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We perform herein a direct observation of shockwave propagation using a high-speed camera and estimate properties, such as acoustic velocity and Hugoniot parameter, using the impedance matching scheme to reveal the dynamic characteristics of Okinawa's unique soil "Shimajiri Mahji." A computational simulation corresponding to the experimental setup is then conducted. A comparison of the numerical and experimental results demonstrates their fairly good agreement, which suggests that the experimentally estimated dynamic characteristics of "Shimajiri Mahji" are valid. In addition, a computational simulation based on the smoothed particle hydrodynamics is also modeled and performed to elucidate the fragment behavior when the unexploded bomb explosive is at the soil surface. From a series of computational results, we have confirmed and clarified that the fragment behavior is significantly dependent on the amount of explosive charge and soil characteristics. [ABSTRACT FROM AUTHOR]

Okinawa National College of Technology has developed a food processing machine using underwater shock waves. Several prototype machines were developed, and experimental results (sterilization, improvement of juice extraction, milling flour, emulsification etc.) were obtained. After deciding food materials to be processed and the desired processing results, we designed and manufactured a pressure vessel for experiments. In this report, the process flow for designing and manufacturing a pressure vessel for softening meat using underwater shock and its concept design are described. The relationships among the number of shock waves, the distance between the shock wave generation point and the meat, the backing material, and the amount of softening ware experimentally compared. We measured the velocity of the shock wave penetrating to the inside of the meat, from which we estimated the particle velocity. We developed computer simulation model using the estimated particle velocity in the meat. Using the results of the analysis obtained from the computer simulation model, we designed and fabricated the pressure vessel. [ABSTRACT FROM AUTHOR]

The magnesium alloy has advantage in strength per mass and it has been widely used on airplane, aerospace, computer, cellphone and automobile industries. However, forming of magnesium alloy plate at the room temperature is very difficult, because it has a dense hexagonal and the basal sliding is easy to happen conspicuously in comparison with other sliding system. We considered that those weak characteristics are reduced by high strain rate forming. Therefore, magnesium alloy forming using shock wave by metal wire electric discharge has been carried out. Thin aluminum alloy was used as the metal wire. Electricity is supplied to this wire from power supply with Cockcroft-Walton circuit. The aluminum wire set underwater and it has instantly molten vaporization, then, the underwater shock wave was generated. The shock loading by the underwater shock wave acts to the magnesium alloy plate. The magnesium alloy plate was AZ31(Al 3%, Zn 1%). In this study, the target is bulge forming of the magnesium alloy plate. Then, some numerical simulations were carried out. These results will be discussed in this paper. [ABSTRACT FROM AUTHOR]

The explosive forming is a characteristic method. An underwater shock wave is generated by underwater explosion of an explosive. A metal plate is affected high strain rate by the shock loading and is formed along a metal die. Although this method has the advantage of mirroring the shape of the die, a free forming was used in this paper. An expensive metal die is not necessary for this free forming. It is possible that a metal plate is formed with simple supporting parts. However, the forming shape depends on the shock pressure distribution act on the metal plate. This pressure distribution is able to change by the shape of explosive, a mass of explosive and a shape of pressure vessel. On the other hand, we need the pressure vessel for food processing by the underwater shock wave. Therefore, we propose making the pressure vessel by this explosive forming. One design suggestion of pressure vessel made of stainless steel was considered. However, we cannot decide suitable conditions, the mass of the explosive and the distance between the explosive and the metal plate to make the pressure vessel. In order to decide these conditions, we have tried the numerical simulation on this explosive forming. The basic simulation method was ALE (Arbitrary Lagrangian-Eulerian) method including with Mie-Grüneisen EOS (equation of state), JWL EOS, Johnson-Cook constitutive equation for a material model. In this paper, the underwater pressure contours to clear the propagations of the underwater shock wave, forming processes and deformation velocity of the metal plate is shown and it will be discussed about those results. [ABSTRACT FROM AUTHOR]

To clarify the shock characteristics of Okinawa's unique soils "Jahgaru" that is widely distributed in southern part of Okinawa Main Island, an experimental investigation of dynamics properties such as shockwave propagation, pressure and particle velocity have been performed using impedance matching method. Therefore, we have also obtained the Hugoniot date of "Jahgaru". And then, to reveal a validity of the material characteristics, a computational model for the experimental procedure using ALE simulation have been developed. A comparison between numerical results and experimental ones, the capability of proposed method through the numerical simulations have been confirmed. [ABSTRACT FROM AUTHOR]

We have been investigating underwater-explosion-induced shockwave-propagation phenomena for use in a robust food-processing system. This system comprises a high-voltage capacitor bank with a gap switch, water tank, and wire explosive. We performed an optical examination of the shockwave generated by a wire explosion using an electrical discharge in the water tank. Simultaneously, we measured the shock pressure and investigated the effects of various electrical characteristics upon the shockwave propagation phenomena. To obtain various strengths of the underwater shockwave, 0.6-, 1.0-, and 1.4-mm width wires made from 1.0-mm-thick aluminum plates were used at various voltages. As an example, a shockwave with a propagation velocity of 1,600 m/s was observed from an explosion generated using a 1.0-mm-width aluminum wire. We found that the strength of the shockwave could be controlled by the applied discharge voltage and wire size. [ABSTRACT FROM AUTHOR]

Background: Accurate preoperative evaluation of renal function in living kidney donor candidates (LKDCs) is crucial to prevent kidney failure after nephrectomy. We examined the performance of various estimated glomerular filtration rate (eGFR) equations, including the new chronic kidney disease epidemiology collaboration (CKD-EPI) equation in LKDCs., Methods: We analyzed 752 LKDCs who were assessed for measured GFR by inulin clearance as part of routine pretransplant examination from 2006 to 2020. CKD-EPI2012 from cystatin C (CKD-EPI12cys), CKD-EPI2021 from creatinine (CKD-EPI21cr), CKD-EPI21cr-cys, Japanese modified (JPN) eGFRcr, and JPN eGFRcys were compared in determining the suitability for LKDCs., Results: CKD-EPI12cys had the lowest absolute and relative biases, with higher P 30 and P 10 , followed by JPN eGFRcys, CKD-EPI21cr, and CKD-EPI21cr-cys. The root mean square error was least for CKD-EPI12cys, then JPN eGFRcys, CKD-EPI21cr-cys, CKD-EPI21cr, and JPN eGFRcr. CKD-EPI21cr, CKD-EPI12cys, and CKD-EPI21cr-cys estimated GFR higher, whereas JPN eGFRcr estimated GFR lower. At the threshold of 90 mL/min/1.73 m 2 , CKD-EPI21cr had the highest percentage of misclassification at 37.37%, whereas JPN eGFRcr had the lowest percentage of misclassification at 6.91%. Using the age-adapted approach, JPN eGFRcr had the lowest percentage of misclassification into overestimation at 7.31%. All eGFR had >5.0%, and CKD-EPI21cr had the highest percentage of misclassification at 21.94%. Conversely, CKD-EPI21cr-cys had the lowest percentage of misclassification into underestimation at 3.19%, both at the threshold of 90 mL/min/1.73 m 2 and the age-adapted approach. JPN eGFRcr had the highest percentage at 33.38% and 40.69%, respectively., Conclusions: In evaluating the renal function of Japanese LKDCs, the new CKD-EPI equation had a lower rate of underestimation but a relatively high rate of overestimation. New GFR estimation formulas are needed to be tailored to each ethnic group to enhance the accuracy and reliability of donor selection processes., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: The Aedes albopictus mosquito is of medical concern due to its ability to transmit viral diseases, such as dengue and chikungunya. Aedes albopictus originated in Asia and is now present on all continents, with the exception of Antarctica. In Mozambique, Ae. albopictus was first reported in 2015 within the capital city of Maputo, and by 2019, it had become established in the surrounding area. It was suspected that the mosquito population originated in Madagascar or islands of the Western Indian Ocean (IWIO). The aim of this study was to determine its origin. Given the risk of spreading insecticide resistance, we also examined relevant mutations in the voltage-sensitive sodium channel (VSSC)., Methods: Eggs of Ae. albopictus were collected in Matola-Rio, a municipality adjacent to Maputo, and reared to adults in the laboratory. Cytochrome c oxidase subunit I (COI) sequences and microsatellite loci were analyzed to estimate origins. The presence of knockdown resistance (kdr) mutations within domain II and III of the VSSC were examined using Sanger sequencing., Results: The COI network analysis denied the hypothesis that the Ae. albopictus population originated in Madagascar or IWIO; rather both the COI network and microsatellites analyses showed that the population was genetically similar to those in continental Southeast Asia and Hangzhou, China. Sanger sequencing determined the presence of the F1534C knockdown mutation, which is widely distributed among Asian populations, with a high allele frequency (46%)., Conclusions: These results do not support the hypothesis that the Mozambique Ae. albopictus population originated in Madagascar or IWIO. Instead, they suggest that the origin is continental Southeast Asia or a coastal town in China., (© 2024. The Author(s).)

Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1β. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.

The Asian tiger mosquito, Aedes albopictus, is a significant public health concern owing to its expanding habitat and vector competence. Disease outbreaks attributed to this species have been reported in areas under its invasion, and its northward expansion in Japan has caused concern because of the potential for dengue virus infection in newly populated areas. Accurate prediction of Ae. albopictus distribution is crucial to prevent the spread of the disease. However, limited studies have focused on the prediction of Ae. albopictus distribution in Japan. Herein, we used the random forest model, a machine learning approach, to predict the current and potential future habitat ranges of Ae. albopictus in Japan. The model revealed that these mosquitoes prefer urban areas over forests in Japan on the current map. Under predictions for the future, the species will expand its range to the surrounding areas and eventually reach many areas of northeastern Kanto, Tohoku District, and Hokkaido, with a few variations in different scenarios. However, the affected human population is predicted to decrease owing to the declining birth rate. Anthropogenic and climatic factors contribute to range expansion, and urban size and population have profound impacts. This prediction map can guide responses to the introduction of this species in new areas, advance the spatial knowledge of diseases vectored by it, and mitigate the possible disease burden. To our knowledge, this is the first distribution-modelling prediction for Ae. albopictus with a focus on Japan., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

During their blood-feeding process, ticks are known to transmit various viruses to vertebrates, including humans. Recent viral metagenomic analyses using next-generation sequencing (NGS) have revealed that blood-feeding arthropods like ticks harbor a large diversity of viruses. However, many of these viruses have not been isolated or cultured, and their basic characteristics remain unknown. This study aimed to present the identification of a difficult-to-culture virus in ticks using NGS and to understand its epidemic dynamics using molecular biology techniques. During routine tick-borne virus surveillance in Japan, an unknown flaviviral sequence was detected via virome analysis of host-questing ticks. Similar viral sequences have been detected in the sera of sika deer and wild boars in Japan, and this virus was tentatively named the Saruyama virus (SAYAV). Because SAYAV did not propagate in any cultured cells tested, single-round infectious virus particles (SRIP) were generated based on its structural protein gene sequence utilizing a yellow fever virus-based replicon system to understand its nationwide endemic status. Seroepidemiological studies using SRIP as antigens have demonstrated the presence of neutralizing antibodies against SAYAV in sika deer and wild boar captured at several locations in Japan, suggesting that SAYAV is endemic throughout Japan. Phylogenetic analyses have revealed that SAYAV forms a sister clade with the Orthoflavivirus genus, which includes important mosquito- and tick-borne pathogenic viruses. This shows that SAYAV evolved into a lineage independent of the known orthoflaviviruses. This study demonstrates a unique approach for understanding the epidemiology of uncultured viruses by combining viral metagenomics and pseudoinfectious viral particles., Competing Interests: Competing interests statement:The authors declare no competing interest.

High pathogenicity avian influenza (HPAI) poses a significant threat to both domestic and wild birds globally. The avian influenza virus, known for environmental contamination and subsequent oral infection in birds, necessitates careful consideration of alternative introduction routes during HPAI outbreaks. This study focuses on blowflies (genus Calliphora), in particular Calliphora nigribarbis, attracted to decaying animals and feces, which migrate to lowland areas of Japan from northern or mountainous regions in early winter, coinciding with HPAI season. Our investigation aims to delineate the role of blowflies as HPAI vectors by conducting a virus prevalence survey in a wild bird HPAI-enzootic area. In December 2022, 648 Calliphora nigribarbis were collected. Influenza virus RT-PCR testing identified 14 virus-positive samples (2.2% prevalence), with the highest occurrence observed near the crane colony (14.9%). Subtyping revealed the presence of H5N1 and HxN1 in some samples. Subsequent collections in December 2023 identified one HPAI virus-positive specimen from 608 collected flies in total, underscoring the potential involvement of blowflies in HPAI transmission. Our observations suggest C. nigribarbis may acquire the HPAI virus from deceased wild birds directly or from fecal materials from infected birds, highlighting the need to add blowflies as a target of HPAI vector control., (© 2024. The Author(s).)

Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs., (© 2024. Japanese Society of Hematology.)

Estrogenic activity in miso was evaluated without in vivo animal experimentation using in vitro method with yeast in a two-hybrid method because of its similarities with human cells. First, the recombinant yeast containing genes of human estrogen receptor (hER) was prepared for modeling human cells. Subsequently, standard solutions of 17β-estradiol and isoflavone (1.0 × 10 -12 - 1.0 × 10 -6 ) were assayed using the yeast. Their yeast produces β-glucosidase according to the concentrations of their solutions. Therefore, the estrogenic activity can be evaluated using recombinant yeast for the yeast two-hybrid method. Results show that 17β-estradiol has affinity to bind with Y187-αα. Genistein has affinity to bind with Y187-ββ. Daidzein, genistein, and glycitein in miso were 2.0-2.2 times the average concentrations of miso. Particularly, Mame miso had the highest concentration of isoflavones among all miso samples. Isoflavone in miso samples showed estrogenic activity against Y187-ββ. Mame miso had particularly high activity (1.97 U/OD 660 1.0) against Y187-ββ modeling hERββ. Finally, the interaction of the human estrogen receptors was analyzed with 17β-estradiol and isoflavones using Y187 strains. Isoflavone inhibited the estrogenic activity of 17β-estradiol using Y187-αα. However, the estrogenic activity of 17β-estradiol against Y187-αβ and Y187-ββ, which model hER-αβ and hER-ββ, was activated by isoflavone. Results showed genistein as the antagonist of estrogenic activity within 17β-estradiol against hERαα. However, it is an agonist of the activity within 17β-estradiol against hERαβ and hERββ. The yeast two-hybrid method has some potential for assessing the estrogenic activity of isoflavone in foods as a human model. PRACTICAL APPLICATION: Today, isoflavones in foods must be evaluated using in vivo methods such as animal experimentation because the estrogenic activities of isoflavones are agonist or antagonist with 17β-estradiol against estrogen receptors. Because animal experimentation is time-consuming and expensive, isoflavones in foods can be evaluated using yeast, a eukaryote that has similarity to human cells, while obviating in vivo methods. The yeast two-hybrid method is useful to assay the estrogenic activity of isoflavones in foods., (© 2023 Institute of Food Technologists.)

Proteasome inhibitors (PIs) can preferentially restore bone in bone-defective lesions of patients with multiple myeloma (MM) who respond favorably to these drugs. Most prior in vitro studies on PIs used continuous exposure to low PI concentrations, although pharmacokinetic analysis in patients has shown that serum concentrations of PIs change in a pulsatile manner. In the present study, we explored the effects of pulsatile treatment with PIs on bone metabolism to simulate in vivo PI pharmacokinetics. Pulsatile treatment with bortezomib, carfilzomib, or ixazomib induced MM cell death but only marginally affected the viability of osteoclasts (OCs) with F-actin ring formation. Pulsatile PI treatment suppressed osteoclastogenesis in OC precursors and bone resorption by mature OCs. OCs robustly enhanced osteoblastogenesis in cocultures with OCs and MC3T3-E1 pre-osteoblastic cells, indicating OC-mediated coupling to osteoblastogenesis. Importantly, pulsatile PI treatment did not impair robust OC-mediated osteoblastogenesis. These results suggest that PIs might sufficiently reduce MM cell-derived osteoblastogenesis inhibitors to permit OC-driven bone formation coupling while suppressing OC differentiation and activity in good responders to PIs. OC-mediated coupling to osteoblastogenesis appears to be a predominant mechanism for preferential occurrence of bone regeneration at sites of osteoclastic bone destruction in good responders., (© 2023. The Author(s).)

Pyrethroid resistance in Aedes aegypti is widespread in southern Vietnam because the photostable 2nd generation pyrethroids have been used in large amounts over extensive areas for malaria and dengue vector control. In our previous report in 2009, F1534C, one of the point mutations in the voltage-sensitive sodium channel (VSSC) in Ae. aegypti, was widespread at high frequency in south and central area. However, no significant correlation between the frequency of F1534C and pyrethroid susceptibility was detected primarily because the F1534C mutation frequency in the southern highland area was very low, despite that the bioassay indicated high pyrethroid resistance. The point mutation in the VSSC, L982W, which was not the target mutation in our previous study, was recently determined to be an important mutation causing high-pyrethroid resistance in Vietnamese Ae. aegypti. In the present study, a re-investigation of L982W in the mosquito samples collected in 2006-2008 revealed a greater distribution of this mutation (allelic percentage 59.2%) than F1534C (21.7%) and the greater proportion of homozygous L982W as compared to F1534C provided a plausible answer to the question concerning the unknown resistance factor in the southern highland area. L982W frequencies were uniformly higher in the southern part of Vietnam, including the highland area with a significantly high positive correlation with pyrethroid resistance in Ae. aegypti., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kawada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In Asia, Culex mosquitoes are of particular interest because of their role in maintaining endemic mosquito-borne viral diseases, including the Japanese encephalitis virus (JEV). Nonetheless, host-feeding preferences, along with naturally infecting RNA viruses in certain Culex species, remain understudied. In this study, selected blood-fed mosquitoes were processed for avian and mammalian blood meal source identification. Concurrently, cell culture propagation and high-throughput sequencing (HTS) approaches were used to determine the RNA virome of Culex mosquitoes collected in Ishikawa Prefecture, Japan. The identification of blood meal sources from wild-caught Culex spp. revealed that Culex (Culex) tritaeniorhynchus Giles, 1901, has a robust preference toward wild boar (62%, 26/42), followed by heron (21%, 9/42). The other two species, Culex (Oculeomyia) bitaeniorhynchus Giles, 1901, and Culex (Culex) orientalis Edwards, 1921, showed a distinct preference for avian species, including migratory birds. From the HTS results, 34 virus sequences were detected, four of which were newly identified virus sequences of unclassified Aspiviridae, Qinviridae, Iflaviridae, and Picornaviridae. The absence of observable cytopathic effects in mammalian cells and phylogenetic analysis suggested that all identified virus sequences were insect-specific. Further investigations involving other mosquito populations collected in different areas are warranted to explore previously unknown vertebrate hosts that may be linked to JEV dispersal in nature., (© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Getah virus (GETV) is a mosquito-borne Alphavirus (family Togaviridae) that is of significant importance in veterinary medicine. It has been associated with major polyarthritis outbreaks in animals, but there are insufficient data on its clinical symptoms in humans. Serological evidence of GETV exposure and the risk of zoonotic transmission makes GETV a potentially medically relevant arbovirus. However, minimal emphasis has been placed on investigating GETV vector transmission, which limits current knowledge of the factors facilitating the spread and outbreaks of GETV., Methods: To examine the range of the mosquito hosts of GETV, we selected medically important mosquitoes, assessed them in vitro and in vivo and determined their relative competence in virus transmission. The susceptibility and growth kinetics of GETVs in various mosquito-derived cell lines were also determined and quantified using plaque assays. Vector competency assays were also conducted, and quantitative reverse transcription-PCR and plaque assays were used to determine the susceptibility and transmission capacity of each mosquito species evaluated in this study., Results: GETV infection in all of the investigated mosquito cell lines resulted in detectable cytopathic effects. GETV reproduced the fastest in Culex tritaeniorhynchus- and Aedes albopictus-derived cell lines, as evidenced by the highest exponential titers we observed. Regarding viral RNA copy numbers, mosquito susceptibility to infection, spread, and transmission varied significantly between species. The highest vector competency indices for infection, dissemination and transmission were obtained for Cx. tritaeniorhynchus. This is the first study to investigate the ability of Ae. albopictus and Anopheles stephensi to transmit GETV, and the results emphasize the role and capacity of other mosquito species to transmit GETV upon exposure to GETV, in addition to the perceived vectors from which GETV has been isolated in nature., Conclusions: This study highlights the importance of GETV vector competency studies to determine all possible transmission vectors, especially in endemic regions., (© 2023. The Author(s).)

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3−L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.

Aedes aegypti (Linnaeus, 1762) is the main mosquito vector for dengue and other arboviral infectious diseases. Control of this important vector highly relies on the use of insecticides, especially pyrethroids. The high frequency (>78%) of the L982W substitution was detected at the target site of the pyrethroid insecticide, the voltage-gated sodium channel (Vgsc) of A. aegypti collected from Vietnam and Cambodia. Alleles having concomitant mutations L982W + F1534C and V1016G + F1534C were also confirmed in both countries, and their frequency was high (>90%) in Phnom Penh, Cambodia. Strains having these alleles exhibited substantially higher levels of pyrethroid resistance than any other field population ever reported. The L982W substitution has never been detected in any country of the Indochina Peninsula except Vietnam and Cambodia, but it may be spreading to other areas of Asia, which can cause an unprecedentedly serious threat to the control of dengue fever as well as other Aedes -borne infectious diseases.

Exercise results in mechanical loading of the bone and stimulates energy expenditure in the adipose tissue. It is therefore likely that the bone secretes factors to communicate with adipose tissue in response to mechanical loading. Interleukin (IL)-11 is known to be expressed in the bone, it is upregulated by mechanical loading, enhances osteogenesis and suppresses adipogenesis. Here, we show that systemic IL-11 deletion (IL-11 -/- ) results in reduced bone mass, suppressed bone formation response to mechanical loading, enhanced expression of Wnt inhibitors, and suppressed Wnt signaling. At the same time, the enhancement of bone resorption by mechanical unloading was unaffected. Unexpectedly, IL-11 -/- mice have increased systemic adiposity and glucose intolerance. Osteoblast/osteocyte-specific IL-11 deletion in osteocalcin-Cre;IL-11 fl/fl mice have reduced serum IL-11 levels, blunted bone formation under mechanical loading, and increased systemic adiposity similar to IL-11 -/- mice. Adipocyte-specific IL-11 deletion in adiponectin-Cre;IL-11 fl/fl did not exhibit any abnormalities. We demonstrate that osteoblast/osteocyte-derived IL-11 controls both osteogenesis and systemic adiposity in response to mechanical loading, an important insight for our understanding of osteoporosis and metabolic syndromes., (© 2022. The Author(s).)

Compact lasers capable of producing kilowatt class peak power are highly desirable for applications in various fields, including laser remote sensing, laser micromachining, and biomedical photonics. In this paper, we propose a high-peak-power chip-scale semiconductor/solid-state vertically integrated laser in which two cavities are optically coupled at the solid-state laser gain medium. The first cavity is for the intra-pumping of ytterbium-doped yttrium aluminum garnet (Yb:YAG) with an electrically driven indium gallium arsenide (InGaAs) quantum well, and the second cavity consists of Yb:YAG and chromium-doped yttrium aluminum garnet (Cr:YAG) for passive Q-switching. The proposed laser produces pulses as short as 450 ps, and an estimated peak power of 57.0 kW with a laser chip dimension of 1 mm 3 . To the best of our knowledge, this is the first monolithic integration of semiconductor and solid-state laser gain mediums to realize a compact high-peak-power laser., (© 2022. The Author(s).)

Avian malaria is a mosquito-borne disease of birds caused by avian Plasmodium spp. in worldwide scale. Some naïve birds show serious symptoms which can result in death. Surveillance of vectors and parasites are important to understand and control this disease. Although avian malaria has been found in Japan, detailed prevalence and dynamics remained understudied. We aimed to observe annual changes in the abundance of mosquitoes and the prevalence of avian Plasmodium parasites in Japan. Mosquitoes were collected using dry ice traps over a 10-year period, at a fixed research area located in Kanagawa prefecture. Collected mosquitoes were investigated for the species composition, population size and prevalence of avian Plasmodium by PCR. Mosquitoes belonging to 13 species in 7 genera were collected (n=8,965). The dominant species were Aedes (Ae.) albopictus and Culex (Cx.) pipiens group (gr.). Seven avian Plasmodium lineages, all of which were previously known, were detected from Cx. pipiens gr., Ae. albopictus, and Tripteroides bambusa. Three genetic lineages were dominant and were probably transmitted by Cx. pipiens gr. whose could be the primary vector of these parasites. Annual variations in the seasonal prevalence of mosquitoes and avian Plasmodium were revealed for the first time during recent 10 years in Japan. Namely, avian Plasmodium occurrence in the vector population peaked often in June to July and September to October when the density of the vector population was presumably high enough for the transmission of avian Plasmodium upon appearance of infected birds.

The Culex vishnui subgroups, particularly Culex tritaeniorhynchus, are considered the primary vectors of the Japanese encephalitis virus (JEV) in Asia. Recent molecular phylogenetic analyses of JEV isolates from Asian countries have shown that JEVs with diverse genetic variants are present in Asia. Furthermore, some JEV strains have been found to have crossed the East China Sea and been introduced into Japan. In this study, the possibility of overseas migration of the JE vector mosquito, Cx. tritaeniorhynchus was examined from the genetic, physical, and meteorological perspectives. Molecular phylogenetic analysis was performed based on both whole coding sequences and on the barcoding region of the mitochondrial cytochrome c oxidase subunit I (COI) gene of Cx. vishnui subgroups collected from Asian countries. Culex tritaeniorhymchus was classified into two genetically independent taxa by COI sequences: the Japanese type (Ct-J), which inhabits Japan except for the Amami Islands of southern Japan, and the continental type (Ct-C), which inhabits the Asian region except for Japan. It was confirmed that approximately 10% of Cx. tritaeniorhynchus trapped during the summer in western Kyushu were Ct-C, and that they could fly for up to 38 h continuously. The meteorological analysis also confirmed that the atmospheric flow occurring over the continent coincided with the date of Ct-C capture. This is the first report showing the existence of two taxa in Cx. tritaeniorhynchus. Their physical and physiological characteristics suggest the possibility of long-distance migration from overseas regions to Japan across the East China Sea. Future efforts are expected to provide evidence to support the occurrence of long-distance migration of Cx. tritaeniorhynchus with JEV., Competing Interests: The authors have declared that no competing interests exist.

Background: Accurate timing of BNT162b2 boosters to prevent breakthrough infections of coronavirus disease 2019 (COVID-19) requires reliable estimates of immune status. We hypothesized that spike IgG levels at 3 months after two doses of the BNT162b2 vaccine might predict subsequent spike IgG levels., Methods and Results: Spike IgG levels were tested at 3, 6, and 8 months after the second dose of the BNT162b2 vaccine in 251 Japanese health care workers (median age: 39 years, female: 187). The median level of spike IgG was 2,882 AU/mL at 3 months. This decreased to 875 AU/mL at 6 months and 579 AU/mL at 8 months. There were good correlations of log-transformed spike IgG levels between 3 and 6 months (r = 0.86) and between 3 and 8 months (r = 0.82). The correlation further improved after excluding three subjects who had possible COVID-19 infections (r = 0.91, r = 0.86). Log-transformed spike IgG levels at 6 or 8 months yields the following equation: log spike IgG at 6 (8) months = 0.92 (0.86) X log spike IgG at 3 months- 0.23 (0.18). Predicted spike IgG at 6 months of ≥ 300 or < 300 AU/mL had 98% sensitivity, 47% specificity, and 94% accuracy for discriminating subjects whose actual spike IgG titers at 6 months were above or below 300 AU/mL. Corresponding values of predicted spike IgG at 8 months were 97%, 70%, and 93%, respectively., Conclusions: We conclude that predictive formulae using spike IgG levels at 3 months after two-dose vaccination with BNT162b2 reliably estimate subsequent spike IgG levels up to 8 months and provide useful information in terms of vaccination booster timing., Competing Interests: MT received a research grant from Abbott. Other authors declare that they have no conflicts of interest. However, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Brain natriuretic peptide (BNP) is an essential cardiac biomarker for diagnosing heart failure and for prognoses in patients with various cardiac diseases. However, measurement requires immunological assays that are not available in every hospital. Recently, a novel BNP kit (Nanopia BNP-A, Sekisui Inc.; BNPn) that uses general-purpose, automated, biochemical analyzers has become commercially available. We assessed how its accuracy and utility compare with those of conventional immunological tests., Methods and Results: We retrospectively collected 1491 conventional BNP measurements (BNPc), which had been clinically indicated for BNP testing and for which residual samples were still stored in the laboratory. We measured BNP using the novel kit and determined the correlation of BNP levels between the two methods. We also assessed the predictive value of both BNP measurements for major cardiac events (MACEs). The analytical performance of both measuring methods was similar. Log-transformed BNP measured by both methods showed strong correlation (r = 0.92); however, log-transformed BNPn was significantly higher than log-transformed BNPc (p<0.001). BNPc of 200 ng/L was used to stratify patients into two groups. According to the regression formula between the two methods, we determined a cut-off value of BNPn as 250 ng/L. During a median of 15 months of follow-up, 43 MACEs developed. Both BNPc and BNPn were associated with MACEs. Kaplan-Meier survival analysis indicated that both BNPc and BNPn cut-off values stratified the high-risk group for prognostication. The diagnostic and prognostic utilities were proven even if the lower cut-off values (BNPc = 100 ng/L, BNPn = 130 ng/L) were employed., Conclusions: A new BNP measurement using biochemical equipment provides prognostic value similar to that of conventional BNP analysis; thus, it should prove useful in hospitals in which conventional immunological examinations are not available., Competing Interests: Masaaki Takeuchi received a research grant from Sekisui Medical Co., Ltd. This funding source had no involvement in analysis or interpretation of data, writing the manuscript or the decision to submit the article for publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declare that they have no conflicts of interest.

Rats are an important maintenance host of Leptospira spp., the causative agents of leptospirosis, a zoonotic disease with worldwide distribution. Rats are traded as food in the Mekong Delta, where Cambodia exports tons of rats to Vietnam. Handling wild rats is a potential health risk, but the information on Leptospira spp. carried by rats traded in the region remains limited. In this study, we investigated the carriage of Leptospira spp. in rats exported from Cambodia to Vietnam using bacterial culture, nested PCR and DNA sequencing. Isolates were then assessed using serological analysis and whole-genome sequencing (WGS), and Leptospira DNA detected in rat kidney tissues was also analysed by multilocus sequence typing (MLST). Seventy-two rats (2 Bandicota indica, 57 Rattus argentiventer, 11 R. losea, 1 R. norvegicus and 1 R. rattus) were subjected to bacterial culture, and three L. borgpetersenii serogroup Javanica isolates were obtained from R. argentiventer (5.3%). WGS revealed that although Cambodian isolates were genetically related to L. borgpetersenii serogroup Javanica strains widely distributed in East and South-East Asian countries, they formed a different cluster from other strains. In addition to the three L. borgpetersenii sequences, the flaB sequence of L. interrogans was detected in 18 R. argentiventer and 7 R. losea kidney tissue samples (38.9%) using nested PCR followed by DNA sequencing. The L. interrogans flaB-positive samples were further analysed by MLST, revealing that seven housekeeping genes (glmU, pntA, sucA, tpiA, pfkB, mreA and caiB) contained novel sequences with distinct lineages from other sequence types. This study revealed a high prevalence of Leptospira spp. among rats exported from Cambodia to Vietnam, indicating a potential risk to people engaging in rat trade and demonstrating that a fastidious L. interrogans strain circulates among Cambodian rats., (© 2021 Wiley-VCH GmbH.)

Japanese encephalitis virus (JEV), a mosquito-borne virus, causes severe clinical symptoms in humans in the Asian-Pacific region, where it circulates in a primary transmission cycle among Culex tritaeniorhynchus mosquitoes, domestic swine (Sus scrofa domesticus), and wading birds. We report here an anomalous result that mosquito-borne JEV was detected in unfed host-questing ticks collected from the field in Japan. JEV genomic RNA was detected in four pools of Haemaphysalis flava nymphs collected in November and December 2019, and March 2020, when Cx. tritaeniorhynchus adults were not presumed to be active. Moreover, JEV antigenomic RNA was detected in some JEV-positive tick samples, suggesting virus replication in ticks. However, taken together with no infectious virus isolated, the possibility that the antigenomic RNA was derived from the undigested bloodmeal source in ticks cannot be ruled out. Thus, the role of the ticks as a natural reservoir for JEV remains to be confirmed.

Viruses belonging to the genus Quaranjavirus in the family Orthomyxoviridae are known as argasid tick-borne viruses. Some viruses in this genus or an unassigned quaranjavirus-like variant can infect humans, although little is known about their pathogenicity. During the surveillance of tick-borne viruses in ixodid ticks in Ehime Prefecture, Japan, novel quaranjavirus-like sequences were detected in 3 pooled samples of Haemaphysalis histricis nymphs. Phylogenetic analysis revealed that the detected viruses formed a cluster with quaranjaviruses and other related viruses. Specifically, the viruses were closely related to Zambezi tick virus 1 and Uumaja virus, which are quaranjavirus-like viruses recently discovered in ixodid ticks in Africa and Europe, respectively. These findings indicate that the viruses detected in this study were probably new members of the Quaranjavirus genus or a related group. The viruses were tentatively named "Ohshima virus" even though only limited sequences of their genomes were available. This is the first report on the detection of a quaranjavirus-like virus in the East Asian region. Further investigations are needed to discern its infectivity and pathogenicity against humans and other animals and to determine the potential risk of an emerging tick-borne viral disease.

Objective: To examine the relationship between temporal asymmetry and complexity of muscle synergy during walking using rhythmic auditory cueing (RAC) and the factors related to changes in muscle synergy during walking with RAC in survivors of stroke., Design: Cross-sectional study., Setting: Wards at 2 medical corporation hospitals., Participants: Forty survivors of stroke (N=40; mean age, 70.4±10.3 years; time since stroke, 72.2±32.3 days) who could walk without physical assistance., Interventions: Not applicable., Main Outcome Measures: The participants were assessed in a random block design under 2 conditions: comfortable walking speed (CWS) and walking with RAC. Single-leg support time, kinematics, and electromyograms were measured. Factors related to the complexity of muscle synergy (variance accounted for by 1 synergy [VAF1]) between the walking conditions were examined using hierarchical multiple regression analysis., Results: In the RAC condition, lower limb flexion and knee flexion angles, single-leg support time on the paretic side, and the symmetry index of single-leg support time were increased compared with those in the CWS condition. VAF1 was decreased in the RAC condition (73.9±0.15) compared with that in the CWS condition (76.9±0.13, P =.002). Hierarchical multiple regression analysis revealed that the change in VAF1 was explained by change in single-leg support time ( R 2 =0.43, P =.002)., Conclusions: The RAC condition demonstrated a more complex representation of muscle synergy than the CWS condition; the change in single-leg support time on the paretic side related to the changes in muscle synergy more than changes in lower limb angle. These findings can help in the walking-training concept to improve muscle synergy deficits in survivors of stroke., (© 2022 The Authors.)

In post-stroke patients, muscle synergy (the coordination of motor modules during walking) is impaired. In some patients, the muscle synergy termed module 1 (hip/knee extensors) is merged with module 2 (ankle plantar flexors), and in other cases, module 1 is merged with module 4 (knee flexors). However, post-stroke individuals with a merging pattern of module 3 (hip flexor and ankle dorsiflexor) and module 4, which is the swing-muscle synergy, have not been reported. This study aimed to determine the muscle-synergy merging subtypes of post-stroke during comfortable walking speed (cws). We also examined the effect of experimental lower-limb angle modulation on the muscle synergy patterns of walking in each subtype. Forty-one participants were assessed under three conditions: cws, long stepping on the paretic side (p-long), and long stepping on the non-paretic side (np-long). Lower-limb flexion and extension angles and the electromyogram were measured during walking. Subtype classification was based on the merging pattern of the muscle synergies, and we examined the effect of different lower-limb angles on the muscle synergies. We identified three merging subtypes: module 1 with module 2 (subtype 1), module 1 with module 4 (subtype 2), and module 3 with module 4 (subtype 3). In the cws condition, the lower-limb flexion angle was reduced in subtype 3, and the lower-limb extension angle was decreased in subtype 1. A more complex muscle synergy was observed only in subtype 3 in the p-long condition versus cws (p = 0.036). This subtype classification of walking impairments based on the merging pattern of the muscle synergies could be useful for the selection of a rehabilitation strategy according to the individual's particular neurological condition. Rehabilitation with increased lower-limb flexion may be effective for the training of patients with merging of modules 3 and 4 in comfortable walking., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Aberrant NLRP3 inflammasome activation has been demonstrated in rheumatoid arthritis (RA), which may contribute to debilitating inflammation and bone destruction. Here, we explored the efficacy of the potent TGF-β-activated kinase-1 (TAK1) inhibitor LL-Z1640-2 (LLZ) on joint inflammation and bone destruction in collagen-induced arthritis (CIA)., Methods: LL-Z1640-2 was administered every other day in CIA mice. Clinical and histological evaluation was performed. Priming and activation of NLRP3 inflammasome and osteoclastogenic activity were assessed., Results: NLRP3 inflammasome formation was observed in synovial macrophages and osteoclasts (OCs) in CIA mice. TACE and RANKL were also overexpressed in synovial macrophages and fibroblasts, respectively, in the CIA joints. Treatment with LLZ mitigated all the above changes. As a result, LLZ markedly suppressed synovial hypertrophy and pannus formation to alleviate pain and inflammation in CIA mice. LLZ could block the priming and activation of NLRP3 inflammasome in RAW264.7 macrophage cell line, primary bone marrow macrophages and OCs upon treatment with LPS followed by ATP, thereby suppressing their IL-1β production. LLZ also suppressed LPS-induced production of TACE and TNF-α in bone marrow macrophages and abolished IL-1β-induced production of MMP-3, IL-6 and RANKL in synovial fibroblasts. In addition, LLZ directly inhibits RANKL-mediated OC formation and activation., Conclusion: TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in joints alongside its potent suppression of TNF-α and IL-6 production and proteinase-mediated pathological processes in RA., Competing Interests: Masahiro Abe received research funding from Chugai Pharmaceutical, Sanofi KK, Pfizer Seiyaku KK, Kyowa Hakko Kirin, MSD KK, Astellas Pharma, Takeda Pharmaceutical, Teijin Pharma and Ono Pharmaceutical, and honoraria from the Daiichi Sankyo Company. The other authors declare no competing financial interests., (© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.)

The Asian tiger mosquito ( Aedes albopictus ) arrived in the USA in the 1980's and rapidly spread throughout eastern USA within a decade. The predicted northern edge of its overwintering distribution on the East Coast of the USA roughly falls across New York, Connecticut, and Massachusetts, where the species has been recorded as early as 2000. It is unclear whether Ae. albopictus populations have become established and survive the cold winters in these areas or are recolonized every year. We genotyped and analyzed populations of Ae. albopictus from the northeast USA using 15 microsatellite markers and compared them with other populations across the country and to representatives of the major global genetic clades to investigate their connectivity and stability. Founder effects or bottlenecks were rare at the northern range of the Ae. albopictus distribution in the northeastern USA, with populations displaying high levels of genetic diversity and connectivity along the East Coast. There is no evidence of population turnover in Connecticut during the course of three consecutive years, with consistent genetic structure throughout this period. Overall, these results support the presence of established populations of Ae. albopictus in New York, Connecticut, and Massachusetts, successfully overwintering and migrating in large numbers. Given the stability and interconnectedness of these populations, Ae. albopictus has the potential to continue to proliferate and expand its range northward under mean warming conditions of climate change. Efforts to control Ae. albopictus in these areas should thus focus on vector suppression rather than eradication strategies, as local populations have become firmly established and are expected to reemerge every summer.

Jingmen tick virus (JMTV) and the related jingmenvirus-termed Alongshan virus are recognized as globally emerging human pathogenic tick-borne viruses. These viruses have been detected in various mammals and invertebrates, although their natural transmission cycles remain unknown. JMTV and a novel jingmenvirus, tentatively named Takachi virus (TAKV), have now been identified during a surveillance of tick-borne viruses in Japan. JMTV was shown to be distributed across extensive areas of Japan and has been detected repeatedly at the same collection sites over several years, suggesting viral circulation in natural transmission cycles in these areas. Interestingly, these jingmenviruses may exist in a host tick species-specific manner. Vertical transmission of the virus in host ticks in nature was also indicated by the presence of JMTV in unfed host-questing Amblyomma testudinarium larvae. Further epidemiological surveillance and etiological studies are necessary to assess the status and risk of jingmenvirus infection in Japan.

Ticks are important vector arthropods that transmit various pathogens to humans and other animals. Tick-borne viruses are of particular concern to public health as these are major agents of emerging and re-emerging infectious diseases. The Phenuiviridae family of tick-borne viruses is one of the most diverse groups and includes important human pathogenic viruses such as severe fever with thrombocytopenia syndrome virus. Phenuivirus-like sequences were detected during the surveillance of tick-borne viruses using RNA virome analysis from a pooled sample of Haemaphysalis formosensis ticks collected in Ehime, Japan. RT-PCR amplification and Sanger sequencing revealed the nearly complete viral genome sequence of all three segments. Comparisons of the viral amino acid sequences among phenuiviruses indicated that the detected virus shared 46%-70% sequence identity with known members of the Kaisodi group in the genus Uukuvirus. Furthermore, phylogenetic analysis of the viral proteins showed that the virus formed a cluster with the Kaisodi group viruses, suggesting that this was a novel virus, which was designated "Toyo virus" (TOYOV). Further investigation of TOYOV is needed, and it will contribute to understanding the natural history and the etiological importance of the Kaisodi group viruses., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: In Hokkaido, northern island of Japan, at least seven cases of falciparum malaria were reported by 1951. A survey conducted at that time was unsuccessful in implicating any mosquito species as the possible vector. Although active anopheline mosquito surveillance continued until the middle of the 1980s, there is very limited information on their current status and distribution in Japan. Therefore, this study is an update on the current status and distribution of anopheline mosquitoes in Hokkaido based on a 15-year entomological surveillance between 2001 and 2015., Methods: A survey of mosquitoes was conducted at 22 sites in Hokkaido, Japan, from 2001 to 2015. Adult mosquitoes were collected from cowsheds, lakesides, shrubs, and habitats ranging from open grassland to coniferous forest using a Centers for Disease Control and Prevention (CDC) miniature light trap enhanced with dry ice, aspirators, and sweeping nets. Larvae were collected from lakes, ponds, swamps, stagnant and flowing rivers, and paddy fields. All specimens were morphologically identified and subjected to polymerase chain reaction (PCR)-based sequence analysis of the internal transcribed spacer 2 ( ITS2) region of rDNA. Phylogenetic trees were reconstructed using the neighbor-joining method with the Kimura 2-parameter model on MEGA X version 10.2.2., Results: A total of 46 anopheline specimens were used for the phylogenetic analysis. During the survey, a new member of the Anopheles hyrcanus group, An. belenrae, was discovered in eastern Hokkaido in 2004. Anopheles belenrae has since then been consistently found and confirmed to inhabit only this area of Japan. Four members of the An. hyrcanus group, namely An. belenrae, An. engarensis, An. lesteri, and An. sineroides, have been found in Hokkaido. The results also suggest that An. sinensis, formerly a dominant species throughout Japan, has become a rarely found species, at least currently in Hokkaido., Conclusion: The updated distribution of anopheline mosquitoes in Hokkaido, Japan, showed considerable differences from that observed in previous surveys conducted from 1969 to 1984. In particular, areas where An. sinensis was previously distributed may have been greatly reduced in Hokkaido. The phylogenetic analysis revealed a novel An. hyrcanus group member identified as An. belenrae, described in South Korea in 2005. It is interesting that An. belenrae was confirmed to inhabit only eastern Hokkaido, Japan., (© 2021. The Author(s).)

Background: Adverse reactions are more common after the second injection of messenger RNA vaccines such as Pfizer/BioNTech's BNT162b2. We hypothesized that the degree and severity of reactogenicity after the second injection reflects the magnitude of antibody production against the SARS CoV-2 virus spike protein (spike IgG)., Methods and Results: Blood samples were obtained from 67 Japanese healthcare workers three weeks after the first injection and two weeks after the second injection of the BNT162b2 vaccine to measure spike IgG levels. Using questionnaires, we calculated an adverse event (AE) score (0-11) for each participant. The geometric mean of spike IgG titers increased from 1,047 antibody units (AU/mL) (95% confidence interval (95% CI): 855-1282 AU/mL) after the first injection to 17,378 AU/mL (95% CI: 14,622-20,663 AU/mL) after the second injection. The median AE score increased from 2 to 5. Spike IgG levels after the second injection were negatively correlated with age and positively correlated with spike IgG after the first injection. AE scores after the second injection were not significantly associated with log-transformed spike IgG after the second injection, when adjusted for age, sex, AE score after the first injection, and log-transformed spike IgG after the first injection., Conclusions: Although the sample size was relatively small, reactogenicity after the second injection may not accurately reflect antibody production., Competing Interests: MT received a research grant from Abbott. Other authors declare that they have no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Linalool odor exposure induces an analgesic effect in mice. This effect disappeared in the anosmic model mice, indicating that olfactory input evoked by linalool odor triggered this effect. Furthermore, hypothalamic orexinergic neurons play a pivotal role in this effect. However, the neuronal circuit mechanisms underlying this effect have not been fully addressed. In this study, we focused on the descending orexinergic projection to the spinal cord and examined whether this pathway contributes to the effect. We assessed the effect of intrathecal administration of orexin receptor antagonists on linalool odor-induced analgesia in the tail capsaicin test. We found that the selective orexin type 1 receptor antagonist, but not the selective orexin type 2 receptor antagonist, prevented the odor-induced analgesic effect. Furthermore, immunohistochemical analyses of c-Fos expression induced by the capsaicin test revealed that neuronal activity of spinal cord neurons was suppressed by linalool odor exposure, which was prevented by intrathecal administration of the orexin 1 receptor antagonist. These results indicate that linalool odor exposure drives the orexinergic descending pathway and suppresses nociceptive information flow at the spinal level.

We had recently reported that linalool odor exposure induced significant analgesic effects in mice and that the effects were disappeared in olfactory-deprived mice in which the olfactory epithelium was damaged, thus indicating that the effects were triggered by chemical senses evoked by linalool odor exposure. However, the peripheral neuronal mechanisms, including linalool receptors that contribute toward triggering the linalool odor-induced analgesia, still remain unexplored. In vitro studies have shown that the transient receptor potential ankyrin 1 (TRPA1) responded to linalool, thus raising the possibility that TRPA1 expressed on the trigeminal nerve terminal detects linalool odor inhaled into the nostril and triggers the analgesic effects. To address this hypothesis, we measured the behavioral pain threshold for noxious mechanical stimulation in TRPA1-deficient mice. In contrast to our expectation, we found a significant increase in the threshold after linalool odor exposure in TRPA1-deficient mice, indicating the analgesic effects of linalool odor even in TRPA1-deficient mice. Furthermore, intranasal application of TRPA1 selective antagonist did not alter the analgesic effect of linalool odor. These results showed that the linalool odor-induced analgesia was triggered by a TRPA1-independent pathway in mice.

Red yeast rice has been used to produce alcoholic beverages and various fermented foods in China and Korea since ancient times; it has also been used to produce tofuyo (Okinawan-style fermented tofu) in Japan since the 18th century. Recently, monacolin K (lovastatin) which has cholesterol-lowering effects, was found in some strains of Monascus fungi. Since statins have been used world-wide as a cholesterol-lowering agent, processed foods containing natural statins are drawing attention as materials for primary prevention of life-style related diseases. In recent years, large-scale commercial production of red yeast rice using traditional solid-state fermentation has become possible, and various useful materials, including a variety of monascus pigments (polyketides) that spread as natural pigments, in addition to statins, are produced in the fermentation process. Red yeast rice has a lot of potential as a medicinal food. In this paper, we describe the history of red yeast rice as food, especially in Japan and East Asia, its production methods, use, and the ingredients with pharmacological activity. We then review evidence of the beneficial effects of red yeast rice in improving lipid metabolism and the circulatory system and its safety as a functional food.