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The patient was an 85-year-old man with a one-year history of difficulty reading kana. Neuropsychological evaluation revealed kana (phonogram)-selective reading impairment and kanji (ideogram)-dominant writing impairment. MRI revealed significant cerebral atrophy in the left occipital cortex, leading to the clinical diagnosis of posterior cortical atrophy (PCA). Cerebrospinal fluid amyloid β 1-42 levels were reduced, and amyloid PET showed accumulation in the posterior cingulate cortex, precuneus, and frontal lobe. In contrast, tau PET showed no accumulation in the atrophied brain areas. Episodes of REM sleep behavior disorder and decreased uptake on meta-iodobenzylguanidine (MIBG) myocardial scintigraphy suggested the involvement of Lewy body pathology. PCA with distinct laterality has been rarely reported, and ‍this is the first case to present Kana-selective reading impairment and Kanji-dominant writing impairment with neurodegenerative background.

The FinRay soft gripper achieves passive enveloping grasping through its functional flexible structure, adapting to the contact configuration of the object to be grasped. However, variations in beam position and thickness lead to different behaviors, making it important to research the relationship between structure and force. Conventional research using FEM simulations has tested various virtual FinRay models but replicating phenomena such as buckling and slipping has been challenging. While hardware-based methods that involve installing sensors on the gripper and the object to analyze their states have been attempted, no studies have focused on the tangential contact force related to slipping. Therefore, we developed a 16-way object contact force measurement device incorporating two-axis force sensors into each of the 16 segmented objects and compared the normal and tangential components of the enveloping grasping force of the FinRay soft gripper under two types of contact friction conditions. In the first experiment, the proposed device was compared with a device containing a six-axis force sensor in one segmented object, confirming that the proposed device has no issues with measurement performance. In the second experiment, comparisons of the proposed device were made under various conditions: two contact friction states, three object contact positions, and two object motion states. The results demonstrated that the proposed device could decompose and analyze the grasping force into its normal and tangential components for each segmented object. Moreover, low friction conditions result in a wide contact area with lower tangential frictional force and a uniform normal pushing force, achieving effective enveloping grasping.

Prior to the formation of amyloid fibrils, the pathological hallmark in tau-related neurodegenerative disease, tau monomers aggregate into a diverse range of oligomers. Granular tau oligomers, consisting of approximately 40 tau protein molecules, are present in the prefrontal cortex of patients at Braak stages I-II, preclinical stages of Alzheimer's disease (AD). Antibodies to granular tau oligomers as antigens have not been reported. Therefore, we generated new rat monoclonal antibodies by immunization with granular tau oligomers. Three antibodies from different hybridoma clones showed stronger immunoreactivity to granular tau oligomers and tau fibrils compared with monomeric tau. Of the three antibodies, 2D6-2C6 showed 3000-fold greater immunoreactivity in P301L-tau transgenic (rTg4510) mice than in non-transgenic mice, while MC1 antibody, which detects pathological conformations of tau, showed a 5.5-fold increase. These results suggest that 2D6-2C6 recognizes aggregates more specifically than MC1. In AD subjects, 2D6-2C6 recognized neurofibrillary tangles and pretangles, and co-localized within AT8-positive cells containing phosphorylated tau aggregates. The epitope of 2D6-2C6 is the 423-430 amino acid (AA) sequence of C-terminal regions. Taken together, a novel monoclonal antibody, 2D6-2C6, generated by immunization with granular tau oligomers binds to tau aggregates at the 423-430 AA sequence., (© 2024. The Author(s).)

Non-high-risk (non-HR) neuroblastoma (NB) patients have excellent outcomes, with more than a 90% survival rate, whereas HR NB patients expect less than a 50% survival rate. Metastatic disease is the principal cause of death among both non-HR and HR NB patients. Previous studies have reported the significant but limited prognostic value of quantitative PCR (qPCR)-based assays, measuring overlapping but different sets of neuroblastoma-associated mRNAs (NB-mRNAs), to detect metastatic disease in both non-HR and HR patient samples. A droplet digital PCR (ddPCR)-based assay measuring seven NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was recently developed and exhibited a better prognostic value for HR patient samples than qPCR-based assays. However, it remained to be tested on non-HR patient samples. In the present study, we employed the ddPCR-based assay to study peripheral blood (PB) and bone marrow (BM) samples collected at diagnosis from eight non-HR and eleven HR cases and characterized the expression profiles of NB-mRNAs. The most highly expressed NB-mRNAs in PB and BM differed between non-HR and HR cases, with the CRMP1 mRNA being predominant in non-HR cases and the GAP43 mRNA in HR cases. The levels of NB-mRNAs in PB and BM were 5 to 1000 times lower in non-HR cases than in HR cases. The PB to BM ratio of NB-mRNAs was 10 to 100 times higher in non-HR cases compared to HR cases. The present case series suggests that non-HR and HR NB patients have the distinct expression profiles of NB-mRNAs in their PB and BM.

Here, doubly protonated Lindqvist-type niobium oxide cluster [H 2 (Nb 6 O 19 )] 6- , fabricated by microwave-assisted hydrothermal synthesis, exhibited superbase catalysis for Knoevenagel and crossed aldol condensation reactions accompanied by activating C-H bond with pK a >26 and proton abstraction from a base indicator with pK a =26.5. Surprisingly, [H 2 (Nb 6 O 19 )] 6- exhibited water-tolerant superbase properties for Knoevenagel and crossed aldol condensation reactions in the presence of water, although it is well known that the strong basicity of metal oxides and organic superbase is typically lost by the adsorption of water. Density functional theory calculation revealed that the basic surface oxygens that share the corner of NbO 6 units in [H 2 (Nb 6 O 19 )] 8- maintained the negative charges even after proton adsorption. This proton capacity and the presence of un-protonated basic sites led to the water tolerance of the superbase catalysis., (© 2024 Wiley‐VCH GmbH.)

Recently, heterozygous loss-of-function NFKB1 variants were identified as the primary cause of common variable immunodeficiency (CVID) in the European population. However, pathogenic NFKB1 variants have never been reported in the Japanese population. We present a 29-year-old Japanese woman with CVID. A novel variant, c.136 C > T, p.(Gln46*), was identified in NFKB1. Her mother and daughter carried the same variant, demonstrating the first Japanese pedigree with an NFKB1 pathogenic variant., (© 2024. The Author(s).)

The Fin Ray-type soft gripper (FRSG) is a typical soft gripper structure and applies the deformation characteristics of the Fin Ray structure. This structure functions to stabilize the grasping of an object by passive deformation due to external forces. To analyze the performance of detailed force without compromising the actual FRSG characteristics, it is effective to incorporate multiple force sensors into the grasping object without installing them inside the Fin Ray structure. Since the grasping characteristics of the FRSG are greatly affected by the arrangement of the crossbeams, it is also important to understand the correspondence between the forces and the geometry. In addition, the grasping characteristics of an angular object have not been verified in actual equipment. Therefore, in this study, a contact force measurement device with 16 force sensors built into the grasping object and a structural deformation measurement device using camera images were used to analyze the correspondence between force and structural deformation on an actual FRSG. In the experiment, we analyzed the influence of the crossbeam arrangement on the grasping force and the grasping conditions of the square (0°) and rectangular (45°) shapes, and state that an ideal grasp in a square-shaped (45°) grasp is possible if each crossbeam in the FRSG is arranged at a different angle.

The molecular mechanism of a Cu-catalysed coupling reaction was theoretically studied using density functional theory (DFT) and the complete active space self-consistent field method followed by the second-order perturbation theory (CASSCF/CASPT2) to investigate the effects of the strong electron correlation of the Cu centre on the reaction profile. Both DFT and CASSCF/CASPT2 calculations showed that the catalytic cycle proceeds via an oxidative addition (OA) reaction, followed by a reductive elimination (RE) reaction, where OA is the rate-determining step. Although the DFT-calculated activation energies of the OA and RE steps are highly dependent on the choice of functionals, the CASSCF/CASPT2 results are less affected by the choice of DFT-optimised geometries. Therefore, with a careful assessment based on the CASSCF/CASPT2 single-point energy evaluation, an optimal choice of the DFT geometry is of good qualitative use for energetics at the CASPT2 level of theory. Based on the changes in the electron populations of the 3d orbitals during the OA and RE steps, the characteristic features of the DFT-calculated electronic structure were qualitatively consistent with those calculated using the CASSCF method. Further electronic structure analysis by the natural orbital occupancy of the CASSCF wavefunction showed that the ground state is almost single-reference in this system and the strong electron correlation effect of the Cu centre can be dealt with using the MP2 or CCSD method, too. However, the slightly smaller occupation numbers of the 3dπ orbital in the course of reactions suggested that the electron correlation effect of the Cu(III) centre appears through the interaction between the 3dπ orbital and the C-I antibonding σ* orbital in the OA step, and between the 3dπ orbital and the Cu-C antibonding σ* orbital in the RE step.

The blood-brain barrier (BBB) is a selective barrier that controls the transport between the blood and neural tissue features and maintains brain homeostasis to protect the central nervous system (CNS). In vitro models can be useful to understand the role of the BBB in disease and assess the effects of drug delivery. Recently, we reported a 3D BBB model with perfusable microvasculature in a Transwell insert. It replicates several key features of the native BBB, as it showed size-selective permeability of different molecular weights of dextran, activity of the P-glycoprotein efflux pump, and functionality of receptor-mediated transcytosis (RMT), which is the most investigated pathway for the transportation of macromolecules through endothelial cells of the BBB. For quality control and permeability evaluation in commercial use, visualization and quantification of the 3D vascular lumen structures is absolutely crucial. Here, for the first time, we report a rapid, non-invasive optical coherence tomography (OCT)-based approach to quantify the microvessel network in the 3D in vitro BBB model. Briefly, we successfully obtained the 3D OCT images of the BBB model and further processed the images using three strategies: morphological imaging processing (MIP), random forest machine learning using the Trainable Weka Segmentation plugin (RF-TWS), and deep learning using pix2pix cGAN. The performance of these methods was evaluated by comparing their output images with manually selected ground truth images. It suggested that deep learning performed well on object identification of OCT images and its computation results of vessel counts and surface areas were close to the ground truth results. This study not only facilitates the permeability evaluation of the BBB model but also offers a rapid, non-invasive observational and quantitative approach for the increasing number of other 3D in vitro models.

Controlling the geometric structures of metal clusters through structural isomerization allows for tuning of their electronic state. In this study, we successfully synthesized butterfly-motif [PdAu 8 (PPh 3 ) 8 ] 2+ (PdAu8-B, B means butterfly-motif) and [PtAu 8 (PPh 3 ) 8 ] 2+ (PtAu8-B) by the structural isomerization from crown-motif [PdAu 8 (PPh 3 ) 8 ] 2+ (PdAu8-C, C means crown-motif) and [PtAu 8 (PPh 3 ) 8 ] 2+ (PtAu8-C), induced by association with anionic polyoxometalate, [Mo 6 O 19 ] 2- (Mo6) respectively, whereas their structural isomerization was suppressed by the use of [NO 3 ] - and [PMo 12 O 40 ] 3- as counter anions. DR-UV-vis-NIR and XAFS analyses and density functional theory calculations revealed that the synthesized [PdAu 8 (PPh 3 ) 8 ][Mo 6 O 19 ] (PdAu8-Mo6) and [PtAu 8 (PPh 3 ) 8 ][Mo 6 O 19 ] (PtAu8-Mo6) had PdAu8-B and PtAu8-B respectively because PdAu8-Mo6 and PtAu8-Mo6 had bands in optical absorption at the longer wavelength region and different structural parameters characteristic of the butterfly-motif structure obtained by XAFS analysis. Single-crystal and powder X-ray diffraction analyses revealed that PdAu8-B and PtAu8-B were surrounded by six Mo6 with rock salt-type packing, which stabilizes the semi-stable butterfly-motif structure to overcome high activation energy for structural isomerization., (© 2023. The Author(s).)

By facilitating a water/water phase separation (w/wPS), crowded biopolymers in cells form droplets that contribute to the spatial localization of biological components and their biochemical reactions. However, their influence on mechanical processes driven by protein motors has not been well studied. Here, we show that the w/wPS droplet spontaneously entraps kinesins as well as microtubules (MTs) and generates a micrometre-scale vortex flow inside the droplet. Active droplets with a size of 10-100 µm are generated through w/wPS of dextran and polyethylene glycol mixed with MTs, molecular-engineered chimeric four-headed kinesins and ATP after mechanical mixing. MTs and kinesin rapidly created contractile network accumulated at the interface of the droplet and gradually generated vortical flow, which can drive translational motion of a droplet. Our work reveals that the interface of w/wPS contributes not only to chemical processes but also produces mechanical motion by assembling species of protein motors in a functioning manner., (© 2023. The Author(s).)

The hepatitis E virus (HEV) causes a common infectious disease that infects pigs, wild boars, deer, and humans. In most cases, humans are infected by eating raw meat. Some essential oils have been reported to exhibit antiviral activities. In this study, in order to investigate the anti-HEV properties of essential oils, the immunoreactivities of HEV antigen proteins against the relevant antibodies were analyzed after the HEV antigens underwent treatment with various essential oils. The essential oils extracted from the tea tree, which was previously reported to exhibit antiviral activity, lavender, and lemon had strongly reduced activity. We found that treatment with the essential oil prepared from Sakhalin spruce was associated with the strongest reduction in immunoreactivity of HEV antigen protein(s) among the tested substances. The main volatile constituents of Sakhalin spruce essential oil were found to be bornyl acetate (32.30 %), α-pinene (16.66 %), camphene (11.14 %), camphor (5.52 %), β-phellandrene (9.09 %), borneol (4.77 %), and limonene (4.57 %). The anti-HEV properties of the various components of the essential oils were examined: treatment with bornyl acetate, the main component of Sakhalin spruce oil, α-pinene, the main component of tea tree oil, and limonene, the main component of lemon oil, resulted in a strong reduction in HEV antigen immunoreactivity. These results indicate that each main component of the essential oils plays an important role in the reduction of the immunoreactivity of HEV antigen protein(s); they also suggest that Sakhalin spruce essential oil exhibits anti-HEV activity. In a formulation with the potential to eliminate the infectivity of HEV in foodborne infections, this essential oil can be applied as an inactivating agent for meat processing and cooking utensils, such as knives and chopping boards., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Numerous biomimetic molecular catalysts inspired by methane monooxygenases (MMOs) that utilize iron or copper-oxo species as key intermediates have been developed. However, the catalytic methane oxidation activities of biomimetic molecule-based catalysts are still much lower than those of MMOs. Herein, we report that the close stacking of a μ-nitrido-bridged iron phthalocyanine dimer onto a graphite surface is effective in achieving high catalytic methane oxidation activity. The activity is almost 50 times higher than that of other potent molecule-based methane oxidation catalysts and comparable to those of certain MMOs, in an aqueous solution containing H 2 O 2 . It was demonstrated that the graphite-supported μ-nitrido-bridged iron phthalocyanine dimer oxidized methane, even at room temperature. Electrochemical investigation and density functional theory calculations suggested that the stacking of the catalyst onto graphite induced partial charge transfer from the reactive oxo species of the μ-nitrido-bridged iron phthalocyanine dimer and significantly lowered the singly occupied molecular orbital level, thereby facilitating electron transfer from methane to the catalyst in the proton-coupled electron-transfer process. The cofacially stacked structure is advantageous for stable adhesion of the catalyst molecule on the graphite surface in the oxidative reaction condition and for preventing decreases in the oxo-basicity and generation rate of the terminal iron-oxo species. We also demonstrated that the graphite-supported catalyst exhibited appreciably enhanced activity under photoirradiation owing to the photothermal effect., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Vapochromic crystals of Ni(II)-quinonoid complexes were theoretically investigated using density functional theory (DFT) calculations. Kato et al. previously reported that the purple crystals of a four-coordinate Ni(II)-quinonoid complex ( 1P ) exhibited vapochromic characteristics upon exposure to methanol gas, resulting in orange crystals of the six-coordinate methanol-bound complex ( 1O ) [ Angew. Chem., Int. Ed. 2017 , 56 , 2345-2349]. However, the authors did not characterize the crystal structure of 1P . In the present study, we computationally predicted the crystal structure of 1P by performing a crystal structure search with classical force-field computations followed by optimization using DFT calculations. The simulated powder X-ray diffraction pattern of the DFT-optimized structure agreed with experimental observations, indicating that our predicted crystal structure is reliable. Investigation of the optimized crystal structure of 1P revealed that its color change arose from changes in its 1D-band structure, which consists of Ni 3d orbitals and quinonoid π-orbitals. Intermolecular interactions were weakened upon the binding of methanol to the Ni(II) center in 1O . Consequently, the intermolecular 3d-π interaction in 1P lowered the band gap and induced the red-shifting of the monomeric four-coordinate Ni(II)-quinonoid complex. Meanwhile, the obtained absorption spectrum of 1O closely corresponded to that of the monomeric six-coordinate Ni(II)-quinonoid complex. Our study provides a new strategy for accurately predicting molecular crystal structures and reveals a new insight into vapochromism based on band structure color switching.

More than half of high-risk neuroblastoma (NB) patients have experienced relapse due to the activation of chemoresistant minimal residual disease (MRD) even though they are treated by high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation. Although MRD in high-risk NB patients can be evaluated by quantitative PCR with several sets of neuroblastoma-associated mRNAs (NB-mRNAs), the prognostic significance of MRD in PBSC grafts (PBSC-MRD) is unclear. In the present study, we collected 20 PBSC grafts from 20 high-risk NB patients and evaluated PBSC-MRD detected by droplet digital PCR (ddPCR) with 7NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNA). PBSC-MRD in 11 relapsed patients was significantly higher than that in 9 non-relapsed patients. Patients with a higher PBSC-MRD had a lower 3-year event-free survival (P = 0.0148). The present study suggests that PBSC-MRD detected by ddPCR with 7NB-mRNAs has a prognostic impact on high-risk NB patients., Competing Interests: The authors declare the following conflict of interests: Noriyuki Nishimura received institutional research funding from Sysmex Corporation to Kobe University., (© 2022 The Author(s).)

The purpose of the present study was to evaluate the predictability of PAMPA for the effect of metal ions on the bioavailability of fluoroquinolones (FQ). Eleven FQs and seven metal ions were employed in this study. The PAMPA membrane consisted of a 10 % soybean lecithin (SL) - decane solution. A drug solution in MES buffer with or without a metal ion (added as a chloride salt) was added to the donor compartment. In the absence of metal ions, FQ showed relatively high permeability (> 5 × 10 -6 cm/sec) in SL-PAMPA despite their hydrophilic and zwitterionic properties. As the PAMPA permeability ratio with/without metal ions became smaller, the urinary excretion and AUC ratios tended to be smaller, suggesting that SL-PAMPA is a suitable in vitro model to evaluate the potential effect of metal ions on the bioavailability of FQ. However, the reduction in AUC and urinary excretion was overestimated for low solubility metal ion formulations (dried aluminum hydroxide gel and La 2 (CO 3 ) 3 ・8H 2 O). In such cases, the dissolution of the metal ion formulations and the permeation of FQs should be simultaneously evaluated., Competing Interests: Conflict of interest: Authors declare no conflict of interest., (Copyright © 2022 by the authors.)

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 (P e ) 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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (© 2022 The Authors.)

Introduction: Although recent echocardiographic studies have suggested that left atrial appendage (LAA) remodeling contributes to the development of LAA thrombus (LAAT), histological evidence is absent. The objective of this study was to examine clinical parameters and histological findings to clarify the factors involved in LAAT formation., Methods: A total of 64 patients (no atrial fibrillation [AF], N = 22; paroxysmal AF, N = 16; nonparoxysmal AF, N = 26) who underwent LAA excision during surgery were enrolled. Transthoracic and transesophageal echocardiography were performed before surgery. We evaluated the fibrosis burden (%) in the excised LAA sections with Azan-Mallory staining in patients with a LAAT compared with those without., Results: Patients with paroxysmal and non-paroxysmal AF had a higher LAA fibrosis burden than those without AF (p = .005 and p < .0001, respectively). Among the patients enrolled, 16 had a LAAT and 15 of them had nonparoxysmal AF. Among the nonparoxysmal AF patients, those with a LAAT had significantly higher LAA fibrosis burden than those without (23.8% [14.8%-40.3%] vs. 12.8% [7.4%-18.2%], p = .004) and echocardiographic parameters of the left atrial volume index (R = 0.543, p = .01), LAA depth (R = 0.452, p = .02), and LAA flow velocity (R = - 0.487, p = .01) were correlated with the LAA fibrosis burden., Conclusion: This study provided histological evidence that LAA fibrosis is related to LAAT formation. Echocardiographic parameters of LAA remodeling and function were correlated with the LAA fibrosis burden., (© 2022 Wiley Periodicals LLC.)

Oxo-Mn(V) porphyrin complexes perform competitive hydroxylation, desaturation, and radical rearrangement reactions using diagnostic substrate norcarane. Initial C-H cleavage proceeds through the two hydrogen abstraction steps from the two adjacent carbon on the norcarane and then through selective reactions various products are generated. Using density functional theory calculations, we show that the hydroxylation and desaturation reactions are triggered by a rate-determining H-abstraction step, whereas the rate-determining step for the radical rearrangement is located at the rebound step (TS2). We find that the endo-2 reaction is favorable over other reactions, which is consistent with the experimental result. Furthermore, the competitive pathways for norcarane oxidation depend on the non-covalent interaction between norcarane and the porphyrin-ring, and orbital energy gaps between donor and acceptor orbitals because of stable or unstable acceptor orbital. The stereo- and regio-selectivities of norcarane oxidation are hardly sensitive to the zero-point energy and thermal free energy corrections., (© 2022 Wiley-VCH GmbH.)