👤 Ken-Ichi Kusakabe

Lymphoplasmacytic lymphoma (LPL) is a type of indolent B-cell lymphoma typically associated with IgM paraproteinemia and does not require immediate treatment until symptoms appear. However, non-IgM LPL has a higher frequency of extramedullary involvement and requires more aggressive therapy than IgM-LPL. A 51-year-old woman in treatment-free follow-up for LPL with IgG-κ paraproteinemia was referred to our hospital with a chief complaint of right coxalgia. A plain MRI scan showed multiple osteolytic bone lesions, including bilateral femoral incomplete fractures. Similar bone lesions were also detected in the right shoulder joint. Pathological examination of the bilateral femurs and the right shoulder revealed LPL lesions with amyloid deposits. MYD88 L265P gene mutations were confirmed by genetic analysis, and all lesions were considered identical. Ibrutinib plus rituximab therapy was administered, resulting in a partial response sustained to date. Bone involvement and amyloidosis are rare but critical extranodal manifestations of LPL, necessitating careful screening and follow-up even in asymptomatic patients. When these manifestations are suspected, prompt pathological and genetic evaluation is warranted, especially in non-IgM LPL cases. Show less

X-linked adrenoleukodystrophy (X-ALD) is a congenital metabolic disorder characterized mainly by inflammatory demyelination and adrenal insufficiency. Newborn screening using hexacosanoyl lysophosphatidylcholine (C26:0-LPC) in dried blood spots as a diagnostic marker can successfully identify potential patients with X-ALD and prevent disease onset. C26:0-LPC accumulates in patients with X-ALD, although the machinery synthesizing it has remained unclear. In this study, we focused on phosphatidylcholine (PC) with C26:0 moiety as a precursor of C26:0-LPC. We identified that lysophospholipid (LPL) acyltransferase 10 (LPLAT10)/LPCAT4/LPEAT2/AGPAT7 (1-acylglycerol-3-phosphate O-acyltransferase 7) is the responsible LPL acyltransferase that produces PC with C26:0 moiety by transferring C26:0-CoA into 2-acyl-LPC. We also found that LPLAT10 deficiency decreased the amount of C26:0-LPC in fibroblasts from X-ALD patients. Mechanistically, LPLAT10 introduced saturated fatty acid-CoA of various chain lengths as substrates into the sn-1 position of LPC but did not transfer C26:0-CoA to other LPL classes, such as lysophosphatidylethanolamine. Structural analysis revealed that a trimethylamine group of PC was placed between two tryptophan residues (W242 and W244), forming a W-X-W motif, possibly through cation-π interaction. Finally, it was shown that exogenously administered C26:0 FFA-d Show less

Passive membrane permeability and an active transport process are key determinants for penetrating the blood-brain barrier. P-glycoprotein (P-gp), a well-known transporter, serves as the primary gatekeeper, having broad substrate specificity. A strategy to increase passive permeability and impair P-gp recognition is intramolecular hydrogen bonding (IMHB). Show less

Ablation of short single cones (SSCs) expressing short-wavelength-sensitive opsin (SWS1) is well analyzed in the field of regenerative retinal cells. In contrast with ablation studies, the phenomena caused by the complete deletion of SWS1 are less well-understood. To assess the effects of SWS1 deficiency on retinal structure, we established and analyzed sws1-mutant medaka. To visualize SWS1, a monoclonal anti-SWS1 antibody and transgenic reporter fish (Tg(sws1:mem-egfp)) were generated. We also developed a CRISPR/Cas-driven sws1-mutant line. Retinal structure of sws1 mutant was visualized using anti-SWS1, 1D4, and ZPR1 antibodies and coumarin derivatives and compared with wild type, Tg(sws1:mem-egfp), and another opsin (lws) mutant. Our rat monoclonal antibody specifically recognized medaka SWS1. Sws1 mutant retained regularly arranged cone mosaic as lws mutant and its SSCs had neither SWS1 nor long wavelength sensitive opsin. Depletion of sws1 did not affect the expression of long wavelength sensitive opsin, and vice versa. ZPR1 antibody recognized arrestin spread throughout double cones and long single cones in wild-type, transgenic, and sws1-mutant lines. Comparative observation of sws1-mutant and wild-type retinas revealed that ZPR1 negativity is not a marker for SSCs with SWS1, but SSCs themselves. Loss of functional sws1 did not cause retinal degeneration, indicating that sws1 is not essential for cone mosaic development in medaka. Our two fish lines, one with visualized SWS1 and the other lacking functional SWS1, offer an opportunity to study neural network synapsing with SSCs and to clarify the role of SWS1 in vision. Show less