Differences in Involucrin Immunolabeling Within Cornified Cell Envelopes in Normal and Psoriatic Epidermis

Epidermal keratinocytes form a cornified cell envelope (CE) beneath the plasma membrane during the late stages of differentiation, This CE is stabilized by cross linking of several precursor proteins, including involucrin, In psoriasis, the expression pattern of the precursor proteins is known to be deranged; involucrin expression is increased and loricrin expression is decreased. However, these changes have not been previously evaluated ultrastructurally. In the present study, we performed light and electron microscopic immunohistochemistry in conjunction with conventional transmission electron microscopy to assess the nature of involucrin involvement in normal and psoriatic CEs. In normal epidermis, CEs were observed from the deepest cornified cells or, when present, from the transitional cells, increasing In thickness and changing electron densities with maturation. In psoriatic epidermis, CE formation started earlier, one to several cells below the cornified layer. Psoriatic CEs were generally thinner and showed a constant high electron density. Immunoelectron microscopy revealed that the normal CE was involucrin positive only at a very early stage, whereas psoriatic CE showed persistent involucrin immunoreactivity. These results suggest that in normal skin, involucrin is the major constituent of the CE only In its early stages of assembly. In contrast, CE formation seems to be initiated prematurely in psoriatic skin, where involucrin remains the major constituent of the CE during maturation

Regulation of Beta-Adrenergic Adenylate Cyclase Responsiveness of Pig Skin Epidermis by Suboptimal Concentrations of Epinephrine

Although receptor-specific refractoriness has been suggested to be one of the regulatory mechanisms of epidermal adenylate cyclase systems, its physiologic significance has been a subject of controversy because of the requirement of unusually high concentrations of agonists to induce refractoriness. In order to determine whether the epidermal adenylate cyclase system is regulated through a refractoriness mechanism by suboptimal concentrations of receptor agonists, this study was undertaken using pig skin epidermal adenylate cyclase systems.Pretreatment of pig skin with 0.1-1 μM epinephrine in vitro resulted in the reduction of the maximal epinephrine response (epinephrine-induced cyclic AMP accumulations) to various degrees without alterations in either low or high Km, cyclic AMP phosphodiesterase activities. Repeated pretreatments were shown to be more effective in inducing refractoriness than a single pretreatment. Apparently there was no change in the Km value for epinephrine, suggesting that the decrease in epinephrine response represents a reduction in the number but not in the affinity of functional beta-adrenergic adenylate cyclase receptor sites. This refractoriness by low concentrations of catecholamine pretreatment was specific to the beta-adrenergic system, since there was no reduction in histamine response after the epinephrine pretreatment.These results indicate that the epidermal beta-adrenergic adenylate cyclase system is regulated by much lower concentrations of catecholamine than were previously described. It was suggested that physiologic fluctuations of plasma catecholamine levels might have a profound effect on epidermal beta-adrenergic adenylate cyclase responsiveness, resulting in the alteration of the minimal catecholamine level required for the successive activation of cyclic AMP-dependent protein kinase, which is the predominant target of cyclic AMP in epidermis

Theoretical Analysis on the Efficiency of Interleaved Comparisons

This study presents a theoretical analysis on the efficiency of interleaving, an efficient online evaluation method for rankings. Although interleaving has already been applied to production systems, the source of its high efficiency has not been clarified in the literature. Therefore, this study presents a theoretical analysis on the efficiency of interleaving methods. We begin by designing a simple interleaving method similar to ordinary interleaving methods. Then, we explore a condition under which the interleaving method is more efficient than A/B testing and find that this is the case when users leave the ranking depending on the item's relevance, a typical assumption made in click models. Finally, we perform experiments based on numerical analysis and user simulation, demonstrating that the theoretical results are consistent with the empirical results.Comment: The 45th European Conference on Information Retrieval (ECIR2023

Cyclic Amp Accumulation in Psoriatic Skin: Differential Responses to Histamine, Amp, and Epinephrine by the Uninvolved and Involved Epidermis

Using the uninvolved and involved skin from psoriatic patients, we investigated the effects of histamine and AMP (or adenosine) in vitro on the intracellular cyclic AMP levels. Both agents activated adenylate cyclase of the uninvolved and involved resulting in the accumulation of cyclic AMP. Without a cyclic nucleotide phosphodiesterase (PDE) inhibitor, these responses were biphasic and the maximal accumulation was observed in 5min. With the PDE inhibitor both responses were markedly potentiated and high levels of cyclic AMP were observed for more than 20mm. The response to histamine by the involved skin was much greater than that by the uninvolved. The degree of the response to adenosine was approximately equal. In accordance with our previous work, the response to epinephrine by the involved skin was much less than that by the uninvolved. Thus adenylate cyclases of involved skin from psoriatic patients exhibit a markedly diminished response to epinephrine while at the same time exhibiting a markedly enhanced response to histamine. This precludes the possibility that the unresponsiveness to epinephrine can be due to a generalized inability of the epidermal psoriatic plaque cell to make a functioning cell membrane

Online Neural Path Guiding with Normalized Anisotropic Spherical Gaussians

The variance reduction speed of physically-based rendering is heavily affected by the adopted importance sampling technique. In this paper we propose a novel online framework to learn the spatial-varying density model with a single small neural network using stochastic ray samples. To achieve this task, we propose a novel closed-form density model called the normalized anisotropic spherical gaussian mixture, that can express complex irradiance fields with a small number of parameters. Our framework learns the distribution in a progressive manner and does not need any warm-up phases. Due to the compact and expressive representation of our density model, our framework can be implemented entirely on the GPU, allowing it produce high quality images with limited computational resources

An Adult Case of Kawasaki Disease in a Pregnant Japanese Woman: A Case Report

Kawasaki disease is an acute febrile disease predominantly seen in young children. We report a case of Kawasaki disease in a 32-year-old pregnant woman. She developed a generalized erythematous skin rash accompanied by high fever. Bilateral conjunctival congestion, tender cervical lymphadenopathy, an edematous lower lip and peripheral edema followed by desquamation were observed. She was successfully treated with aspirin and intravenous gammaglobulin (1 g/kg/day). Her course was not complicated by coronary artery aneurysm and she delivered a healthy baby. To the best of our knowledge, this is the first case of Kawasaki disease in a pregnant woman. We suggest that Kawasaki disease should be included in the differential diagnosis of a generalized, erythematous skin rash accompanied by high fever in adults

Decreased Deiminated Keratin K1 in Psoriatic Hyperproliferative Epidermis

Citrulline-containing proteins, mainly originating from keratin K1 and formed by enzymatic deimination of arginine residues, have been identified in the cornified layers of human epidermis. We analyzed the localization and nature of the deiminated proteins in psoriatic epidermis. Immunostaining based on chemical modification of citrulline residues showed that the normal and psoriatic uninvolved epidermis contained deiminated proteins diffusely in the cornified cell layer, whereas the involved epidermis had no detectable or markedly reduced levels of deiminated proteins. Immunolabeling with polyclonal antibodies against a synthetic citrulline-containing peptide corresponding to a deiminated sequence of mouse K1 also suggested markedly decreased deiminated K1 in psoriatic involved lesions. Keratin analyses indicated that deiminated K1 present in normal and psoriatic uninvolved epidermis was not detected in the psoriatic involved epidermis. Double staining with a monoclonal antibody, 34βB4, and the polyclonal antibodies demonstrated that epidermis with low suprabasal keratin expression was negative for deiminated K1. In contrast, intralesional acrosyringia showing decreased suprabasal keratin immunoreactivity like that of the surrounding psoriatic epidermis showed strong deiminated K1 staining. This suggests that abnormal keratin deimination is restricted to the psoriatic hyperproliferative epidermis, without affecting sweat ductal epithelia

Increased Cholera Toxin-, and Forskolin-induced Cyclic AMP Accumulations in Psoriatic Involved Versus Uninvolved or Normal Human Epidermis

Psoriatic involved epidermis reveals variously altered receptor-adenylate cyclase responses; among them the most prominent is defective beta-adrenergic adenylate cyclase response, which is normally the major receptor-adenylate cyclase system of human epidermis. It is known that activation of hormone-stimulated adenylate cyclase, a membrane-bound enzyme complex, requires functional coupling of at least 3 distinct subunits: 1) receptor subunit (R), 2) guanine nucleotide binding protein (G), and 3) catalytic subunit (C). The precise nature of the beta-adrenergic defect in the psoriatic epidermis, however, remains to be determined, especially in terms of G and C function. Using the involved and uninvolved skin from psoriatic patients, we investigated effects of cholera toxin (which monitors G-C interaction) and forskolin (which monitors C function) on the adenylate cyclase system of epidermis, which were compared with those of normal human epidermis. Both agents increased cyclic AMP levels of involved, uninvolved, and normal human epidermis. Marked accumulations were observed in the presence of cyclic nucleotide phosphodiesterase inhibitor, isobutyl- methyixanthine (IBMX); without the phosphodiesterase inhibitor, the effect of each agent was minimal. Comparison of the effects of cholera toxin revealed that the psoriatic involved epidermis accumulates much more cyclic AMP than the uninvolved epidermis (involved: 193 ± 65; uninvolved: 117 ± 54 pmoles/mg protein/5 h). Similarly forskolin-induced cyclic AMP accumulations of the involved epidermis were much more than those of uninvolved epidermis (involved: 374 ± 152; uninvolved: 101 ± 41 pmoles/mg protein/2 h). Those of normal human epidermis were not significantly different from those of uninvolved epidermis (cholera toxin: 99 ± 36 pmoles/mg protein/5 h; forskolin: 84 ± 22 pmoles/mg protein/2 h). Our results indicate that G and C function and their interaction is not defective (but rather increased) in the posoriatic involved epidermis. This suggests that the defective beta-adrenergic response of psoriatic involved epidermis reflects defective R or R-G interaction of the epidermal adenylate cyclase system

Mutant PKC gamma in Spinocerebellar Ataxia Type 14 Disrupts Synapse Elimination and Long-Term Depression in Purkinje Cells In Vivo

Cerebellar Purkinje cells (PCs) express a large amount of the gamma isoform of protein kinase C (PKC gamma) and a modest level of PKC alpha. The PKC gamma is involved in the pruning of climbing fiber (CF) synapses from developing PCs, and PKC alpha plays a critical role in long-term depression (LTD) at parallel fiber (PF)-PC synapses. Moreover, the PKC signaling in PCs negatively modulates the nonselective transient receptor potential cation channel type 3 (TRPC3), the opening of which elicits slow EPSCs at PF-PC synapses. Autosomal dominant spinocerebellar ataxia type 14 (SCA14) is caused by mutations in PKC gamma. To clarify the pathology of this disorder, mutant (S119P) PKC gamma tagged with GFP was lentivirally expressed in developing and mature mouse PCs in vivo, and the effects were assessed 3 weeks after the injection. Mutant PKC gamma-GFP aggregated in PCs without signs of degeneration. Electrophysiology results showed impaired pruning of CF synapses from developing PCs, failure of LTD expression, and increases in slow EPSC amplitude. We also found that mutant PKC gamma colocalized with wild-type PKC gamma, which suggests that mutant PKC gamma acts in a dominant-negative manner on wild-type PKC gamma. In contrast, PKC alpha did not colocalize with mutant PKC gamma. The membrane residence time of PKC alpha after depolarization-induced translocation, however, was significantly decreased when it was present with the mutant PKC gamma construct. These results suggest that mutant PKC gamma in PCs of SCA14 patients could differentially impair the membrane translocation kinetics of wild-type gamma and alpha PKCs, which would disrupt synapse pruning, synaptic plasticity, and synaptic transmission