Lysophospholipids (LPLs), such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and lysophosphatidylserine (LysoPS), are attracting attention as second-generation lipid mediators. In our laboratory, the functional roles of these lipid mediators and the mechanisms by which the levels of these mediators are regulated in vivo have been studied. Based on these studies, the clinical introduction of assays for LPLs and related proteins has been pursued and will be described in this review. Although assays of these lipids themselves are possible, autotaxin (ATX), apolipoprotein M (ApoM), and phosphatidylserine-specific phospholipase A1 (PS-PLA1) are more promising as alternate biomarkers for LPA, S1P, and LysoPS, respectively. Presently, ATX, which produces LPA through its lysophospholipase D activity, has been shown to be a useful laboratory test for the diagnosis and staging of liver fibrosis, whereas PS-PLA1 and ApoM are considered to be promising clinical markers reflecting the in vivo actions induced by LysoPS and S1P.
γ-aminobutyric acid type B (GABAB) receptors are broadly expressed in the nervous system and play an important role in neuronal excitability. GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. Functional GABAB receptors are obligate heterodimers formed by the co-assembly of R1 and R2 subunits. It is well established that GABAB receptors interact not only with G proteins and effectors but also with various proteins. This review summarizes the structure, subunit isoforms, and function of GABAB receptors, and discusses the complexity of GABAB receptors, including how receptors are localized in specific subcellular compartments, the mechanism regulating cell surface expression and mobility of the receptors, and the diversity of receptor signaling through receptor crosstalk and interacting proteins.
IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder recognized as a novel clinical entity with either synchronous or metachronous multi-organ involvement. Patients with IgG4-RD show diffuse or focal organ enlargement and mass-forming or nodular/thickened lesions with abundant infiltration of IgG4-positive plasmacytes and fibrosis, and such patients respond well to steroid treatment. It should be differentiated from mimics by a combination of serum IgG4 level, imaging features, and histopathological findings. The current first-line drug is corticosteroids, or rituximab in high-risk patients for steroid intolerance. Although relapse rates are high, standardized protocols for relapsed cases have not been approved yet. Based on genetic factors, disease-specific or -related antigens, abnormal innate and adaptive immunity may be involved, although the precise pathogenic mechanism and long-term outcome still remain unclear.
Single-molecule atomic-resolution real-time electron microscopic movie imaging is an emerging new tool for obtaining dynamic structural information on molecules and molecular assemblies. This method provides a hitherto inaccessible possibility to in situ observe the time evolution of chemical events at various temperatures from the beginning till the end, as demonstrated for the kinetics study of [2 + 2] cycloaddition of fullerene molecules, which was found to occur via an excited state or via radical cation depending on the temperature. One unique feature of this methodology is that, by observing directly the reaction events, one can obtain information on the frequency of events unperturbed by molecular diffusion. With the obtained experimental data set, we provided the first experimental proof of what the quantum mechanical transition state theory predicted, in that isolated molecules behave as if all their accessible states were occupied in a random order. We also found that, under the 1-D reaction conditions, molecular-level information on a few hundred molecules suffices to deduce statistically meaningful kinetics data that match with those obtained by bulk experiments.
Non-human primates such as rhesus macaque and cynomolgus macaque are important animals for medical research. These species are classified as Old-World monkeys (Cercopithecidae), in which the immune-related genome structure is characterized by gene duplications. In the present study, we investigated polymorphisms in two genes for ULBP5 encoding ligands for NKG2D. We found 18 and 11 ULBP5.1 alleles and 11 and 13 ULBP5.2 alleles in rhesus macaques and cynomolgus macaques, respectively. In addition, phylogenetic analyses revealed that ULBP5.2 diverged from a branch of ULBP5.1. These data suggested that human ULBP genes diverged from an ancestral gene of ULBP2-ULBP5 and that ULBP6/RAET1L, specifically identified in human, diverged from an ancestral ULBP2 by a recent gene duplication after the diversification of homininae (human and other higher great apes), which were consistent with the findings in our previous analysis of ULBP2 genes in rhesus and cynomolgus macaques.