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TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured [beta] cell line (MIN6) and [beta] cell-specific Tardbp-knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp- knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and, thus, plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons, but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS., Introduction Amyotrophic lateral sclerosis (ALS) is a selective motor neuron disorder leading to death in 3-5 years after the onset, due to rapid progression of muscle atrophy, including atrophy of [...]

This study is the first attempt to analyze the articles in several journals, in order to disclose the development of academic educational studies in Japan. In this paper, my examination was not limited to one journal, but covered six education journals listed below and all their issues until 2005. I chose, from a methodological viewpoint, four journals that have been most important for the philosophical, historical, sociological and comparative research on education and, from thematic viewpoints, two celebrated Japanese journals for the study of educational method and that of educational administration. The development of educational studies shown in the articles of the journals reviewed was diverse and complex. On the one hand, the home institutions of the authors were not only traditional research universities, but also other types of universities. On the other hand, the former institutions are still the center of training for (graduate) students who make up the largest number of authors of the articles today. The analyzed six journals had such heterogeneous character as to have oriented themselves to different areas (theory, school, society [public]) to a varied extent. The articles targeted several historical periods and countries/areas and their distribution of these factors was relatively balanced. Although the studies were based, methodologically, primarily on the analysis of certain kinds of text, in other words on the philosophical method, the object of the studies was mostly not the ideas of certain persons. The articles referred, topically, to a certain philosopher or education researcher/theorist less often than to secondary/higher education. Furthermore, the research methods, objects and topics of the articles in one journal were far from homogeneous. (Contains 11 figures, 15 tables, and 3 notes.)

Tropical south-western Pacific temperatures are of vital importance to the Great Barrier Reef (GBR), but the role of sea surface temperatures (SSTs) in the growth of the GBR since the Last Glacial Maximum remains largely unknown. Here we present records of Sr/Ca and δ(18)O for Last Glacial Maximum and deglacial corals that show a considerably steeper meridional SST gradient than the present day in the central GBR. We find a 1-2 °C larger temperature decrease between 17° and 20°S about 20,000 to 13,000 years ago. The result is best explained by the northward expansion of cooler subtropical waters due to a weakening of the South Pacific gyre and East Australian Current. Our findings indicate that the GBR experienced substantial meridional temperature change during the last deglaciation, and serve to explain anomalous deglacial drying of northeastern Australia. Overall, the GBR developed through significant SST change and may be more resilient than previously thought.

Buckling-restrained braced frames (BRBFs) are attracting interest worldwide by virtue of their extraordinary response reduction performance. The system relies strongly on the energy dissipation of buckling-restrained braces (BRBs). Therefore, the surrounding members (beams, columns, or gusset plates) must sustain the force imposed by a BRB. Notably, beams are not designed primarily to support the axial force. The sections consequently tend to become deep and slender to enhance the flexural strength and stiffness effectively, thereby leading to local buckling, which lessens the reaction force to the BRB. Moreover, the instability is activated by the compressive axial force transferred from the BRB. However, beams in the BRBFs generally become composite beams through an assemblage with a concrete slab by stud shear connectors. The concrete slab shifts the neutral axis of the beam, which imposes more strain on the bottom flange. The BRB axial force and composite effect therefore influence the steel beam buckling behavior. Eventually, the beam might be subjected to instability at a smaller-than-expected deformation. However, the rotation capacity of the composite beam in BRBFs has not been clarified yet. To address this concern, this study established a finite-element analysis (FEA) model referring to a former specimen and an experiment scheme. Additionally, a parametric study of the influential factors was conducted using the experimentally validated FEA model. This study examined a proposed evaluation equation of an apparent axial force issued from the composite effect based on the obtained results. An earlier evaluation index established for bare steel beams was ultimately modified to include the axial force influence. Eventually, the results demonstrated that the structural performance can be assessed appropriately using the existing evaluation equations proposed using a steel frame subassembly. [ABSTRACT FROM AUTHOR]

Background: A left atrial posterior wall isolation (LAPWI) is one of the atrial fibrillation (AF) ablation strategies. Hypothesis: We hypothesized that an additional empirical LAPWI would increase the freedom from recurrent atrial arrhythmias as compared to standard AF ablation in persistent AF patients. Methods: The CORNERSTONE AF study is a prospective, randomized, multicenter study investigating patients with AF persisting for >7 days and <3 years undergoing first‐time AF ablation. They will be randomized to pulmonary vein isolation (PVI) or PVI + LAPWI in a 1:1 manner. Although PVI can be performed with either radiofrequency catheters or cryoballoons, only radiofrequency catheters will be permitted to achieve LAPWIs. Additional focal ablation targeting non‐pulmonary vein triggers will be allowed. A total of 516 patients will be enrolled in 17 centers between August 2022 and February 2024 based on the calculation with 80% power, considering the assumption that 65% and 75% of the PVI and PVI + LAPWI group patients will be free from atrial arrhythmia recurrence 18‐months postprocedure (10% of dropout). The primary endpoint is freedom from documented atrial arrhythmias 18 months postsingle procedures. Clinical follow‐up will include 7‐day ambulatory electrocardiograms and routine outpatient consultations by electrophysiologists at 1, 3, 6, 9, 12, and 18 months postprocedure. Results: As of August 2023, a total of 331 patients (68 ± 9 years, 270 men, 43 longstanding persistent AF) have been enrolled. Conclusions: The CORNERSTONE AF study is a prospective, randomized, multicenter trial designed to evaluate the efficacy and safety of an adjunctive empirical LAPWI following standard AF ablation in persistent AF patients. [ABSTRACT FROM AUTHOR]

Direct reprogramming, inducing the conversion of one type of somatic cell into another by the forced expression of defined transcription factors, is a technology with anticipated medical applications. However, due to the many unresolved aspects of the induction mechanisms, it is essential to thoroughly analyze the epigenomic state of the generated cells. Here, we performed comparative genome-wide DNA methylation analyses of mouse embryonic fibroblasts (MEFs) and cells composing organoids formed by intestinal stem cells (ISCs) or induced ISCs (iISCs) that were directly induced from MEFs. We found that the CpG methylation state was similar between cells forming ISC organoids and iISC organoids, while they differed widely from those in MEFs. Moreover, genomic regions that were differentially methylated between ISC organoid- and iISC organoid-forming cells did not significantly affect gene expression. These results demonstrate the accuracy and safety of iISC induction, leading to the medical applications of this technology. [ABSTRACT FROM AUTHOR]

The addition of copper bromide to the perovskite precursor solutions increased the conversion efficiencies of the devices. On the other hand, the short-circuit current densities decreased with an increase in the added amounts of copper (Cu). From first-principles calculations, the partial substitution of lead with Cu resulted in the formation of a Cu d orbital energy level in the forbidden band, which worked as a recombination center, causing the generated carriers to disappear. Experiments and calculations show the effects of Cu substitution on the electronic structures and the ability of the addition of Cu compounds to further improve the device performance. [ABSTRACT FROM AUTHOR]

First-principle calculation analysis on electronic structures and molecular dynamics was performed to investigate the addition of gadolinium ion into a formamidinium lead iodine (FAPbI3) perovskite crystal for use in the application of photovoltaic devices with stability of performance. Band dispersion, density of state, enthalpy, and kinetic energy were predicted during the relaxation process. The Gd2+-doped FAPbI3 perovskite crystal had an effective mass ratio of 0.02 in narrow band dispersion, consisting of 5d and 4f orbitals of gadolinium ion, a 6p orbital of lead ion, and a 5p orbital of iodine ion, supporting the charge transfer and carrier diffusion related to carrier mobility as a photovoltaic parameter. The molecular dynamics of the Gd2+-doped perovskite crystal indicate dynamic stability while suppressing decomposition, with separation between nitrogen and hydrogen ions on FA in the crystal. The first-principle calculation predicts that it is advantageous to apply the Gd2+-doped FAPbI3 perovskite crystal to the perovskite solar cell, providing stability of photovoltaic performance. [ABSTRACT FROM AUTHOR]