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Immune potentiators, termed adjuvant, trigger early innate immune responses to ensure the generation of robust and long‐lasting adaptive immune responses of vaccines. Here we present study that takes advantage of a self‐assembling small molecule library for the development of a novel vaccine adjuvant. Cell‐based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6 , also named cholicamide) whose well‐defined nano‐assembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus‐like assembly is engulfed inside cells and stimulates the innate immune response through toll‐like receptor 7 (TLR7), an endosomal TLR that detects single‐stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here paves the way for a new approach to discovering and designing self‐assembling small‐molecule adjuvants against pathogens, including emerging viruses., 自己集合性ワクチンアジュバントの発見. 京都大学プレスリリース. 2020-10-07., Vaccine ingredients could be hiding in small molecule libraries. 京都大学プレスリリース. 2020-10-07.

Mycobacteria often cause chronic infection. To establish persistence in the host, mycobacteria need to evade host immune responses. However, the molecular mechanisms underlying the evasion strategy are not fully understood. Here, we demonstrate that mycobacterial cell wall lipids trigger an inhibitory receptor to suppress host immune responses. Mycolic acids are major cell wall components and are essential for survival of mycobacteria. By screening inhibitory receptors that react with mycobacterial lipids, we found that mycolic acids from various mycobacterial species bind to mouse Clec12A, and more potently to human Clec12A. Clec12A is a conserved inhibitory C-type lectin receptor containing immunoreceptor tyrosine-based inhibitory motif (ITIM). Innate immune responses, such as MCP-1 production, and PPD-specific recall T cell responses were augmented in Clec12A-deficient mice after infection. In contrast, human Clec12A transgenic mice were susceptible to infection with M. tuberculosis. These results suggest that mycobacteria dampen host immune responses by hijacking an inhibitory host receptor through their specific and essential lipids, mycolic acids. The blockade of this interaction might provide a therapeutic option for the treatment or prevention of mycobacterial infection.

Immunoglobulin A (IgA) vasculitis is generally triggered by infectious causes, but it has also been reported after immunisation with various vaccines. Herein, we report two cases of IgA vasculitis after receiving the first or second dose of the Pfizer-BioNTech BNT16B2b2 mRNA vaccine. Two men, aged 22 and 30 years, developed palpable purpura on the extremities and arthritis. One patient also complained of fever and gastrointestinal symptoms. Laboratory findings revealed mild leucocytosis and slightly elevated C-reactive protein levels, although the platelet count and coagulation profile were within normal levels in both cases. Proteinuria and microhaematuria were seen in one patient. Skin biopsies were performed in both patients and revealed leucocytoclastic vasculitis. The deposits of IgA and C3 were shown in immunofluorescence studies in one patient. Both patients were diagnosed with IgA vasculitis and treated with prednisolone, and their symptoms resolved within 1 week after initiation of treatment. The coronavirus disease 2019 mRNA vaccine could trigger IgA vasculitis; however, a coincidence cannot be ruled out.

We describe a fatal case of diffuse alveolar hemorrhage (DAH) complicated by rheumatoid arthritis (RA). A female patient was diagnosed with RA two months earlier and was treated with prednisolone and tacrolimus due to abnormalities in chest images. The patient was admitted to Hamanomachi Hospital for exertional dyspnea and was treated for exacerbation of chronic heart failure. Even after treatment for heart failure, exertional dyspnea remained. Chest CT imaging revealed contractile, patchy consolidations and ground-glass opacities (GGO) with a peribronchial distribution, suggesting an organizing pneumonia (OP) pattern. She was then treated with an additional 25 mg/day of prednisolone following a clinical diagnosis of OP. When the prednisolone dose was tapered, chest imaging showed worsening infiltration. A bronchoscopy was conducted, and bronchoalveolar lavage fluid was sanguineous, indicating DAH. Given that additional workup for the other etiology of DAH was negative, DAH was thought to be related to RA. Intensive treatment, including pulse dose methylprednisolone, failed to halt progression of respiratory failure, leading to a fatal outcome. The clinical presentation proved challenging due to its rarity. DAH might be a differential diagnosis in RA patients with consolidations and GGO in chest CT images. We review past cases of RA-associated DAH and assess potential treatment choices for future cases.

Clozapine is the most effective antipsychotic medication for refractory schizophrenia, but it has many possible serious side effects, including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the rare case reports available have not presented sufficient characteristic features of drug-induced AAV. Herein, we report a case of a 48-year-old Japanese woman with schizophrenia who presented with fever, arthralgia, myalgia and skin rash after 2 years of clozapine treatment. Her C-reactive protein (CRP) level increased, myeloperoxidase ANCA was positive and skin biopsy revealed leukocytoclastic vasculitis. Initially, steroid administration achieved remission, but her symptoms and high CRP levels relapsed every time the steroid dosage was tapered down. Upon discontinuation of clozapine, her symptoms and elevated CRP level immediately improved and the steroid was successfully tapered and discontinued. This outcome suggested that clozapine was the main cause of AAV.

We examined the efficacy and safety of rituximab (RTX) maintenance therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan.We conducted a retrospective study using a multi-center cohort database of vasculitis patients. All maintenance treatment courses were divided into three groups: a RTX group, a group treated with other immunosuppressant drugs (IS) and a group receiving glucocorticoid monotherapy (GC). The primary endpoint was the comparison of relapse-free survival after 1 year. We also analyzed the occurrence of severe adverse events (SAEs) to assess safety.We included 123 courses of 107 patients (RTXRTX maintenance therapy could be effective and safe in Japanese GPA patients.

Neuronal cells possess a certain degree of plasticity to recover from cell damage. When the stress levels are higher than their plasticity capabilities, neuronal degeneration is triggered. However, the factors correlated to the plasticity capabilities need to be investigated. In this study, we generated a novel mouse model that able to express in an inducible manner a dominant-negative form of MFN2, a mitochondrial fusion factor. We then compared the phenotype of the mice continuously expressing the mutated MFN2 with that of the mice only transiently expressing it. Remarkably, the phenotypes of the group transiently expressing mutant MFN2 could be divided into 3 types: equivalent to what was observed in the continuous expression group, intermediate between the continuous expression group and the control group, and equivalent to the control group. In particular, in the continuous expression group, we observed remarkable hyperactivity and marked cognitive impairments, which were not seen, or were very mild in the transient expression group. These results indicate that abnormal mitochondrial dynamics lead to stress, triggering neuron degeneration; therefore, the neurodegeneration progression can be prevented via the normalization of the mitochondrial dynamics. Since the availability of mouse models suitable for the reproduction of both neurodegeneration and recovery at least partially is very limited, our mouse model can be a useful tool to investigate neuronal plasticity mechanisms and neurodegeneration.

The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor that recognizes trehalose dimycolate (TDM), and trehalose dibehenate (TDB) and related trehalose diesters, and thus represents a promising target for the development of vaccine adjuvants based on the trehalose glycolipid scaffold. To this end, we report on the synthesis of a series of long-chain α-branched, β-modified trehalose monoesters and diesters to explore how glycolipid structure affects signaling through Mincle. Key steps in our synthetic strategy include a Frater-Seebach α-alkylation to install the C20 aliphatic lipid on a malic acid derivative, and the formation of a β,γ-epoxide as an intermediate from which modifications to the β-position of the lipid can be made. Biological evaluation of the derivatives using nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cell lines expressing mMincle or hMincle revealed that the hMincle agonist activity of all diesters was superior to that of...

This paper focuses on the developed of spall-damage that occurs in pure iron as a result of repeated impact. The employed low-frequency scanning acoustic microscopy (LF-SAM) observations combined with the measurements of ultrasonic wave velocity, attenuation, backscattering intensity and amplitude spectrum of the reflected wave, enabled us to provide a nondestructive evaluation. The spall-damage distribution was analyzed in the C-scan images, and we found the spall-damage increase with impact stress when the latter exceeds the characteristic spall-threshold stress. Moreover, we recorded the decreased sound velocity, amplitude ratio, and the increase of backscattering intensity, significant attenuation (the high frequency component of the reflected wave) for enhanced impact stress. It was also demonstrated that the tiny cracks generated in iron develop significantly during subsequent impacts either with lower or higher impact stress. Since the presented results concern for the first time the multiple-impact experiments, we contend that the applied ultrasonic investigations constitute the effective method of nondestructive spall-damage evaluation.

A previously healthy 44-year-old male presented with fever, abdominal pain, liver dysfunction and lymphadenopathy. He was diagnosed as having acute cytomegalovirus (CMV) infection with elevated CMV-IgG and IgM, and observed with supportive therapy. He was admitted to our hospital with prolonged fever lasting for a month. Enhanced CT revealed multiple thromboses in the right pulmonary artery and superior mesenteric vein. Follow-up CT after one week revealed new-onset thromboses in the left pulmonary artery and common iliac vein. Screening tests for thrombophilia were negative. His symptoms were improved with anticoagulant therapy with intravenous heparin, followed by oral warfarin. He was discharged on admission day 28 with good condition. Follow-up CT after 6 months revealed complete resolution of the thromboses. Anticoagulant therapy was stopped after 9 months, and he has been well without recurrence. Though vascular thrombosis is a rare complication, we must be alert to the signs and symptoms of thrombosis in patients with acute CMV infection.

The on-chip quantum dot (QD) microcavity laser engineered on an annular groove made of fused silica was demonstrated based on the external quasi-cavity configuration. By incorporating an appropriate dose of polymer into QD film, the spectral purity of the lasing spectrum was significantly enhanced. In contrast to the dye microcavity laser embedded on the same trench profile, a QD laser possesses a lifetime that is over 10 times longer. We have introduced a unique two-step quantum gain deposition process that has remarkably reduced the wavelength drifts of laser emissions in an aqueous environment by approximately 400%. The reconfigurable cavity platform in combination with an appropriately engineered quantum gain medium embedded onto it promises to enable photostable chip-scale coherent light sources for various photonic, chemical, and biochemical sensing applications.

We developed an ink-jet printing method for fabricating inorganic microdisks at room temperature, which is much lower than the melting point of solid-state inorganic oxide, and have fabricated an organic-inorganic hybrid microdisk laser. Silica was used as the inorganic disk material, and microdisk-shaped aggregates were formed by the ink-jet printing method using a solution in which nanosilica particles were dispersed in propylene glycol monomethylether (PGME) solvent. Then, a microdisk capable of laser oscillation was also prepared by preliminarily adding the laser dye rhodamine 6G to the ink to form a mixed organic material. The structural evaluation of the printed microdisk was first conducted using an optical microscope, a scanning electron microscope (SEM), and an atomic force microscope (AFM). The results of laser oscillation evaluation by optical excitation showed that the printed microdisk sufficiently functions as an optical resonator with a low optical loss. In these evaluations, excellent values such as a surface roughness of 5.83 nm from root mean square (R. M. S.) which is one forth smaller than the particle diameter, and a laser oscillation threshold of 4.76 µJ/mm2 at a wavelength of 601.4 nm were obtained. To the best of our knowledge, this is the first time that an inorganic microdisk has been fabricated at room temperature to realize an organic-inorganic hybrid microdisk laser.

We experimentally demonstrated the fabrication and the fundamental lasing evaluation of a printed microdisk cavity by focusing on a fluorinated spherical polymer FZ-001 to achieve a microdisk with small absorption loss in the visible range.

The relative proportion of kynurenine aminotransferase (KAT) I-IV activities in the brain is similar between humans and rats. Moreover, KAT II is considered to be the main enzyme for kynurenic acid production in the brain. Taken together, human KAT II knock-in (hKAT II KI) rats will become a valuable tool for the evaluation of KAT II targeted drugs as a human mimetic model. Although we initially tried the approach by conventional gene-targeting via embryonic stem cells (ESCs) to generate them, we had to give up the production because of no recombinant ESCs. Accordingly, we developed a method to improve the efficiency of homologous recombination (HR) in ESCs by the combination with the CRISPR/Cas system. Co-electroporation of Cas9 plasmid, single guide RNA plasmid and hKAT II KI vector increased the number of drug-resistant colonies and greatly enhanced the HR efficiency from 0 to 36 %. All the clones which we obtained showed the same sequence as designed. These recombinant clones resulted in chimeras that transmitted the hKAT II KI allele to their offspring. hKAT II KI rats showed no reduction of KATs mRNA expression and the amount of kynurenic acid was similar between the hKAT II KI rats and the wild type in their brains. These results indicate that the methodology presented in this report can overcome the problem encountered in conventional gene-targeting that prevented production of humanized rats.

Streptococcus suis is a major swine pathogen. It has recently been recognized as an emerging zoonosis that causes mainly meningitis and sepsis in human. In particular, toxic shock-like syndrome (TSLS) caused by this pathogen has a high mortality rate. However, misidentification of S. suis by conventional biochemical and commercial identification tests is not rare. The patient was a 71-year-old man who worked as a pig farmer who was admitted for fever, oliguria and subcutaneous hemorrhage. He was diagnosed as having septic shock and blood culture was positive for Gram-positive cocci, mainly diplococcus. This pathogen was identified with S. suis with using MALDI-TOF MS analysis, though a commercial Gram-Positive bacteria identification kit revealed viridans streptococci. His clinical features met the diagnostic criteria of TSLS, and ceftriaxone and clindamycin were administered. On admission day 28, he was discharged in good condition.

Microdisk cavities are a kind of whispering gallery mode (WGM) resonators, which are continually studied owing to their high quality factor (Q factor) and small mode volume. These microdisks were previously fabricated using a subtractive method [1, 2] such as photolithography method. These subtractive methods are suitable for the mass-produced industrial structure due to an ability of the mass fabrication in large areas. On the other hand, we recently developed an ink-jet printing method as a novel, simple fabrication process for a full-polymeric fine microdisk, which is very superior at producing low waste materials, requires little energy consumption, and is suitable for on-site and on-demand fabrication because it is an additive method [3]. Since this method provides a completely organic microdisk platform, it is highly compatible with the biosensor. However, since the refractive index of used hyper-branched polymers (HBP) (n = 1.45–1.89) is a relatively high among organic materials, it is not preferable to use previous HBPs in a biosensor using a water-based liquid sample (n ∼ 1.33) because of the short interaction length owing to reducing the evanescent part. In this study, we experimentally succeeded fabrication of microdisks with water-like refractive index by the ink-jet printing method. Additionally, the low-refractive-index microdisks doped with Rhodamine6G dye successfully achieved WGM lasing. This low-refractive-index microdisk cavity by ink-jet printing method is the first demonstration under atmospheric pressure and RT among inorganic microdisks.

We report on the characterization of volume holographic gratings recorded in photopolymerizable nanocomposites incorporated with hyperbranched polymer (HBP) acting as transporting organic nanoparticles. The HBP possesses ultrahigh index of refraction owing to the inclusion of triazine and aromatic ring units. Such an HBP was easy to disperse into acrylate monomer without any aggregation, so that films with good optical quality are available. A transmission volume grating with refractive index changes up to 2.3×10-2 was obtained at 27 vol.% HBP concentration and 7 vol.% multifunctional acrylate monomer at a wavelength of 532 nm.

We experimentally succeeded fabrication and WGM lasing of inorganic microdisks by the ink-jet printing method. This silica-based microdisk cavity is the first demonstration in ordinary pressure and temperature among inorganic microdisks.

In this study, collision and braking behavior and braking distance of the enforcement device were investigated for characteristic evaluation. The basic theory for the braking distance was derived using the law of the energy conservation. In this basic theory, the braking distance was compared with difference collision speed and arm angles of enforcement device. And also, the collision experiment was carried out by simple model of the enforcement device and the car. The behavior of the enforcement device was examined by the simple model with 3 kinds of different arm angles. The braking distance by the experiment was well agreement with theoretical result. It is possible to optimize and improve the enforcement device by these evaluations of collision behavior.

When a simple structure collides with inclined barrier, behavior and deformation of the structure after impact are different in the case in which the structure slides on a contact surface or the case in which it does not slide. In order to investigate the structural collapse behavior for oblique collided structure, therefore, it is important to clarify the sliding behavior of the structure on the contact surface. The sliding behavior of the structure during collision was estimated according to theoretically obtained the equation considering the equilibrium of change in the momentum and the impulse before and after the collision. For evaluating the sliding behavior of the simple structure, the impact test by the drop type impact testing machine was carried out to collide with inclined barrier. In the impact test, the circular plate of 60 mm diameter and 10 mm thickness was used as the simple structure, and impacted with various collision velocities (range from 2 to 6 m/s). The sliding behavior of the simple structure at the collided surface was observed by high speed camera, and evaluated by the image analysis. The theoretical result was compared to evaluate with experimental results.

Neurons have high plasticity in developmental and juvenile stages that decreases in adulthood. Mitochondrial dynamics are highly important in neurons to maintain normal function. To compare dependency on mitochondrial dynamics in juvenile and adult stages, we generated a mouse model capable of selective timing of the expression of a mutant of the mitochondrial fusion factor Mitofusin 2 (MFN2). Mutant expression in the juvenile stage had lethal effects. Contrastingly, abnormalities did not manifest until 150 d after mutant expression during adulthood. After this silent 150 d period, progressive neurodegeneration, abnormal behaviors, and learning and memory deficits similar to those seen in human neurodegenerative diseases were observed. This indicates that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. Our findings highlight the need to consider the timing of disease onset in mimicking human neurodegenerative diseases. SIGNIFICANCE STATEMENT To compare the dependency on mitochondrial dynamics in neurons in juvenile and adult stages, we generated a mouse model expressing a mutant of the mitochondrial fusion factor MFN2 in an arbitrary timing. Juvenile expression of the mutant showed acute and severe phenotypes and had lethal effects; however, post-adult expression induced delayed but progressive phenotypes resembling those found in human neurodegenerative diseases. Our results indicate that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. This strongly suggests that the timing of expression should be considered when establishing an animal model that closely resembles human neurodegenerative diseases.

The electrocatalysis of heat-treated Co-TPP/carbon for O 2 reduction and H 2 O 2 formation using a fuel cell reactor with an H 2 SO 4 aqueous electrolyte was studied (TPP: 5,10,15,20-tetrakis(phenyl)-21 H ,23 H -porphyrin). Carbon supports, including vapor grown carbon fiber (VGCF), activated carbon (AC), carbon black XC-72 (XC72), and carbon black Black-Pearl-2000/3500 (BP2000/3500), strongly affected the electrocatalysis of the Co-TPP/carbon. The Co-TPP/VGCF heat-treated at 1023 K, abbreviated as Co-TPP/VGCF(1073), showed a good electrocatalytic activity for H 2 O 2 formation (1.0 mol dm −3 with 40% current efficiency (CE)); however, other carbon supports were unfavorable. Electrocatalytic activities were Co-TPP/VGCF(1073) >> Co-TPP/XC72(1073) > Co-TPP/AC(1073) > Co-TPP/BP2000(1073). Their electrocatalysis were studied by rotating ring-disk electrode voltammetry and kinetic studies of the decomposition of H 2 O 2 and the electroreduction of H 2 O 2 to water. These studies indicated that the electrocatalytic activities for the successive reduction of H 2 O 2 to water determined the final H 2 O 2 concentrations and CEs. An active site of heat-treated Co-TPP/VGCF was characterized by X-ray photoelectron spectroscopy, and X-ray absorption near-edge fine structure spectroscopy. Partial pyrolysis of Co-TPP on the carbon surface was essential to generate the active site for the H 2 O 2 formation. A model of the Co active site, CoN 2 –carbon, was proposed.

We report the thermal design of 28-Gb/s × 24-channel CDR-integrated VCSEL-based transceiver optical module for high density optical interconnects. The transceiver module realizes a very high data rate density of 1346 Gb/s/inch2 at a total power consumption of 9.1 W. A unique design of this optical module realizes to use the whole top surface for thermal dissipation. We performed thermal simulations to reduce the temperature difference between case temperature and device temperatures. As investigated the thermal characteristics in both calculation and measurement, the maximum temperature difference can be suppressed to ∼8 °C. All device temperatures are within their operating temperature at the maximum case temperature of 70 °C. Activating all 24 channels, we operated the optical module by a 28.05-Gb/s 231−1 PRBS for each channel. All channels exhibited clearly opened eye diagrams and a total jitter margin of ∼0.48 U.I. at a case temperature of 70 °C.

To realize simple and low-cost VCSEL-based parallel-optical modules mounted onto a polymer-waveguide-embedded PCB in high density, we propose a new mounting technology using a guide pin-assisted optical coupling stabilization during a Sn-Ag-Cu solder -- reflow process. The guide holes of the 12-channel optical module and the guide pins of optical PCB are precisely shaped by a high-precision machining and photolithography technologies, respectively. The allowable optical axis displacement is +/-12 um in both x-and y-axes between the parallel-optical module and the arrayed polymer-waveguide. We fabricated VCSEL-based 14-Gb/s x 12-channel transmitter/receiver modules and 25-Gb/s x 4-channel transceiver modules based on the 12-channel packaging. The module was soldered on a polymer waveguide-embedded PCB to achieve a sufficiently low optical coupling loss. In the link tests, we successfully achieved a BER of 10^-12 for both 14-Gb/s x 12-channel and 25-Gb/s x 4-channel optical links.

Streptococcus suis is a major swine pathogen. It has recently been recognized as an emerging zoonosis that causes mainly meningitis and sepsis in human. In particular, toxic shock-like syndrome (TSLS) caused by this pathogen has a high mortality rate. However, misidentification of S. suis by conventional biochemical and commercial identification tests is not rare. The patient was a 71-year-old man who worked as a pig farmer who was admitted for fever, oliguria and subcutaneous hemorrhage. He was diagnosed as having septic shock and blood culture was positive for Gram-positive cocci, mainly diplococcus. This pathogen was identified with S. suis with using MALDI-TOF MS analysis, though a commercial Gram-Positive bacteria identification kit revealed viridans streptococci. His clinical features met the diagnostic criteria of TSLS, and ceftriaxone and clindamycin were administered. On admission day 28, he was discharged in good condition.

We demonstrate a very high density 28-Gb/s × 24-channel CDR-integrated VCSEL-based optical transceiver module. The optical module achieves a very high data rate density of 1344 Gb/s/inch2 (2.08 Gb/s/mm2). An optical link employing the optical module achieved a jitter margin of 0.48 U.I. at a BER of 10−12 at case temperatures ranging from 31 °C to 70 °C with a very low link power of 13.5 mW/channel/Gb/s.

This paper address the examination of spall damage in medium carbon steel subjected to a repeated impact testing. The experiments were performed well below the threshold spall-stress of 2.6 GPa and the damage introduced in the subsurface volume was investigated using the low frequency scanning acoustic microscopy. Based on B- and C-scan images (the images taken along and perpendicular to the impact surface) we made a qualitative and semi-quantitative evaluation of the damage type (voids in a ductile material or cracks in a brittle one) and its distribution. We found the spall damage development dependent on the amplitude and the duration of the stress pulses. In particular, we proved that the high, long stress pulses induce damage that resembles tensile failure of material, in which voids or cracks nucleate along the spall plane to form macro-cracks. This explains why spall-damage is not seen when the first impact is below the characteristic threshold spall-stress. However, when the tests consist of more than four impacts the spall damage is produced already under stress below the threshold-value.