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Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the regulation of vital cellular processes. The rafts at the cell surface play important functions in signal transduction. Recent reports have demonstrated that lipid rafts are spatially and compositionally heterogeneous in the single-cell membrane. In this review, we summarize our recent data on living platelets using two specific probes of raft components: lysenin as a probe of sphingomyelin-rich rafts and BCθ as a probe of cholesterol-rich rafts. Sphingomyelin-rich rafts that are spatially and functionally distinct from the cholesterol-rich rafts were found at spreading platelets. Fibrin is translocated to sphingomyelin-rich rafts and platelet sphingomyelin-rich rafts act as platforms where extracellular fibrin and intracellular actomyosin join to promote clot retraction. On the other hand, the collagen receptor glycoprotein VI is known to be translocated to cholesterol-rich rafts during platelet adhesion to collagen. Furthermore, the functional roles of platelet glycosphingolipids and platelet raft-binding proteins including G protein-coupled receptors, stomatin, prohibitin, flotillin, and HflK/C-domain protein family, tetraspanin family, and calcium channels are discussed.

While various glycosphingolipids were identified as cancer‐associated carbohydrate antigens to be used as tumor markers, disialylated gangliosides such as GD3 and GD2 have particularly attracted attention from many researchers as promising cancer‐associated antigens. Simultaneously, their functions in cancer and normal tissues have also been reported. Although GD3 is expressed at the early neural developmental stage and in various cancers, it is also found in the activated status of some normal cells such as astrocytes and lymphocytes. On the other hand, GD2 is expressed in more restricted cells than GD3, enabling anti‐GD2 immune therapy to be more applicable for immunotherapy. Recently, the expression of GD2 has been reported in various epithelial cancers and neuroectoderm‐derived tumors. The involvement of GD2 in cancer stem cell propertiesand the roles of GD2 in the signal modulation to bring about cancer stemness are now some of the most fascinating research topics. Cancer immunotherapy targeting GD2 by anti‐GD2 antibody or anti‐GD2 CAR‐T is now widely being challenged with various modifications such as combination with cytokines, chemotherapy, or immune checkpoint blocking. Among cancer‐associated antigens, ganglioside GD2 is the most crucial and essential carbohydrate antigen as a modulator of malignant signals and as a target of immunotherapy for refractory cancers. In particular, GD2 is now believed to be a marker of cancer stem cells and to be essentially involved in the features of cancer stemness.

Gender differences in interoceptive awareness—awareness of internal bodily signals such as heartbeat perception—have been suggested, with some findings indicating behaviourally reduced but subjectively enhanced awareness in women, though these findings are still contentious. This study aimed to comprehensively examine gender differences in three aspects of interoceptive awareness: behavioural accuracy, subjective confidence, and relationship between them (i.e., metacognition). We used a modified heartbeat counting task that prohibited estimation strategies and increased the number of trials up to 20. Using data from 74 healthy young adults (39 women and 35 men), we evaluated gender differences and practice effects for each measure via Bayesian linear mixed models, controlling for individual heart rate and trial duration on a trial-by-trial basis. Contrary to previous research, the results revealed no reduced interoceptive accuracy in women; instead, higher interoceptive accuracy score was associated with shorter trial durations and lower heart rates regardless of gender. Moreover, women exhibited underconfidence about their performance, and therefore lower metacognition scores, compared to men. Trial repetitions moderated women’s lowered metacognition but did not affect accuracy or confidence. These findings highlight potential physiological and psychological confounding factors in the heartbeat counting task, such as heart rate and reporting style, and emphasise several cautions for studying gender differences in interoceptive awareness.

Exosomes (small extracellular vesicles: EVs) have attracted increasing attention from basic scientists and clinicians since they play important roles in cell-to-cell communication in various biological processes. Various features of EVs have been elucidated regarding their contents, generation and secretion mechanisms, and functions in inflammation, regeneration, and cancers. These vesicles are reported to contain proteins, RNAs, microRNAs, DNAs, and lipids. Although the roles of individual components have been rigorously studied, the presence and roles of glycans in EVs have rarely been reported. In particular, glycosphingolipids in EVs have not been investigated to date. In this study, the expression and function of a representative cancer-associated ganglioside, GD2, in malignant melanomas was investigated. Generally, cancer-associated gangliosides have been shown to enhance malignant properties and signals in cancers. Notably, EVs derived from GD2-expressing melanomas enhanced the malignant phenotypes of GD2-negative melanomas, such as cell growth, invasion, and cell adhesion, in a dose-dependent manner. The EVs also induced increased phosphorylation of signaling molecules such as EGF receptor and focal adhesion kinase. These results suggest that EVs released from cancer-associated ganglioside-expressing cells exert many functions that have been reported as a function of these gangliosides and regulate microenvironments, including total aggravation of heterogeneous cancer tissues, leading to more malignant and advanced cancer types.

Extracellular vesicles (EVs) play important roles in intercellular communication in various biological events. In particular, EVs released from cancer cells have attracted special attention. Although it has been reported that cancer-associated glycosphingolipids play important roles in the enhancement of malignant properties of cancer cells, the presence, behavior, and roles of glycosphingolipids in EVs have not been elucidated. Recently, we reported crucial roles of EVs expressing gangliosides, GD2, and/or GD3 in the enhancement of cancer properties in malignant melanomas and gliomas. However, how EVs containing cancer-associated glycosphingolipids play their roles has not been reported to date. Here, we studied spatio-temporal mechanisms for GD3/GD2-containing EVs released from gliomas in the actions toward target cells. Proteome analyses of EVs with/without GD3/GD2 revealed an equally high concentration of integrin isoforms in both GD3/GD2+ and GD3/GD2- EVs. PKH26-labeled EVs attached, invaded, and distributed to/in the target cells within 1 h. GD3/GD2 formed molecular complexes with integrins on EVs as elucidated by immunoprecipitation/immunoblotting and immunocytostaining. The addition of antibodies reactive with GD3, GD2, or integrins resulted in the suppression of the enhancing effects of EVs in the cell adhesion assay. The addition of GD3/GD2 + EVs to GD3/GD2- cells clearly increased the phosphorylation levels of the PDGF receptor, FAK, and Erk1/2 in immunoblotting, suggesting GD3/GD2+ EVs activate the signaling pathway in the target cells within 15 min after addition. Anti-ganglioside antibodies clearly blocked signaling with EVs. In conclusion, EVs released from GD3/GD2-expressing glioma cells enhance cancer phenotypes and malignant signals via the cluster formation of integrins and GD3/GD2 on EVs, leading to the regulation of the cancer microenvironment.

Immunotherapy of malignant cancers is now becoming one of representative approaches to overcome cancers. To construct strategies for immunotherapy, presence of tumor-specific antigens should be a major promise. A number of cancer specific- or cancer-associated antigens have been reported based on various experimental sets and various animal systems. The most reasonable strategy to define tumor-specific antigens might be “autologous typing” performed by Old’s group, proposing three classes of tumor-antigens recognized by host immune systems of cancer patients. Namely, class 1, individual antigens that is present only in the patient’s sample analyzed; class 2, shared antigens that can be found only in some group of cancers in some patients, but not in normal cells and tissues; class 3, universal antigens that are present in some cancers but also in normal cells and tissues with different densities. Sen Hakomori reported there were novel carbohydrates in cancers that could not be detected in normal cells mainly by biochemical approaches. Consequently, many of class 2 cancer-specific antigens have been revealed to be carbohydrate antigens, and been used for cancer diagnosis and treatment. Not only as cancer markers, but roles of those cancer-associated carbohydrates have also been recognized as functional molecules in cancer cells. In particular, roles of complex carbohydrates in the regulation of cell signaling on the cell surface microdomains, glycolipid-enriched microdomain (GEM)/rafts have been reported by Hakomori and many other researchers including us. The processes and present status of these studies on cancer-associated glycolipids were summarized.

We present our recent development of the surface-emitting quantum cascade laser with a PC (photonic crystal) resonator and a strain-compensated MQW (multiple quantum well) active layer operating at around 4.3 μm. We describe the laser performance mainly from the viewpoint of the design and analysis of the PC resonators, which include both numerical calculations by FEM (finite element method) and analytical calculations using the k·p perturbation theory and group theory. We analyze the resonance quality factor, overlap factor, extraction efficiency, and far-field pattern, and show how the output power and beam quality have been improved by the appropriate design of the PC resonator.

Gangliosides are expressed in nervous systems and some neuroectoderm-derived tumors at high levels and play pivotal roles. However, mechanisms for the regulation of glycosyltransferase genes responsible for the ganglioside synthesis are not well understood. In this study, we analyzed DNA methylation patterns of promoter regions of GD3 synthase (ST8SIA1) as well as mRNA levels and ganglioside expression using human glioma cell lines. Among 5 cell lines examined, 4 lines showed changes in the expression levels of related genes after treatment with 5-aza-dC. LN319 showed up-regulation of St8sia1 and increased b-series gangliosides after 5-aza-dC treatment, and an astrocytoma cell line, AS showed high expression of ST8SIA1 and b-series gangliosides persistently before and after 5-Aza-2’-deoxycytidine treatment. Using these 2 cell lines, DNA methylation patterns of the promoter regions of the gene were analyzed by bisulfite-sequencing. Consequently, 2 regions that were methylated before 5-Aza-2’-deoxycytidine treatment were demethylated in LN319 after the treatment, while those regions were persistently demethylated in AS. These 2 regions corresponded with sites defined as promoter regions by Luciferase assay. Taken together, it was suggested that ST8SIA1 gene is regulated by DNA methylation at the promoter regions, leading to the regulation of tumor phenotypes.

Gangliosides have been considered to modulate cell signals in the microdomain of the cell membrane, lipid/rafts, or glycolipid-enriched microdomain/rafts (GEM/rafts). In particular, cancer-associated gangliosides were reported to enhance the malignant properties of cancer cells. In fact, GD2-positive (GD2+) cells showed increased proliferation, invasion, and adhesion, compared with GD2-negative (GD2−) cells. However, the precise mechanisms by which gangliosides regulate cell signaling in GEM/rafts are not well understood. In order to analyze the roles of ganglioside GD2 in the malignant properties of melanoma cells, we searched for GD2-associating molecules on the cell membrane using the enzyme-mediated activation of radical sources combined with mass spectrometry, and integrin β1 was identified as a representative GD2-associating molecule. Then, we showed the physical association of GD2 and integrin β1 by immunoprecipitation/immunoblotting. Close localization was also shown by immuno-cytostaining and the proximity ligation assay. During cell adhesion, GD2+ cells showed multiple phospho-tyrosine bands, i.e., the epithelial growth factor receptor and focal adhesion kinase. The knockdown of integrin β1 revealed that the increased malignant phenotypes in GD2+ cells were clearly cancelled. Furthermore, the phosphor-tyrosine bands detected during the adhesion of GD2+ cells almost completely disappeared after the knockdown of integrin β1. Finally, immunoblotting to examine the intracellular distribution of integrins during cell adhesion revealed that large amounts of integrin β1 were localized in GEM/raft fractions in GD2+ cells before and just after cell adhesion, with the majority being localized in the non-raft fractions in GD2− cells. All these results suggest that GD2 and integrin β1 cooperate in GEM/rafts, leading to enhanced malignant phenotypes of melanomas.

Photonic crystals (PCs) offer unique ways to control light-matter interactions. The measurement of dispersion relations is a fundamental prerequisite if we are to create novel functionalities in PC devices. Angle-resolved spectroscopic techniques are commonly used for characterizing PCs that work in the visible and near-infrared regions. However, the techniques cannot be applied to the mid- and long-wavelength infrared regions due to the limited sensitivity of infrared detectors. Here, we propose an alternative approach to measuring infrared dispersion relations. We construct a high-precision angle-resolved setup compatible with a Fourier-transform spectrometer with an angle resolution as high as 0.3 degrees. Hence, the reflection spectra are mapped to the 2D photonic band structures of In(Ga,Al)As/InP based PC slabs, which are designed as mid-infrared PC surface-emitting lasers. We identify complex PC modes with the aid of polarization selection rules derived by the group theory. Spectral analysis makes it possible to evaluate the mode quality (Q) factors. Therefore, angle-resolved reflection is a useful way of optimizing 2D PC parameters for mid-infrared devices.