Cutting Edge of the Pathogenesis of Atopic Dermatitis: Sphingomyelin Deacylase,the Enzyme Involved in Its Ceramide Deficiency,Plays a Pivotal Role

Atopic dermatitis (AD) is characterized clinically by severe dry skin and functionally by both a cutaneous barrier disruption and an impaired water-holding capacity in the stratum corneum (SC) even in the nonlesional skin. The combination of the disrupted barrier and water-holding functions in nonlesional skin is closely linked to the disease severity of AD, which suggests that the barrier abnormality as well as the water deficiency are elicited as a result of the induced dermatitis and subsequently trigger the recurrence of dermatitis. These functional abnormalities of the SC are mainly attributable to significantly decreased levels of total ceramides and the altered ceramide profile in the SC. Clinical studies using a synthetic pseudo-ceramide (pCer) that can function as a natural ceramide have indicated the superior clinical efficacy of pCer and, more importantly, have shown that the ceramide deficiency rather than changes in the ceramide profile in the SC of AD patients plays a central role in the pathogenesis of AD. Clinical studies of infants with AD have shown that the barrier disruption due to the ceramide deficiency is not inherent and is essentially dependent on postinflammatory events in those infants. Consistently, the recovery of trans-epidermal water loss after tape-stripping occurs at a significantly slower rate only at 1 day post-tape-stripping in AD skin compared with healthy control (HC) skin. This resembles the recovery pattern observed in Niemann–Pick disease, which is caused by an acid sphingomyelinase (aSMase) deficiency. Further, comparison of ceramide levels in the SC between before and after tape-stripping revealed that whereas ceramide levels in HC skin are significantly upregulated at 4 days post-tape-stripping, their ceramide levels remain substantially unchanged at 4 days post-tape-stripping. Taken together, the sum of these findings strongly suggests that an impaired homeostasis of a ceramide-generating process may be associated with these abnormalities. We have discovered a novel enzyme, sphingomyelin (SM) deacylase, which cleaves the N-acyl linkage of SM and glucosylceramide (GCer). The activity of SM deacylase is significantly increased in AD lesional epidermis as well as in the involved and uninvolved SC of AD skin, but not in the skin of patients with contact dermatitis or chronic eczema, compared with HC skin. SM deacylase competes with aSMase and β-glucocerebrosidase (BGCase) to hydrolyze their common substrates, SM and GCer, to yield their lysoforms sphingosylphosphorylcholine (SPC) and glucosylsphingosine (GSP), respectively, instead of ceramide. Consistently, those reaction products (SPC and GSP) accumulate to a greater extent in the involved and uninvolved SC of AD skin compared with chronic eczema or contact dermatitis skin as well as HC skin. Successive chromatographies were used to purify SM deacylase to homogeneity with a single band of ≈43 kDa and with an enrichment of >14,000-fold. Analysis of a protein spot with SM deacylase activity separated by 2D-SDS-PAGE using MALDI-TOF MS/MS allowed its amino acid sequence to be determined and to identify it as the β-subunit of acid ceramidase (aCDase), an enzyme consisting of α- and β-subunits linked by amino-bonds and a single S-S bond. Western blotting of samples treated with 2-mercaptoethanol revealed that whereas recombinant human aCDase was recognized by antibodies to the α-subunit at ≈56 and ≈13 kDa and the β-subunit at ≈43 kDa, the purified SM deacylase was detectable only by the antibody to the β-subunit at ≈43 kDa. Breaking the S-S bond of recombinant human aCDase with dithiothreitol elicited the activity of SM deacylase with an apparent size of ≈40 kDa upon gel chromatography in contrast to aCDase activity with an apparent size of ≈50 kDa in untreated recombinant human aCDase. These results provide new insights into the essential role of SM deacylase as the β-subunit aCDase that causes the ceramide deficiency in AD skin.     

The Attenuated Secretion of Hyaluronan by UVA-Exposed Human Fibroblasts Is Associated with Up- and Downregulation of HYBID and HAS2 Expression via Activated and Inactivated Signaling of the p38/ATF2 and JAK2/STAT3 Cascades

Little is known about the effects on hyaluronan (HA) metabolism of UVA radiation. This study demonstrates that the secretion of HA by human dermal fibroblasts (HDFs) is downregulated by UVA, accompanied by the down- and upregulation of mRNA and protein levels of the HA-synthesizing enzyme (HAS2) and the HA-degrading protein, HYaluronan Binding protein Involved in HA Depolymerization(HYBID), respectively. Signaling analysis revealed that the exposure distinctly elicits activation of the p38/MSK1/CREB/c-Fos/AP-1 axis, the JNK/c-Jun axis, and the p38/ATF-2 axis, but downregulates the phosphorylation of NF-kB and JAK/STAT3. A signal inhibition study demonstrated that the inhibition of p38 significantly abrogates the UVA-accentuated mRNA level of HYBID. Furthermore, the inhibition of STAT3 significantly downregulates the level of HAS2 mRNA in non-UVA exposed HDFs. Analysis using siRNAs demonstrated that transfection of ATF-2 siRNA but not c-Fos siRNA abrogates the increased protein level of HYBID in UVA-exposed HDFs. An inhibitor of protein tyrosine phosphatase but not of protein serine/threonine phosphatase restored the diminished phosphorylation level of STAT3 at Tyr 705, accompanied by a significant abolishing effect on the decreased mRNA expression level of HAS2. Silencing with a protein tyrosine phosphatase PTP-Meg2 siRNA revealed that it abrogates the decreased phosphorylation of STAT3 at Tyr 705 in UVA-exposed HDFs. These findings suggest that the UVA-induced decrease in HA secretion by HDFs is attributable to the down- and upregulation of HAS2 and HYBID expression, respectively, changes that are mainly ascribed to the inactivated signaling of the STAT3 axis due to the activated tyrosine protein phosphatase PTP-Meg2 and the activated signaling of the p38/ATF2 axis, respectively.     

New Preparation Method of CdS Clusters Encapsulated in Y-Type Zeolites

CdS clusters encapsulated in Y-type zeolite were prepared by a novel technique with non-aqueous systems. The mechanical mixture of CdCl₂· 2.5H₂O crystal with Y-type zeolite was heated at 773 K, followed by the H₂S treatment at 373 K, resulting in the formation of CdS clusters with the size <2.3 nm.     

Building more solid bridges between Buddhism and Western psychology.

Introducing the ways of cultivating mental balance, B. A. Wallace and S. L. Shapiro (see record 2006-12925-003) attempted to build bridges between Buddhism and psychology. Their systematic categorization of Buddhist teachings and extensive review of empirical support from Western psychology are valuable for future study. However, it remains a matter of concern that some more profound parts of Buddhist philosophy can be disregarded by focusing only on practical aspects of Buddhism within the context of mental health. In this comment, the authors briefly address four substantial themes to be considered: reality, identity, causality, and logicality. They suggest that the way to interpret Buddhism as techniques for well-being would certainly be viable in encouraging the study of Buddhist teachings in psychology. Yet, such attempts should not result in superficial imports and applications of Buddhist practices but give due weight to the deeper philosophical issues to build more solid bridges between Buddhism and psychology. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Maximum capacity of distributed generators connected to a distribution system with a step voltage regulator,as determined with an electric power density model

In a distribution system containing a step voltage regulator (SVR), the maximum capacity of distributed generators (DGs) is calculated for DGs completely dispersed on a distribution line. The maximum capacity of the DGs is calculated under the constraint of an upper or lower voltage regulation value and an allowable current value by using voltage and current profiles expressed analytically in terms of our proposed power density model. As the voltage control method for the SVRs, we consider the conventional SVR, whose transformation ratio is fixed to 1 if it detects reverse power flow, and a reverse power flow SVR which operates appropriately even if it detects reverse power flow. Calculation of the maximum capacity of DGs with respect to the power factor of the DGs indicates which parameters, including the power factor of the DGs, the distribution of the DGs, and the load, influence the maximum DG capacity. Calculation of the maximum capacity of DGs versus the system length indicates that the constraints can be subdivided into two modes in the conventional SVR and four modes in the reverse power flow SVR. The maximum DG capacity in the system with a reverse power flow SVR is larger than that in a system with the conventional SVR. © 2008 Wiley Periodicals, Inc. Electr Eng Jpn, 165(4): 41–51, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/eej.20591     

Harmonic compensation using a synchronous machine with resonantfield circuits

This paper deals with a harmonic compensation method using a synchronous machine with resonant field circuits. Harmonics have become one of the major problems in power systems and a lot of methods of harmonic suppression have been studied. The authors have proposed a new method of harmonic suppression using a synchronous machine excited with the 6th harmonic current. This paper shows that armature inductances for the 5th or 7th harmonics decrease when the field circuits are connected to capacitors resonating at the 6th harmonic. The variations of armature impedances are explained theoretically by Park's equations. The optimal capacitances are selected so as to resonate with field inductances for the short-circuited armature. The experiments to suppress the 5th and 7th harmonics using the synchronous machine are successful     

Finding optimal SVR placement in distribution systems using power density model

In long distribution systems, Step Voltage Regulators (SVRs) are installed to regulate the system voltage. There are some papers on finding optimal placements of SVRs in the system. However, there is no analytic method that focuses on the voltage margin, that is, the optimal placement with respect to the system voltage. The authors propose a method of finding the placement of an SVR so that the voltage margin from the upper (or lower) voltage limit is the largest under heavy load. In order to deal with sets of loads that are dispersed over the entire distribution line, we derive the differential equation of the complex power and that of the voltage drop, which are expressed as functions of distance from a substation. The voltage profile is obtained as a cubic equation by solving the voltage equation if the load distribution is trapezoidal. The method of finding the optimal SVR placement distinguishes three modes with three different voltage profiles. One is the case in which the transformation ratio of the SVR is small and the system length is short, one is the case in which the transformation ratio of the SVR is large and the system length is short, and the third is the case in which the transformation ratio of the SVR is large and the system length is long. The optimal placement and tap position of the SVR are calculated by solving the above‐mentioned equations in these three modes. It is confirmed that the proposed analytical method is appropriate by model calculation results. © 2007 Wiley Periodicals, Inc. Electr Eng Jpn, 158(4): 11–21, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/eej.20481     

Hybrid evolutionary method for obstacle location-allocation

In this paper we propose a hybrid evolutionary method for Obstacle Location-allocation problem. This problem can be described as a tri-level mixed integer programming problem. Since this problem is very complex and with many local solutions, no direct method is effective to solve it. Heuristic methods were proposed to it, but optimality is not guaranteed yet. Our hybrid evolutionary method adopts the main structure of Genetic Algorithms (GA) absorbing ideas from Evolutionary Strategy (ES) and combines with some traditional optimization techniques. In this way we can pursue global optimization maintaining a good efficiency of our method. A case study shows the effectiveness of this method.