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A new compound [Y 2 (sq) 3 (H 2 O) 4 ] (Y-sq; sq = squarate (C 4 O 4 2- )) was prepared and structurally characterized. Since the RE-sq family (RE = Y, Dy, Yb, Lu) gave isostructural crystals, the objective of this study is to explore the effects of diamagnetic dilution on the SIM behavior through systematic investigation and comparison of diamagnetically diluted and undiluted forms. The 1%-Diluted Dy compounds, Dy@Y-sq and Dy@Lu-sq, showed AC magnetic susceptibility peaks without any DC bias field ( H DC ), whereas undiluted Dy-sq showed no AC out-of-phase response under the same conditions. The Orbach and Raman mechanisms are assumed in the Arrhenius plots, giving U eff / k B = 139(5) and 135(8) K for Dy@Y-sq and Dy@Lu-sq, respectively, at H DC = 0 Oe. In contrast, Yb@Y-sq and Yb@Lu-sq behaved different; Yb@Y-sq can be regarded as a field-induced SIM because AC out-of-phase response was recorded only when H DC was present. On the other hand, Yb@Lu-sq showed a relaxation independent from temperature around 2 K at H DC = 0 Oe, possibly ascribed to a quantum-tunneling-magnetization mechanism. Applying H DC = 400 Oe afforded U eff = 61.2(14) and 62.5(16) K for Yb@Y-sq and Yb@Lu-sq, respectively. The Y/Lu matrix dependence may be related to spin-phonon coupling. The dilution technique is a facile and versatile tool for modification of SIM characteristics.

The title compound was synthesized, and ESR and magnetic analysis revealed diamagnetic properties below 400 K. The crystal structure analysis clarified that the molecule possesses an approximate C 2 symmetry with a head-to-tail (N-O) 2 four-membered ring. The N···O distances are 2.349(4) - 2.374(4) Å, belonging to the class found in diamagnetic phases of dimerized nitroxide materials. A zero-field splitting pattern appeared in the solid-state ESR around 440 K on heating. The density functional theory (DFT) calculations supported the formation of a biradical.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

C9-methylated quazepam 1 was prepared, and its physicochemical properties were investigated. The atropisomers of 1 were isolated as (a 1 R, a 2 S) and (a 1 S, a 2 R) isomers. Their absolute configurations were determined based on ECD spectra in comparison with those calculated using the time-dependent density functional theory. Preliminary examination of affinity for the GABA A receptor revealed that the (a 1 R, a 2 S) isomer of 1 possessed higher activity than its antipode (a 1 S, a 2 R) isomer. The active configuration of C9-methylated quazepam 1 is the same as that of 1,4-benzodiazepin-2-ones., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In recent research, dendritic neuron-based models have shown promise in effectively learning and recognizing object motion direction within binary images. Leveraging the dendritic neuron structure and On-Off Response mechanism within the primary cortex, this approach has notably reduced learning time and costs compared to traditional neural networks. This paper advances the existing model by integrating bio-inspired components into a learnable dendritic neuron-based artificial visual system (AVS), specifically incorporating mechanisms from horizontal and bipolar cells. This enhancement enables the model to proficiently identify object motion directions in grayscale images, aligning its threshold with human-like perception. The enhanced model demonstrates superior efficiency in motion direction recognition, requiring less data (90% less than other deep models) and less time for training. Experimental findings highlight the model's remarkable robustness, indicating significant potential for real-world applications. The integration of bio-inspired features not only enhances performance but also opens avenues for further exploration in neural network research. Notably, the application of this model to realistic object recognition yields convincing accuracy at nearly 100%, underscoring its practical utility.

Purpose: To assess the efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive unresectable or recurrent/metastatic salivary gland carcinoma., Patients and Methods: This trial was an open-label, single-arm, multicenter phase II study. Patients with histologically confirmed unresectable or recurrent/metastatic salivary gland carcinoma with AR expression were included. The primary endpoint was the overall response rate (ORR) according to RECIST v1.1 by an independent central radiology review in the first 24 response-evaluable (RE) patients who had been observed at least 24 weeks from study initiation (primary RE patients). The efficacy was to be declared when at least 8 of the 24 primary RE patients responded., Results: A total of 31 patients were enrolled. In the first 24 primary RE patients with a median follow-up of 7.4 months, confirmed ORR by independent central radiology review was 25.0% [6/24 patients; 95% confidence interval, 9.8%-46.7%; P = 0.11 (one-sided)], which did not meet the predefined criteria of efficacy. Clinical benefit rate (ORR + rate of stable disease for at least 24 weeks) and median progression-free survival were 50.0% and 7.4 months, respectively. Both median duration of response and overall survival were not reached. Exploratory analyses showed a better ORR of 54.5% (6/11) in patients with AR positivity ≥70% and no history of prior systemic therapy. Grade 3 or higher treatment-emergent adverse events were reported in 35.5% (11/31), which included skin rash, anemia, leukopenia, and cancer pain., Conclusions: Although this study did not meet the predefined efficacy criteria, apalutamide plus goserelin showed clinically meaningful efficacy in a subset of patients with AR-positive salivary gland carcinoma and safety consistent with prior experience in prostate cancer., (©2024 American Association for Cancer Research.)

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Major depressive disorder is a prevalent psychiatric illness characterized by mood disturbances and influenced by various environmental and genetic factors, yet its etiology remains largely unknown., Methods: We profiled a self-reported depressive population in Japan with a focus on sociodemographic background, lifestyle, comorbidities, and genetic background, using data from two cohorts, a population-based cohort and a three-generation cohort, recruited by the Tohoku Medical Megabank Organization until December 2021., Results: Our findings revealed that depression in the Japanese population is strongly associated with certain sociocultural features prevalent in Japan, such as social isolation, neuroticism, and introversion, as well as with well-known risk factors that include age and gender. Environmental factors related to the Great East Japan Earthquake, considered as cohort characteristics, were also strongly associated with the onset of depression. Moreover, using GWAS analysis of whole-genome sequencing data, we identified novel candidate genetic risk variants located on chromosomes 21 and 22 that are associated with depression in Japanese individuals; further validation of these risk variants is warranted., Limitations: Our study has limitations, including uncertain clinical relevance resulting from the use of self-reported questionnaires for depression assessment. Additionally, the cohort exhibited a population bias, with greater representation of women than men., Conclusions: Our results provide holistic insights into depression risk factors in Japanese adults, although their associations with depression are correlations. This supports the idea that targeted interventions and individualized approaches are important for addressing depression in the Japanese population., Competing Interests: Declaration of competing interest We declare that all authors of this paper are employees of the Janssen Pharmaceutical Companies of Johnson & Johnson, and some are stockholders of Johnson & Johnson., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system to specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) and non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 blockade and their association with irAEs. Methods: We examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), and proinflammatory cytokine levels by ELISA in plasma samples from 117 GC patients prior to surgery and 72 NSCLC patients prior to and at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, n = 24). In mice treated with anti-PD-1/PD-L1 antibodies (Abs), sPD-L1 levels and localization of Abs were examined by ELISA and immunohistochemistry, respectively. Results: sPD-L1 was detected with higher frequency in GC patients than in NSCLC patients, whereas bsPD-L1 was detected with similar frequencies in GC and NSCLC patients. sPD-L1 levels were correlated with IL-1α, IL-1β, TNF-α, and IL-6 levels, while bsPD-L1 levels were correlated with MMP13, MMP3, and IFN-γ levels. In NSCLC patients, anti-PD-L1, but not anti-PD-1, treatment increased sPD-L1, which was associated with irAE development, but not with clinical outcomes. In mice, trafficking of anti-PD-L1 Abs to lysosomes in F4/80 + macrophages resulted in sPD-L1 production, which was suppressed by treatment with lysosomal degradation inhibitor chloroquine and macrophage depletion. Conclusion: Anti-PD-L1-mediated lysosomal degradation induces sPD-L1 production, which can serve as an indicator to predict irAE development during anti-PD-L1 treatment., Competing Interests: YI has patent applications for immunopotentiating compositions (WO/2009/0297518, 2011/0081341, 2014/0314714, 2015/0093380, 2015/0197572, 2016/0158356, 2016/0158355, 2017/0051060, and 2020/0062846) and an immune function evaluation method (WO/2019/049974). YI reports research grants from the Japan Society for the Promotion of Science (JP19K07783 and JP22K07262 to YI) and Sysmex Corporation. AG reports consulting fees from MSD, Nippon Kayaku, and Daiichi-Sankyo Company outside the submitted work. MS reports receiving research grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, and Kyowa Hakko Kirin and honoraria from AstraZeneca, MSD, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer, Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-Sankyo Company, Merck Biopharma, and Amgen outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kashiwada, Takano, Ando, Kuroda, Miyabe, Owada, Miyanaga, Asatsuma-Okumura, Hashiguchi, Kanazawa, Yoshida, Seike, Gemma and Iwai.)

Background: The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade., Methods: We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients ( n = 117) prior to surgery and NSCLC patients ( n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively., Results: bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1 + MMP13 high in GC and bsPD-L1 + (MMP3 and MMP13) increased in NSCLC were associated with poor prognosis, whereas bsPD-L1 + MMP13 low in GC and bsPD-L1 + (MMP3 or MMP13) decreased in NSCLC were associated with favorable prognosis., Conclusion: Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC., Competing Interests: YI has patent applications for immunopotentiating compositions (WO/2009/0297518, 2011/0081341, 2014/0314714, 2015/0093380, 2015/0197572, 2016/0158356, 2016/0158355, 2017/0051060, and 2020/0062846) and an immune function evaluation method (WO/2019/049974). YI reports research grants from the Japan Society for the Promotion of Science (JP19K07783 and JP22K07262 to YI) and Sysmex Corporation. AG reports consulting fees from MSD, Nippon Kayaku, and Daiichi-Sankyo Company outside the submitted work. MS reports receiving research grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, and Kyowa Hakko Kirin and honoraria from AstraZeneca, MSD, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer, Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-Sankyo Company, Merck Biopharma, and Amgen outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ando, Kashiwada, Kuroda, Fujii, Takano, Miyabe, Kunugi, Sakatani, Miyanaga, Asatsuma-Okumura, Hashiguchi, Kanazawa, Ohashi, Yoshida, Seike, Gemma and Iwai.)

Background: Balloon pulmonary angioplasty improves the hemodynamics of patients with inoperable chronic thromboembolic pulmonary hypertension; however, the clinical impact of recurrent pulmonary hypertension after balloon pulmonary angioplasty remains unclear., Methods: We retrospectively reviewed 262 consecutive patients with chronic thromboembolic pulmonary hypertension who underwent balloon pulmonary angioplasty between July 2009 and December 2020; 158 (65 ± 12 years; males, 20%; median follow-up period, 45 [26, 66] months) with follow-up right heart catheterization and no residual pulmonary hypertension were included. Recurrent pulmonary hypertension was defined as mean pulmonary arterial pressure <25 mm Hg at the first evaluation after balloon pulmonary angioplasty and ≥25 mm Hg at follow-up evaluation requiring additional treatment with balloon pulmonary angioplasty or pulmonary vasodilators., Results: Recurrent pulmonary hypertension was observed in 11 patients; the state occupation probability of recurrence at 5 years was 9.0% (95% confidence interval: 5.0%-18.9%). Only 1 case (0.6%) of recurrent pulmonary hypertension showed vascular restenosis and reocclusion of previously treated lesions, with more significant hemodynamic and exercise capacity deterioration than the other cases. Additional treatments for recurrent pulmonary hypertension (balloon pulmonary angioplasty in 9 patients, pulmonary vasodilators in 4 patients) improved the mean pulmonary arterial pressure from 27 [26, 29] to 22 [19, 23] mm Hg (p < 0.01). Recurrence had a low probability of transitioning to death in an illness-death model. No specific risk factors for recurrent pulmonary hypertension were identified., Conclusions: Symptomatic recurrent pulmonary hypertension due to vascular restenosis or reocclusion after balloon pulmonary angioplasty was extremely rare. Most cases of recurrent pulmonary hypertension were mild, did not worsen clinically, and had favorable prognoses., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sea slugs are always covered in a mucus layer that has various functions including chemical defense that often involves aposematism and mimicry. Therefore, it is necessary for sea slugs to exhibit their body colors and patterns exactly, and the optical properties of mucus should support this requirement. We examined body mucus from heterobranch sea slugs collected in the Okinawan coral reefs. The refractive indices of mucus from 32 species ranged from 1.3371 to 1.3854 and were similar or slightly greater than the refractive index of seawater (ca. 1.34), indicating that light reflectance on the mucus layer is generally small. Moreover, dissolution of mucus into seawater would form a gradient of refractive indices and enhance the reduction of reflectance. We also obtained relative absorption spectra of the mucus from 32 species. In the range of visible light, absorption spectra of mucus suggest that the mucus layer is almost transparent and is not likely to interfere with the body colors. The presence of absorption peaks and/or shoulders in the UV (ultraviolet) range (280-400 nm) indicates that the mucus layer potentially serves as a sunscreen that absorbs UV radiation in 23 species, whereas prominent UV absorption was not found in the other 9 species. In a kleptoplasty sacoglossan Plakobranchus ocellatus , the refractive indices and presence or absence of UV-absorption showed that the optical properties of the mucus varied to some extent but did not show seasonal fluctuation. The UV-absorption in the mucus may also protect kleptoplasts in kleptoplasty sacoglossans. The present results support the importance of mucus as a functional optical layer for the shell-less life of sea slugs.

This study examined the relationships between positive/negative spirituality and meaning in life at two religious sites in Japan. Participants reported greater sadness and less meaning in life at Koyasan Okunoin, a temple with graves surrounded by nature, than at Nachi Kumano Taisha, a shrine with a waterfall. However, greater feelings of happiness protected meaning in life in the presence of sadness at Koyasan. Additionally, participants who felt a sense of awe reported greater meaning in life through self-liberation, regardless of the sites. The results provide new insights into meaning in life from the two sides of spirituality., (© 2023. The Author(s).)

In the management of ulcerative colitis (UC), colonoscopy (CS) is considered essential for diagnosis;however, its invasiveness poses a challenge. Conversely, recent advancements in ultrasound diagnostic devices have improved imaging quality for the digestive tract, rendering them valuable in UC management. Therefore, this study aimed to elucidate the correlation between abdominal ultrasonography (AUS) and CS in assessing UC activity. The indices adopted for UC evaluation using AUS were as follows:1) bowel wall stratification, 2) bowel wall thickness, 3) bowel wall flow at power Doppler, 4) presence of increased brightness of inflammatory fat, and 5) presence of mesenteric lymph node swelling greater than 5mm. Subsequently, we developed a new AUS index for UC, termed the UCUS score, which comprises the aforementioned five indices. Finally, we compared the UCUS score with representative endoscopic indices, the Mayo endoscopic sub-score, and the Ulcerative Colitis Endoscopic Index of Severity. The results demonstrated that our proposed UCUS score better reflected disease activity than individual items assessed separately. ROC curve analysis revealed a UCUS score cutoff of 3 points. Therefore, a UCUS score of ≥3 points indicates the need for further examination with CS. Conversely, a score below 3 points suggests low disease activity, and in situations when evaluating treatment effectiveness, AUS could potentially substitute for CS. We believe that the UCUS score is an important source of information to understand the patient's condition and to motivate the patient to undergo endoscopy.

The structure and function of awe have been examined by focusing on the average level of outcomes during awe experiences. In the present study, we tested the psychophysiological process of experiencing awe, focusing on time-series changes in skin conductance responses (SCRs), a moment-by-moment measure of sympathetic nervous responses, and pupil diameter, which is dilated or constricted through the sympathetic and parasympathetic nervous system. The responses were measured through an experiment where 77 Japanese university students watched emotional (awe, amusement, or neutral) videos while moving a joystick when they felt supernatural agency or non-agency, examining the underlying psychological processes. We found that experiencing awe was associated with frequent and steep changes in SCRs and frequent changes in pupil diameter. The joystick inclination, the perceptions of the supernatural, was kept at a high level from the start to the end of awe experiences. These results may reflect the psychophysiological processes of awe: the "fluctuation" of the sympathetic nervous system might underlie awe-specific experiences. Our findings shed new light on the mechanisms of the body-mind interaction in awe experiences., (© 2023. The Author(s).)

Afterglow room-temperature emission that is independent of autofluorescence after ceasing excitation is a promising technology for state-of-the-art bioimaging and security devices. However, the low brightness of the afterglow emission is a current limitation for using such materials in a variety of applications. Herein, the continuous formation of condensed triplet excitons for brighter afterglow room-temperature phosphorescence is reported. (S)-(-)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl ((S)-BINAP) incorporated in a crystalline host lattice showed bright green afterglow room-temperature phosphorescence under strong excitation. The small triplet-triplet absorption cross-section of (S)-BINAP in the whole range of visible wavelengths greatly suppressed the deactivation caused by Förster resonance energy transfer from excited states of (S)-BINAP to the accumulated triplet excitons of (S)-BINAP under strong continuous excitation. The steady-state concentration of the triplet excitons for (S)-BINAP reached 2.3 × 10 -2  M, producing a bright afterglow. Owing to the brighter afterglow, afterglow detection using individual particles with sizes approaching the diffraction limit in aqueous conditions and irradiance-dependent anticounterfeiting can be achieved., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N -alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

Background: Awe, a complex emotion, arises in response to perceptually and conceptually vast stimuli that transcend one's current frames of reference, which is associated with subjective psychological phenomena, such as a sense of self and consciousness. This study aimed to develop a Japanese version of the Awe Experience Scale (AWE-S), a widely used questionnaire that robustly measured the state of awe, and simultaneously investigated how the multiple facets of awe related to the narrative representations of awe experiences., Methods: The Japanese AWE-S was created via back-translation and its factor structure and validity was investigated through an online survey in Japan., Results: The results revealed that the Japanese AWE-S consisted of the same six factors as the original (i.e., time, self-loss, connectedness, vastness, physiological, and accommodation) and had sufficient internal consistency, test-retest reliability, construct validity, and also Japan-specific characteristics. The structured topic modeling generated seven potential topics of the descriptions of awe experiences, which were differently associated with each factor of the Japanese AWE-S., Conclusions: Our findings contribute to a deeper understanding of awe and reveal the constructs of awe in Japan through cross-cultural comparisons. Furthermore, this study provides conceptual and methodological implications regarding studies on awe., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Takano R et al.)

Biological nitrogen fixation (BNF) is important to sustain nitrogen fertility of paddy soil and rice yield, while could be affected by nitrogen fertilization. Iron-reducing bacteria, Anaeromyxobacter and Geobacter, are newly found diazotrophic bacteria predominant in paddy soil. Experimental field of this study is a long-term (35 years) nitrogen fertilized (6.0 g N/m 2 /year) and unfertilized paddy field, where ca. 70% of rice yield was obtained yearly in nitrogen unfertilized plot (443 ± 37 g/m 2 ) compared to fertilized plot (642 ± 64 g/m 2 ). Effects of long-term nitrogen fertilization/unfertilization on soil properties related to BNF were investigated with special reference to diazotrophic iron-reducing bacteria. Soil chemical/biochemical properties, soil nitrogen-fixing activity, and community composition of diazotrophic bacteria were similar between nitrogen fertilized and unfertilized plot soils. In both plot soils, Anaeromyxobacter and Geobacter were the most predominant diazotrophs. Their nifD transcripts were detected at similar level, while those of other general diazotrophs were under detection limit. It was concluded that long-term use/unuse of nitrogen fertilizer in this field did not affect the predominance and nitrogen-fixing activity of diazotrophic iron-reducing bacteria, composition of other general diazotrophs, and the resulting soil nitrogen-fixing activity. BNF, primarily driven by diazotrophic iron-reducing bacteria, might significantly contribute to sustain soil nitrogen fertility and rice yield in both plot soils. Appropriate soil management to maintain BNF, including diazotrophic iron-reducing bacteria, will be important for sustainable soil nitrogen fertility and rice production., (© 2023. The Author(s).)

A squarate (sq) bridge was applied to heavy lanthanide (Ln) complexes for possible development of high-performance single-ion magnets (SIMs). A selective synthetic method for lanthanide squarate hydrates [Ln 2 (sq) 3 (H 2 O) 8 ] n (abbreviated as Ln-sq) has been established, where Ln stands for Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu. As the crystallographic analysis clarified, they all form a bilayer polymeric structure, which is isomorphic to known Eu-sq and Tb-sq. The coordination structures are described as an almost ideal square antiprism with D 4d symmetry. Frequency-dependent susceptibility was recorded in alternating-current magnetic measurements for Ln = Tb, Dy, Er, Tm, and Yb. In particular, as for less studied Ln-based SIMs, the effective magnetization-reversal barriers, U eff / k B = 21.4 ± 0.4 K (in a bias field of 1800 Oe) and 57.0 ± 0.4 K (400 Oe), were characterized for Tm-sq and Yb-sq, respectively, according to the Orbach-type relaxation mechanism plus a direct or the Raman mechanism. The barrier found for Yb-sq is the highest among those for all the compounds investigated here, and also regarded as one of the largest values for the Yb-based SIMs known so far. The complete-active-space self-consistent-field (CASSCF) calculation was applied to Tm- and Yb-sq. The ground doublet states with m J = ±6 for the Tm 3+ ion and m J = ±7/2 for the Yb 3+ ion were reproduced.

Threat-awe, a negatively valenced variant of awe, is thought to strengthen social ties among community members. However, few empirical studies have examined the social functions of threat-awe. This study investigated whether threat-awe is linked to interdependent worldviews through feelings of powerlessness in comparison with positive awe. After remembering and describing their experiences of positive-or threat-awe, 486 Japanese participants reported on items regarding a small self, a sense of powerlessness, and interdependent worldviews. The results demonstrated that threat-awe encouraged interdependent worldviews via an increased sense of powerlessness, rather than the small self, compared to the positive awe condition. From textual perspectives, the semantic networks between awe-related and other words differed from the descriptions of threat-awe and positive awe experiences. These results provide a more nuanced understanding of the emotions of awe as well as new insights into human cooperation in the context of disasters., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Takano, Nomura. 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.)

The present study investigated the fracture strength of hybrid abutment crowns (HACs) in the premolar region that were fabricated with different restorative computer-aided design/computer-aided manufacturing (CAD/CAM) materials. The abutment-implant structures were randomly assigned into four groups (n=11 per group): bi-layered zirconia restorations (BL), translucent zirconia (4Y-PSZ) restorations (TZ), lithium disilicate ceramic restorations (LD), and dispersed nanoparticle-filled composite resin restorations (CM). All restorations were adhesively bonded to the titanium abutments. After the restoration-abutment complex was tightened onto the implant, the fracture strength was measured. The TZ (2.06 kN) and LD (1.87 kN) groups had significantly higher median fracture strengths than the BL (1.12 kN) and CM (1.10 kN) groups. In terms of fracture resistance, the 4Y-PSZ and lithium disilicate ceramic monolithic restorations would be superior to bi-layered 3Y-TZP and composite resin monolithic restorations for HACs in the premolar region.

Under aquaculture conditions, Japanese eels ( Anguilla japonica ) produce a high percentage of males. However, females gain higher body weight and have better commercial value than males, and, therefore, a high female ratio is required in eel aquaculture. In this study, we examined the effects of isoflavones, genistein, and daidzein on sex differentiation and sex-specific genes of eels. To investigate the effects of these phytoestrogens on the gonadal sex, we explored the feminizing effects of soy isoflavones, genistein, and daidzein in a dose-dependent manner. The results showed that genistein induced feminization more efficiently than daidzein. To identify the molecular mechanisms of sex-specific genes, we performed a comprehensive expression analysis by quantitative real-time PCR and RNA sequencing. Phenotypic males and females were produced by feeding elvers a normal diet or an estradiol-17β- or genistein-treated diet for 45 days. The results showed that female-specific genes were up-regulated and male-specific genes were down-regulated in the gonads, suggesting that genistein induces feminization by altering the molecular pathways responsible for eel sex differentiation.

Complex formation of 5- tert -butyl-1,3-phenylene bis( tert -butyl nitroxide) and rare-earth (RE) metal ions gave a linear chain where each nitroxide O atom is directly bonded to the RE ion. The bridge was proven to be a ground triplet molecule in the complexes. A hysteresis loop was recorded below 2.8 K as a single-chain magnet for the RE = Tb derivative.

Optimizing linker design is important for ensuring efficient degradation activity of proteolysis-targeting chimeras (PROTACs). Therefore, developing a straightforward synthetic approach that combines the protein-of-interest ligand (POI ligand) and the ligand for E3 ubiquitin ligase (E3 ligand) in various binding styles through a linker is essential for rapid PROTAC syntheses. Herein, a solid-phase approach for convenient PROTAC synthesis is presented. We designed azide intermediates with different linker lengths to which the E3 ligand, pomalidomide, is attached and performed facile PROTACs synthesis by forming triazole, amide, and urea bonds from the intermediates., (© 2022 The Authors. Published by Wiley-VCH GmbH.)

Awe is an emotional response to perceptually vast stimuli that transcend one's current frames of reference. The psychological form and function of awe differ between two types: positive-awe, which arises from perceptually aesthetic experiences (e.g., the beauty of nature, spiritual experiences, or the virtue of a leader), and threat-awe, which is triggered by threatening stimuli (e.g., natural disasters, wrathful god, or a leader's coercive charisma). Here, using functional MRI, we investigated common and distinct neural responses to experiences of positive- and threat-awe, elicited by watching awe-inspiring videos. We found that both awe experiences deactivated the left middle temporal gyrus (MTG) in contrast to control conditions (positive-awe vs. amusement; threat-awe vs. fear), which suggest that awe experiences generally involve the "schema liberation" process since the left MTG plays a critical role in matching existing schema to events. In addition, positive-awe was associated with increased functional connectivity between the MTG and the anterior/posterior cingulate cortex, which are associated with the aesthetic reward process, and the supramarginal gyrus (SMG), which is involved in the self-other representation. Threat-awe was associated with increased functional connectivity between the MTG and amygdala, which detects and processes threat stimuli, as well as between the amygdala and SMG. These findings suggest that the neural mechanisms underlying the complex psychological processes of awe vary as a function of the type of awe. The implications of these results regarding our understanding of the neural basis of awe and the future directions of human social cognition research are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N-methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di-l-tartrate (DS-3801b) was selected as a clinical candidate for further evaluation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Four tetranuclear heterobimetallic triangle complexes [L 3 Co 3 Dy(NO 3 ) 2 (H 2 O)(MeOH) 5 ](NO 3 ) (C1), [L 3 Co 3 Gd(NO 3 ) 3 (MeOH) 4 ] (C2), [L 3 Co 3 La(NO 3 ) 2 (H 2 O) 6 ](NO 3 )(H 2 O) (C3), and [L 3 Co 3 TbCl(NO 3 ) 2 (H 2 O) 0.5 (MeOH) 3.5 ] (C4), where H 2 L = 1,4-bisformylnaphthalene-2,3-diol, have been synthesised and structurally characterised. Each complex crystallises with a complete molecule in the asymmetric unit ( Z ' = 1) and displays near perfect octahedrality in two out of three Co II centres. The third Co II ion assumes a different coordination geometry in each complex: six-coordinate octahedral in C1, six-coordinate with a distortion towards trigonal prismatic in C2, five-coordinate trigonal bipyramidal in C3, and five-coordinate square pyramidal in C4; which has been attributed to increasing lanthanide cation size, coupled with a non-macrocyclic coordination environment. Continuous Shape Measurement (CShM) calculations and octahedral distortion parameter calculations were performed, using the SHAPE and OctaDist software packages, respectively, in order to aid in the assessment of each metal centre's local coordination geometry. The preliminary magnetic investigation of C3 found χ m T = 9.4 cm 3 K mol -1 at 300 K and M = 7.1 μ B at 1.8 K, which are approximately two thirds the maximum theoretical values for three Co II ions and indicates the presence of a relatively large zero-field splitting parameter ( D / k B = 65 K) operative in each Co II ion rather than exchange coupling between the Co II centres., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

We report the synthesis and characterization of seven new tetranuclear 3d-4f complexes derived from the 3:3:1 reaction of 1,4-diformylnaphthalene-2,3-diol (H 2 L ) with copper(II) nitrate and a lanthanide salt, Ln = Tb [ L 3 Cu 3 TbCl 2 (NO 3 ) 2 (H 2 O) 2 ] ( C1 ), Ho [ L 3 Cu 3 HoCl 3 (H 2 O) 3 (MeOH)](H 2 O) ( C2 ), Er [ L 3 Cu 3 ErCl 3 (H 2 O) 3.5 (MeOH) 0.5 ](H 2 O) ( C3 ), Gd [ L 3 Cu 3 Gd(NO 3 ) 2 (H 2 O) 2 (MeOH)](NO 3 ) ( C4 ), Dy [ L 3 Cu 3 Dy(NO 3 ) 2 (H 2 O) 2 (MeOH)](NO 3 ) ( C5 ), Yb [ L 3 Cu 3 Yb(NO 3 ) 2 (H 2 O) 2 (MeOH)](NO 3 ) ( C6 ), and La [ L 3 Cu 3 La(NO 3 ) 2 (H 2 O) 2 (MeOH)](NO 3 ) ( C7 ). Structural elucidation showed that the self-assembly using the acyclic ligand system was successful for all seven complexes, which exhibit the same near-planar Cu 3 LnO 12 core. Five complexes ( C1 , C2 , and C4 - C6 ) were magnetically characterized at 300 K and 1.8 K. Complexes C1 , C4 , and C5 were observed to have ferromagnetic ground states and showed appreciable frequency dependence in their AC magnetic measurements, which yielded effective barriers between 7.82(4) and 13.2(3) K, confirming the presence of single-molecule magnet properties., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

The synthesis and structural characterisation of four new heterometallic tetranuclear complexes is reported. Three L 3 Ni 3 Ln type complexes, where Ln = La (C1), Eu (C2), and Gd (C3), have been fully characterised including DC and AC magnetic measurements. A fourth complex featuring a diamagnetic Ba II ion at its centre is also reported with structural characterisation. Structural elucidation showed that all four complexes successfully self-assembled from a stoichiometric mixture of the acyclic ligand, 1,4-diformylnaphthalene-2,3-diol, with nickel(II) nitrate and the appropriate heavy metal salt to produce the same near planar Ni 3 MO 12 core. Ferromagnetic interactions were found to dominate the ground state of C3, exhibiting a maximal spin ground state of 13/2. The exchange coupling is quantitatively discussed along with the nickel(II) zero-field splitting effect. AC magnetic susceptibility experiments were carried out, but no frequency dependent signals were observed and thus no observable slow relaxation of magnetisation.

Abstract: The Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) was recently reported as a new scoring system to evaluate the mucosal lesions of patients with Crohn's disease (CD). We investigated whether CECDAI is useful for assessing the necessity of early additional treatment in patients with CD in clinical remission.Twenty-one patients with small intestinal CD in clinical remission underwent capsule endoscopy (CE). The CECDAI and Lewis score (LS) were used to evaluate the intestinal lesions. We analyzed the correlations between several biomarkers and CECDAI or LS and examined the changes in therapeutic regimens based on the CECDAI.CE identified intestinal abnormalities in most CD patients in clinical remission: 81.0% and 85.7%, as assessed using CECDAI and LS, respectively. A significant positive correlation was observed between the CDAI and LS (P = .025), as well as between CDAI and CECDAI (P = .014) in these cases. Compared to LS, CECDAI scores were more evenly distributed. No significant correlations were observed between endoscopic scores and serum markers, including CRP, hemoglobin, and albumin levels. Additional treatment was performed significantly more often in patients with moderate-severe disease activity (CECDAI ≥5.8) (P = .012) than in those with normal (CECDAI <3.5) and mild (3.5≤CECDAI<5.8) disease activity. Resection of the small intestine did not affect the small bowel transit time or CE score.CECDAI is useful in evaluating mucosal lesions in small bowel CD patients in clinical remission and helps in assessing the requirement for additional treatment for these patients, including those who undergo intestinal resection., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

While molecular oxygen is essential for aerobic organisms, its utilization is inseparably connected with generation of oxidative insults. To cope with the detrimental aspects, cells evolved antioxidative defense systems, and insufficient management of the oxidative insults underlies the pathogenesis of a wide range of diseases. A battery of genes for this antioxidative defense are regulated by the transcription factors nuclear factor-erythroid 2-like 1 and 2 (NRF1 and NRF2). While the regulatory steps for the activation of NRFs have been investigated with particular emphasis on nuclear translocation and proteosomal degradation, unknown redundancy may exist considering the indispensable nature of these defense systems. Here we unraveled that C-terminal binding protein 2 (CtBP2), a transcriptional cofactor with redox-sensing capability, is an obligate partner of NRFs. CtBP2 forms transcriptional complexes with NRF1 and NRF2 that is required to promote the expression of antioxidant genes in response to oxidative insults. Our findings illustrate a basis for understanding the transcriptional regulation of antioxidative defense systems that may be exploited therapeutically., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this short communication., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Adalimumab (ADA) trough level and anti-ADA antibody (AAA) positivity influence mucosal healing and loss of response in patients with inflammatory bowel disease (IBD). In this study, we clarified the correlation between ADA monitoring, including non-trough level, and real-world IBD clinical outcomes. This retrospective, observational, single-center study involved patients with ulcerative colitis (19) and Crohn's disease (33) treated with ADA from January 2007 to August 2018. Serum ADA and AAA levels were measured 4‒14 days after ADA administration. The AAA positivity rate was 23.1% (12/52). ADA continuity was higher in AAA-negative patients than in AAA-positive patients (P = 0.223). Receiver operating characteristic (ROC) analysis revealed that a serum AAA cut-off of 9.2 μg/mL was associated with ADA continuity. The ADA level was significantly higher in the endoscopic remission group than in the non-remission group (P = 0.02). Based on the ROC curve analysis results of serum ADA level and endoscopic remission, the cut-off value of the serum ADA level was set to 11.1 μg/mL. Under the combined use of ADA with immunomodulators and AAA positivity, ADA continuity was significantly higher when the serum AAA level at 4-14 days after ADA administration was ≥9.2 μg/mL. Furthermore, endoscopic remission can be expected with a serum ADA level of ≥11.1 μg/mL. Overall, to predict clinical outcomes, it would be useful to measure the blood level of ADA regardless of the timing of the trough., Competing Interests: The authors have declared that no competing interests exist.

Awe is an emotional response to perceptually vast stimuli that transcend one's current frames of reference. Previous research indicated that awe promotes a smaller self, which led to the creation of a small-self hypothesis. Thus, we shed new light on this hypothesis in terms of sense of body ownership using a rubber hand illusion experiment; through it, we showed that awe evokes an increased sense of body ownership over the rubber hand and this effect was prominent among participants who experienced small self. Our findings suggest that awe might provoke a "liberation of the self" in terms of a sense of body ownership as awe has been thought to liberate existing schemas, hence informing the demonstrable implications of the psychological mechanisms of awe.

This study investigated the influence of roughening procedures and application of primers on shear bond strengths of CAD/CAM composite resin material or ceramic material to zirconia frameworks. A CAD/CAM composite resin block (Katana Avencia Block; AVE) and lithium disilicate glass-ceramic block (IPS e.max CAD; IEC) were used as veneer materials. The veneers were divided into three surface treatment groups; HF, hydrofluoric acid etching; AB, airborne-particle abrasion; and CON, no surface treatment. Each veneer was primed with four agents: Clearfil Porcelain Bond Activator (ACT), Clearfil Photo Bond (CPB), Clearfil Photo Bond with Porcelain Bond Activator (CPB+ACT), and no priming (UP). The zirconia frameworks and AVE or IEC veneers were resin-bonded. In the AVE specimen, AB treatment showed significantly higher shear bond strength than the other treatments at 0 and 20,000 thermocycles, except for UP and CPB+ACT groups at 20,000 thermocycles. Airborne-particle abrasion is necessary for resin bonding to Avencia blocks.

Purpose: Portal vein thrombosis (PVT) following hepatectomy is potentially life-threatening. We aimed to evaluate the incidence of PVT after hepatectomy for hepatocellular carcinoma and identify coagulation and fibrinolytic factors that could predict early-stage postoperative PVT., Methods: A retrospective analysis was conducted on 65 hepatocellular carcinoma patients who underwent radical hepatectomy. The risk factors for postoperative PVT were identified based on univariate and multivariate analyses, and the levels of coagulation and fibrinolytic factors were measured during the perioperative period., Results: The incidence of PVT after hepatectomy was 20.0%. The patients were divided into two groups: those with PVT (n=13; PVT group) and those without PVT (n=52; no-PVT group). The frequency of the use of the Pringle maneuver during surgery was higher in the PVT group than in the no-PVT group, and the postoperative/preoperative ratios of thrombin-antithrombin III complex (TAT) and of D-dimer were significantly higher in the PVT group., Conclusion: A high incidence of PVT was found in hepatocellular carcinoma patients after hepatectomy. The frequency of the Pringle maneuver is a potential risk factor for postoperative PVT, and the postoperative/preoperative TAT and D-dimer ratios may be used as early predictors of PVT after hepatectomy for hepatocellular carcinoma.

This study determined the shear bond strength (SBS) between an indirect gingival composite resin and glazed gingival porcelain after various surface treatments. A total of 176 porcelain disks with natural glazing were used and assigned to one of four groups: no surface treatment, airborne-particle abrasion, hydrofluoric acid etching, or a combination of airborne-particle abrasion followed by hydrofluoric acid etching. Each group was divided into two subgroups: one subgroup was unprimed, and the other was silanized. An indirect composite resin was then bonded to the porcelain disks. Half of the specimens in each group (n = 11) were exposed to 5000 thermocycles. SBSs were measured, and data were analyzed with the Kruskal-Wallis and Steel-Dwass tests. Among silanized specimens, those treated with the combination of airborne-particle abrasion and hydrofluoric acid etching exhibited the highest bond strengths both before and after thermocycling. However, the SBS values of the silanized and unprimed hydrofluoric acid etched specimens did not differ significantly. Airborne-particle abrasion followed by hydrofluoric acid etching with silane application yielded stronger, more durable bonds between the indirect gingival composite resin and glazed gingival porcelain., (© 2021 European Journal of Oral Sciences.)

We identified (5R)-6-methyl-5-phenyl-1,3,4,5,6,7-hexahydro-2,5-methano-2,6-benzodiazonine (DS21980956: 4-(R)) as a novel [5.2.1]bicyclic basic compound. The scaffold was inspired by fentanyl or pethidine, which possess potent analgesic activities. DS21980956 had potent analgesic activity in the mouse acetic acid writhing test or tail flick test without agonistic activity at the µ opioid receptor (MOR). The mechanism of analgesic action of DS21980956 was considered to differ from a biased ligand, for example, TRV-130 (3, oliceridine)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Malaria remains one of the most important infectious diseases in the world. In 2017 alone, approximately 219 million people were infected with malaria, and 435,000 people died of this disease. Plasmodium falciparum, which causes falciparum malaria, is becoming resistant to artemisinin (ART) in Southeast Asia; therefore, new antimalarial drugs are urgently needed. Some excellent antimalarial drugs, such as quinine and ART, were originally obtained from plants. Hence, we analyzed the antimalarial effects of marine natural products to find new antimalarial agents. We used a malaria growth inhibition assay to determine the antimalarial ability and half-maximal inhibitory concentration (IC50) values of the marine organism-derived compounds. Three compounds (kapakahine A, kapakahine B, and kulolide-1) showed antimalarial effects, and one (kapakahine F) showed selective antimalarial effects on the Dd2 clone. Although the IC50 values obtained for these compounds were greater than that of ART, their potency against P. falciparum is sufficient to warrant further investigation of these compounds as possible drug leads., (© American Society of Parasitologists 2021.)

Background & Aims: The new curcumin derivative Theracurmin® has a 27-fold higher absorption rate than natural curcumin powder. Theracurmin® is an inhibitor of nuclear factor-κB, which mediates the expression of inflammatory cytokines. The effect of Theracurmin® on inflammatory bowel disease in humans has not been explored; therefore, we investigated the efficacy and safety of Theracurmin® in patients with Crohn's disease., Methods: In this randomized, double-blinded study performed at 5 independent medical centers in Japan, Theracurmin® (360 mg/day, n = 20) or placebo (n = 10) was administered to patients with active mild-to-moderate Crohn's disease for 12 weeks. The agent's efficacy was assessed by evaluating clinical and endoscopic remission, healing of anal lesions, and blood levels of inflammatory markers., Results: In the Theracurmin® group, a significant reduction in clinical disease activity was observed in week 12 relative to that in week 0 (p = 0.005). On intention-to-treat analysis, clinical remission rates were 35%, 40%, and 40% at weeks 4, 8, and 12, respectively, which were significantly higher than those in the placebo group (all 0%; p = 0.033, p = 0.020, and p = 0.020, respectively). Furthermore, reduction in endoscopic Crohn's disease severity (p = 0.032) was observed at week 12 in the Theracurmin® group. The endoscopic remission rates were 15% and 0% in the Theracurmin® and placebo groups, respectively. Significant healing of anal lesions (p = 0.017) was observed at week 8 in the Theracurmin® group. No serious adverse events were observed in either group throughout the study., Conclusions: Theracurmin® shows significant clinical and endoscopic efficacy together with a favorable safety profile in patients with active mild-to-moderate Crohn's disease., Clinical Trial Umin Registration Id: UMIN000015770., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Primary racemose hemangioma of the bronchial artery is a rare congenital disease that is occasionally complicated by aneurysms. An asymptomatic 78-year-old man was referred to our hospital with an esophageal submucosal tumor that was endoscopically found in the upper thoracic esophagus in a health check-up. Physical examination findings were unremarkable. Contrast-enhanced chest computed tomography with three-dimensional image reconstruction and selective bronchial arteriography resulted in a definitive diagnosis of primary racemose hemangiomas of the bronchial arteries accompanied by left bronchial artery aneurysm. Because rupture of a bronchial artery aneurysm can cause critical life-threatening hemorrhage, bronchial arterial embolization using coils and a mixture of N-butyl-2-cyanoacrylate and iodized oil was thus performed for bronchial artery aneurysm. Postoperative course was uneventful, and the patient was discharged on the third postoperative day. Computed tomography performed after 6 months revealed no enhancement of the aneurysms. In conclusion, we report a case of an asymptomatic primary racemose hemangioma of the bronchial artery accompanied by an aneurysm that mimicked a submucosal esophageal tumor. We also reviewed other Japanese case of primary racemose hemangioma of the bronchial artery accompanied by aneurysm based on the literature.

Purpose: The effects of ulcerative colitis (UC) duration on biomarker accuracy are unknown. We investigated the effects of UC duration on the predictive accuracy of biomarkers including immunochemical fecal occult blood test (FOBT, also known as FIT), prostaglandin E-major urinary metabolite (PGE-MUM), and C-reactive protein (CRP)., Methods: We divided 133 samples into groups based on disease duration. Clinical and endoscopic remission was defined as Lichtiger's clinical activity index (CAI) of ≤ 4, Mayo endoscopic subscore (MES) of 0, and UC endoscopic index of severity (UCEIS) of ≤ 1., Results: FIT results were significantly correlated with all activity scores when the disease duration was < 4 years. When the disease duration was ≥ 4 years, FIT results were significantly correlated with the CAI and MES but not with UCEIS. When the disease duration was ≥ 5 years, FIT and CAI were significantly correlated, whereas FIT and MES or FIT and UCEIS did not show any correlation. When the duration was ≥ 4 years, PGE-MUM and CRP showed a significant correlation with CAI, MES, and UCEIS. Receiver operating characteristic curve analysis of biomarker data for predicting endoscopic remission showed that the accuracy of FIT was superior to that of PGE-MUM and CRP in the < 4-year group., Conclusions: FIT is an accurate biomarker reflecting the endoscopic score until 4 years in patients with UC. However, owing to the increased number of false negatives, the usefulness of FIT may decline after 4 years. Hence, evaluation of UC in combination with other biomarkers is recommended.

Amorphous solid dispersions (ASD) are increasingly used to improve the oral bioavailability of poorly water-soluble compounds. However, hydrophilic polymers in ASD have high water-binding properties and, upon water contact, they often form a gel on the surface of the tablet, impacting the rate and extent of drug release. Most inorganic salts decrease water solubility of organic solutes, changing the gel properties of hydrophilic polymers. In this study, the effect of inorganic salts on drug release from a tablet formulation containing an itraconazole (ITZ)-hydroxypropyl methyl cellulose (HPMC) extrudate was investigated. The cloud point of a 1% HPMC solution with and without inorganic salts (KCl, KH 2 PO 4 , KHCO 3 , and potassium iodate (KI)) was determined to classify the salts according to their salting-out or salting-in effect. A kosmotropic effect on HPMC was observed for KCl, KH 2 PO 4 , and KHCO 3 , whereas KI exhibited a chaotropic effect. To prove the effect of these salts on drug release, tablets containing 66% of ITZ-HPMC extrudate (20:80 w/w %), 4% croscarmellose sodium, 30% microcrystalline cellulose, and different types and amounts of KHCO 3 , KH 2 PO 4 , KCl, and KI were compressed (same solid fraction of 0.83-0.85). Tablets without salts showed a slow release and low peak concentrations during dissolution in simulated gastric fluids. By adding the kosmotropic salts to the tablets, the rate and extent of drug release were increased, whereas the chaotropic anion iodide had no effect. The effect was pronounced even with the addition of as little as 2% of inorganic salts and tended to increase with the increasing amount of salt in the formulation. Tablets without salt stored under either dry or humid conditions exhibited a large difference in dissolution profiles, whereas little variation was observed for tablets with kosmotropic salts. In conclusion, the effect of inorganic salts was mechanistically clarified on ASD containing commonly used HPMC. This approach can be beneficial to successfully develop robust formulations containing ASD.

Background: Prostaglandin E-major urinary metabolite (PGE-MUM) may be a novel biomarker for evaluating disease activity in ulcerative colitis (UC). We compared its usefulness to that of the fecal immunochemical occult blood test (FIT)., Methods: PGE-MUM and FIT measurements were performed of 92 urinary and fecal samples obtained from 60 patients with UC. Endoscopic activity was determined by Mayo endoscopic subscore (eMayo) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score., Results: PGE-MUM levels and FIT results showed a significant correlation with respect to eMayo (P <  0.001 and P < 0.001, respectively), and there was a significant difference in PGE-MUM values between the groups below eMayo1 and above eMayo2 (P = 0.012). Both biomarkers were significantly correlated with the UCEIS score (P < 0.001 and P < 0.001, respectively), and the PGE-MUM values were significantly different between groups below UCEIS1 and above UCEIS2 (P = 0.012). PGE-MUM and FIT were significantly correlated with eMayo in the group with a disease duration < 5 years (P = 0.041 and P < 0.001, respectively). Although PGE-MUM and eMayo differed significantly between groups over 5 years (P = 0.012), FIT was not correlated with eMayo (P = 0.101)., Conclusions: PGE-MUM is useful as a biomarker as FIT for evaluating the endoscopic activity, particularly in long-term affected patients with UC.

The pathogenesis of malaria parasites depends on host erythrocyte modifications that are facilitated by parasite proteins exported to the host cytoplasm. These exported proteins form a trafficking complex in the host cytoplasm that transports virulence determinants to the erythrocyte surface; this complex is thus essential for malaria virulence. Here, we report a comprehensive interaction network map of this complex. We developed authentic, unbiased, highly sensitive proteomic approaches to determine the proteins that interact with a core component of the complex, SBP1 (skeleton-binding protein 1). SBP1 interactomes revealed numerous exported proteins and potential interactors associated with SBP1 intracellular trafficking. We identified several host-parasite protein interactions and linked the exported protein MAL8P1.4 to Plasmodium falciparum virulence in infected erythrocytes. Our study highlights the complicated interplay between parasite and host proteins in the host cytoplasm and provides an interaction dataset connecting dozens of exported proteins required for P. falciparum virulence., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Elderly people show a decline in the ability to decode facial expressions, but also experience age-related facial structure changes that may render their facial expressions harder to decode. However, to date there is no empirical evidence to support the latter mechanism. The objective of this study was to assess the effects of age on facial morphology at rest and during smiling, in younger (n = 100; age range, 18-32 years) and older (n = 30; age range, 55-65 years) Japanese women. Three-dimensional images of each subject's face at rest and during smiling were obtained and wire mesh fitting was performed on each image to quantify the facial surface morphology. The mean node coordinates in each facial posture were compared between the groups using t-tests. Further, the node coordinates of the fitted mesh were entered into a principal component analysis (PCA) and a multifactor analysis of variance (MANOVA) to examine the direct interactions of aging and facial postures on the 3D facial morphology. The results indicated that there were significant age-related 3D facial changes in facial expression generation and the transition from resting to smiling produced a smaller amount of soft tissue movement in the older group than in the younger group. Further, 185 surface configuration variables were extracted and the variables were used to create four discriminant functions: the age-group discrimination for each facial expression, and the facial expression discrimination for each age group. For facial expression discrimination, the older group showed 80% accuracy with 2 of 66 significant variables, whereas the younger group showed 99% accuracy with 15 of 144 significant variables. These results indicate that in both facial expressions, the facial morphology was distinctly different in the younger and older subjects, and that in the older group, the facial morphology during smiling could not be as easily discriminated from the morphology at rest as in the younger group. These results may help to explain one aspect of the communication dysfunction observed in older people., Competing Interests: The authors declare the following interest: "This work was partially supported by Shiseido Co., ltd. ST, RT, and HY are employed by Shiseido Co., ltd. Further, the funder (Shiseido Co., ltd.) and Osaka University have submitted a patent application based on the results of the present study (Device, method, program, and system for determining three-dimensional facial form, PCT/JP2019/012719). This does not alter our adherence to PLoS ONE policies on sharing data and materials.