Chemical labelling for visualizing native AMPA receptors in live neurons

The location and number of neurotransmitter receptors are dynamically regulated at postsynaptic sites. However, currently available methods for visualizing receptor trafficking require the introduction of genetically engineered receptors into neurons, which can disrupt the normal functioning and processing of the original receptor. Here we report a powerful method for visualizing native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) which are essential for cognitive functions without any genetic manipulation. This is based on a covalent chemical labelling strategy driven by selective ligand-protein recognition to tether small fluorophores to AMPARs using chemical AMPAR modification (CAM) reagents. The high penetrability of CAM reagents enables visualization of native AMPARs deep in brain tissues without affecting receptor function. Moreover, CAM reagents are used to characterize the diffusion dynamics of endogenous AMPARs in both cultured neurons and hippocampal slices. This method will help clarify the involvement of AMPAR trafficking in various neuropsychiatric and neurodevelopmental disorders

Chemical trends of superconducting properties in pyrochlore oxides

Chemical trends of fundamental superconducting parameters and normal-state properties are described for a family of pyrochlore oxide superconductors. Particularly, the change of Tc from 1.0 K for alpha-pyrochlore Cd2Re2O7 to 3.3 K (A = Cs), 6.3 K (Rb), and 9.6 K (K) for beta-pyrochlore AOs2O6 is discussed on the basis of the conventional BCS scheme. Enhanced Tc and anomalous features observed for KOs2O6 are ascribed to low-energy phonons probably coming from the rattling of the K cations.Comment: 8 pages, to be published in the Proceedings of M2S-HTSC2006 (Physica C

Pre- and Postoperative Ocular Events in Cataract Patients with Small Pupils who Underwent Cataract Surgery

Purpose：To analyze pre- and postoperative surgical events in cataract patients with small pupils who underwent cataract surgery.Patients and methods：We reviewed the medical records of patients who underwent cataract surgery between January 2009 and May 2014 at Dokkyo Medical University Koshigaya Hospital. Surgery was performed by four experienced surgeons. We included 106 eyes from 83 patients with pupil sizes ＜5 mm in diameter who required iris retractors during the cataract surgery （small pupil group）. The control group was comprised of 447 eyes from 319 patients with pupil sizes ＞5 mm in diameter who did not require a mechanical dilatation of the pupil during cataract surgery. Pre- and postoperative intra- or extraocular surgical events were analyzed.Results：Preoperative intra- or extraocular surgical events were observed in 36 eyes （34.0％） in the small pupil group and 72 eyes （16.1％） in the control group, with a significant difference observed for those who underwent laser iridotomy （P＜0.001） and trabeclectomy （P＜0.01）. Postoperative intra- or extraocular events were observed in 25 eyes （23.6％） in the small pupil group and 61 eyes （13.7％） in the control group, with significant differences observed for those who underwent the following procedures：trabeculectomy （P＜0.001）, sub-Tenon’s injection of triamcinolone acetonide （P＜0.001）, and posterior capsulotomy （P＝0.012）.Conclusion：Cataract patients with small pupils often have pre- and postoperative intra- or extraocular surgical events. It should be recognized that cataract surgery is only one step in the treatment of cataract patients with small pupils

Associations of family histories of diabetes mellitus and hypertension with the occurrence of gestational diabetes mellitus, gestational hyper tension, and preeclampsia: multivariate analysis.

Objective: We herein determined whether family histories of hypertension (HT) and diabetes mellitus (DM) were independent risk factors for gestational hypertension (GH), preeclampsia (PE) and gestational diabetes mellitus (GDM). Methods: A prospective cohort study was conducted using 1,737 pregnant women. We evaluated five factors：a family history of HT （father, mother, or both）, a family history of DM, age ≥40 years old, obesity, and high blood pressure (mean blood pressure level ≥90 mmHg at 16-19 gestational weeks), and three outcomes: GH, PE, and GDM. Univariate and multivariate logistic regression analyses were performed. Results: High blood pressure was an independent risk factor for the occurrence of PE (OR [95% CI]: 4.6 [2.3-9.2]), pre-pregnancy obesity was an independent risk factor for the occurrence of GH (4.4 [1.3-15]), whereas a family history of HT or DM was not an independent risk factor for either PE or GH. Independent risk factors for the occurrence of GDM were a family history of DM (5.5 [3.3-9.1]), age ≥40 years old (2.2 [1.1-4.1]), and pre-pregnancy obesity (4.2 [2.5-6.9]). Conclusions: After adjusting for other factors, a family history of DM was not associated with the occurrence of either PE or GH. In addition, a family history of HT was not an independent risk factor for GDM.departmental bulletin pape

Idiopathic Inflammatory Myopathies-Associated Interstitial Lung Disease in Adults

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of autoimmune diseases characterized by muscle involvement and various extramuscular manifestations. Interstitial lung disease (ILD) is one of the most common extramuscular manifestations of IIM and is associated with significant mortality and morbidity. The clinical phenotypes, treatment responses, and prognosis of IIM-ILD are significantly related to myositis-specific antibody (MSA) profiles, with some racial differences. The features associated with MSA in IIM-ILD could also be relevant to cases of ILD where MSA is present but does not meet the criteria for IIM. The anti-melanoma differentiation-associated gene 5 antibody is highly associated with rapidly progressive ILD (RP-ILD), especially in Asian populations, and with characteristic cutaneous manifestations, such as skin ulcers. Radiologically, ground-glass opacities, consolidations, and nonsegmental linear opacities were more predominant than reticular opacities and honeycombing. While the mortality rate is still around 30%, the prognosis can be improved with early intensive therapy with corticosteroids and multiple immunosuppressants. In contrast, anti-aminoacyl-tRNA synthetase (ARS) antibodies are associated with chronic ILD, although RP-ILD is also common. Patients with anti-ARS antibodies often show lung-predominant presentations, with subtle muscle and skin involvement. Radiologically, reticular opacities, with or without consolidation, are predominant and may progress to honeycombing over time. Combination therapy with corticosteroids and a single immunosuppressant is recommended to prevent relapses, which often lead to a decline in lung function and fatal long-term outcomes. Significant advances in immunology and genetics holds promise for fostering more personalized approaches to managing IIM-ILD

Bioorthogonal chemical labeling of endogenous neurotransmitter receptors in living mouse brains

生きた動物脳内で発現する神経伝達物質受容体に目印を付ける新手法を開発 --遺伝子操作を伴わず、生体内でたんぱく質の機能解析が可能に--. 京都大学プレスリリース. 2024-02-05.Neurotransmitter receptors are essential components of synapses for communication between neurons in the brain. Because the spatiotemporal expression profiles and dynamics of neurotransmitter receptors involved in many functions are delicately governed in the brain, in vivo research tools with high spatiotemporal resolution for receptors in intact brains are highly desirable. Covalent labeling by chemical reaction (chemical labeling) of proteins without genetic manipulation is now a powerful method for analyzing receptors in vitro. However, selective target receptor labeling in the brain has not yet been achieved. This study shows that ligand-directed alkoxyacylimidazole (LDAI) chemistry can be used to selectively tether synthetic probes to target endogenous receptors in living mouse brains. The reactive LDAI reagents with negative charges were found to diffuse well over the whole brain and could selectively label target endogenous receptors, including AMPAR, NMDAR, mGlu1, and GABAAR. This simple and robust labeling protocol was then used for various applications: three-dimensional spatial mapping of endogenous receptors in the brains of healthy and disease-model mice; multi-color receptor imaging; and pulse–chase analysis of the receptor dynamics in postnatal mouse brains. Here, results demonstrated that bioorthogonal receptor modification in living animal brains may provide innovative molecular tools that contribute to the in-depth understanding of complicated brain functions

Japan Perspectives Recent Articles from the Tokyo Foundation Website No.17

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Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73

Transcriptional disturbance is implicated in the pathology of polyglutamine diseases, including Huntington's disease (HD). However, it is unknown whether transcriptional repression leads to neuronal death or what forms that death might take. We found transcriptional repression-induced atypical death (TRIAD) of neurons to be distinct from apoptosis, necrosis, or autophagy. The progression of TRIAD was extremely slow in comparison with other types of cell death. Gene expression profiling revealed the reduction of full-length yes-associated protein (YAP), a p73 cofactor to promote apoptosis, as specific to TRIAD. Furthermore, novel neuron-specific YAP isoforms (YAPΔCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPΔCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPΔCs also markedly attenuated Htt-induced neuronal death in primary neuron and Drosophila melanogaster models. Collectively, transcriptional repression induces a novel prototype of neuronal death associated with the changes of YAP isoforms and p73, which might be relevant to the HD pathology

Personalized prediction of overall survival in patients with AML in non‐complete remission undergoing allo‐HCT

Allogenic hematopoietic stem cell transplantation (allo-HCT) is the standard treatment for acute myeloid leukemia (AML) in non-complete remission (non-CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non-CR AML undergoing allo-HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo-HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266-0.554; p < 0.0001). A conditioning regimen of ≥3 drugs with CBT also showed the best leukemia-free survival among all conditioning regimens. Based on the results of the multivariable analysis, we developed prognostic models showing adequate calibration and discrimination (the c-indices for CBT, BMT, and PBSCT were 0.648, 0.600, and 0.658, respectively). Our prognostic models can help in assessing individual risks and designing future clinical studies. Furthermore, our study indicates the effectiveness of multi-drug conditioning regimens in patients undergoing CBT