18]FE-SA5845. Cortical areas (cingulate, frontal, occipital, parietal, temporal), striatum, and thalamus showed high radioactivity uptake. Infusion of haloperidol displaced the radioactivity levels of the two radioligands. The same effect was found for [18F]FE-SA4503 after SA4503 displacement. Pretreatment with haloperidol blocked the [F-18]FE-SA5845 binding to give PET-images with low and uniform uptake in the brain. The findings demonstrated the reversible binding of the two radioligands. Metabolite analysis showed that 14% and 23% parent compound of [F-18]FE-SA5845 and [F-18]FE-SA4503, respectively, at 120 min postinjection was present in plasma. Kinetic analysis showed that the binding potential of [F-18]FE-SA5845 was higher in all brain regions than that of [F-18]FE-SA4503 (4.75-8.79 vs. 1.65-4.04). The highest binding potential was found in the hippocampus, followed by the cortical regions, thalamus, cerebellar hemisphere, striatum and vermis. Both [F-18]FE-SA compounds bound specifically to cerebral sigma receptors of the monkey and have potential for mapping sigma receptors in the human brain. (C) 2004 Wiley-Liss, Inc.

We evaluated in vivo the effect of aging on the sigma 1 receptors in the monkey brain by the quantitative analysis of the binding of [ 11 C ]SA4503 to sigma 1 receptors with positron emission tomography. Based on a three-compartment model, the influx rate constant K 1 of [ 11 C ]SA4503 from plasma to brain across the blood–brain barrier in all 10 regions investigated became smaller in the aged monkeys (20–28 years old, n =5) than in the young adult monkeys (4–8 years old, n =5), but the reduction was not significant due to the individual differences. On the other hand, the binding potential, which was calculated as the ratio of the association rate constant k 3 to the dissociation rate constant k 4 for the binding of [ 11 C ]SA4503 to sigma 1 receptors in the brain, significantly increased in nine of the brain regions of the aged monkeys to the 160–210% levels of the young monkeys. We concluded that the sigma 1 receptor binding sites increased in the aging process of the monkey brain.

We prepared sigma(1)-receptor selective 1-([4-methoxy-C-11]-3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([C-11]SA4503) and its fluorinated analog 1-([4-methoxy-C-11]3,4-dimethoxyphenethyl)-4-[3-(4-fluorophenyl)propyl]piperazine ([C-11]SA5845), and their [C-11]ethoxy and [F-18]fluoroethoxy analogs, and evaluated their potential for positron emission tomography studies. [C-11]SA4503 is most selective for sigma(1) receptors. and the other five showed affinities for sigma(1) and sigma(2) receptors with a different extent. All radioligands showed the receptor-specific binding in the brain, and Visualized similar regional brain distributions by ex vivo autoradiography. The [C-11]ethoxy analogs were relatively labile for metabolism. (C) 2003 Elsevier Science Inc. All rights reserved.

We compared the brain kinetics of radiolabeled (+)-pentazocine and SA4503, which have a high and selective affinity for sigma1 receptors. Brain uptake of [11C]SA4503 was high after intravenous injection followed by a gradual decrease in mice, whereas that of [3H](+)-pentazocine rapidly decreased. The brain uptake of the two radioligands was dose-dependently reduced, but the reduction of [3H](+)-pentazocine was found at higher doses. Percentages of the saturable binding of [3H](+)-pentazocine was much lower than that of [11C]SA4503. The brain uptake of [3H](+)-pentazocine was greatly blocked by SA4503 at a dose of 2 μmol/kg, while that of [11C]SA4503 was blocked by (+)-pentazocine at a dose of 20 μmol/kg and over. When mice were treated with cyclosporin A, a P-glycoprotein modulator, the uptake of [3H](+)-pentazocine was enhanced, but that of [11C]SA4503 was not. Under control and P-glycoprotein-modulated conditions, the brain uptake of both radioligands was reduced by haloperidol, another representative sigma receptor ligand, to a different extent. We concluded that the P-glycoprotein modulation resulted in the different brain kinetics of the two radioligands. The radiolabeled SA4503 is suitable as an in vivo probe, but radiolabeled (+)-pentazocine is not. Synapse 48:80–86, 2003. © 2003 Wiley-Liss, Inc.

In this paper, we report on misaligned Bi–Sr–Ca–Cu–O (2212) films that have been deposited on vicinal strontium titanate substrates using a dc sputtering system. We measured the temperature dependences of resistivity across and along the terrace, and only the resistivity across the terrace slightly decreased with the increase of the temperature in the normal state region. The estimated anisotropy parameter γ was smaller than that of single crystal, but a significant anisotropy was observed. Submicrometre bridges were fabricated, and the temperature dependence of the critical current density was investigated. The value of the critical current density across the terrace is smaller than the value of that along the terrace. This suggests that the current partially flows along the c-axis. However, a multi-branch structure was not observed even after post annealing in oxygen atmosphere at low pressure.

The sigma receptor might be involved in several diseases in the central nervous system. It occurs in the endocrine, immune, and other peripheral organ systems and is expressed in a variety of human tumors. The [18F]fluoroethyl analog of the sigma1-selective ligand SA4503 ([18F]FE-SA4503) was prepared and evaluated in animals to investigate its suitability for in vivo measurement of sigma receptors with positron emission tomography (PET). [18F]FE-SA4503 was synthesized by [18F]fluoroethylation of the corresponding O-demethyl precursor in an overall radiochemical yield of 4-7% (EOB) with a specific activity of >100 TBq/mmol. The radioligand had higher in vitro affinity for the sigma receptor than SA4503 (IC(50) sigma1 6.48 nM, IC50 sigma2 2.11 nM). [18F]FE-SA4503 was injected into mice. Uptake could be blocked by co-injection of the sigma receptor ligands haloperidol, pentazocine, and cold SA4503, but not with other receptor ligands. Ex vivo autoradiography studies in rats showed regional distribution in the brain similar to [11C]SA4503. Hippocampus, thalamus, and cortical areas were clearly delineated by [18F]FE-SA4503. The uptake was blocked by SA4503 treatment. In the rat brain, only a small portion of metabolites (6.6% of brain radioactivity) was detected at 30 min postinjection, whereas in plasma the fraction of metabolites amounted to 51.3% of plasma radioactivity. The kinetics of [18F]FE-SA4503 was measured with PET in the conscious monkey brain. High uptake values were found in the cortex, thalamus, cerebellum, and striatum, reaching a plateau value at 30 min postinjection. It is concluded that [18F]FE-SA4503 showed specific binding to sigma receptors in three animal species.

A conventional voltage multiplier cell in a rapid-single-flux-quantum (RSFQ) digital-to-analog converter is composed of an output dc-superconducting quantum interference device (dc-SQUID) magnetically coupled to an input Josephson transmission line. The authors previously demonstrated the operation of a voltage doubler cell that doubled the input voltage by introducing the second-mode operation. In this paper, we propose another type of a voltage multiplier cell, a voltage quadrupler, where the output dc-SQUID is replaced with two dc-SQUIDs sharing one coupling inductor. The proposed cell quadruples the input voltage when each SQUID is operated in the second-mode. A single voltage quadrupler has been designed and fabricated using the ISTEC standard process (STP2). Although operation margins for the bias current and the input SFQ repetition frequency are smaller than the values expected from simulation, its fundamental operation has been confirmed in experiment.

[11C]Raclopride is widely used as a representative dopamine D(2)-like receptor ligand in positron emission tomography (PET) studies, and [11C]1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride ([11C]SA4503) is a recently developed selective ligand for mapping sigma(1) receptors in the brain. The striatal uptake of [11C]raclopride in mice was reduced by co-injection of an excess amount of SA4503, in spite of the fact that raclopride had no effect on the brain uptake of [11C]SA4503 as shown in a previous study. The blocking effect of SA4503 on the striatal uptake of [11C]raclopride was dose-dependent, but disappeared by 1 h or 6 h after intraperitoneal injection of SA4503. The brain uptake of [11C]SA4503 was not affected by a dopamine transporter inhibitor GBR 12909, nor was [11C]beta-CIT-FP inhibited by SA4503. The IC(50) values of raclopride for sigma(1) and sigma(2) receptor subtypes measured in vitro were 11800 nM and 4950 nM, respectively, suggesting that the affinity was too low for [11C]raclopride to bind in vivo to sigma receptors. On the other hand, the IC(50) value of SA4503 for dopamine D(2) receptors was 470 nM, that is approximate 1/25 of the affinity of raclopride for the dopamine D(2) receptors. Therefore, possible explanations for the partial blocking effects of SA4503 on the striatal uptake of [11C]raclopride are: (1) an excess amount of SA4503 may reduce the [11C]raclopride uptake due to its low affinity for dopamine D(2) receptors, or (2) SA4503 may enhance endogenous dopamine release, which results in the competitive inhibition of the [11C]raclopride uptake. These findings support that both [11C]raclopride and [11C]SA4503 are selective in vivo ligands for dopamine D(2)-like receptors and sigma(1) receptors, respectively, in spite of the partial blocking effect of SA4503 on the striatal uptake of [11C]raclopride.

We present analytical expression for inductance of a superconducting stripline, a strip sandwiched by two superconducting ground planes. In our method, we utilize the analytical formula for a perfect-conducting stripline derived by Chang in 1976. To utilize Chang's formula, we first transform the structure of a superconducting stripline into that of a perfect-conducting stripline by reducing the thicknesses of the superconducting layers. The thickness reduction is "λ coth(t/λ)" for each (upper or lower) side, where λ and t are the field penetration depth and the layer thickness, respectively. Then, we apply Chang's formula to the transformed stripline model. The calculated results are in good agreement with the numerical and experimental results.

Although sapphire has superior high frequency properties, an adequate buffer layer is required to form a high-Tc film. We deposited a CeO/sub 2/ buffer layer by ion beam sputtering in high oxygen pressure, and investigated the influence of the deposition conditions on the superconducting properties of YBa/sub 2/Cu/sub 3/O/sub 7-y/ (YBCO) films. CeO/sub 2/ films deposited at higher than 600/spl deg/C were c-axis oriented and YBCO films deposited on the top at 700/spl deg/C were also c-axis oriented. T/sub /spl alpha//(R=0)=89 K and J/sub c/>10/sup 6/A/cm/sup 2/ were obtained for a 120 nm thick YBCO film deposited on 50 nm thick CeO/sub 2/ layer. High oxygen pressure /spl sim/1 Pa is desirable. Grain boundary Josephson junctions were also successfully fabricated on bicrystal sapphire substrate. It was found that high pressure ion beam sputtering is a promising method for superconductive electron devices.

Self-organized microcones were grown on an n-Si(100) substrate by microwave plasma chemical vapor deposition. It was found that microcones having a cross section of an isosceles triangle were successfully grown on the Si substrate and that all the microcones had almost the same sizes. From the results of X-ray photoelectron spectroscopy (XPS), we concluded that the microcones consist of SiC covered with a thin carbon-based material. A model of the growth mechanism of the microcones was derived assuming that thermally assisted field emission and bombardment with ions accelerated by an electric field in the ion sheath of microwave plasma play an important role in the growth of the microcones. The field dependence of emission current from the microcones in vacuum agreed with the Fowler–Nordheim model, which indicates that these microcones can be used as field emission arrays.

We fabricated single-electron transistors (SETs) with ferromagnetic (FM) Co leads and superconducting (SC) Al islands, and measured their tunnel magnetoresistances. Under the antiparallel magnetization state of the two FM leads, current increase due to the SC gap suppression by spin accumulation was observed. Tunnel magnetoresistance ratios of the antiparallel state to the parallel state were investigated for 10 FM SETs with different spacings between the two FM leads, from 0.35 to 50 µm. Spin valve effects were confirmed in the SETs with an FM lead spacing not only on the submicron order but also of 50 µm.

Digital-to-analog converters based on rapid single flux quantum circuits (RSFQ-D/A converters) are candidates for the next generation of ac voltage standard. We re-optimized the device parameters of a voltage multiplier (VM) cell, one of the important components in the RSFQ-D/A converter, to implement a new voltage doubler (VD) cell. The output voltage of the VD cell was twice as high as that of the conventional VM cell. We fabricated VD cells using a Nb technology. We confirmed correct operation of the VD cells at input frequencies up to 30 GHz.

A set of the title compounds having different substituents (R1, R2) on their phenyl groups was synthesized to find sigma receptor binding affinity. Among the compounds, 2b (R1 = R2 = Cl) has the most potent sigma 1-binding activity, while 2a (R1 = R2 = H, SA4503) was most selective to sigma 1 over sigma 2 receptor. The crystal structures of 2a and 2b were shown, by X-ray crystallography, to be similar except for the one torsional angle of their propylene parts. Quantitative structure-activity relationship study suggested the affinity of the compounds to the sigma 1 receptor was dependent on the electronic feature, Swain-Lupton's R or Sz that was derived by molecular orbital method, of R1 and R2.

We have fabricated Au/SrTiO/sub 3/(STO)/YBa/sub 2/Cu/sub 3/O/sub 7-x/ (YBCO) trilayer structures and superconducting field effect transistors (SuFETs). Insulating STO films were deposited by the ion beam sputtering (IBS) method at high oxygen pressure (/spl sim/10/sup -2/ Torr). (l00) peaks were observed in the X-ray diffraction (XRD) patterns of STO films deposited at temperatures higher than about 400/spl deg/C. The leakage current characteristics of a 400-nm-thick STO film were almost symmetric at different polarities and low leakage current of the order of 10/sup -9/ A was obtained up to around /spl plusmn/25 V at 4.2 K. The dielectric constant electric field product /spl epsiv//sub rS/E/sub BD/ of the STO film was estimated to be about 2.2/spl times/10/sup 8/ V/cm. In the SuFET fabrication process, a 10-nm-thick YBCO film covered with the STO layer was hardly degraded. The modulation of the normal state resistance of a sample almost corresponds to that of the induced carrier at positive bias. When a voltage of +20 V was applied to the gate electrode at 4.2 K, the current decreased by about 5% and the mutual conductance was 3.8 /spl mu/S at a drain voltage of 10 mV.

We found that sigma receptor ligands differentially regulated the acetylcholine (ACh) neurotransmission in the rat brain. Acute administration of (+)-N-allylnormetazocine [(+)-SKF-10,047], a prototype sigma 1 receptor ligand, and 1,3-di(2-tolyl)guanidine (DTG), a non-specific sigma receptor ligand, increased the extracellular ACh level in the rat hippocampus. This increase of hippocampal extracellular ACh level elicited by (+)-SKF-10,047 was more potent than that elicited by DTG. On the other hand, the striatal extracellular ACh level was slightly affected by (+)-SKF-10,047. In addition, DTG did not affect the striatal extracellular ACh level. Our previous studies have shown that both (+)-SKF-10,047 and DTG increased the extracellular ACh level in the rat frontal cortex. Taking all these data into consideration, the regulation of ACh neurotransmission by sigma receptor ligands are different depending upon the brain region.

The σ₁ligands are considered to be a new class of potential therapeutic agents for several types of central nervous system disorder. Carbon-11-labeled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([¹¹C]SA4503) was shown to be a promising PET ligand for mapping σ(1) receptors, and was applied to measure receptor occupancy with several therapeutic drugs in the living human brain. In this study, we applied this technique for preclinical in vivo screening of novel σ₁ selective agonists.Six newly synthesized piperazine derivatives containing arylalkylamine groups and cyclohexylamine derivatives containing phenyl groups were selected and tested for their in vivo σ₁ receptor binding with [¹¹C]SA4503. The test compounds were administered by intravenous co-injection or oral administration. The in vivo receptor binding of [¹¹C]SA4503 was evaluated by a tissue dissection method at a single time point.Our in vivo screen identified the most promising candidate of novel σ(1) agonist in the piperazine derivatives. Some correlations between in vitro affinity and in vivo receptor blocking rate were observed when considering oral bioavailability. In vivo receptor blocking of piperazine derivatives after oral administration may be predictable by simple co-injection study.Ligand selection with [¹¹C]SA4503 by the in vivo receptor binding assay was performed successfully. This technique is a practical and high-throughput method that can directly evaluate blood-brain barrier permeability, receptor binding, and bioavailability of drug candidates at the same time.

Tunneling junction Josephson devices with an Nb/NbOx/Pb structure were fabricated using Nb-based superconducting films deposited by the biased-sputtering method. Prior to forming the junction, 100 to 400 eV low-energy Ar ion beam cleaning was employed instead of RF sputter-cleaning which has conventionally been used. An etching condition suitable for cleaning the junction was obtained experimentally by evaluating the relationship between the gap parameters obtained from the I—V characteristic and etching energy. It was found that since energy control was easy in ion beam cleaning, the etching could be carried out under optimum conditions. Also, when ion beam cleaning was used, the increase in the gap voltage and the current spikes in the I—V characteristic were much less than when RF sputtercleaning was used. Using ion-beam etching under controlled energy, the junction could be cleaned with minimum damage, resulting in the improvement of the Josephson device properties.

Planar type devices were fabricated by patterning in-plane aligned YBa2Cu3O7−δ (YBCO) films. The current–voltage characteristics along the c-axis at various temperatures and oxygen contents were measured. The current voltage curves showing supercurrent and hysteresis were obtained for the samples annealed at an oxygen pressure of 1.3 × 104 Pa, while the supercurrent and hysteresis became smaller and even disappeared as the oxygen pressure decreased. The relationships between the critical currents and temperatures are similar to those of d-wave superconducting tunnel junctions. These results indicate the formation of stacks of intrinsic Josephson junctions, which are useful for developing high-frequency electron devices.

The YBCO films with high-temperature were prepared on a MgO(100) substrate by DC hollow cathode sputtering using a stoichiometric YBa 2 Cu 3 O y target. The VTB was fabricated on the use of Al slant evaporation and Ar ion beam etching(IBE) techniques. The voltage-current characteristics, microwave and millimeter-wave response of the VTBs were investigated. The responses of microwave radiation (f=9.67 GHz) and millimeter-wave radiation (f=94 GHz) to VTBs show well-defined constant voltage steps of 20 μV and 194 μV interval, respectively. Magnetic response was also observed in DC-SQUID structure consisting of them

Using hexamethyldisilane (HMDS), high Tc super-conductor/HMDS/metal superconductor junctions were fabricated. First, a YBa2Cu3O7 - x YBCO film was made by dc hollow cathode sputtering or rf off-axis sputtering. Then HMDS was absorbed in the film. In this case, one molecular layer (about 1 nm) was formed; Pb (Tc = 7.2 K) was deposited as a counterelectrode. Measurements of current-voltage characteristics were made for this tunnel junction thus obtained. As a result, an energy gap and Josephson current were observed. Also, a microwave response and a magnetic field dependence of Josephson current were investigated.

Thin films of YBaCuO were deposited onto polished MgO(100) substrates by a dc hollow cathode sputtering with stoichiometric YBa2Cu3Oz targets. The films of Tc zero with a good c-axis orientation were fabricated successfully under the condition of a sputtering gas Ar + 5% o2, sputter-pressure 820 m torr, and substrate temperature during deposition 700°C. The present study aims to realize a variable thickness bridge (VTB) device with thin bridge portions. VTB devices were fabricated by using photolithography, oblique incident evaporation of Al, and fine fabrication of 85 to 410 nm by low-energy ion-beam etching. Measurements were made for a frequency from microwave (9.67 GHz) to millimeter wave (94 GHz). Those devices were found to respond properly to a millimeter wave.

In situ grown superconducting Y-Ba-Cu-O films were deposited on a MgO substrate by rf sputtering with dc biased substrate holder using a mosaic YBaxCuyOztarget, which was composed of 9 pieces of ceramic of a nominal composition of x = 2, 4, 6, and y =3, 5, 7. The films were deposited at a substrate temperature Ts of 660°C and at various substrate holder voltages VH. After deposition, the films were immediately cooled in the chamber vented with 400 Torr of oxygen. The dependence of the critical temperature on the substrate position was investigated. The critical temperature higher than 70K was obtained at the substrate position above the target composition of x=2-6 and y=3-5 for VH= -80 V to -120 V.The deposition rate at finite negative holder voltage was higher than that at zero holder voltage. It was shown that the film composition approached to the target composition by the substrate holder negative voltage. The film with short c-lattice parameter showed high Tc, but the shortest one was somewhat longer than the bulk value.