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The use of partially quaternized, chloromethylated polystyrene as a covalent scavenger of cholate ion in aqueous media has been demonstrated. The ability of such polymers to scavenge organic anions by covalent as well as by ionic means has important implications in the areas of medicinal and environmental chemistry, which are briefly discussed.

Fas (APO-1/CD95), which is a member of the tumor necrosis factor receptor superfamily, is a cell surface receptor that induces apoptosis. A protein tyrosine phosphatase, Fas-associated phosphatase-1 (FAP-1), that was previously identified as a Fas binding protein interacts with the C-terminal 15 amino acids of the regulatory domain of the Fas receptor. To identify the minimal region of the Fas C-terminal necessary for binding to FAP-1, we employed an in vitro inhibition assay of Fas/FAP-1 binding using a series of synthetic peptides as well as a screen of random peptide libraries by the yeast two-hybrid system. The results showed that the C-terminal three amino acids (SLV) of human Fas were necessary and sufficient for its interaction with the third PDZ (GLGF) domain of FAP-1. Furthermore, the direct cytoplasmic microinjection of this tripeptide (Ac-SLV) resulted in the induction of Fas-mediated apoptosis in a colon cancer cell line that expresses both Fas and FAP-1. Since t(S/T)X(V/L/I) motifs in the C termini of several other receptors have been shown to interact with PDZ domain in signal transducing molecules, this may represent a general motif for protein-protein interactions with important biological functions.

1. After bilateral ureteral obstruction there is an enhanced production of thromboxane A2 by the kidney which contributes to a decline in renal function. An acute interstitial macrophage infiltrate also occurs. 2. The relative contribution of infiltrating cells and intrinsic renal cells to the enhanced production of thromboxane A2 by the hydronephrotic kidney were determined. The effects of both irradiation and subsequent administration of the thromboxane synthesis inhibitor OKY-046 on both thromboxane B2 excretion and renal function were examined in rats with 24 h bilateral ureteral obstruction. 3. Irradiation effectively prevented the leucocyte infiltrate after bilateral ureteral obstruction (1.2 ± 0.8 × 105 versus 27.1 ± 0.1 × 105 cells/g of cortex, n = A in each group), resulted in a significantly higher inulin clearance (2.78 ± 0.27 versus 1.49 ± 0.17 ml min−1 kg−1 body weight, n = 7 and n = 8, respectively, P < 0.001) and reduced thromboxane B2 excretion to 39% of non-irradiated values. Subsequent administration of OKY-046 to previously irradiated animals further reduced thromboxane B2 excretion to 20% of the value in non-irradiated rats with bilateral obstruction and further increased inulin clearance to 3.34 ± 0.26 ml min−1 kg−1 body weight. 4. Glomerular macrophage numbers were decreased after bilateral ureteral obstruction (in contrast to the interstitium). However, glomeruli isolated from rats with 24 h bilateral ureteral obstruction exhibited enhanced production of thromboxane B2 compared with sham-operated control rats (855.6 ± 31.1 versus 392.2 ± 25.5 pg 60 min−1 mg−1 of protein, P < 0.001). 5. These data suggest that the increased renal production of thromboxane A2 after bilateral ureteral obstruction results from both renal infiltration by metabolically active macrophages and enhanced prostanoid production by the glomeruli. Both sources of thromboxane A2 contribute to altered renal function after bilateral ureteral obstruction.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by combined systemic degeneration of the dentatofugal and pallidofugal pathways. We investigated a candidate gene and found that DRPLA patients had an expanded CAG trinucleotide repeat in a gene on the short arm of chromosome 12. The repeat size varied from 7–23 in normal individuals. In patients one allele was expanded to between 49–75 repeats or occasionally even more. Expansion was usually associated with paternal transmission and only occasionally with maternal transmission. Repeat size showed a close correlation with age of onset of symptoms and disease severity. We conclude that DRPLA is the seventh genetic disorder known to be associated with expansion of an unstable trinucleotide repeat.

A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2‘-1H-tetrazol-5-ylbiphenyl-4-yl)methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.

The role of nuclear protooncogenes during erythroid cell differentiation was examined by transfecting exogenous c-fos and c-myb genes into mouse erythroleukemia cells, which can be induced to differentiate either with erythropoietin (Epo) or dimethyl sulfoxide. Expression of exogenous c-myb or c-fos oncogene completely inhibited Epo-induced erythroid differentiation but only partially inhibited dimethyl sulfoxide-induced differentiation. Normally Epo-induced differentiation leads to a drastic decline of c-myb mRNA levels and an increase of c-myc transcripts in the early stage of differentiation. Cells expressing exogenous c-fos gene, however, maintained high levels of c-myb mRNA after Epo treatment. This high level of c-myb transcripts was found to be due to block of transcription shutoff (or transcriptional activation) rather than to mRNA stabilization. It is concluded that the down-regulation of endogenous c-myb gene expression is a prerequisite for commitment of Epo-induced erythroid differentiation and that expression of c-myb gene may be indirectly regulated by c-fos gene product. We also concluded that early down-regulation of c-myc gene expression is not essential for erythroid differentiation and that gene regulation of chemically induced erythroid differentiation may differ from that of Epo-induced differentiation.

The embryonic vasculature develops from endothelial cells that form a primitive vascular plexus which recruits smooth muscle cells to form the arterial and venous systems. The MADS-box transcription factor MEF2C is expressed in developing endothelial cells and smooth muscle cells (SMCs), as well as in surrounding mesenchyme, during embryogenesis. Targeted deletion of the mouse MEF2C gene resulted in severe vascular abnormalities and lethality in homozygous mutants by embryonic day 9.5. Endothelial cells were present and were able to differentiate, but failed to organize normally into a vascular plexus, and smooth muscle cells did not differentiate in MEF2C mutant embryos. These vascular defects resemble those in mice lacking the vascular-specific endothelial cell growth factor VEGF or its receptor Flt-1, both of which are expressed in MEF2C mutant embryos. These results reveal multiple roles for MEF2C in vascular development and suggest that MEF2-dependent target genes mediate endothelial cell organization and SMC differentiation.

Recent gene targeting studies have revealed unexpected roles for endothelins in the development of neural crest-derived tissues. Endothelin converting enzyme-1 (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to endothelin-1(ET-1) in vitro. However, the importance of ECE-1 cleavage in the multiple endothelin pathways in vivo is unknown. Here we generated a targeted null mutation in the mouse ECE-1 gene. ECE-1-/- term embryos exhibited craniofacial and cardiac abnormalities virtually identical to the defects seen in ET-1 and endothelin A receptor (ETA)-deficient embryos. Epidermal melanocytes as well as enteric neurons of the distal gut were also absent in ECE-1-/- embryos, reproducing the developmental phenotype seen in ET-3-/- and endothelin B receptor (ETB)-/- mice. Surprisingly, large amounts of mature ET-1 peptide are found in ECE-1-/- embryos, indicating that non-ECE-1 protease(s) can activate ET-1 at certain sites. However, these enzymes cannot produce sufficient mature endothelin at the locations crucial for normal embryonic development. These findings reveal that ECE-1 is a bona fide activating protease for both big ET-1 and big ET-3 in vivo, and that the cell-cell communication pathways represented by the ET-1/ECE-1/ETA axis and the ET-3/ECE-1/ETB axis are each involved in the development of distinct subsets of neural crest cell lineages. Mutations in ECE-1 may cause developmental defects in humans, such as Hirschsprung disease, velocardiofacial syndrome and related neurocristopathies.

Neural crest cells arise in the dorsal aspect of the neural tube and migrate extensively to differentiate into a variety of neural and non-neural tissues. While interactions between neural crest cells and their local environments are required for the proper development of these tissues, little information is available about the molecular nature of the cell-cell interactions in cephalic neural crest development. Here we demonstrate that mice deficient for one type of endothelin receptor, ETA, mimic the human conditions collectively termed CATCH 22 or velocardiofacial syndrome, which include severe craniofacial deformities and defects in the cardiovascular outflow tract. We show that ETA receptor mRNA is expressed by the neural crest-derived ectomesenchymal cells of pharyngeal arches and cardiac outflow tissues, whereas ET-1 ligand mRNA is expressed by arch epithelium, paraxial mesoderm-derived arch core and the arch vessel endothelium. This suggests that paracrine interaction between neural crest-derived cells and both ectoderm and mesoderm is essential in forming the skeleton and connective tissue of the head. Further, we find that pharyngeal arch expression of goosecoid is absent in ETA receptor-deficient mice, placing the transcription factor as one of the possible downstream signals triggered by activation of the ETA receptor. These observations define a novel genetic pathway for inductive communication between cephalic neural crest cells and their environmental counterparts.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder associated with the expansion of a CAG repeat at chromosome band 12p13. Epidemiological studies have demonstrated an increased prevalence of DRPLA in Japan, although several DRPLA kindreds of non-Japanese ancestry have been identified. To define the molecular basis for this geographic variation in prevalence, we have analyzed haplotypes around the repeat in several different ethnic groups. Two intragenic biallelic polymorphisms distinguished three haplotypes, each of which formed a predominant haplotype found in the three major racial populations. All the expanded repeats of Japanese and Caucasian patients studied were associated with a particular haplotype, which otherwise was associated with longer repeats commonly found in Asians. Our results support a multi-step model for repeat expansion, and suggest that expanded DRPLA repeats may have evolved from an ancient chromosomal haplotype of Asian origin. We also propose that a combination of a highly polymorphic microsatellite marker with relatively stable biallelic markers in a range of PCR amplification is a powerful tool for studies on human genome diversity, which may reveal the ancient human migration and the formation of ethnic groups.

Abstract.: Using a diffraction approach the convolution-type integral equation for the laser schlieren signal created by an arbitrary disturbance at low pressure, where refractive index of disturbance is close to unity, in a shock tube (thin optical layer) has been deduced. In the equation electric circuit relaxation processes were taken into account by a response function. The equation was solved with the aid of the regularization method worked out for ill-posed problems. The density structures of the strong shock waves in air have numerically been reconstructed from experimental data ranging shock wave Mach number of –30, and –30 Pa.

The object of this work was to develop a monitoring device for measuring the volume of urine in the bladder to signal, in advance, the need to urinate and thus help prevent urinary incontinence. A high-frequency electric current of 50 KHz transmitter was applied to a pair of terminals placed on the surface of a human body. The constant current was 2mA (p-p). A pair of voltage electrodes was placed in the path of the electric current to pick up high-frequency voltage signals. The best position for current electrodes was found to be on the surface of both femoral joints. Positioning the voltage electrode above the bladder on the lower abdomen was most efficient for detecting the volume of urine. New current electrodes sutured onto underpants were fitted on the surface above the femoral joints, which did not shift in the case of movement by the subjects. The reproducibility and stability were remarkably good with this electrode. The alarm level which foretold both maximum storage volume and maximum desire to void was examined. After that, when the alarm level was set within the range of impedance charge, 60% to 70%, the possibility of prediction of urination exists.

Summary: In order to clarify the mechanism of crystallization under molecular orientation, crystallization of poly(vinyl alcohol) from solution was studied under the steady-state flow brought about under such conditions that the distance between the surface of the rod for stirring and the inner surface of glass vessel was 4 mm and the speed of rotation was 2070 rpm. The process of crystallization was classified in three types. (1): When air bubbles were scarcely formed by stirring, many bulk crystals were produced successively falling downward from the surface of solution irregularity arranged. (2): When a large quantity of air bubble was formed, finally film-like precipitates wound around the stirrer were obtained. (3): Two kinds of processes described above occurred simultaneously. In this condition, the nucleation and crystallization of PVA from solution by shearing force are considered to be caused by the turbulent flow at the surface of solution and that owing to air bubbles. The first type was observed when the molecular weight of PVA and the polymer concentration are low and the temperature of solution is high. The type was transferred to (3) or (2) with increasing molecular weight and polymer concentration and decreasing temperature. The rate of precipitation decreased with increasing temperature and with decreasing molecular weight and polymer concentration. Furthermore, the temperature at which no precipitates were produced increased with increasing molecular weight.

Summary The poly(vinyl alcohol) (VTFA-PVA) derived from vinyl trifluoracetate and the poly(vinyl alcohol) (VAc-PVA) derived from vinyl acetate, that differ in the stereoregularity, were blended and fractionated by the stress-induced crystallization. The mixture of PVA's which have nearly the same degree of polymerization but different tacticity, especially, the different syndiotacticity (B-1) was separated clearly by stirring. On the other hand, when the degree of polymerization of raw PVA that had higher syndiotacticity was lower than that of raw PVA that has the lower syndiotacticity (B-2), the mixture was not separated clearly. The relation between the percentages of syndiotactic diads of the fractions and the cumulative weight fraction (CWF) for B-1 was represented with two different curves for CWF of below and above 50%, whereas the percentages of syndiotactic diads of the fractions for B-2 decreased monotonously in the order of fractionation. The relation between the degree of polymerization and CWF for B-2 was similar to that obtained in the stirring fractionation of VTFA-PVA. Therefore, VAc-PVA was crystallized together with VTFA-PVA by shearing force from the initial stage of fractionation, though the contents of VTFA-PVA in crystals were greater than those of VAc-PVA.

The optimum design for tensile-strained quantum-well structures, and the laser characteristics of AlGaInP LDs emitting at 615-635 nm are investigated. MQW structures are effective in reducing threshold currents at wavelengths shorter than 620 nm. The lowest threshold current of 95 mA at 20°C is attained in a quaternary MQW LD emitting at 615 nm.

A low threshold current of 47 mA at 20°C has been obtained in a tensile-strained index-guided AlGaInP LD emitting at 625nm, which has an active region consisting of five 8 nm-thick QWs with a lattice mismatch of −0.9%. It is shown that optimisation of the tensile-strained QW structure is very useful in improving the performance of AlGaInP LDs at wavelengths shorter than 630 nm.

The effects of substrate misorientation and the optimisation of QWs in AlGaInP MQW LDs in the wavelength range around 630nm are examined in pursuit of high-temperature operation. Continuous-wave lasing up to 88°C is attained for a narrow-strip quaternary MQW LD emitting at 637nm, which is grown on 7°-off misoriented substrates.

CW oscillation at a wavelength shorter than 630 nm, which depends on the Al content incorporated into a tensile-strained single-quantum-well active region of AlGaInP LDs, is investigated. A threshold current of 112 mA at 20°C is attained in a quaternary (AlxGa1−x)InP (x = 0.1) SQW LD emitting at 615 nm.

Thoracic aortic aneurysms are life-threatening lesions that afflict young and old individuals alike. They frequently associate with genetic mutations and are characterized by reduced elastic fibre integrity, dysfunctional smooth muscle cells, improperly remodelled collagen and pooled mucoid material. There is a pressing need to understand better the compromised structural integrity of the aorta that results from these genetic mutations and renders the wall vulnerable to dilatation, dissection or rupture. In this paper, we compare the biaxial mechanical properties of the ascending aorta from 10 murine models: wild-type controls, acute elastase-treated, and eight models with genetic mutations affecting extracellular matrix proteins, transmembrane receptors, cytoskeletal proteins, or intracellular signalling molecules. Collectively, our data for these diverse mouse models suggest that reduced mechanical functionality, as indicated by a decreased elastic energy storage capability or reduced distensibility, does not predispose to aneurysms. Rather, despite normal or lower than normal circumferential and axial wall stresses, it appears that intramural cells in the ascending aorta of mice prone to aneurysms are unable to maintain or restore the intrinsic circumferential material stiffness, which may render the wall biomechanically vulnerable to continued dilatation and possible rupture. This finding is consistent with an underlying dysfunctional mechanosensing or mechanoregulation of the extracellular matrix, which normally endows the wall with both appropriate compliance and sufficient strength.

The amount of tensile strain introduced into QWs and the optimum QW structure are evaluated for low-threshold operation of AlGaInP LDs in the wavelength range 630–640nm. Very low threshold current of 32mA under CW operation at 20°C is achieved in an index-guided SQW LD emitting at 632nm.

The letter illustrates that the frequency characteristics of a three-line microstrip directional coupler can be greatly improved by using the dielectric overlay. We show the method of analysis in detail. The examples of design data are shown with the graphs of frequency characteristics of the coupler

This letter describes a method for improving the directivity of the edge-coupled microstrip couplers; the coupler is made up of the suspended microstrip lines. The gap between the dielectric substrate and the ground plane is adjusted to get equal mode velocities under perfect matching conditions. Design data for optimum structure and experimental results are presented and discussed.

The epoxy sugar (I) is cleaved with the Grignard compounds (II) and then converted into the azides (VIII).

Starting with the 1,4‐thiazepine (I), the potent angiotensin‐converting enzyme (ACE) inhibitor (XI) is synthesized.

The optically active seven‐membered lactams (VII) and (IX) are prepared in order to obtain conformationally restricted analogues of the angiotensin‐converting enzyme inhibitor enalapril.

The perhydro‐1,4‐thiazepin‐5‐ones (X) with hydrophobic substituents at the 2‐position are prepared from Boc‐L‐cysteine (I) as outlined in the reaction scheme.

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