An autopsy case of diffuse atypical argyrophilic grain disease (AGD) with presenile onset and three-year course of motor and cognitive impairment.

We report a case of argyrophilic grain disease (AGD) with unique clinical and pathological presentations. A 52-year-old man presented with spastic quadriparesis, bulbar palsy, and mild cognitive decline. His condition deteriorated rapidly and he died of pneumonia three years from onset. Pathologically, neuronal degeneration was involved severely in the amygdala, ambient gyrus, midbrain tegmentum, and reticular formation. The neurons of the temporal lobe, cingulate gyrus, brainstem, and spinal gray matter were also lost moderately. There was diffuse 4-repeat tau-pathology with argyrophilic grains. There were pretangles, globose-type neurofibrillary tangles, and coiled bodies in the cerebral cortices, basal ganglia, thalami, brainstem, and the spinal cord except for the cerebellar cortices. There was no pathologic mutation in MAPT.

Color-controlled nonstoichiometric spinel-type cobalt gallate nanopigments prepared by supercritical hydrothermal synthesis.

Spinel-type inorganic pigments with intensive color and chemical/thermal stability are showing extensive applications that could be further broadened by color manipulation and improvement of the material properties through nanosizing. In this study, we report the supercritical hydrothermal synthesis of nonstoichiometric spinel-type cobalt gallate nanoparticles (Co-Ga NPs) with controlled color. Without the conventional calcination procedure, NPs with greenish-blue, blue, and yellowish-green colors were synthesized from precursor solutions at pH 7, 9, and 11, respectively, with a low Co/Ga molar ratio of 0.25. X-ray diffraction, scanning/transmission electron microscopy, and inductively coupled plasma-atomic emission spectroscopy methods suggest that the products were spinel-type cobalt gallate NPs with high crystallinity and a nonstoichiometric composition. Based on an X-ray absorption fine structure investigation, the prepared nonstoichiometric Co-Ga NPs were found to have different cationic configurations from stoichiometric CoGa2O4 produced by a solid-state reaction during calcination. Meanwhile, the degrees of distortions at tetrahedral and octahedral sites in the NPs were evaluated by Raman spectroscopy. In particular, nonstoichiometric Co-Ga NPs with a blue color were prepared without calcination for the first time and were found to have lower tetrahedral cobalt occupancy but comparable octahedral cobalt occupancy and larger polyhedral distortions at tetrahedral sites when compared to calcined CoGa2O4. We also discuss strategies that could realize Co-Ga NPs with a more brilliant blue color using the present technique based on an investigation of the growth process.

Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19.

The coronavirus disease 2019 (COVID-19) remains an epidemic worldwide. Most patients suffer residual symptoms, the so-called "Long COVID," which includes respiratory and neuropsychiatric symptoms. Brain Fog, one of the symptoms of Long COVID, is a major public health issue because it can impair patients' quality of life even after recovery from the disease. However, neither the pathogenesis nor the treatment of this condition remains unknown. We focused on serum ferritin levels in this study and collected information on the onset of Brain Fog through questionnaires and found that high ferritin levels during hospitalization were associated with the occurrence of Brain Fog. In addition, we excluded confounders as far as possible using propensity score analyses and found that ferritin was independently associated with Brain Fog in most of the models. We conducted phase analysis and evaluated the interaction of each phase with ferritin levels and Brain Fog. We found a positive correlation between serum ferritin levels during hospitalization and Brain Fog after COVID-19. High ferritin levels in patients with Brain Fog may reflect the contribution of chronic inflammation in the development of Brain Fog. This study provides a novel insight into the pathogenic mechanism of Brain Fog after COVID-19.

Room-Temperature Type-II Multiferroic Phase Induced by Pressure in Cupric Oxide.

According to previous theoretical work, the binary oxide CuO can become a room-temperature multiferroic via tuning of the superexchange interactions by application of pressure. Thus far, however, there has been no experimental evidence for the predicted room-temperature multiferroicity. Here, we show by neutron diffraction that the multiferroic phase in CuO reaches 295 K with the application of 18.5 GPa pressure. We also develop a spin Hamiltonian based on density functional theory and employing superexchange theory for the magnetic interactions, which can reproduce the experimental results. The present Letter provides a stimulus to develop room-temperature multiferroic materials by alternative methods based on existing low temperature compounds, such as epitaxial strain, for tunable multifunctional devices and memory applications.

Bottom-up synthesis of 2D layered high-entropy transition metal hydroxides.

Low-dimensional high-entropy materials, such as nanoparticles and two-dimensional (2D) layers, have great potential for catalysis and energy applications. However, it is still challenging to synthesize 2D layered high-entropy materials through a bottom-up soft chemistry method, due to the difficulty of mixing and assembling multiple elements in 2D layers. Here, we report a simple polyol process for the synthesis of a series of 2D layered high-entropy transition metal (Co, Cr, Fe, Mn, Ni, and Zn) hydroxides (HEHs), involving the hydrolysis and inorganic polymerization of metal-containing species in ethylene glycol media. The as-synthesized HEHs demonstrate 2D layered structures with interlayer distances ranging from 0.860 to 0.987 nm and homogeneous elemental distribution of designed equimolar stoichiometry in the layers. These 2D HEHs exhibit a low overpotential of 275 mV at 10 mA cm-2 in a 0.1 M KOH electrolyte for the oxygen evolution reaction. Superparamagnetic spinel-type high-entropy nanoparticles can also be obtained by annealing these HEHs. Our polyol approach creates opportunities for synthesizing low-dimensional high-entropy materials with promising properties and applications.

Humidity Sensitivity of Chemically Synthesized ZnAl2O4/Al.

Humidity sensitivity is evaluated for chemically synthesized ZnAl2O4/Al devices. We succeeded in synthesizing the ZnAl2O4/Al device by applying chemical techniques only. Hydrothermal treatment for the anodized aluminum (AlOx/Al) gives us the device of the ZnAl2O4/Al structure. All fabrication processes were conducted under 400 °C. The key was focusing on ZnAl2O4 as the sensing material instead of MgAl2O4, which is generally investigated as the humidity sensor. The evaluation of this ZnAl2O4/Al device clarified its effectiveness as a sensor. Both electrical capacitance, Cp, and the resistivity, Rp, measured by an LCR meter, obviously responded to the humidity with good sensitivity and appreciable repeatability. Our synthesis technique is possible in principle to improve on the process for the device with a complex structure providing a large surface area. These characteristics are believed to expand the application study of spinel aluminate devices as the sensor.

[Rippling muscle disease with myasthenia gravis].

In February 2020, a 51-year-old woman experienced leg myalgia and noticed calf muscle movements that resembled a rippling wave while crouching down. In June 2020, she complained of bilateral arm myalgia. In August 2020, she developed left ptosis, had difficulty raising her bilateral arms, and developed diplopia and was admitted to our hospital. Anti-acetylcholine receptor antibodies turned out to be positive. We made a diagnosis of myasthenia gravis and acquired rippling muscle disease (RMD). Her myasthenia gravis symptoms and myalgia decreased with oral prednisolone. Contrast-enhanced computed tomography revealed thymoma. She underwent extended thymectomy and was discharged from the hospital. Her myalgia worsened, but it was responsive to methylprednisolone pulse therapy. CAV3 gene mutations are recognized as causes of congenial RMD whereas acquired RMD is associated with myasthenia gravis. Acquired RMD is rarely reported in Japan, but should be kept in mind as a condition treatable with immunotherapy.

Ferromagnetism and exchange bias in compressed ilmenite-hematite solid solution as a source of planetary magnetic anomalies.

We propose a compressed ilmenite-hematite solid solution as a new potential source of Earth's magnetic anomalies. The 0.5FeTiO3·0.5Fe2O3 solid solution compressed by collision synthesis with super-high-energy ball milling showed a decrease in molar volume of approximately 1.8%. Consequently, the sample showed a saturation magnetization of 1.5 ampere square meter per kilogram (Am2/kg) at 300 kelvin, a Curie temperature of 990 kelvin, and a magnetic exchange bias below 100 kelvin, e.g., 1.7 × 105 ampere per meter at 60 kelvin. Ilmenite-hematite solid solutions are common mineral systems in most mafic igneous and metamorphic rocks, and the compressive force in the rocks is generated by the high pressure in the upper mantle or by shock events with high pressure such as the collision of these rocks with meteorites. Therefore, we consider that the compressed ilmenite-hematite solid solution is an additional candidate source of other planetary magnetic anomalies including those in the Moon and Earth.

The partition representation of enzymatic reaction networks and its application for searching bi-stable reaction systems.

The signal transduction system, which is known as a regulatory mechanism for biochemical reaction systems in the cell, has been the subject of intensive research in recent years, and its design methods have become necessary from the viewpoint of synthetic biology. We proposed the partition representation of enzymatic reaction networks consisting of post-translational modification reactions such as phosphorylation, which is an important basic component of signal transduction systems, and attempted to find enzymatic reaction networks with bistability to demonstrate the effectiveness of the proposed representation method. The partition modifiers can be naturally introduced into the partition representation of enzymatic reaction networks when applied to search. By randomly applying the partition modifiers as appropriate, we searched for bistable and resettable enzymatic reaction networks consisting of four post-translational modification reactions. The proposed search algorithm worked well and we were able to find various bistable enzymatic reaction networks, including a typical bistable enzymatic reaction network with positive auto-feedbacks and mutually negative regulations. Since the search algorithm is divided into an evaluation function specific to the characteristics of the enzymatic reaction network to be searched and an independent algorithm part, it may be applied to search for dynamic properties such as biochemical adaptation, the ability to reset the biochemical state after responding to a stimulus, by replacing the evaluation function with one for other characteristics.

An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy, Neurogenic Bladder Dysfunction, and Diaphragmatic Weakness.

Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral polyneuropathy encompassing distinct monogenetic disorders. Pathogenic mutations in mitofusin 2 (MFN2) are the most frequent cause of its axonal type, CMT type 2A, with diverse phenotypes. We herein report a Japanese patient with a novel heterozygous MFN2 pathogenic variant (c.740 G>C, p.R247P) and severe CMT phenotypes, including progressive muscle weakness, optic atrophy, urinary inconsistency, and restrictive pulmonary dysfunction with eventration of the diaphragm that developed over her 60-year disease course. Our case expands the clinico-genetic features of MFN2-related CMT and highlights the need to evaluate infrequent manifestations during long-term care of CMT patients.

Size-tunable synthesis of iron oxide nanocrystals by continuous seed-mediated growth: role of alkylamine species in the stepwise thermal decomposition of iron(II) oxalate.

The properties of inorganic nanoparticles (NPs) are governed by their size. Therefore, tuning the size of NPs is a fundamental technique in nanoscience. However, the size-tunable synthesis of inorganic NPs is generally carried out in a dilute solution, which produces large quantities of waste. Herein, we report the predictable size-tunable synthesis of Fe3O4 NPs by the stepwise thermal decomposition of iron(II) oxalate (Fe(ox)). Monodisperse Fe3O4 seed crystals were synthesized by the thermal decomposition of oleylamine-coordinated iron oxalate (Fe(ox)-OAm) in a small amount of oleylamine, followed by continuous seed-mediated growth of Fe3O4 NPs. The thermal decomposition behavior of Fe(ox) in oleylamine with and without N,N-diethyl-1,3-diaminopropane (dedap) revealed the important role of dedap in the stepwise thermal decomposition of Fe(ox). The size of the Fe3O4 NPs was easily tuned via the stepwise thermal decomposition of Fe(ox) by controlling the amount of decomposed Fe(ox) in a small amount of an alkylamine mixture. The particle diameter was predicted from the size of the Fe3O4 seed crystals and the amount of decomposed Fe(ox). Finally, the size dependency of magnetic properties of the synthesized Fe3O4 NPs was studied. This continuous seed-mediated growth method based on the stepwise thermal decomposition of metal oxalate can be applied to control the size of a variety of metal and metal oxide NPs.

Synthesis of novel hexamolybdenum cluster-functionalized copper hydroxide nanocomposites and its catalytic activity for organic molecule degradation.

A novel heterogeneous catalytic nanomaterial based on a molybdenum cluster-based halide (MC) and a single-layered copper hydroxynitrate (CHN) was first prepared by colloidal processing under ambient conditions. The results of the elemental composition and crystalline pattern indicated that CHN was comprehensively synthesized with the support of the MC compound. The absorbing characteristic in the ultraviolet and near-infrared regions was promoted by both of the ingredients. The proper chemical interaction between the materials is a crucial reason to modify the structure of the MCs and only a small decrease in the magnetic susceptibility of CHN. The heterogeneous catalytic activity of the obtained MC@CHN material was found to have a high efficiency and excellent reuse when it is activated by hydrogen peroxide (H2O2) for the degrading reaction of the organic pollutant at room temperature. A reasonable catalytic mechanism was proposed to explain the distinct role of the copper compound, Mo6 compound, and H2O2 in the production of the radical hydroxyl ion. This novel nanomaterial will be an environmentally promising candidate for dye removal.

Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. METHODS: COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. RESULTS: A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. CONCLUSIONS: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. TRIAL REGISTRATION: Clinicaltrials.jp number: JapicCTI-205238.

Emergence of ferromagnetism due to charge transfer in compressed ilmenite powder using super-high-energy ball milling.

Ilmenite, FeTiO3, is a common mineral in nature, existing as an accessory phase in the most basic igneous and metamorphic rocks, for example, it is derived from the upper mantle. Therefore, an understanding of the high-pressure physics of FeTiO3 is of fundamental importance in the study of rock magnetization. Here, we provide experimental evidence of lattice compression of FeTiO3 powder using super-high-energy ball milling, enabling the very high collision energy of 420 times gravitational acceleration. A sample obtained as an ilmenite- hematite 0.5FeTiO3·0.5Fe2O3 solid solution showed a decrease in molar volume of approximately 1.8%. Consequently, the oxidation state in FeTiO3 powder was changed into almost Fe3+Ti3+, corresponding to 87% Fe3+ of the total Fe for FeTiO3, resulting in the emergence of ferromagnetism. This new ferromagnetic behaviour is of crucial importance in the study of rock magnetization which is used to interpret historical fluctuations in geomagnetism. In addition, the super-high-energy ball mill can be used to control a range of charge and spin states in transition metal oxides with high pressure.

Shape-Controlled Syntheses of Magnetite Microparticles and Their Magnetorheology.

Magnetic microspheres in a concentrated suspension can be self-assembled to form chain structures under a magnetic field, resulting in an enhanced viscosity and elasticity of the suspension (i.e., the magnetorheological (MR) effect). Recently, interest has been raised about the relationship between nonspherical particles, such as octahedral particles and the MR effect. However, experimental studies have not made much progress toward clarifying this issue due to the difficulty associated with synthesizing microparticles with well-defined shapes and sizes. Here, we presented a method for the shape-controlled synthesis of magnetite (Fe3O4) microparticles and investigated the MR effects of two suspensions prepared from the two shape-controlled samples of Fe3O4 microparticles. Our method, which was based on the polyol method, enabled the preparation of spherical and octahedral Fe3O4 microparticles with similar sizes and magnetic properties, through a reduction of α-FeOOH in a mixed solvent of ethylene glycol (a polyol) and water. The water played an important role in both the phase transition (α-FeOOH to Fe3O4) and the shape control. No substantial difference in the MR effect was observed between an octahedral-particle-based suspension and a spherical-particle-based one. Therefore, in this study, the shape of the microparticles did not strongly influence the MR effect, i.e., the properties of the chain structures.

Spodiobacter cordis gen. nov. sp. nov., a member of the family Flavobacteriaceae isolated from patients with infective endocarditis.

Two gram-negative, catalase-negative, oxidase-positive strains (PAGU 1467T and PAGU 1468) isolated from patients with infective endocarditis were investigated to determine their taxonomic status. 16S rRNA gene sequence analysis indicated that the two strains were members of the Bergeyella-Chryseobacterium-Riemerella branch of the family Flavobacteriaceae. Strains PAGU 1467T and PAGU 1468 were highly related to each other (98.8% 16S rRNA gene sequence similarity). Phylogenetically closely-related species to PAGU 1467T comprised Bergeyella zoohelcum (95.0% 16S rRNA gene sequence similarity), Riemerella anatipestifer (94.3%) and Cloacibacterium normanense (94.3%). The major fatty acids of the two isolates were iso-C15:0 , iso-C17:0 3-OH and iso-C15:0 3-OH. The presence of C16:0 3-OH and iso-C15:0 2-OH allowed these isolates to be distinguished from B. zoohelcum. Menaquinone MK-6 was the only respiratory quinone in these organisms; this is a consistent characteristic of the family Flavobacteriaceae. The guanine-plus-cytosine content of the genomic DNA was 42.0%, which is higher than that of other close phylogenetic relatives. On the basis of their phenotypic properties and genetic distinctiveness, isolates PAGU 1467T and PAGU 1468 were classified within the novel genus Spodiobacter, as Spodiobacter cordis gen. nov., sp. nov., which is also the type species. The type strain of S. cordis is PAGU 1467T ( = CCUG 65564T = NBRC 109998T ).

Cationized liposomal keto-mycolic acids isolated from Mycobacterium bovis bacillus Calmette-Guérin induce antitumor immunity in a syngeneic murine bladder cancer model.

Intravesical therapy using Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most established cancer immunotherapy for bladder cancer. However, its underlying mechanisms are unknown. Mycolic acid (MA), the most abundant lipid of the BCG cell wall, is suspected to be one of the essential active components of this immunogenicity. Here, we developed cationic liposomes incorporating three subclasses (α, keto, and methoxy) of MA purified separately from BCG, using the dendron-bearing lipid D22. The cationic liposomes using D22 were efficiently taken up by the murine bladder cancer cell line MB49 in vitro, but the non-cationic liposomes were not. Lip-kMA, a cationic liposome containing keto-MA, presented strong antitumor activity in two murine syngeneic graft models using the murine bladder cancer cell lines MB49 and MBT-2 in comparison to both Lip-aMA and Lip-mMA, which contained α-MA and methoxy-MA, respectively. Interestingly, Lip-kMA(D12), which was made of D12 instead of D22, did not exhibit antitumor activity in the murine syngeneic graft model using MB49 cells, although it was successfully taken up by MB49 cells in vitro. Histologically, compared to the number of infiltrating CD4 lymphocytes, the number of CD8 lymphocytes was higher in the tumors treated with Lip-kMA. Antitumor effects of Lip-kMA were not observed in nude mice, whereas weak but significant effects were observed in beige mice with natural killer activity deficiency. Thus, a cationized liposome containing keto-MA derived from BCG induced in vivo antitumor immunity. These findings will provide new insights into lipid immunogenicity and the underlying mechanisms of BCG immunotherapy.

Observation of the First Spin Crossover in an Iron(II) Complex with an S6 Coordination Environment: Tris[bis(N,N-diethylamino)carbeniumdithiocarboxylato]iron(II) Hexafluorophosphate.

For the first time, the spin-crossover (SCO) phenomenon has been observed in an FeII -S6 system in a tris(chelate)-type iron(II) complex with a zwitterionic sulfur donor bidentate, bis(N,N-diethylamino)carbeniumdithiocarboxylate (EtL), [FeII (EtL)3 ](PF6 )2 (1), as synthesized by the reaction of a precursor complex [FeII (CH3 CN)6 ](PF6 )2 with EtL. In the solid state, the high-spin (HS) d6 state at ambient temperature and the low-spin (LS) d6 state at temperatures lower than approximately 240 K were evidenced by magnetic measurements with SQUID and Mössbauer spectra in the temperature range 4-290 K. X-ray analyses of the crystals at various temperatures disclosed that the distorted trigonal prismatic coordination environments essentially do not change; however, contraction of Fe-S distances by approximately 10 % (0.22 Å), ordering of alkyl groups in EtL and PF6 - counteranions, and formation of significant intermolecular S⋅⋅⋅S interactions between adjacent molecules (average distances of 3.59 Å) take place during the transition from the HS to the LS state. A large decrease in the volume of the formula unit (78.1 Å3 ) might be responsible for the large activation barrier, thereby resulting in a slow phase transition upon cooling.

Evidence that glial cells attenuate G47R transthyretin accumulation in the central nervous system.

Amyloidogenic protein forms amyloid aggregations at membranes leading to dysfunction of amyloid clearance and amyloidosis. Glial cells function in the clearance and degradation of amyloid ß (Aß) in the brain. This study aimed to clarify the reason why amyloid transthyretin (ATTR) rarely accumulates in the CNS. We pathologically analyzed the relationship between amyloid deposition with basement membranes or glial cells in a rare case of ATTR leptomeningeal amyloidosis. In addition, we compared the cytotoxicity of ATTR G47R, the amyloidosis-causing mutation in the case studied (n = 1), and Aß in brains from patients with cerebral amyloid angiopathy (n = 6). In the subarachnoid space of the ATTR G47R case, most amyloids accumulated at the components of basement membranes. On the CNS surface, ATTR accumulations were retained by astrocytic end feet. In areas where glial end feet enveloped ATTR, ubiquitination and micro-vacuolation of ATTR was evident. The colocalization of GFAP and ubiquitin was also evident. The accumulation of ATTR G47R in the CNS was negatively correlated with the prevalence of astrocytes. Quantitatively, amyloid deposits along the vessels were mostly partial in cerebral Aß angiopathy cases and nearly complete along the basement membrane in the ATTR G47R case. The vascular expressions of type IV collagen and smooth muscle actin were severely reduced in areas with ATTR G47R deposition, but not in areas with Aß deposition. The vascular protein level recovered in the ATTR G47R case when vessels entered into areas of parenchyma that were rich in astrocytes. In addition, the strong interactions between the transthyretin variant and basement membranes may have led to dysfunction of transthyretin clearance and leptomeningeal amyloidosis. The present study was the first to show that glial cells may attenuate G47R transthyretin accumulation in the CNS.

An autopsy case of leptomeningeal amyloidosis associated with transthyretin Gly47Arg mutation.

We report the case of a 47-year-old woman with a 4-year history of progressive numbness in the distal portions of both her lower limbs, diarrhea alternating with periods of constipation, and orthostatic syncope. She demonstrated sensory dominant neuropathy and dysautonomia including orthostatic hypotension, paralytic ileus, and urinary retention. A systemic mutation analysis revealed a G47R mutation in transthyretin (TTR). Her general condition was so poor that we could not perform active treatment. Her consciousness had been impaired for a few months. She died at the age of 47 due to multiple organ failure. An autopsy revealed amyloid deposits in the subarachnoid space of the brainstem and the spinal cord as well as in the peripheral nerve and other organs. To date, this is the first case in which a G47R mutation is associated with leptomeningeal amyloidosis.