Search

Abstract Using the Japanese Atmospheric General circulation model for the Upper Atmosphere Research-Data Assimilation System (JAGUAR-DAS), a whole neutral atmosphere reanalysis dataset (JAWARA) over about 19 years from September 2004 to December 2023 is produced. JAWARA is the first long-period reanalysis covering the height region from the surface to the lower thermosphere (~ 110 km). This wide height coverage is a notable advantage over other operational reanalysis datasets, which cover up to the middle mesosphere. Key dynamical characteristics are compared between JAWARA and two satellite observations and three other operational reanalysis datasets in their covered height regions. The seasonal variations of zonal mean temperature and zonal wind are similar between JAWARA and the datasets used for comparison. The climatologies of zonal mean temperature, zonal wind, residual-mean circulation, and E-P flux in the meridional cross section are also broadly consistent with other reanalysis datasets. The analyzed residual-mean vertical flow in the northern high latitudes in the middle atmosphere exhibits the well-known patterns of upwelling in summer and downwelling in winter. JAWARA also shows a prominent feature of strong downward propagating anomalies from the lower thermosphere to the upper stratosphere after sudden stratospheric warmings. This analysis takes full advantage of the JAWARA data, which cannot be made using satellite observations and other reanalysis datasets. This reanalysis product is expected to contribute broadly to future research on the characteristics of observed mesospheric phenomena, thermosphere–ionosphere coupling, space weather, and improvement of middle atmospheric meteorological systems, including their interannual and decadal scale variability.

The blood–brain barrier (BBB) blocks harmful substances from entering the brain and dictates the central nervous system (CNS)-specific pharmacokinetics. Recent studies have shown that perivascular astrocytes and microglia also control BBB functions, however, information about the formation of BBB glial architecture remains scarce. We investigated the time course of the formation of BBB glial architecture in the rat brain cerebral cortex using Evans blue (EB) and tissue fixable biotin (Sulfo-NHS Biotin). The extent of the leakage into the brain parenchyma showed that the BBB was not formed at postnatal Day 4 (P4). The BBB gradually strengthened and reached a plateau at P15. We then investigated the changes in the configurations of blood vessels, astrocytes, and microglia with age by 3D image reconstruction of the immunohistochemical data. The endfeet of astrocytes covered the blood vessels, and the coverage rate rapidly increased after birth and reached a plateau at P15. Interestingly, microglia were also in contact with the capillaries, and the coverage rate was highest at P15 and stabilized at P30. It was also clarified that the microglial morphology changed from the amoeboid type to the ramified type, while the areas of the respective contact sites became smaller during P4 and P15. These results suggest that the perivascular glial architecture formation of the rat BBB occurs from P4 to P15 because the paracellular transport and the arrangements of perivascular glial cells at P15 are totally the same as those of P30. In addition, the contact style of perivascular microglia dramatically changed during P4-P15.

Abstract Different meteor radars at low latitudes observed abnormally strong westward mesospheric winds around the March Equinox of 2023, that is, during the first phase of the Mesospheric Semiannual Oscillation. This event was the strongest of at least the last decade (2014–2023). The westward winds reached −80 m/s at 82 km of altitude in late March, and decreased with increasing altitude and latitude. A considerable increase in the diurnal tide amplitude was also observed. The Whole Atmosphere Community Climate Model with thermosphere‐ionosphere eXtension constrained to meteorological reanalysis up to ∼50 km does not capture the observed low‐latitude behavior. Additionally, these strong mesospheric winds developed during the westerly phase of the Quasi‐Biennial Oscillation, in accordance with the filtering mechanism of gravity waves in the stratosphere proposed in previous works. Finally, analysis of SABER temperatures strongly suggests that the breaking of the migrating diurnal tide may be the main driver of these strong winds.

Background: The blood–brain barrier (BBB) strictly regulates the penetration of substances into the brain, which, although important for maintaining brain homeostasis, may delay drug development because of the difficulties in predicting pharmacokinetics/pharmacodynamics (PKPD), toxicokinetics/toxicodynamics (TKTD), toxicity, safety, and efficacy in the central nervous system (CNS). Moreover, BBB functional proteins show species differences; therefore, humanized in vitro BBB models are urgently needed to improve the predictability of preclinical studies. Recently, international trends in the 3Rs in animal experiments and the approval of the FDA Modernization Act 2.0 have accelerated the application of microphysiological systems (MPSs) in preclinical studies, and in vitro BBB models have become synonymous with BBB–MPSs. Recently, we developed an industrialized humanized BBB–MPS, BBB–NET. In our previous report, we reproduced transferrin receptor (TfR)–mediated transcytosis with high efficiency and robustness, using hydrogels including fibrin and collagen I microfibers (CMFs). Methods: We investigated how adding CMFs to the fibrin gel benefits BBB-NETs. Results: We showed that CMFs accelerate capillary network formation and maturation by promoting astrocyte (AC) survival, and clarified that integrin β1 is involved in the mechanism of CMFs. Conclusions: Our data suggest that the quality control (QC) of CMFs is important for ensuring the stable production of BBB–NETs.

ABSTRACT: Koji mold, classified in the genus Aspergillus, is used to produce traditional Japanese fermented foods such as miso, soy sauce, and sake. In recent years, the application of koji mold to cheese ripening has attracted attention, and cheese surface-ripened with koji mold (koji cheese) has been studied. In this study, to evaluate the taste characteristics of koji cheese, an electronic tongue system was employed to measure the taste values of cheese samples ripened using 5 strains of koji mold in comparison with commercial Camembert cheese. All koji cheese samples exhibited lower sourness and greater bitterness, astringency, saltiness, and umami richness than the Camembert cheese samples. The intensity of each taste characteristic differed depending on the koji mold strain. These results indicate that koji cheese has a different taste value than conventional mold-ripened cheese. Furthermore, the results also indicate that various taste characteristics can be achieved by selecting different koji molds.

Summary: A current challenge is the emergence of SARS-CoV-2 variants, such as BQ.1.1 and XBB.1.5, that can evade immune defenses, thereby limiting antibody drug effectiveness. Emergency-use antibody drugs, including the widely effective bebtelovimab, are losing their benefits. One potential approach to address this issue are bispecific antibodies which combine the targeting abilities of two antibodies with distinct epitopes. We engineered neutralizing bispecific antibodies in the IgG-scFv format from two initially non-neutralizing antibodies, CvMab-6 (which binds to the receptor-binding domain [RBD]) and CvMab-62 (targeting a spike protein S2 subunit epitope adjacent to the known anti-S2 antibody epitope). Furthermore, we created a bispecific antibody by incorporating the scFv of bebtelovimab with our anti-S2 antibody, demonstrating significant restoration of effectiveness against bebtelovimab-resistant BQ.1.1 variants. This study highlights the potential of neutralizing bispecific antibodies, which combine existing less effective anti-RBD antibodies with anti-S2 antibodies, to revive the effectiveness of antibody therapeutics compromised by immune-evading variants.

Abstract Energetic particles from space deposit their energies on the Earth's atmosphere and contribute to variations in the concentration of neutral components such as ozone which controls the atmospheric temperature balance. Comprehensive understandings of their global impact on the atmosphere require whole pictures of spatiotemporal ionization distributions due to them. We first attempt to evaluate and summarize the altitude profiles of ionization for the September 2017 space weather event with cutting‐edge space‐borne and ground‐based observations of different types of particle inputs. In early September 2017, the Sun showed notable activity, including X‐class flares and solar proton events. During this period, ground‐based radar observations have confirmed atmospheric ionization events by energetic particle precipitations of solar flare X‐rays, solar protons, and radiation belt electrons, the main sources of ionization into the Earth's atmosphere. We estimate the altitude profiles of the ionization rate by using the Particle and Heavy Ion Transport code System (PHITS) with the input of the particle fluxes obtained by satellites. The estimates are then compared with measurements of the ionization altitude, ionization intensity, and electron density by the radars in the polar region, such as the PANSY radar at Syowa Station and the EISCAT in Tromsø, Norway. We conclude that the PHITS simulation results reasonably reproduce (within the error of a factor of two) those ionizations measured by ground‐based instruments with inputs of observed ionization sources by satellites.

Abstract Advances in image processing technology have made it possible to measure the surface shape of the road ahead while driving. A new semi‐active suspension control method considering the forward road surface shape is proposed. A vehicle model equipped with a semi‐active suspension can be expressed as an mixed logical dynamical model. When the shape of the road ahead can be measured, the information on future disturbances is available before the vehicle undergoes. In this paper, the finite time optimization problem for the mixed logical dynamical model is formulated to consider the future disturbances as a mixed integer quadratic programming problem in the same way as the conventional control problem without future disturbance. However, the mixed integer quadratic programming problem is hard to obtain the control action within the control cycle period required in the real‐time vibration control with general computers for vehicles. In this paper, the reduction of the computational load is achieved by constructing an approximation function of the designed controller. A neural network is adopted for the approximation. The performance evaluation of the proposed method is evaluated by simulations. In the simulation study, the proposed method achieves better ride comfort with the equivalent suspension stroke compared to the traditional methods.

Microphysiological system (MPS), a new technology for in vitro testing platforms, have been acknowledged as a strong tool for drug development. In the central nervous system (CNS), the blood‒brain barrier (BBB) limits the permeation of circulating substances from the blood vessels to the brain, thereby protecting the CNS from circulating xenobiotic compounds. At the same time, the BBB hinders drug development by introducing challenges at various stages, such as pharmacokinetics/pharmacodynamics (PK/PD), safety assessment, and efficacy assessment. To solve these problems, efforts are being made to develop a BBB MPS, particularly of a humanized type. In this study, we suggested minimal essential benchmark items to establish the BBB-likeness of a BBB MPS; these criteria support end users in determining the appropriate range of applications for a candidate BBB MPS. Furthermore, we examined these benchmark items in a two-dimensional (2D) humanized tricellular static transwell BBB MPS, the most conventional design of BBB MPS with human cell lines. Among the benchmark items, the efflux ratios of P-gp and BCRP showed high reproducibility in two independent facilities, while the directional transports meditated through Glut1 or TfR were not confirmed. We have organized the protocols of the experiments described above as standard operating procedures (SOPs). We here provide the SOPs with the flow chart including entire procedure and how to apply each SOP. Our study is important developmental step of BBB MPS towards the social acceptance, which enable end users to check and compare the performance the BBB MPSs.

In our recent report, we clarified the direct interaction between the excitatory amino acid transporter (EAAT) 1/2 and polyunsaturated fatty acids (PUFAs) by applying electrophysiological and molecular biological techniques to Xenopus oocytes. Xenopus oocytes have a long history of use in the scientific field, but they are still attractive experimental systems for neuropharmacological studies. We will therefore summarize the pharmacological significance, advantages (especially in the study of EAAT2), and experimental techniques that can be applied to Xenopus oocytes; our new findings concerning L-glutamate (L-Glu) transporters and PUFAs; and the significant outcomes of our data. The data obtained from electrophysiological and molecular biological studies of Xenopus oocytes have provided us with further important questions, such as whether or not some PUFAs can modulate EAATs as allosteric modulators and to what extent docosahexaenoic acid (DHA) affects neurotransmission and thereby affects brain functions. Xenopus oocytes have great advantages in the studies about the interactions between molecules and functional proteins, especially in the case when the expression levels of the proteins are small in cell culture systems without transfections. These are also proper to study the mechanisms underlying the interactions. Based on the data collected in Xenopus oocyte experiments, we can proceed to the next step, i.e., the physiological roles of the compounds and their significances. In the case of EAAT2, the effects on the neurotransmission should be examined by electrophysiological approach using acute brain slices. For new drug development, pharmacokinetics pharmacodynamics (PKPD) data and blood brain barrier (BBB) penetration data are also necessary. In order not to miss the promising candidate compounds at the primary stages of drug development, we should reconsider using Xenopus oocytes in the early phase of drug development.

While estrogens are well known for their pivotal role in the female reproductive system, they also play a crucial function in regulating physiological processes associated with learning and memory in the brain. Moreover, they have neuroprotective effects in the pathogenesis of Alzheimer’s disease (AD). Importantly, AD has a higher incidence in older and postmenopausal women than in men, and estrogen treatment might reduce the risk of AD in these women. In general, estrogens bind to and activate estrogen receptors (ERs)-mediated transcriptional machineries, and also stimulate signal transduction through membrane ERs (mERs). Estrogen-related receptors (ERRs), which share homologous sequences with ERs but lack estrogen-binding capabilities, are widely and highly expressed in the human brain and have also been implicated in AD pathogenesis. In this review, we primarily provide a summary of ER and ERR expression patterns in the human brain. In addition, we summarize recent studies on their role in learning and memory. We then review and discuss research that has elucidated the functions and importance of ERs and ERRs in AD pathogenesis, including their role in Aβ clearance and the reduction of phosphorylated tau levels. Elucidation of the mechanisms underlying ER- and ERR-mediated transcriptional machineries and their functions in healthy and diseased brains would provide new perspectives for the diagnosis and treatment of AD. Furthermore, exploring the potential role of estrogens and their receptors, ERs, in AD will facilitate a better understanding of the sex differences observed in AD, and lead to novel sex-specific therapeutic approaches.

ABSTRACT: More than 2,000 varieties of cheese currently exist in the world, and cheese manufacture continues to flourish. To develop the cheese ripening process, additional ingredients are used during cheese production. In this study, the effect of sake lees as an additional ingredient on the fermentation of cheese using Aspergillus oryzae (koji mold), known as koji cheese, was investigated. Aspergillus oryzae is used in the fermentation of Japanese traditional foods, such as sake and soy sauce, given its strong enzymatic activities, as well as in cheese production (i.e., koji cheese). Sake lees, a by-product of the fermentation of rice with A. oryzae and yeasts in the sake brewing process, contains various metabolites, such as amino acids. Here, supplementation with sake lees enhanced the activities of lactic acid bacteria and affected the color of the cheese. Metabolome analysis revealed that sake lees altered the balance of carbohydrates and fatty acids in the cheese. Remarkably, supplementation with sake lees enhanced the production of umami-enhancing γ-glutamyl (kokumi-active) peptides. This study suggests that a new type of cheese can be produced using A. oryzae and sake lees, and information on the synergistic effects of A. oryzae and sake lees will aid the development of cheese production.

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by neuronal loss and dysfunction. Despite remarkable improvements in our understanding of these pathogeneses, serious worldwide problems with significant public health burdens are remained. Therefore, new efficient diagnostic and therapeutic strategies are urgently required. PIWI-interacting RNAs (piRNAs) are a major class of small non-coding RNAs that silence gene expression through transcriptional and post-transcriptional processes. Recent studies have demonstrated that piRNAs, originally found in the germ line, are also produced in non-gonadal somatic cells, including neurons, and further revealed the emerging roles of piRNAs, including their roles in neurodevelopment, aging, and neurodegenerative diseases. In this review, we aimed to summarize the current knowledge regarding the piRNA roles in the pathophysiology of neurodegenerative diseases. In this context, we first reviewed on recent updates on neuronal piRNA functions, including biogenesis, axon regeneration, behavior, and memory formation, in humans and mice. We also discuss the aberrant expression and dysregulation of neuronal piRNAs in neurodegenerative diseases, such as AD, PD, and ALS. Moreover, we review pioneering preclinical studies on piRNAs as biomarkers and therapeutic targets. Elucidation of the mechanisms underlying piRNA biogenesis and their functions in the brain would provide new perspectives for the clinical diagnosis and treatment of AD and various neurodegenerative diseases.

Abstract Background Angiomyolipoma is a benign mesenchymal tumor that develops commonly in the kidney and rarely in other organs. The involvement of the spleen in angiomyolipoma is extremely rare, and only one such case has been reported in the English literature. Case presentation A 27-year-old man presented with adenoid hyperplasia and bilateral palatal tonsillar hyperplasia. During the treatment for adenoid hyperplasia, a 15-cm tumor was detected in the spleen using abdominal ultrasonography and enhanced computed tomography. Partial resection of the spleen was successfully performed. A giant tumor of approximately 13 cm with a smooth surface was observed in the upper left quadrant of the abdomen. The tumor was confirmed to be continuous with the upper spleen, and there was no invasion of the other organs. The postoperative course was good, and the patient was discharged on the 7th postoperative day. The excised specimen was a smooth, extremely soft tumor measuring 123 × 120 × 82 mm. The cleaved surface of the tumor was reddish brown, and a distressing yellow color was observed. Pathological examination revealed a proliferation of mature adipocytes and an increase in the number of blood vessels of various sizes. Furthermore, spindle-shaped cell proliferation foci were visible between the adipocytes and the surrounding blood vessels. Profuse leakage of erythrocytes from the blood vessels, hemosiderin deposition, and small round cell infiltration were also noted. Immunostaining disclosed that the spindle-shaped cells were weakly positive for smooth muscle antibody and were identified as smooth muscle cells. The adipocytes and spindle cells were negative for HMB 45, Melan A, MDM, and CDK4. However, some parts of the cells were positive for estrogen and progesterone receptors. Besides, vascular endothelial cells were positive for CD31 and CD34 and negative for CD8. Based on these findings, the patient was diagnosed to have primary angiomyolipoma of the spleen. Conclusions We have reported the surgical treatment for an extremely rare case of giant splenic angiomyolipoma in a young man. Globally, this is the second report on this condition. We believe that partial splenic resection is a feasible option for the management of giant tumors.

Background The AT(N) classification was proposed for categorising individuals according to biomarkers. However, AT(N) profiles may vary depending on the markers chosen and the target population.Methods We stratified 177 individuals who participated in the Japanese Alzheimer’s Disease Neuroimaging Initiative by AT(N) classification according to cerebrospinal fluid (CSF) biomarkers. We compared the frequency of AT(N) profiles between the classification using total tau and neurofilament light chain (NfL) as N markers (AT(N)tau and AT(N)NfL). Baseline characteristics, and longitudinal biological and clinical changes were examined between AT(N) profiles.Results We found that 9% of cognitively unimpaired subjects, 49% of subjects with mild cognitive impairment, and 61% of patients with Alzheimer’s disease (AD) dementia had the biological AD profile (ie, A+T+) in the cohort. The frequency of AT(N) profiles substantially differed between the AT(N)tau and AT(N)NfL classifications. When we used t-tau as the N marker (AT(N)tau), those who had T− were more frequently assigned to (N)−, whereas those who had T+were more frequently assigned to (N)+ than when we used NfL as the N marker (AT(N)NfL). During a follow-up, the AD continuum group progressed clinically and biologically compared with the normal biomarker group in both the AT(N)tau and AT(N)NfL classifications. More frequent conversion to dementia was observed in the non-AD pathological change group in the AT(N)tau classification, but not in the AT(N)NfL classification.Conclusions AT(N)tau and AT(N)NfL in CSF may capture different aspects of neurodegeneration and provide a different prognostic value. The AT(N) classification aids in understanding the AD continuum biology in various populations.

An experiment study was conducted on the operational characteristics of the JEST-type loop thermosyphon when an initial liquid level of a working fluid was lowered. This thermosyphon was invented in 2012 by one of the authors with a jet explosion stream technology (JEST) for cooling high-heat-generation and high-heat-flux CPUs. The present experiment aims at lowering the height of the thermosyphon for rack-level thermal management in a datacenter. Hydrofluoroether (HFE)-7000 was used as the working fluid. In experiment, an evaporator section of the thermosyphon was heated with a heating block while a condenser section was water-cooled using a thermostatic bath. Temporal changes in temperatures of the thermosyphon were obtained with thermocouples. Moreover, the circulation flow rate of the working fluid in the thermosyphon was obtained with a simple measurement method. The initial liquid level of the working fluid was changed as 166, 268, 368 mm while the height of the thermosyphon was 1200 mm. Experimental results are shown regarding the effect of the initial liquid level on the circulation flow rates of the vapor and liquid phases of the working fluid as well as the heat transfer coefficient at the evaporator section. An additional experiment was also conducted when the height of the thermosyphon was lowered from 1200 mm to 480 mm. It was confirmed that the thermal performance of the thermosyphon decreased when the initial liquid level was lowered; however, the thermal performance was recovered by lowering the height of the thermosyphon. Therefore, the JEST-type loop thermosyphon can be applied to the rack-level thermal management in a datacenter.

The blood-brain barrier (BBB), a selective barrier regulating the active and passive transport of solutes in the extracellular fluid of the central nervous system, prevents the delivery of therapeutics for brain disorders. The BBB is composed of brain microvascular endothelial cells (BMEC), pericytes and astrocytes. Current in vitro BBB models cannot reproduce the human structural complexity of the brain microvasculature, and thus their functions are not enough for drug assessments. In this study, we developed a 3D self-assembled microvascular network formed by BMEC covered by pericytes and astrocyte end feet. It exhibited perfusable microvasculature due to the presence of capillary opening ends on the bottom of the hydrogel. It also demonstrated size-selective permeation of different molecular weights of fluorescent-labeled dextran, as similarly reported for in vivo rodent brain, suggesting the same permeability with actual in vivo brain. The activity of P-glycoprotein efflux pump was confirmed using the substrate Rhodamine 123. Finally, the functionality of the receptor-mediated transcytosis, one of the main routes for drug delivery of large molecules into the brain, could be validated using transferrin receptor (TfR) with confocal imaging, competition assays and permeability assays. Efficient permeability coefficient (Pe) value of transportable anti-TfR antibody (MEM-189) was seven-fold higher than those of isotype antibody (IgG1) and low transportable anti-TfR antibody (13E4), suggesting a higher TfR transport function than previous reports. The BBB model with capillary openings could thus be a valuable tool for the screening of therapeutics that can be transported across the BBB, including those using TfR-mediated transport.

In S. pombe, small non-coding RNA mediates heterochromatin formation by recruiting the nucleosome remodeling and histone deacetylase complex. Here, the authors show that fly nucleosome remodeler Mi-2 and histone deacetylase Rpd3 are involved in piRNA-dependent transcriptional silencing of transposable elements.

Advances in image processing technology have made it possible to measure the surface shape of the road ahead while driving. We propose a new semi-active suspension control method considering the forward road surface shape. A vehicle model equipped with a semi-active suspension can be expressed as an MLD (Mixed Logical Dynamical) model. When the shape of the road ahead can be measured accurately, it can be considered that the information on the future disturbances is available before the vehicle undergoes. In this paper, we formulate the finite time optimization problem of an MLD model to consider future disturbances as an MIQP (Mixed Integer Quadratic Programming) problem in the same way as the conventional optimal control problem without future disturbance. The solution to an MIQP problem can be obtained by a commonly available solver software. The performance evaluation of the proposed method was carried out by a simulation, and the simulation was performed on the road surface shape generated based on ISO 8608. In the simulation study, the proposed method achieved better ride comfort, i.e., equivalent suspension stroke, compared to the traditional MLD predictive control and the Skyhook approximation methods.

The blood-brain barrier (BBB), a selective barrier formed by brain microvascular endothelial cells (BMEC), represents a major challenge for the efficient accumulation of pharmaceutical drugs into the brain. The receptor-mediated transcytosis (RMT) has recently gained increasing interest for pharmaceutical industry as it shows a great potential to shuttle large-sized therapeutic cargos across the BBB. Confirming the presence of the RMT pathway by BMEC is therefore important for the screening of peptides or antibody libraries that bind RMT receptors. Herein, a comparative study was performed between a human cell line of BMEC (HBEC) and human induced pluripotent stem cells-derived BMEC-like cells (hiPS-BMEC). The significantly higher gene and protein expressions of transporters and tight junction proteins, excepting CD31 and VE-cadherin were exhibited by hiPS-BMEC than by HBEC, suggesting more biomimetic BBB features of hiPS-BMEC. The presence and functionality of transferrin receptor (TfR), known to use RMT pathway, were confirmed using hiPS-BMEC by competitive binding assays and confocal microscopy observations. Finally, cysteine-modified T7 and cysteine modified-Tfr-T12 peptides, previously reported to be ligands of TfR, were compared regarding their permeability using hiPS-BMEC. The hiPS-BMEC could be useful for the identification of therapeutics that can be transported across the BBB using RMT pathway.

We propose a new semi-active vibration control method of structural systems subject to seismic disturbances based on the optimal control for MLD models incorporating future seismic waveforms. In the proposed preview control method, we aim to realize the higher control performance than the conventional predictive control for the MLD model by considering future seismic waveforms. In the preview control law for the MLD model, a future data series of the seismic waveform is necessary. Because the future seismic waveform is not available, the method is generally impossible. In this paper, the control input data of the preview optimal control of the MLD model using future seismic waveforms are collected in advance subject to the recoded seismic waves, and the control inputs are trained with a multi-layered artificial neural network by using the past seismic waveforms. By replacing the preview optimal control for MLD model with the neural network, we are able to construct an implementable preview control system that shows high control performance using past seismic waveforms. Besides, the conventional method to obtain the control inputs of optimal control for MLD model has a problem on the high computational load, because it is MIQP that is NP-hard problem to obtain control inputs. Therefore, there are two difficulties in the real time implementation of the control method. By using the proposed neural network as the control law, the problem on the computational load can also be solved. The effectiveness of the proposed method is confirmed by a simulation using seismic waveforms observed in Japan. In the simulation study, the high control performance and the reduction of the computational load are demonstrated in comparison with implementable conventional methods.

Background: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. Methods: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34+CD38−CD45RA− haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/SCID/Il2rgKO (NSG) newborns, and compared GVHD progression with NSG newborns receiving CB CD34− cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice. Findings: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. Interpretation: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD. Keywords: Acute GVHD, Chronic GVHD, IL-6, Humanised mouse

Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive impairment of memory, thinking, behavior, and dementia. Based on ample evidence showing neurotoxicity of amyloid-β (Aβ) aggregates in AD, proteolytically derived from amyloid precursor protein (APP), it has been assumed that misfolding of Aβ plays a crucial role in the AD pathogenesis. Additionally, extra copies of the APP gene caused by chromosomal duplication in patients with Down syndrome can promote AD pathogenesis, indicating the pathological involvement of the APP gene dose in AD. Furthermore, increased APP expression due to locus duplication and promoter mutation of APP has been found in familial AD. Given this background, we aimed to summarize the mechanism underlying the upregulation of APP expression levels from a cutting-edge perspective. We first reviewed the literature relevant to this issue, specifically focusing on the transcriptional regulation of APP by transcription factors that bind to the promoter/enhancer regions. APP expression is also regulated by growth factors, cytokines, and hormone, such as androgen. We further evaluated the possible involvement of post-transcriptional regulators of APP in AD pathogenesis, such as RNA splicing factors. Indeed, alternative splicing isoforms of APP are proposed to be involved in the increased production of Aβ. Moreover, non-coding RNAs, including microRNAs, post-transcriptionally regulate the APP expression. Collectively, elucidation of the novel mechanisms underlying the upregulation of APP would lead to the development of clinical diagnosis and treatment of AD.

Abstract Transient mesospheric echo in the VHF range was detected at an altitude of 65–70 km during the auroral breakup that occurred from 2220 to 2226 UT on June 30, 2017. During this event, the footprint of the Arase satellite was located within the field of view of the all-sky imagers at Syowa Station in the Antarctic. Auroral observations at Syowa Station revealed the dominant precipitation of relatively soft electrons during the auroral breakup. A corresponding spike in cosmic noise absorption was also observed at Syowa Station, while the Arase satellite observed a flux enhancement of > 100 keV electrons and a broadband noise without detecting chorus waves or electromagnetic ion cyclotron waves. A general-purpose Monte Carlo particle transport simulation code was used to quantitatively evaluate the ionization in the middle atmosphere. Results of this study indicate that the precipitation of energetic electrons of > 100 keV, rather than X-rays from the auroral electrons, played a dominant role in the transient and deep (65–70 km) mesospheric ionization during the observed auroral breakup.

Abstract We investigate numerical models that display the transition of global climate modeling from coarse grids, at which convection and gravity waves are still parameterized, toward finer resolutions, where both are treated explicitly. Gravity waves generated by deep, tropical convection are examined by means of spectral analysis. We make use of the models' different setups to discuss the impacts of spatial resolution, the treatment of moist convection and the degree of model complexity, on convectively generated gravity waves. We find that substantially more gravity wave momentum flux is resolved by models with fine horizontal grid spacing, as the spectral slope is almost flat in zonal wave number space (∼k−1), until scales at which numerical diffusion sets in. However, we also find that, when well‐organized tropical storm systems of large scale are simulated with convection‐permitting resolution, the gravity wave variance may be enhanced at small scales and the spectral slope may flatten. We propose an explanation for this in the dynamical overshooting of convective updrafts that is expected to mechanically generate gravity waves. Further, we find that a parameterization of convection drastically reduces gravity wave momentum flux associated with tropical convection, as deep modes of latent heating and gravity waves are underestimated. Thus, its application is expected to have consequences for wave mean‐flow interaction in the middle atmosphere. The universal properties of the gravity wave spectrum that were found in observations and confirmed in analytical gravity wave models are successfully reproduced in our numerical simulations of tropical dynamics.

Various biological factors have been implicated in convulsive seizures, involving side effects of drugs. For the preclinical safety assessment of drug development, it is difficult to predict seizure-inducing side effects. Here, we introduced a machine learning-based in vitro system designed to detect seizure-inducing side effects. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices, while 14 drugs were bath-perfused at 5 different concentrations each. For each experimental condition, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events and identified diphenhydramine, enoxacin, strychnine and theophylline as “seizure-inducing” drugs, which indeed were reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to detect the seizure-inducing side effects of preclinical drugs.

Background. Primary omental leiomyosarcoma is an extremely rare type of tumor. Leiomyosarcomas originating from the lesser omentum have not been reported since immunohistochemical staining for c-kit has been used for the diagnosis of mesenchymal abdominal tumors. They are yet to be reported since gastrointestinal stromal tumors were categorized. Here we reported a case of successful resection of a lesser omental leiomyosarcoma. Case Presentation. A 71-year-old man underwent ultrasonography at the outpatient clinic through which an upper abdominal tumor was identified. Following computed tomography and endoscopy, a 4.5 cm submucosal tumor in the lesser curvature of the stomach was highly suspected. A laparoscopic partial resection of the stomach was performed. Histopathological examination revealed the tumor to be a leiomyosarcoma arising from the lesser omentum that did not invade the stomach. Immunohistochemical staining showed that the tumor was negative for CD34, c-kit, and S-100 and positive for desmin and α-smooth muscle actin. No recurrence had been observed 1 year after surgery without adjuvant chemotherapy. Conclusions. Primary lesser omental leiomyosarcoma, which is difficult to diagnose before surgery given the location of the primary tumor in the lesser omentum, has rarely been reported. Considering the high possibility of malignancy, close observation is essential.

Severe neuroinflammation is associated with blood brain barrier (BBB) disruption in CNS diseases. Although microglial activation and the subsequent changes in cytokine/chemokine (C/C) concentrations are thought to be key steps in the development of neuroinflammation, little data are available concerning the interaction of microglia with BBB cells. In this study, we investigated this interaction by adding LPS-activated microglia (LPS-MG) to the abluminal side of a BBB model composed of endothelial cells (EC), pericytes (Peri) and astrocytes (Ast). We then examined the abluminal concentrations of 27 C/Cs and the interactions between the LPS-MG and BBB cells. LPS-MG caused collapse of the BBB, revealed by decreases in the trans-endothelial electrical resistance (TEER) and by changes in the expression levels of tight junction (TJ) proteins. Under these conditions, 19 C/Cs were markedly increased on the abluminal side. Unexpectedly, although LPS-MG alone released 10 of the 19 C/Cs, their concentrations were much lower than those detected on the abluminal side of the BBB model supplemented with LPS-MG. Co-culture of LPS-MG with Ast caused marked increases in 12 of the 19 C/Cs, while co-culture of LPS-MG with EC and Peri resulted in a significant increase in only 1 of the 19 C/Cs (fractalkine). These results suggest that C/C dynamics in this system are not only caused by activated microglia but also are due to the interaction between activated microglia and astrocytes.

Bioconvection is a convective flow found in a suspension of motile cells that swim against gravity, and is a primitive form of order formation of cells, which has been studied both experimentally and theoretically. We formulate here an inverted bioconvection occurring in a suspension of phototactic cells in a high-density medium, which is illuminated from the bottom. We used a highly phototactic strain 137c of Chlamydomonas reinhardtii in the experiments. Using a custom-made lateral microscope, we observed a close view of cellular dynamics in the initiation of inverted bioconvection. In conventional bioconvection, convective flows of cells are formed spontaneously with or without formation of the surface cell layer. In inverted convection, a crowded cell layer was initially formed at the bottom, which was a prerequisite for the subsequent emergence of plumes, namely, floating populations of cells. The plume formation was a result of neither uneven initial cell density nor unequal light intensity. Based on detailed analysis of individual cells, we constructed a model of inverted bioconvection, in which each cell experiences a transition between two modes of movement: phototactically swimming cell and non-motile cell aggregate. A simulation using the CompuCell3D software reproduced basic behaviors of the plume formation. The modal transition has not been a subject of basic studies, but provides an interesting target of study of cell-to-cell interactions.

PIWI-interacting RNAs (piRNAs) protect the genome from transposons in animal gonads. Maelstrom (Mael) is an evolutionarily conserved protein, composed of a high-mobility group (HMG) domain and a MAEL domain, and is essential for piRNA-mediated transcriptional transposon silencing in various species, such as Drosophila and mice. However, its structure and biochemical function have remained elusive. Here, we report the crystal structure of the MAEL domain from Drosophila melanogaster Mael, at 1.6 Å resolution. The structure reveals that the MAEL domain has an RNase H-like fold but lacks canonical catalytic residues conserved among RNase H-like superfamily nucleases. Our biochemical analyses reveal that the MAEL domain exhibits single-stranded RNA (ssRNA)-specific endonuclease activity. Our cell-based analyses further indicate that ssRNA cleavage activity appears dispensable for piRNA-mediated transcriptional transposon silencing in Drosophila. Our findings provide clues toward understanding the multiple roles of Mael in the piRNA pathway.

The extracellular L-glutamate (L-Glu) concentration is elevated in neuroinflammation, thereby causing excitotoxicity. One of the mechanisms is down-regulation of astrocyte L-Glu transporters. Some antidepressants have anti-inflammatory effects. We therefore investigated effects of various antidepressants on the down-regulation of astrocyte L-Glu transporters in the in vitro neuroinflammation model. Among these antidepressants, only paroxetine was effective. We previously demonstrated that the down-regulation of astrocyte L-Glu transporters was caused by L-Glu released from activated microglia. We here clarified that only paroxetine inhibited L-Glu release from microglia. This is the novel action of paroxetine, which may bring advantages on the therapy of neuroinflammation.

Motile filamentous cyanobacteria, such as Oscillatoria, Phormidium and Arthrospira, are ubiquitous in terrestrial and aquatic environments. As noted by Nägeli in 1860, many of them form complex three-dimensional or two-dimensional structures, such as biofilm, weed-like thalli, bundles of filaments and spirals, which we call supracellular structures. In all of these structures, individual filaments incessantly move back and forth. The structures are, therefore, macroscopic, dynamic structures that are continuously changing their microscopic arrangement of filaments. In the present study, we analyzed quantitatively the movement of individual filaments of Phormidium sp. KS grown on agar plates. Junctional pores, which have been proposed to drive cell movement by mucilage/slime secretion, were found to align on both sides of each septum. The velocity of movement was highest just after the reversal of direction and, then, attenuated exponentially to a final value before the next reversal of direction. This kinetics is compatible with the “slime gun” model. A higher agar concentration restricts the movement more severely and, thus, resulted in more spiral formation. The spiral is a robust form compatible with non-homogeneous movements of different parts of a long filament. We propose a model of spiral formation based on the microscopic movement of filaments.

The in vitro use of neurons that are differentiated from human induced pluripotent stem cells (hiPSC-neurons) is expected to improve the prediction accuracy of preclinical tests for both screening and safety assessments in drug development. To achieve this goal, hiPSC neurons are required to differentiate into functional neurons that form excitatory networks and stably express N-methyl-D-aspartate receptors (NMDARs). Recent studies have identified some astrocyte-derived factors that are important for the functional maturation of neurons. We therefore examined the effects of the astrocyte-derived factor glypican 6 (GPC6) on hiPSC-neurons. When we pharmacologically examined which receptor subtypes mediate L-glutamate (L-Glu)-induced changes in the intracellular Ca2+ concentrations in hiPSC neurons using fura-2 Ca2+ imaging, NMDAR-mediated responses were not detected through 7 days in vitro (DIV). These cells were also not vulnerable to excitotoxicity at 7DIV. However, a 5-d treatment with GPC6 from 3DIV induced an NMDAR-mediated Ca2+ increase in hiPSC-neurons and increased the level of NMDARs on the cell surface. We also found that GPC6-treated hiPSC-neurons became responsive to excitotoxicity. These results suggest that GPC6 increases the level of functional NMDARs in hiPSC-neurons. Glial factors may play a key role in accelerating the functional maturation of hiPSC neurons for drug-development applications.

Type II Polar Stratospheric Clouds (PSCs) were observed by micropulse lidar (MPL) at Syowa Station in the Antarctic on 30 June and on 1 July 2001. The vertical profiles of the PSCs had a wavy structure that was synchronized with the temperature fluctuations. A wave analysis using radiosonde data shows that the wavy fluctuations were associated with an inertia gravity wave that was not forced by ground topography, but probably by spontaneous adjustment in association with synoptic-scale wave-breaking processes in the upper troposphere. It is suggested that the observed PSCs were generated under the low-temperature conditions induced by these waves and that such gravity waves generated by spontaneous adjustment of large-scale fields can be more important to the formation of PSC particles, in both the Antarctic and Arctic stratospheres, than topographically forced gravity waves, because the former are not fixed to the ground topography.

The 44th Japanese Antarctic Research Expedition (JARE-44) performed intensive ozonesonde observations at Syowa Station (69.0゜S, 39.6゜E) from June 2003 through January 2004 to clarify the time evolution and mechanism of the Antarctic ozone hole dissipation as well as its formation. From analysis of the ozonesonde and satellite observational data, it was found that ozone concentration inside the Antarctic ozone hole began to increase due to the Brewer-Dobson circulation and the lateral mixing between inside and outside the polar vortex even before its breakup. In addition, the ozone increase was dependent on longitude because of the zonal wavenumber 1 quasi-stationary planetary waves. It is also reported that the ozone enhanced layers frequently observed inside the Antarctic ozone hole mostly originated from the vortex boundary region.

In the last recent ten years, our knowledge of gravity waves in the Antarctic has been significantly improved through numerous studies using balloon and satellite observations and high-resolution model simulations. In this report, we introduce results from two studies which were performed as a part of the NIPR project "Integrated analysis of the material circulation in the Antarctic atmosphere-cryosphere-ocean" (2004-2009), i.e., Yoshiki et al. (2004) and Sato and Yoshiki (2008). These two studies focused on the seasonal variation and sources of the gravity waves in the Antarctic, because horizontal wavelengths and phase velocities depend largely on the wave sources. The former study used original high-resolution data from operational radiosonde observations at Syowa Station. In the lowermost stratosphere, gravity waves do not exhibit characteristic seasonal variation; instead, the wave energy is intensified when lower latitude air intrudes into the area near Syowa Station in the upper troposphere. This intrusion is associated with blocking events or developed synoptic-scale waves. In the lower and middle stratosphere, the gravity wave energy is maximized in spring and particularly intensified when the axis of the polar night jet approaches Syowa Station. The latter study is based on intensive radiosonde observation campaigns that were performed in 2002 at Syowa Station as an activity of JARE-43. Gravity wave propagation was statistically examined using two dimensional (i.e., vertical wavenumber versus frequency) spectra in each season. It was shown that the gravity waves are radiated upward and downward from an unbalanced region of the polar night jet. This feature is consistent with the gravity-wave resolving GCM simulation.

We investigated the effects of non-steroidal anti-inflammatory drugs on substrate-induced currents of l-glutamate (l-Glu) transporter EAAT1 expressed in Xenopus laevis oocytes. Niflumic acid (NFA) and diclofenac inhibited l-Glu-induced current through EAAT1 in a noncompetitive manner. NFA produced a leftward shift in reversal potential (Erev) of l-Glu-induced current and increased current amplitude at the potentials more negative than −100 mV. Diclofenac had no effects on E rev and inhibited the current amplitude to the same extent at all negative potentials. These results indicate that NFA and diclofenac inhibit the l-Glu-induced EAAT1 current via different mechanisms.[Supplementary methods and Figure: available only at http://dx.doi.org/10.1254/jphs.09260SC] Keywords:: l-glutamate transporter, niflumic acid, diclofenac

Tamoxifen (Tam) decreased the clearance of L-glutamate (L-Glu) by cultured astrocytes at 1 pM, 1 nM, and 1 μM, but became toxic at 10 μM. When L-Glu transporters were mostly inhibited by threo-β-benzyloxyaspartate (TBOA) (1 mM) or D,L-threo-β-hydroxyaspartate (THA) (1 mM), Tam (1 nM) did not change extracellular L-Glu concentration, confirming that Tam attenuates L-Glu transport through L-Glu transporters. ICI182,780, LY294002, and U0126 inhibited the effect of Tam dose-dependently, suggesting the involvement of estrogen receptors (ERs), the phosphatidylinositol 3-kinase (PI3K) cascade, and the mitogen-activated protein kinase (MAPK) cascade in the effect of Tam. Keywords:: tamoxifen, L-glutamate transporter, astrocyte

The blood-brain barrier (BBB) restricts the entry of circulating drugs and xenobiotics into the brain, and thus its permeability to substances is a critical factor that determines their central effects. The infant brain is vulnerable to neurotoxic substances partly due to the immature BBB. The employment of in vitro BBB models to evaluate permeability of compounds provides higher throughput than that of in vivo animal experiments. However, existing in vitro BBB models have not been able to simulate the intrinsic neonatal BBB. To establish a neonatal BBB model that mimics age-related BBB properties, the neonatal and adult in vitro BBB models were constructed with brain endothelial cells isolated from 2- and 8-week-old rats, respectively. To evaluate BBB functions, transendothelial electrical resistance, permeability of sodium fluorescein and Evans blue-albumin, and transport of rhodamine123 were measured. Radiolabelled drugs were used for BBB permeability studies in the neonatal and adult BBB models (in vitro) and in age-matched rats (in vivo). The neonatal BBB model showed lower barrier and p-glycoprotein (P-gp) functions than the adult BBB model; these were well associated with lower expressions of the barrier-related proteins and P-gp, and a different distribution pattern of immunostained barrier-related proteins. Verapamil (a P-gp inhibitor) significantly increased the influx of rhodamine 123, supporting functional P-gp expression in the neonatal BBB model. Valproic acid, but not nicotine, showed higher BBB permeability in the neonatal BBB model, which was well in accordance with the in vivo BBB property. We established a neonatal BBB model in vitro. This could allow us to assess the age-dependent BBB permeability of drugs.

Simultaneous observations using a long-duration balloon and the PANSY radar, a large-scale atmospheric radar, were performed at Syowa Station in the Antarctic, from January to February 2022. They captured near-inertial frequency gravity waves (NIGWs) in the lower stratosphere. The analysis using both datasets and the latest reanalysis ERA5 revealed that two NIGW packets with an upward group velocity and short vertical wavelengths of less than 3 km propagated northeastward and eastward above Syowa Station. Although the NIGWs over Syowa Station were qualitatively represented by ERA5, their amplitudes were underestimated. In addition, the latter NIGW packet was observed by the long-duration balloon, but not represented by ERA5. It could be because the vertical wavelength of NIGW became shorter than the lower limit of vertical wavelength explicitly represented in ERA5 by entering the high static stability region around the balloon, or due to explicit and implicit diffusion and/or misrepresentation of the position of the NIGW packet in the model. This result implies the difficulty to explicitly represent the behavior of NIGWs with short vertical wavelengths even in the high-resolution simulation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by cognitive decline and learning/memory impairment associated with neuronal cell loss. Estrogen-related receptor α (ERRα) and ERRγ, which are highly expressed in the brain, have emerged as potential AD regulators, with unelucidated underlying mechanisms. Here, we identified genome-wide binding sites for ERRα and ERRγ in human neuronal cells. They commonly target a subset of genes associated with neurodegenerative diseases, including AD. Notably, Dickkopf-1 (DKK1), a Wnt signaling pathway antagonist, was transcriptionally repressed by both ERRα and ERRγ in human neuronal cells and brain. ERRα and ERRγ repress RNA polymerase II (RNAP II) accessibility at the DKK1 promoter by modulating a specific active histone modification, histone H3 lysine acetylation (H3K9ac), with the potential contribution of their corepressor. This transcriptional repression maintains Wnt signaling activity, preventing tau phosphorylation and promoting a healthy neuronal state in the context of AD. [ABSTRACT FROM AUTHOR]