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Future-generation wireless networks should accommodate surging growth in mobile data traffic and support an increasingly high density of wireless devices. Consequently, as the demand for spectrum continues to skyrocket, a severe shortage of spectrum resources for wireless networks will reach unprecedented levels of challenge in the near future. To deal with the emerging spectrum-shortage problem, dynamic spectrum access techniques have attracted a great deal of attention in both academia and industry. By exploiting the cognitive radio techniques, secondary users (SUs) are capable of accessing the underutilized spectrum holes of the primary users (PUs) to increase the whole system's spectral efficiency with minimum interference violations. In this paper, we mathematically formulate the spectrum access problem for interweave cognitive radio networks, and propose a usage-aware deep reinforcement learning based scheme to solve it, which exploits the historical channel usage data to learn the time correlation and channel correlation of the PU channels. We evaluated the performance of the proposed approach by extensive simulations in both uncorrelated and correlated PU channel usage cases. The evaluation results validate the superiority of the proposed scheme in terms of channel access success probability and SU-PU interference probability, by comparing it with ideal results and existing methods.

Effector-memory T cells are strategically placed to epithelial tissues to provide frontline immune protection against pathogens. Their detrimental effects, however, have been rarely examined because of difficulty in sampling these T cells in pathological settings. Our previous studies suggested persistence of a similar subset of intraepidermal CD8(+) T cells at high frequencies in the lesions of fixed drug eruption, a localized variant of drug-induced dermatoses. In situ activation of this subset resulting in localized epidermal injury can be traced in the lesions after antigen challenge by paired immunohistochemical staining, reverse transcriptase-polymerase chain reaction in situ, and flow cytometry of dispersed cells. Here we show that effector-memory T cells were greatly enriched in these intraepidermal CD8(+) T cells, but not dermal and circulating counterparts, and that they constitutively express an early activation marker CD69 even before challenge. Surprisingly, a large proportion of these T cells expressed immediate effector function as evidenced by the rapid production of high levels of interferon-gamma in situ with much faster kinetics than their counterparts at the mRNA and protein levels after challenge. This was followed by localized epidermal injury. The intracellular cytokine assay ex vivo shows that the great majority of these dispersed T cells produce interferon-gamma. This study provides the first in situ description of the detrimental effects specifically mediated by effector-memory T cells residing at the effector site of immunopathology.

Although evidence is accumulating that type 2 cytokines play a part in the pathogenesis of bullous pemphigoid, little information is available concerning characterization of the cellular source of these cytokines involved in the pathogenesis of bullous pemphigoid. By using multiparameter flow cytometry, we investigated T cells capable of producing interleukin-2, -4, -10, and -13, interferon-gamma, and tumor necrosis factor-alpha and their correlated expression of skin-homing receptor (cutaneous lymphocyte-associated antigen) in peripheral blood and skin blister of patients with bullous pemphigoid. In peripheral blood of bullous pemphigoid patients, significantly increased frequencies of interleukin-4- and interleukin-13-producing cells were found as compared with those of healthy controls, and the majority of these type 2 cells was found in the cutaneous lymphocyte-associated antigen-positive population. The frequency of interferon-gamma-producing cells was also increased as compared with healthy subjects; however, the majority of this subset was found in the cutaneous lymphocyte-associated antigen-negative population. In the skin blister, the frequencies of interleukin-13- and interleukin-4-producing cells were much higher than those in the peripheral blood of bullous pemphigoid, whereas that of interferon-gamma producing cells was significantly lower. Furthermore, in bullous pemphigoid patients after therapy with systemic corticosteroids, the frequency of cutaneous lymphocyte-associated antigen-positive, but not cutaneous lymphocyte-associated antigen-negative, interleukin-13-producing cells was significantly decreased accompanied by an increased frequency of interleukin-10-producing cells, which was associated with clinical improvement. Thus, our results suggest that bullous pemphigoid is a unique organ-specific autoimmune disease characterized by an expansion of skin-homing interleukin-13-producing cells. In addition, corticosteroids may control such type 2 biased inflammatory responses in bullous pemphigoid by promoting the expansion of interleukin-10-producing cells.

Although cutaneous lymphocyte-associated antigen (CLA) is thought to be specifically expressed on skin "homing" T cells, it has become clear that CLA is not directly involved in binding to E-selectin but represents an excellent marker for high levels of fucosyltransferase VII (Fuc-TVII): Fuc-TVII can regulate the ability of T cells to migrate into the skin by generating a binding site for E-selectin. In this study, by using a novel monoclonal antibody for Fuc-TVII, we investigated whether expression of Fuc-TVII could be selectively detected in various CLA+ cell lines and peripheral blood T cells. Fuc-TVII was readily detected in the cytoplasm, but not in the membrane, of CLA+ cell lines. Cytoplasmic Fuc-TVII expression was also detectable in both CD4+ and CD8+ T cells purified from peripheral blood mononuclear cells. Nevertheless, there were significant numbers of CLA-expressing CD4+ or CD8+ T cells that did not coexpress Fuc-TVII, and vice versa: either the CD4+ or the CD8+ T cell population consisted of a variable ratio of CLA+ Fuc-TVII+, CLA+ Fuc-TVII-, and CLA- Fuc-TVII+ cells; and CLA+ Fuc-TVII- cells were the most abundantly identifiable phenotype in peripheral blood CD4+ and CD8+ T cells. Thus, according to their expression pattern, skin "homing" T cells can be subdivided into at least three populations, CLA+ Fuc-TVII+, CLA+ Fuc-TVII-, and CLA- Fuc-TVII+ cells. Our study provides convincing evidence that skin "homing" T cells are phenotypically heterogenous and that Fuc-TVII expression, in combination with CLA expression, is a useful phenotypic marker for identifying skin "homing" T cells in mixed cell populations.

Cutaneous lymphocyte-associated antigen (CLA), which plays a key part in skin homing of human CD4+ memory T cells via CLA/E-selectin binding, is upregulated by IL-12 and downregulated by IL-4. Although alpha1,3-fucosyltransferase VII is essential for synthesis of the CLA carbohydrate epitope, little is known about how the CLA expression is regulated by a number of glycosyltransferases. A 6 wk long-term culture for the in vitro differentiation of naïve Th cells to memory Th1 cells was employed. By repeated activation in the presence of IL-12, naïve T cells differentiated into memory Th1 cells, resulting in the upregulation of CLA expression. The switching of cytokine from IL-12 to IL-4 at three cycles resulted in a marked downregulation of CLA. The transcript levels of 16 glycosyltransferases and P-selectin glycoprotein ligand-1, all considered to be potentially involved in CLA synthesis, were determined after each cycle. The level of CLA expression was well correlated with the amounts of alpha1,3-fucosyltransferase VII and beta1,4-galactosyltransferase I. Both were upregulated by IL-12 and downregulated by IL-4. In particular, alpha1,3-fucosyltransferase VII levels decreased markedly in the presence of IL-4. P-selectin glycoprotein ligand-1 and Core 2 beta1, 6-N-acetylglucosaminyltransferase were progressively up-regulated by repeated IL-12 stimulation, but they were not downregulated by IL-4. The transcript levels of some genes examined were constitutive without any correlation to CLA expression. These results suggest that the level of CLA expression is determined by alpha1, 3-fucosyltransferase VII and beta1,4-galactosyltransferase I, the other enzymes merely participating in the synthesis of CLA. In peripheral blood mononuclear cells, IL-12 and IL-4 profoundly upregulated and downregulated the alpha1,3-fucosyltransferase VII transcripts, respectively, but not the beta1,4-galactosyltransferase I ones, within only 2 h of in vitro culture. This suggested that alpha1,3-fucosyltransferase VII is transcriptionally regulated directly by IL-12 and IL-4.

Recent studies have suggested that cytokines play a critical role in the pathophysiology of alopecia areata; however, no information is available regarding the difference in cytokine profiles in these patients. Serum levels of cytokines, including interferon gamma (IFN-gamma), tumor necrosis factor alpha, interleukin 1 alpha (IL-1 alpha), IL-2, IL-4, and IL-6, were measured using radioimmunoassay or enzyme-linked immunosorbent assay techniques in patients with the localized form and the extensive form (alopecia universalis). The serum levels of IL-1 alpha and IL-4 were significantly elevated in patients with the localized form. In contrast, the serum levels of IFN-gamma and IL-2 were significantly elevated in patients with the extensive form. These results indicate that immune responses in the localized form and the extensive form of alopecia areata are regulated by Th2 cytokines and Th1 cytokines, respectively.

The mechanism(s) and the factor(s) that contribute to preferential localization of fixed drug eruption (FDE) lesions to certain skin sites remain speculative. Previous studies suggested that populations of T cells residing in the lesional epidermis may be involved in selective destruction of the epidermis in FDE. In this study, to define the earliest cellular and molecular events with potential relevance to activation of the epidermal T cells, expression of adhesion molecules on keratinocytes (KC) and vascular endothelium was examined sequentially in the lesional skin of FDE patients after challenge with the causative drug. Rapid and intense intercellular adhesion molecule-1 (ICAM-1) expression was induced on the vascular endothelium and KC as early as 1.5 hours after challenge, at which time E-selectin and vascular cell adhesion molecule-1 (VCAM-1) were not up-regulated. In vitro studies using skin organ culture showed that the lesional KC and endothelium responded more rapidly and intensely to express ICAM-1 to tumor necrosis factor-alpha or interferon-gamma compared with those in the nonlesional skin. Surprisingly, such selective induction of KC ICAM-1 restricted to the lesional skin was also observed after exposure to the causative drug alone in skin organ culture. Pretreatment of the lesional skin with anti-tumor necrosis factor completely abrogated in vitro induction of KC ICAM-1 expression by the drug. Drug-induced, TNF-alpha-dependent KC ICAM-1 expression in the lesional skin suggests that induction of ICAM-1 expression by the lesional KC after ingestion of the drug would probably provide a localized initiating stimulus for activation of the disease-associated epidermal T cells.

The localization of spot 35 protein, a cerebellar Purkinje cell-specific protein, was studied in guinea pig taste buds by means of electron-microscopic immunocytochemistry. The immunoreactivity was localized in the cytoplasmic matrix of discrete bud cells. The ultrastructural features of the reactive cells indicated that they corresponded to the Type III or gustatory cells making a synaptic contact with the intragemmal nerves. All other cells specified as basal, Type I, and Type II were immunonegative for spot 35 protein. This finding indicates a method for specifically demonstrating the gustatory cells in the guinea pig taste bud and, further, gives new evidence that paraneurons may share neuron-specific substances with neurons.

Histological features of the tooth plate of lungfish were investigated by light and electron microscopy and contact microradiography with primary reference to the fine structure and formation of petrodentine, one of the principal constituents of the tooth plates. Petrodentine is a highly mineralized tissue noticeably analogous to that of enameloid, and is deposited intermittently in a proximal direction by the sole participation of mesenchymal petroblasts. The petroblasts appear very likely to have prominent biphasic functions of secreting the petrodentine matrix and of eliminating the matrix by resorption. The petrodentine thus may be capable of attaining hypermineralization with the participation mesenchymal cells alone. Mineral crystals constituting the petrodentine are large, hexagonal or similar but irregularly shaped columns. Initially these crystals appeared extremely thin, with curled ones frequently noted. The petrodentine of lungfish tooth plates is considered to be structurally distinct from the pleromin (Kosmin) of holocephalian tooth plates because of the difference between their constituent crystals.

Guinea pig taste buds were observed by transmission electron microscopy with special reference to cell types and innervation. The taste bud comprised four distinct cell types: basal, type I, type II, and type III cells. Basal cells, residing at the baso-lateral region of the taste bud without extending to the taste pore, were considered precursors of the other types of cells. The rest were all spindle-shaped cells reaching apically to the taste pit. Type I cells were characterized by the darkest appearance of the cytoplasm, apically possessing large, electron-dense granules and basally enveloping intragemmal nerves. This cell type, intervening between the other types of cells, was postulated to be sustentacular in nature. Type II cells, the largest and lightest cells in the taste bud, possessed a conspicuous stack of smooth endoplasmic reticulum above the nucleus. Due to their intimate and specialized relationships with nerves, the type II cells were presumed to receive an efferent innervation. Type III cells made synaptic contacts with nerves and contained dense-cored vesicles, which accumulated in the synaptic areas. This finding strongly suggests a gustatory function for the cells. The occurrence of such numerous peptidergic-type granules gathering to gustatory synapses as demonstrated in this report has not been recorded in previous papers on mammalian taste buds. The nerve terminals on the type III cell also contained synaptic vesicles, thus suggesting a reciprocal synapse here. The taste bud often included degenerating cells which were demonstrated to be phagocytosed by extrinsic cells identified as macrophages.

The taste buds and their nerves in the guinea pig were immunocytochemically investigated with regard to the localization of spot 35 protein, neuron-specific enolase (NSE), neurofilament protein (NFP), and S-100 protein. The spot 35 protein-like immunoreactivity was confined to slender cells comprising half the number of taste bud cells. NSE-like immunoreactivity was recognized in some taste bud cells as well as nerve fibers both within the taste bud and in the subepithelial connective tissue. The NSE-immunoreactive cells were divided into two cell populations: one weakly and the other intensely immunoreactive. The former cells proved to be spot 35 protein-immunoreactive. Moreover, the cells immunoreactive for both spot 35 protein and NSE were frequently associated with nerve fibers immunostained intensely for NSE. The NFP- and S-100 protein-like immunoreactivities were found in none of cells in the taste bud, but exclusively in the subepithelial neural elements.

The taste buds and associated nerves in the guinea pig, rat, cat, and mouse were investigated by immunocytochemistry and formaldehyde-induced fluorescence histochemistry. The antisera used were against spot 35 protein, neuron-specific enolase (NSE), neurofilament protein (NFP), and substance P. The spot 35 protein immunoreactivity was confined to taste bud cells in the guinea pig and rat; the immunoreactive cells, slender in shape, comprised half the number of the total taste bud cells in the guinea pig but were fewer in the rat. For NSE, on the other hand, taste bud cells as well as neural elements localized in both the taste bud and the subepithelial connective tissue were immunoreactive in all the species investigated. Furthermore, all of the spot 35 protein-immunoreactive cells proved to be NSE-immunoreactive in the guinea pig and rat. For NFP, neither the bud cells nor the nerves in the taste bud were reactive, whereas a part of nerves in the connective tissue was immunostained in all the species. The antiserum against substance P exclusively detected some parts of nerves in and out of the taste buds in the cat, rat, and mouse. The aminergic innervation was rather meager and appeared in the nerve fibers localized in the taste buds and connective tissue of the cat and mouse.