Identification of Physiological and Toxic Conformations in Aβ42 Aggregates

Aggregation of the 42‐residue amyloid β‐protein (Aβ42) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Despite numerous structural studies on Aβ aggregates, the relationship between tertiary structure and toxicity remains unclear. Our proline scanning and solid‐state NMR studies suggested that aggregates both of wild‐type Aβ42 and of E22K‐Aβ42 (one of the mutants related to cerebral amyloid angiopathy) contain two conformers: a major one with a turn at positions 25 and 26, and a minor one with a turn at positions 22 and 23. To identify the toxic conformer, the derivative Aβ42‐lactam(22K–23E), in which the side chains at positions 22 and 23 were covalently linked, was synthesized as a minor conformer surrogate, along with Aβ42‐lactam(25K–26E) as a major conformer surrogate. The Aβ42‐lactam(22K–23E) showed stronger aggregation, neurotoxicity, radical generation, and oligomerization than wild‐type Aβ42, whereas in Aβ42‐lactam(25K–26E) were weak. The transition from the physiological conformation with a turn at positions 25 and 26 to the toxic conformation with a turn at positions 22 and 23 might be a key event in the pathogenesis of AD.     

TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase

Ceramide has been proposed as a second messenger molecule implicated in a variety of biological processes. It has recently been reported that ceramide activates stress-activated protein kinase (SAPK, also known as c-Jun NH2-terminal kinase JNK), a subfamily member of mitogen-activated protein kinase superfamily molecules and that the ceramide/SAPK/JNK signaling pathway is required for stress-induced apoptosis. However, the molecular mechanism by which ceramide induces SAPK/JNK activation is unknown. Here we show that TAK1, a member of the mitogen-activated protein kinase kinase kinase family, is activated by treatment of cells with agents and stresses that induce an increase in ceramide. Ceramide itself stimulated the kinase activity of TAK1. Expression of a constitutively active form of TAK1 resulted in activation of SAPK/JNK and SEK1/MKK4, a direct activator of SAPK/JNK. Furthermore, expression of a kinase-negative form of TAK1 interfered with the activation of SAPK/JNK induced by ceramide. These results indicate that TAK1 may function as a mediator of ceramide signaling to SAPK/JNK activation.     

Possible involvement of differential splicing in regulation of the activity of Arabidopsis ANP1 that is related to mitogen-activated protein kinase kinase kinases (MAPKKKs)

Retrospective study about 10 verrucous carcinomas of the larynx surgically treated in a 20-year-term. This variety accounted por the 1.9 percent of the cancers seen in that period of time. Tabagism and alcoholism predominated in 8 and 6 patients respectively. Glottis was the localization and dysphony the paramount symptom. In the paper are emphasized the most important histologic features. Koilocytosis was present in 6 cases. Four patients developed a second tumor of epidermoid carcinoma type. No one exitus due to the verrucous growth. Only in 3 the death was attributed to the second malignancy.     

Pitchfork bifurcation polarization bistability in laser diodes withexternal cavities

A new pitchfork bifurcation polarization bistability in laser diodes with a two-armed polarization-selective external cavity is examined theoretically and experimentally. The rate-equation analysis taking into account gain saturation has been carried out using the model for a laser diode whose laser thresholds of the TE and the TM modes can be changed independently through the changing of their photon lifetimes. It is shown from the analysis that pitchfork bifurcation polarization bistability appears when the laser thresholds for both modes are very close to each other and the switching between two stable states is obtained by means of a photon lifetime changing or a coherent or incoherent light injection. In the experiment, a 1.3-μm InGaAsP laser diodes with a T-shaped polarization-selective external cavity mas used. A new type of polarization bistability was observed when one arm was blocked and then recoupled. The two stable states mere also switched by means of an optical injection. All-optical flip-flop operation has been successfully demonstrated by using both TE and TM trigger inputs     

System for coil simulation measurements of losses and instabilities in superconducting wires

A new system for measuring ac losses in superconductors under coil simulation conditions is described. It is aimed to investigate instabilities in local points of a coil. Currents up to 150 A and magnetic fields up to 0.4 T can be applied simultaneously and can be varied independently. The magnetic and electric fields on both sides of the sample are measured by means of pick-up coilds and potential leads, respectively. By this method the instantaneous values of the power introduced through each of both sample surfaces can be measured separately. The validity of the method and the performance of the system are demonstrated by measuring the losses of a copper-clad single-core Nb---Ti---Zr wire for several values of the ratio between the current and the magnetic field, which are inphase.     

Homogeneous assay for measuring low-density lipoprotein cholesterol in serum with triblock copolymer and alpha-cyclodextrin sulfate

We have developed a fully automated method for measuring LDL-cholesterol (LDL-C) in human serum without the need for prior separation, using a nonionic surfactant, polyoxyethylene-polyoxypropylene block copolyether (POE-POP), and a sodium salt of sulfated cyclic maltohexaose, alpha-cyclodextrin sulfate. Of the surfactants tested, POE-POP with a higher molecular mass of the POP block and a greater hydrophobicity reduced the reactivity of cholesterol in lipoprotein fractions; the reactivity in descending order was LDL > VLDL > chylomicron approximately HDL. Gel filtration chromatographic studies revealed that POE-POP removed lipids selectively from the LDL fraction and allowed them to participate in the cholesterol esterase-cholesterol oxidase coupling reaction system. By contrast, alpha-cyclodextrin sulfate reduced the reactivity of cholesterol, especially in chylomicrons and VLDL. A combination of POE-POP with alpha-cyclodextrin sulfate provided the required selectivity for the determination of LDL-C in serum in the presence of magnesium ions and a small amount of dextran sulfate without precipitating lipoprotein aggregates. There was a good correlation between the results of LDL-C assayed by the proposed method and the beta-quantification reference method involving 161 sera with triglyceride concentrations ranging from 0.3 to 22.6 mmol/L.     

Synthesis of Novel Photochromic Films by Oxidation Polymerization of Diarylethenes Containing Phenol Groups

We report the synthesis of some diarylethene derivatives attached to phenol moieties, which show remarkable photochromic reactions. A dithienylethene group attached to the o‐phenol moiety (1,2‐bis[2,4‐dimethyl‐5‐(o‐hydroxyphenyl)‐3‐thienyl]hexafluorocyclopentene) was polymerized according to Hay's method; the resulting film was insoluble to any solvents, and showed no absorption band attributable OH group in its IR spectrum. Isomeric dithienylethenes attached to m‐ and p‐phenol moieties did not form films under the same oxidation conditions, but instead formed films by copolymerization with 4,4′‐dihydroxyphenyl ether. Although the homopolymer film and copolymer films showed reversible photochromic reactions by alternate irradiation with UV and visible light, the coloration was not remarkable. Polymerization of closed‐ring isomers of the dithienylethenes did not give pre‐polymers and instead decomposed, while the closed‐ring isomer of a bisbenzothienylethene derivative attached to the o‐phenol moiety (1,2‐bis[2‐methyl‐6‐(o‐hydroxyphenyl)‐1‐benzothiophen‐3‐yl]hexafluorocyclopentene) formed a polymer film by the same procedure. This polymer film showed a remarkable photochromic reaction, indicating the photo‐reactive conformation was fixed in polymer matrix, and X‐ray diffraction measurements show that the film is in the amorphous phase. The photochromic reaction can also be monitored by IR spectroscopy, making it applicable for non‐destructive read‐out recording films.     

The effect of PTA on cerebral vessels in experimental vasospasm: a histopathological study

Although the percutaneous transluminal angioplasty (PTA) is an useful procedure for the treatment of symptomatic vasospasm after subarachnoid hemorrhage, the morphological changes in spastic intracranial vessels after PTA are not yet clear. The purpose of this study was to evaluate the effects of PTA angiographically and histologically. Chronic cerebral vasospasm was induced by producing a blood clot in the subarachnoid space around the top of internal carotid siphon in Japanese monkey. After angiographic recognition of vasospasm, PTA was carried out with silicone microballoon at 1 atmosphere, 3 times for 10 seconds. Angiography after PTA disclosed significant dilatation at the site of PTA, without any significant dilatation of distal spastic vessels. Papaverine hydrochloride was then infused intra-arterially, which resulted in significant dilatation of distal spastic vessels. Upon histological examination, deformation and some denudation of endothelial cells were noted in the intimal layer. At the site of denudation, attachment of platelets was observed despite generalized heparinization. Internal elastic lamina and the media were also stretched and myocytes were deformed and arranged irregularly. These changes were not uniform all over the vascular walls. We conclude that the prolonged effect of PTA may be caused by mechanical damage of endothelial cells and myocytes, and the nonuniformity of histological changes in vascular wall may be a leading cause of its rupture during PTA.     

Early HCC and adenomatous hyperplasia: evaluation of arterial and portal blood flow with CTA, CTAP, and pathologic correlation

In order to analyze the hemodynamic properties of early hepatocellular carcinoma (HCC) and adenomatous hyperplasia (AH), three lesions (two HCCs, one AH) depicted as hypoattenuating at CTA and iso attenuating at CTAP were correlated with the histopathological findings. The number of normal hepatic arteries in the tumor was lower than in the liver. Degeneration and narrowing of the lumens were also seen microscopically. All tumors showed the replacing growth pattern and had similar numbers of the portal tracts in the tumor to the liver. The decreased number of intratumoral normal arteries is suspected to be a characteristic finding of the early stage of HCC.