Model for the Architecture of Claudin-Based Paracellular Ion Channels through Tight Junctions

AbstractClaudins are main cell–cell adhesion molecules of tight junctions (TJs) between cells in epithelial sheets that form tight barriers that separate the apical from the basolateral space but also contain paracellular channels that regulate the flow of ions and solutes in between these intercellular spaces. Recently, the first crystal structure of a claudin was determined, that of claudin-15, which indicated the parts of the large extracellular domains that likely form the pore-lining surfaces of the paracellular channels. However, the crystal structure did not show how claudin molecules are arranged in the cell membrane to form the backbone of TJ strands and to mediate interactions between adjacent cells, information that is essential to understand how the paracellular channels in TJs function. Here, we propose that TJ strands consist of claudin protomers that assemble into antiparallel double rows. This model is based on cysteine crosslinking experiments that show claudin-15 to dimerize face to face through interactions between the edges of the extracellular β-sheets. Strands observed by freeze-fracture electron microscopy of TJs also show that their width is consistent with the dimensions of a claudin dimer. Furthermore, we propose that extracellular variable regions are responsible for head-to-head interactions of TJ strands in adjoining cells, thus resulting in the formation of paracellular channels. Our model of the TJ architecture provides a basis to discuss structural mechanisms underlying the selective ion permeability and barrier properties of TJs

ノリナガ ブンガク ロン エノ イチシカク ヤマガソコウ ト モトオリノリナガ

日本文学(Japanese Literature

ノリナガ ガク ノ セイリツ ト ソウシ ジュヨウ カモノ マブチ トノ ヒカク オ ツウジテ

日本文学(Japanese Literature

Evaluating on-demand video lectures

The popularity of online classes in university education has grown rapidly since the COVID-19 outbreak. This study aims to examine the association between the detailed characteristics / various contexts of students and the evaluation of online classes. An online questionnaire survey administered to third- and fourth-grade medical students of Tokushima University in September 2021—with 101 (42.8%) valid responses—showed the respondents’ general impressions, comprehension, convenience, and desire for online classes even after the pandemic ends were significantly higher for the on-demand lectures than for simultaneous online classes. Notably, students who did not do other things while watching video lectures (10.9%) rated on-demand lectures as facilitating significantly higher impression, comprehension, and convenience than those who did other things (89.1%). A multivariate analysis revealed that students who did not do anything else while watching, whose waking time changed slightly, who commuted to school for shorter periods, who were not good at morning lectures, and who watched at high speed rated the video lectures highly. Thus, video lectures are appreciated by students who are committed to learning, which is a positive result for the future of on-demand education

Immunosuppressants Tacrolimus and Sirolimus revert the cardiac antifibrotic properties of p38-MAPK inhibition in 3D-multicellular human iPSC-heart organoids

Immunosuppressive regimens after a heart transplant can hamper good therapeutic progressions in fibrosis. 京都大学プレスリリース. 2022-11-15.より本物の心臓に近い心臓オルガノイドによる薬剤の効果を評価するシステム --細胞間コミュニケーションを研究できるツールの開発--. 京都大学プレスリリース. 2022-11-21.Cardiac reactive fibrosis is a fibroblast-derived maladaptive process to tissue injury that exacerbates an uncontrolled deposition of large amounts of extracellular matrix (ECM) around cardiomyocytes and vascular cells, being recognized as a pathological entity of morbidity and mortality. Cardiac fibrosis is partially controlled through the sustained activation of TGF-β1 through IL-11 in fibroblasts. Yet, preclinical studies on fibrosis treatment require human physiological approaches due to the multicellular crosstalk between cells and tissues in the heart. Here, we leveraged an iPSC-derived multi-lineage human heart organoid (hHO) platform composed of different cardiac cell types to set the basis of a preclinical model for evaluating drug cardiotoxicity and assessing cardiac fibrosis phenotypes. We found that the inhibition of the p38-MAPK pathway significantly reduces COL1A1 depositions. Yet, concomitant treatment with organ-rejection immunosuppressant drugs Tacrolimus or Sirolimus reverts this effect, opening new questions on the clinical considerations of combined therapies in reducing fibrosis after organ transplantation

CRP in PMR and RS3PE syndrome

Polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome are common inflammatory rheumatic diseases in the elderly. In this study, we investigate predictive factors which correspond to subsequent disease control of PMR and RS3PE syndrome. Twenty four patients, which contained 18 PMR and 6 RS3PE syndrome, were treated with initial dosages of 10-20 mg per day oral prednisolone, and the dosage of prednisolone was then tapered. Significantly higher initial CRP was observed in patients with poor disease control than in those with good disease control afterwards. The number of patients with negative CRP after 4 weeks was significantly more in patients with good disease control after 1 year than in those with poor disease control. Patients were shown to be in good disease control status after 1 year when CRP after 4 weeks became negative even if they had initial high CRP. Our study clarify that to make CRP negative after 4 weeks is associated with subsequent suppression of the disease activity and with decreased dosages of corticosteroids

Elevation of macrophage-derived chemokine in eosinophilic pneumonia : a role of alveolar macrophages

Macrophage-derived chemokine (MDC/CCL22) and thymus-and activation-regulated chemokine (TARC/CCL17) are ligands for CC chemokine receptor 4. Recently, TARC has been reported to play a role in the pathogenesis of idiopathic eosinophilic pneumonia (IEP). The purpose of this study was to evaluate the role of MDC in IEP and other interstitial lung diseases (ILDs). MDC and TARC in the bronchoalveolar lavage fluid (BALF) were measured by enzymelinked immunosorbent assay in patients with ILDs and healthy volunteers (HV). We also examined the expression of MDC mRNA in alveolar macrophages (AM) by real-time quantitative reverse transcriptase-polymerase chain reaction. Both MDC and TARC were detected only in BALF obtained from IEP patients. The concentration of MDC was higher than that of TARC in all cases. The level of MDC in IEP correlated with that of TARC. AM from IEP patients expressed a significantly higher amount of MDC than that from HV at the levels of protein and mRNA. MDC in BALF from IEP dramatically decreased when patients achieved remission. These findings suggest that MDC, in addition to TARC, might be involved in the pathogenesis of IEP, and AM play a role in the elevation of MDC in IEP

ヘキチ イリョウ キョテン ビョウイン ニオケル センモン ガイライ ノ カンジャ ジュリョウ ドウコウ ニ オヨボス エイキョウ

There were few reports about the role of medical specialists in community medicine organizations such as hospitals in rural area where the number of doctors is insufficient. The aim of this study was to investigate the effect of a medical specialist for collagen vascular diseases having started periodically ambulatory care in the medical institution of the area where the specialist was absent. We examined the trend of outpatients with a collagen vascular disease about moving the hospital comparing before and after the specialist started to work in the medical institution. The number of outpatients with a collagen vascular disease in the medical institution became 95 at 3 years and a half after the specialist started to work there. There were many transfer patients from medical institutions other than the area, and the distance from their home to the hospital was shortened by changing the hospital in most of patients. The ambulatory care performed periodically and continuously by the specialist in a community medicine organization showed significances that patients became to receive the special medical care by the specialist

Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A(1) activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.ArticleSCIENTIFIC REPORTS. 4:7132 (2014)journal articl