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Generation of dihydrogen from water splitting, also known as water reduction, is a key process to access a sustainable hydrogen economy for energy production and usage. The key step is the selective reduction of a protic hydrogen to an accessible and reactive hydride, which has proven difficult at a p-block element. Although frustrated Lewis pair (FLP) chemistry is well known for water activation by heterolytic H-OH bond cleavage, to the best of our knowledge, there has been only one case showing water reduction by metal-free FLP systems to date, in which silylene (Si II ) was used as the Lewis base. This work reports the molecular design and synthesis of an ortho -phenylene linked bisborane-functionalized phosphine, which reacts with water stoichiometrically to generate H 2 and phosphine oxide quantitatively under ambient conditions. Computational investigations revealed an unprecedented multi-centered electron relay mechanism offered by the molecular framework, shuttling a pair of electrons from hydroxide (OH - ) in water to the separated proton through a borane-phosphonium-borane path. This simple molecular design and its water reduction mechanism opens new avenues for this main-group chemistry in their growing roles in chemical transformations., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Multiple sclerosis is an organ-specific autoimmune disease that targets the myelin antigen in the central nervous system. Nobiletin is a dietary polymethoxylated flavonoid found in citrus fruits. In this study, we investigated how nobiletin affects the disease state and immune responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis mice. Nobiletin was administered orally from 14 days before immunization until the end of the experiment, and clinical scores were determined. The production levels of interleukin-17A and interferon-γ were measured in a culture supernatant of splenocytes stimulated with myelin oligodendrocyte glycoprotein. In addition, flow cytometric analysis was performed to examine the effect of nobiletin on T cell differentiation in vitro . Admin-istration of nobiletin significantly decreased the clinical score and interleukin-17A production in splenocytes. Furthermore, in vitro analysis showed that nobiletin significantly suppressed Th17 cell differentiation and interleukin-17A production in a dose-dependent manner. The results suggest that nobiletin attenuates experimental autoimmune encephalomyelitis severity through modulation of Th17 cell differentiation., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2021 JCBN.)

Whole-genome duplication and genome compaction are thought to have played important roles in teleost fish evolution. Ayu (or sweetfish), Plecoglossus altivelis, belongs to the superorder Stomiati, order Osmeriformes. Stomiati is phylogenetically classified as sister taxa of Neoteleostei. Thus, ayu holds an important position in the fish tree of life. Although ayu is economically important for the food industry and recreational fishing in Japan, few genomic resources are available for this species. To address this problem, we produced a draft genome sequence of ayu by whole-genome shotgun sequencing and constructed linkage maps using a genotyping-by-sequencing approach. Syntenic analyses of ayu and other teleost fish provided information about chromosomal rearrangements during the divergence of Stomiati, Protacanthopterygii and Neoteleostei. The size of the ayu genome indicates that genome compaction occurred after the divergence of the family Osmeridae. Ayu has an XX/XY sex-determination system for which we identified sex-associated loci by a genome-wide association study by genotyping-by-sequencing and whole-genome resequencing using wild populations. Genome-wide association mapping using wild ayu populations revealed three sex-linked scaffolds (total, 2.03 Mb). Comparison of whole-genome resequencing mapping coverage between males and females identified male-specific regions in sex-linked scaffolds. A duplicate copy of the anti-Müllerian hormone type-II receptor gene (amhr2bY) was found within these male-specific regions, distinct from the autosomal copy of amhr2. Expression of the Y-linked amhr2 gene was male-specific in sox9b-positive somatic cells surrounding germ cells in undifferentiated gonads, whereas autosomal amhr2 transcripts were detected in somatic cells in sexually undifferentiated gonads of both genetic males and females. Loss-of-function mutation for amhr2bY induced male to female sex reversal. Taken together with the known role of Amh and Amhr2 in sex differentiation, these results indicate that the paralog of amhr2 on the ayu Y chromosome determines genetic sex, and the male-specific amh-amhr2 pathway is critical for testicular differentiation in ayu., Competing Interests: The authors have declared that no competing interests exist.

Intravascular ultrasound (IVUS) is a diagnostic modality used during percutaneous coronary intervention. However, specialist skills are required to interpret IVUS images. To address this issue, we developed a new artificial intelligence (AI) program that categorizes vessel components, including calcification and stents, seen in IVUS images of complex lesions. When developing our AI using U-Net, IVUS images were taken from patients with angina pectoris and were manually segmented into the following categories: lumen area, medial plus plaque area, calcification, and stent. To evaluate our AI's performance, we calculated the classification accuracy of vessel components in IVUS images of vessels with clinically significantly narrowed lumina (< 4 mm2) and those with severe calcification. Additionally, we assessed the correlation between lumen areas in manually-labeled ground truth images and those in AI-predicted images, the mean intersection over union (IoU) of a test set, and the recall score for detecting stent struts in each IVUS image in which a stent was present in the test set. Among 3738 labeled images, 323 were randomly selected for use as a test set. The remaining 3415 images were used for training. The classification accuracies for vessels with significantly narrowed lumina and those with severe calcification were 0.97 and 0.98, respectively. Additionally, there was a significant correlation in the lumen area between the ground truth images and the predicted images (ρ = 0.97, R2 = 0.97, p < 0.001). However, the mean IoU of the test set was 0.66 and the recall score for detecting stent struts was 0.64. Our AI program accurately classified vessels requiring treatment and vessel components, except for stents in IVUS images of complex lesions. AI may be a powerful tool for assisting in the interpretation of IVUS imaging and could promote the popularization of IVUS-guided percutaneous coronary intervention in a clinical setting., Competing Interests: The authors have declared that no competing interests exist.

A biomimetic of endogenous tissue inhibitors of metalloproteinases (TIMPs) was engineered by introducing three binding elements to a synthetic tetrapolymer. We evaluated the contribution of composition, size, and shape of the TIMP-mimicking polymers to the inhibition of BaP1, a P-I class snake venom metalloproteinase (SVMP). Inhibition was achieved when the size of the linear polymer (LP) was comparable to or greater than that of the enzyme, indicating the efficacy requires binding to a significant portion of the enzyme surface in the vicinity of the active site. The efficacy of a low cross-linked polymer hydrogel nanoparticle (NP) of substantially greater molecular weight was comparable to that of the LPs despite differences in size and shape, an important finding for in vivo applications. The abiotic TIMP was effective against two classes of SVMPs in whole snake venom. The results can serve as a design principle for biomimetic polymer inhibitors of enzymes.

Meridional tridentate N-heterocyclic carbene (NHC)-based pincer ligands contribute to a substantial growth in modern organometallic chemistry in both homogeneous catalysis and luminescence materials. Among all NHC-based pincer ligands, the dianionic LX 2 -type CCC-pincer ones constitute the smallest subcategory owing to their limited ligand frameworks suitable for complexation. This work reports a one-pot, high-yield synthesis of a homoleptic anionic all-carbon bis-pincer iridium(III) complex ( 4 ) directly from a bis(aryl)-substituted dipyrido-annulated (dpa Ar2 ) imidazolium salt and [Ir(COD)Cl] 2 via a cascade of deprotonation/C-H activation processes. Both experimental complexation chemistry and computational mechanistic investigation suggest that the large bite angle and π-rich character of the dpa Ar2 NHC are responsible for its facile complexation as a dianionic LX 2 -type CCC-pincer ligand precursor. The all-carbon ligated iridium(III) complex ( 4 ) bearing a π-conjugated ligand scaffold showed remarkably low oxidation potentials, which allows future investigations in its redox chemistry and photophysical properties.

Purpose: Tamibarotene is a synthetic retinoid that inhibits proliferation and induces differentiation of malignant cells by binding to the retinoic acid receptor α/β. Previous in vitro studies have shown that some pediatric solid tumors with retinoic acid receptors differentiate in response to retinoic acid. We conducted a phase I dose-escalation study to determine the recommended dose of tamibarotene for further study in pediatric and young adult patients with recurrent/refractory solid tumors., Methods: Pediatric and young adult patients with recurrent/refractory solid tumors were administered tamibarotene at 4, 6, 8, 10, and 12 mg/m 2 /day for 14 or 21 days of a 28 day cycle. Safety, efficacy, and pharmacokinetics of tamibarotene were evaluated., Results: Twenty-two patients (median age 8 years) were enrolled in this study. No dose-limiting toxicity (DLT) was encountered, and tamibarotene was generally well tolerated. Two patients experienced severe adverse events (AEs), leading to discontinuation of the treatment. One grade 4 venous thrombosis and one grade 2 erythema multiforme were observed, which promptly resolved after tamibarotene discontinuance. The grade 4 venous thrombosis was a severe AE but not DLT because it occurred after the evaluation period. Pharmacokinetic analyses showed a dose-dependent increase in the maximum drug concentration (C max ) and area under the concentration-time curve (AUC). None of the patients achieved a complete response or partial response. Seven patients had stable disease lasting longer than 18 weeks., Conclusions: The recommended dose for phase II study of tamibarotene in pediatric and young adult patients with refractory solid tumors is 12 mg/m 2 /day for 21 days in a 28 day cycle.

The study of sex determination and sex chromosome organization in nonmodel species has long been technically challenging, but new sequencing methodologies now enable precise and high-throughput identification of sex-specific genomic sequences. In particular, restriction site-associated DNA sequencing (RAD-Seq) is being extensively applied to explore sex determination systems in many plant and animal species. However, software specifically designed to search for and visualize sex-biased markers using RAD-Seq data is lacking. Here, we present RADSex, a computational analysis workflow designed to study the genetic basis of sex determination using RAD-Seq data. RADSex is simple to use, requires few computational resources, makes no prior assumptions about the type of sex-determination system or structure of the sex locus, and offers convenient visualization through a dedicated R package. To demonstrate the functionality of RADSex, we re-analysed a published data set of Japanese medaka, Oryzias latipes, where we uncovered a previously unknown Y chromosome polymorphism. We then used RADSex to analyse new RAD-Seq data sets from 15 fish species spanning multiple taxonomic orders. We identified the sex determination system and sex-specific markers in six of these species, five of which had no known sex-markers prior to this study. We show that RADSex greatly facilitates the study of sex determination systems in nonmodel species thanks to its speed of analyses, low resource usage, ease of application and visualization options. Furthermore, our analysis of new data sets from 15 species provides new insights on sex determination in fish., (© 2021 John Wiley & Sons Ltd.)

To explore impact of enhancing social advancement of females in Japan, this study determined the effects of the dual-income household rate on suicide mortalities disaggregated by attributes of gender, age, and motives between 2009 and 2017 in Japan. This study analysed impact of dual-income household rate, other household-related factors (savings, liabilities and yearly incomes per household, minors and elderly rate per household), and social/employment factors (complete unemployment rate, employment rate, temporary male and female employment rates and certification rate of long-term care insurance) on suicide mortalities disaggregated by attributes of gender, age, and motives using hierarchical linear-regression model. Dual-income household rate was significantly/negatively related to suicide mortality of the working-age female population, but significantly/positively related to that of the elderly female population. Suicide mortalities of the working-age male population and the elderly male population were significantly/positively related to dual-income household rate. Male suicide mortalities caused by family-, health-, economy- and employment-related motives were significantly/positively related to dual-income household rate; however, the dual-income household rate was significantly/positively related to female suicide mortalities caused by family-, health-, economy- and school-related motives, but significantly/negatively related to suicide mortalities caused by romance-related motives. Dual-income households suppress social-isolation and develop economical/psychological independence of females, leading to reduced suicide mortality in working-age females. However, elderly and school-age populations, who are supported by the working-age female, suffer from isolation. Working-age males also suffer from inability to adapt from the traditional concept of work-life and work-family balances to the novel work-family balance concept adapted to dual-income households. These results suggest occurrence of new social/family problems in the 21st century due to vulnerability of traditional Japanese culture and life-working-family balance concepts as well as novel sociofamilial disturbances induced by declining birth rate and ageing population in Japan.

Why can beetles such as the ladybird beetle Coccinella septempunctata walk vertically or upside-down on a smooth glass plane? Intermolecular and/or capillary forces mediated by a secretion fluid on the hairy footpads have commonly been considered the predominant adhesion mechanism. However, the main contribution of physical phenomena to the resulting overall adhesive force has yet to be experimentally proved, because it is difficult to quantitatively analyse the pad secretion which directly affects the adhesion mechanism. We observed beetle secretion fluid by using inverted optical microscopy and cryo-scanning electron microscopy, which showed the fluid secretion layer and revealed that the contact fluid layer between the footpad and substrate was less than 10-20 nm thick, thus indicating the possibility of contribution of intermolecular forces. If intermolecular force is the main physical phenomenon of adhesion, the force will be proportional to the work of adhesion, which can be described by the sum of the square roots of dispersive and polar parts of surface free energy. We measured adhesion forces of ladybird beetle footpads to flat, smooth substrates with known surface free energies. The adhesive force was proportional to the square-root of the dispersive component of the substrate surface free energy and was not affected by the polar component. Therefore, intermolecular forces are the main adhesive component of the overall adhesion force of the ladybird beetle. The footpads adhere more strongly to surfaces with higher dispersive components, such as wax-covered plant leaves found in the natural habitat of ladybird beetles. Based on the present findings, we assume ladybird beetles have developed this improved performance as an adaptation to the variety of plant species in its habitat.

Deep learning models can be applied to electrocardiograms (ECGs) to detect left ventricular (LV) dysfunction. We hypothesized that applying a deep learning model may improve the diagnostic accuracy of cardiologists in predicting LV dysfunction from ECGs. We acquired 37,103 paired ECG and echocardiography data records of patients who underwent echocardiography between January 2015 and December 2019. We trained a convolutional neural network to identify the data records of patients with LV dysfunction (ejection fraction < 40%) using a dataset of 23,801 ECGs. When tested on an independent set of 7,196 ECGs, we found the area under the receiver operating characteristic curve was 0.945 (95% confidence interval: 0.936-0.954). When 7 cardiologists interpreted 50 randomly selected ECGs from the test dataset of 7,196 ECGs, their accuracy for predicting LV dysfunction was 78.0% ± 6.0%. By referring to the model's output, the cardiologist accuracy improved to 88.0% ± 3.7%, which indicates that model support significantly improved the cardiologist diagnostic accuracy (P = 0.02). A sensitivity map demonstrated that the model focused on the QRS complex when detecting LV dysfunction on ECGs. We developed a deep learning model that can detect LV dysfunction on ECGs with high accuracy. Furthermore, we demonstrated that support from a deep learning model can help cardiologists to identify LV dysfunction on ECGs.

Background: Endoscopic submucosal dissection (ESD) is recognized as a minimally invasive and curative treatment for superficial gastrointestinal (GI) cancers. However, ESD is still challenging and time-consuming with a high risk of adverse events such as bleeding and perforation. Various traction methods have been explored for maintaining good visualization of the submucosal layer during ESD. We developed a novel traction device (the EndoTrac) which can easily tie the thread and has the ability to change the towing direction. The aim of this study is to evaluate safety and feasibility of ESD using the EndoTrac for GI neoplasms., Patients and Methods: We retrospectively analyzed 44 patients (45 lesions) with esophageal, gastric, duodenal, and colorectal neoplasms who had undergone ESD using the EndoTrac device between June 2018 and May 2019. Primary outcome measures were preparation time, procedural success using the EndoTrac device, and ease of ability to change towing direction., Results: Mean preparation time was 2 (2-5) min in esophagus, 3 (1-5) min in stomach, 6 (5-9) min in duodenum, and 4 (2-8) min in colorectum. The procedural success rate was 100% (8/8) in esophagus, 100% (21/21) in stomach, 100% (4/4) in duodenum, and 100% (12/12) in colorectum. The rate of successful towing to both proximal and distal sides was 100% (8/8) in esophagus, 100% (21/21) in stomach, 0% (0/4) in duodenum, and 100% (12/12) in colorectum., Conclusions: Use of the EndoTrac device appears to be a feasible approach to ESD for GI neoplasms., (© 2020 S. Karger AG, Basel.)

Objective: A survey was implemented for early assessment of pandemic-related practice processes and quality improvement (QI)., Background: In response to the public health measures in Hawaii to curtail the coronavirus 2019 pandemic, Hawaii Pacific Neuroscience (HPN) adapted their patient care to ensure continuity of neurological treatment., Methods: The telephone survey was conducted on patients seen at HPN during the period of April 22, 2020-May 18, 2020 to address four areas related to patients' outpatient experience: delivery of care, general well-being, experience with telemedicine, and disease-specific questions., Results: A total of 928 patients were contacted of which 429 (46.2%) patients responded and 367 (85.5%) agreed to participate. A total of 133 patients with migraine and 234 patients with other neurological conditions provided responses. Our migraine patients' survey responses suggest that their well-being was disproportionately negatively affected by the pandemic. Survey respondents with migraine were significantly more likely than their non-migraine peers to report worsening anxiety and sleep problems [62/132 (47.0%) vs. 78/234 (33.3%), χ 2  = 6.64, p = 0.010, and 64/132 (48.5%) vs. 73/234 (31.2%), χ 2  = 10.77, p = 0.001]; migraine patients also reported worsening of depression as a result of the pandemic more than patients with other diagnoses, though this was not statistically significant [44/132 (33.3%) vs. 57/234 (24.4%), χ 2  = 3.40, p = 0.065]. In regard to access to healthcare, significantly more migraine patients reported running out of medications than those with other diagnoses [20/133 (15.0%) vs. 18/234 (7.7%), χ 2  = 4.93, p = 0.026]. More avoided seeking medical help for new health problems because of the pandemic [30/133 (22.6%) vs. 30/234 (12.8%), χ 2  = 5.88, p = 0.015]. Migraine patients were also significantly impacted economically by the pandemic; 43/132 (32.4%) of migraine patients reported losing their jobs as the result of the pandemic versus 34/234 (14.5%) of their peers (χ 2  = 11.20, p < 0.001). An increase in headache severity or frequency was reported in 39/118 (33.1%) of respondents and 19/118 (16.1%) reported to using more abortive therapy than usual. Telemedicine was well received by almost all patients who took advantage of the option. Most of those patients found telemedicine to be easy to use and as valuable as an in-person visit. Migraine patients indicated with more frequency that without the telemedicine option, they would have missed their medical appointments [37/68 (54.4%) vs. 56/144 (38.6%), χ 2  = 4.31, p = 0.038]; a majority would prefer or consider telemedicine for future appointments over in-person visits., Conclusions: Insights gained from this QI survey to the practice's new pandemic-related processes include stressing lifestyle modification, optimizing treatment plans, and continuing the option of telemedicine., (© 2020 American Headache Society.)

Objective: To evaluate the ability of extensive hemilaminectomy and durotomy (EHLD) to control progressive myelomalacia (PMM) in dogs., Study Design: Retrospective clinical study., Animals: Twenty-eight client owned dogs that underwent EHLD (n = 10) or HL alone (n = 18)., Methods: After diagnosis by MRI, dogs were immediately treated with HL alone or EHLD at the site of intramedullary hyperintensity on T2-weighted (T2W)-MRI. Medical records were retrospectively reviewed. Follow-up data were collected via telephone interviews with the referring veterinarian and a standardized questionnaire. Postoperative survival outcome between groups was compared (log-rank test) by using Cox's proportional hazard analysis with baseline characteristics entered as covariates., Results: The survival rate was higher in the EHLD group (P = .03) compared with the HL-alone group. Eleven of 18 dogs treated with HL survived, while seven of 18 dogs died (median, 5 days after surgery). In the EHLD group, 10 of 10 dogs survived postoperatively. Baseline characteristics were not associated with postoperative survival outcomes. According to multivariate analysis, EHLD was the independent factor associated with an increase in survival rate (P = .0002)., Conclusion: EHLD durotomy at the intramedullary hyperintense region on T2W-MRI improved the survival rate of dogs with PMM compared with dogs treated with standard HL., Clinical Significance: This study provides evidence that supports treatment with EHLD in dogs with PMM. Additional prospective studies are required., (© 2020 American College of Veterinary Surgeons.)

Mood disorders remain a major public health concern worldwide. Monoaminergic hypotheses of pathophysiology of bipolar and major depressive disorders have led to the development of monoamine transporter-inhibiting antidepressants for the treatment of major depression and have contributed to the expanded indications of atypical antipsychotics for the treatment of bipolar disorders. In spite of psychopharmacological progress, current pharmacotherapy according to the monoaminergic hypothesis alone is insufficient to improve or prevent mood disorders. Recent approval of esketamine for treatment of treatment-resistant depression has attracted attention in psychopharmacology as a glutamatergic hypothesis of the pathophysiology of mood disorders. On the other hand, in the last decade, accumulated findings regarding the pathomechanisms of mood disorders emphasised that functional abnormalities of tripartite synaptic transmission play important roles in the pathophysiology of mood disorders. At first glance, the enhancement of astroglial connexin seems to contribute to antidepressant and mood-stabilising effects, but in reality, antidepressive and mood-stabilising actions are mediated by more complicated interactions associated with the astroglial gap junction and hemichannel. Indeed, several depressive mood-inducing stress stimulations suppress connexin43 expression and astroglial gap junction function, but enhance astroglial hemichannel activity. On the other hand, monoamine transporter-inhibiting antidepressants suppress astroglial hemichannel activity and enhance astroglial gap junction function, whereas several non-antidepressant mood stabilisers activate astroglial hemichannel activity. Based on preclinical findings, in this review, we summarise the effects of antidepressants, mood-stabilising antipsychotics, and anticonvulsants on astroglial connexin, and then, to establish a novel strategy for treatment of mood disorders, we reveal the current progress in psychopharmacology, changing the question from "what has been revealed?" to "what should be clarified?".

By including oligonucleotide-labeled antibodies into high-throughput single-cell RNA-sequencing protocols, combined transcript and protein expression data can be acquired on the single-cell level. Here, we describe a protocol for the combined analysis of over 40 proteins and 400 genes on over 10 4 cells using the nano-well based Rhapsody platform. We also include a workflow for sample multiplexing, which uniquely identifies the initial source of cells (such as tissue type or donor) in the downstream analysis after upstream pooling. For complete information on the use and execution of this protocol, please refer to Mair et al. (2020)., Competing Interests: DECLARATION OF INTERESTS J.R.E., F.M. G.B., and M.P. declare no competing interests. J.M., A.J.T., S.M., and M.N. are employees of BD Biosciences.

Background: Oral squamous cell carcinoma (OSCC) has increased morbidity, and its high metastatic potential affects patient survival. Bromodomain containing 4 (BRD4) is a chromatin protein that associates with acetylated histone lysines and facilitates transcription. BRD4 has been implicated in cell proliferation, metastasis, and prognosis in several types of cancer. However, the role of BRD4 in OSCC remains to be elucidated., Methods: We investigated the role of BRD4 and its potential utility as a therapeutic target in OSCC., Results: JQ1, the BRD4 inhibitor, suppressed the cell proliferation, migration, and invasion in the OSCC cell lines and in vivo. JQ1 reduced the expression levels of 15 metastasis genes in OSCC, including matrix metallopeptidase 2 (MMP2). Our chromatin immunoprecipitation assay showed that JQ1 reduced the BRD4 binding to the histone H3 lysine 27 acetylation-enriched sites in the MMP2 locus. Analyses of biopsy specimens from OSCC patients revealed that the BRD4 and MMP2 expression levels were correlated in the cancerous regions, and both were highly expressed in lymph node metastasis cases, including delayed metastasis., Conclusions: BRD4 contributes to metastasis in OSCC, through the epigenetic regulation of the MMP2 gene, and thus BRD4 may represent a therapeutic target and a novel prediction indicator for metastasis.

Abiotic oligomeric ligands with a strong affinity for a target peptide sequence were isolated by affinity purification from a pool of 30-mer acrylic random ter-oligomers that were synthesized via a controlled radical polymerization process. Our results indicate that the oligomeric ligands with suitable sequence and/or stereochemical configurations for the target can be isolated from as-polymerized random co-polymers based on the affinity to the target. This process will be a powerful tool for the development of stable and inexpensive ligands that can be used to detect, neutralize and purify proteins with a target epitope sequence.

Isolation and structural characterization of hypervalent electron-rich pentacoordinate nitrogen species have not been achieved despite continuous attempts for over a century. Herein we report the first synthesis and isolation of air stable hypervalent electron-rich pentacoordinate nitrogen cationic radical ( 11-N-5 ) species from oxidation of their corresponding neutral ( 12-N-5 ) species. In the cationic radical species, the nitrogen centers adopt a trigonal bipyramidal geometry featuring a 3-center-5-electron hypervalent attractive interaction. The combination of single crystal X-ray diffraction analysis and computational studies revealed weak N-O interactions between the central nitrogen cation and oxygen atoms. This successful design strategy and isolation of air-stable pentacoordinate hypervalent nitrogen species allow further investigations on reactivity and properties resulting from these unusually weakly coordinating interactions in nitrogen compounds., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

It has been reported that 20% of early-stage oral squamous cell carcinoma (OSCC) patients treated with surgery alone (SA) may exhibit postoperative relapse within 2-3 years and have poor prognoses. We aimed to determine the safety of S-1 adjuvant chemotherapy and the potential differences in the disease-free survival (DFS) between patients with T2N0 (stage II) OSCC treated with S-1 adjuvant therapy (S-1) and those treated with SA. This single-center retrospective cohort study was conducted at Kumamoto University, between April 2004 and March 2012, and included 95 patients with stage II OSCC. The overall cohort (OC), and propensity score-matched cohort (PSMC) were analyzed. In the OC, 71 and 24 patients received SA and S-1, respectively. The time to relapse (TTR), DFS, and overall survival were better in the S-1 group, but the difference was not significant. In the PSMC, 20 patients each received SA and S-1. The TTR was significantly lower in the S-1 group than in the SA group, while the DFS was significantly improved in the former. S-1 adjuvant chemotherapy may be more effective than SA in early-stage OSCC., Competing Interests: The authors have declared that no competing interests exist.

Rhizotaxis is established under changing environmental conditions via periodic priming of lateral root (LR) initiation at the root tips and adaptive LR formation along the primary root (PR). In contrast to the adaptable LR formation in response to nutrient availability, there is little information on root development during interactions with beneficial microbes. The Arabidopsis root system is characteristically modified upon colonization by the root endophytic fungus Serendipita indica, accompanied by a marked stimulation of LR formation and the inhibition of PR growth. This root system modification has been attributed to endophyte-derived indole-3-acetic acid (IAA). However, it has yet to be clearly explained how fungal IAA affects the intrinsic LR formation process. In this study, we show that diffusible compounds (chemical signals) other than IAA are present in the coculture medium of Arabidopsis and S. indica and induce auxin-responsive DR5::GUS expression in specific sections within the pericycle layer. The DR5::GUS expression was independent of polar auxin transport and the major IAA biosynthetic pathways, implicating unidentified mechanisms responsible for the auxin response and LR formation. Detailed metabolite analysis revealed the presence of multiple compounds that induce local auxin responses and LR formation. We found that benzoic acid (BA) cooperatively acted with exogenous IAA to generate a local auxin response in the pericycle layer, suggesting that BA is one of the chemical signals involved in adaptable LR formation. Identification and characterization of the chemical signals will contribute to a greater understanding of the molecular mechanisms underlying adaptable root development and to unconventional technologies for sustainable agriculture., (© The Author(s) 2020. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We describe a process for engineering a synthetic polymer nanoparticle (NP) that functions as an effective, broad-spectrum metalloproteinase inhibitor. Inhibition is achieved by incorporating three functional elements in the NP: a group that interacts with the catalytic zinc ion, functionality that enhances affinity to the substrate-binding pocket, and fine-tuning of the chemical composition of the polymer to strengthen NP affinity for the enzyme surface. The approach is validated by synthesis of a NP that sequesters and inhibits the proteolytic activity of snake venom metalloproteinases from five clinically relevant species of snakes. The mechanism of action of the NP mimics that of endogenous tissue inhibitors of metalloproteinases. The strategy provides a general design principle for synthesizing abiotic polymer inhibitors of enzymes.

Raw garlic contains characteristic compounds, such as S -alk(en)ylcysteine sulfoxides, γ-glutamyl- S -alk(en)-ylcysteines and polysaccharides. These compounds undergo various transformation processes during the aging process. Among these compounds, the change of sulfur-containing molecules is diverse and time-dependent. Previously, by means of the liquid chromatography (LC)/LC-mass spectrometry (MS) method, a number of unidentified peaks corresponding to candidates of sulfur-containing molecules were detected in the chromatogram of aged garlic extract (AGE), and identified using MS and nuclear magnetic resonance (NMR). The production mechanisms of these compounds were then examined by model reactions and laboratory experiments mimicking the aging process. Three γ-glutamyl tripeptides [γ-glutamyl-γ-glutamyl- S -methylcysteine, γ-glutamyl-γ-gluta-myl- S -allylcysteine (GGSAC), γ-glutamyl-γ-glutamyl- S -1-propenylcysteine], γ-glutamyl- S -allylmercaptocysteine (GSAMC) and cis-S -1-propenylcysteine ( cis -S1PC) were isolated and identified. GGSAC was produced from GSAC through the enzymatic reaction catalyzed by γ-glutamyltranspeptidase (GGT), and two other tripeptides could be produced in similar reactions. GSAMC was produced by the reaction between γ-glutamyl dipeptides and allicin. Furthermore, GSAMC was a precursor compound of S -allyl-mercaptocysteine (SAMC), and thus it was produced from GSAMC by GGT. cis -S1PC was produced from trans -S1PC by the isomerization reaction. A number of other compounds were also identified, including Maillard reaction products; however, their production mechanisms have not been elucidated. In this review, we present the changes in characteristic constituents in raw garlic and garlic extract during the aging process and discuss their production mechanisms involving the various chemical and enzymatic reactions., (Copyright: © Kodera et al.)

Allium plants, such as garlic, onion and leek have long been known to be effective in the therapy of infectious diseases. In particular, garlic has a greater antimicrobial activity than other Allium plants as it contains several hydrophobic antimicrobial compounds, such as allicin, vinyldithiins, ajoenes and diallyl polysulfides. Allicin is a characteristic sulfur-containing compound found in raw garlic produced from alliin and exhibits antimicrobial activity against both Gram-positive and Gram-negative bacteria. In addition, allicin has been reported to inhibit the biofilm formation of bacteria, which is a major cause of bacterial resistance to the antibiotic treatment of infections, by regulating quorum sensing in microorganisms. Other hydrophobic compounds also have similar inhibitory effects on bacteria as allicin. These biological properties of garlic-derived hydrophobic compounds can be used to enhance the effects of existing drugs and may thus be used in the treatment of infections, such as by preventing drug resistance through the inhibition of biofilm formation. In this review, we summarize the effects of hydrophobic compounds of garlic on bacteria., (Copyright: © Nakamoto et al.)

Fractional flow reserve (FFR) is an established method for diagnosing physiological coronary artery stenosis. A method for computing FFR using coronary computed tomography (CT) images was recently developed. However, its calculation requires off-site supercomputer analysis. Here, we report the preliminary result of a method using simple estimation of boundary conditions. The lumen boundaries of the coronary arteries were semi-automatically delineated using full width at half maximum of CT number profiles. The computational fluid dynamics (CFD) of the blood flow was performed using the boundary conditions of a fixed pressure at the coronary ostium and flow rates at each outlet. The total inflow at the coronary ostium was estimated based on the uniform wall shear stress hypothesis and corrected using a hyperemic multiplier to gain a hyperemic flow rate. The flow distribution from a parent vessel to the downstream daughter vessels was determined according to Murray's law. FFR estimated by CFD was calculated as FFR CFD = Pd/Pa. We collected patients who underwent coronary CT and coronary angiography followed by invasively measured FFR and compared FFR CFD with FFR. Sensitivity, specificity, and correlations were assessed. A total of 48 patients and 72 arteries were assessed. The correlation coefficient of FFR CFD with FFR was 0.56. The cut-off value was ≤ 0.80, sensitivity was 59.1%, and specificity was 94.0%. CFD-based FFR using simple boundary conditions for on-site clinical computation provided FFR CFD values that were moderately correlated with invasively measured FFR.

The prevalence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli is increasing rapidly and spreading worldwide, particularly in Asia, compared to other regions. In the last ten years, in our hospital, in particular, there has been a < 30% increase. To prevent the spread of ESBL in hospitals and the community, the ultraviolet (UV) A-light-emitting diode (LED) irradiation device was used to inactivate ESBL-E. coli in human livestock and the environment. ESBL-E. coli and E. coli bacterial samples were collected from patients at Tokushima University Hospital (Tokushima City, Japan). The UVA-LED irradiation system had 365 nm single wavelength, and the current of the circuit was set to 0.23 or 0.50 A consistently. Results demonstrated that UVA-LED was useful for the inactivation of ESBL-E. coli and E. coli. The minimum energy dosage required to inactivate ESBL-E. coli and E. coli was 40.76 J/cm2 (45 min) in the first type of UVA-LED and 38.85 J/cm2 (5 min) in the second type. There were no significant differences between ESBL-E. coli and E. coli. The inactivation of ESBL-E. coli was dependent on energy. These findings suggest that UVA-LED with 365 nm single wavelength could be useful for surface decontamination in healthcare facilities. J. Med. Invest. 67 : 163-169, February, 2020.

The embryonic chick has long been a favorite model system for in vivo studies of vertebrate development. However, a major technical limitation of the chick embryo has been the lack of efficient loss-of-function approaches for analyses of gene functions. Here, we describe a methodology in which a transgene encoding artificial microRNA sequences is introduced into embryonic chick retinal cells by in ovo electroporation and integrated into the genome using the Tol2 transposon system. We show that this methodology can induce potent and stable suppression of gene expression. This technique therefore provides a rapid and robust loss-of-function approach for studies of gene function in the developing retina.

The aim of this study was to clarify the characteristics of lifestyle and health awareness according to dietary diversity in a Japanese worksite population. The participants were 1,312 men and women aged 20 to 63 years who were living in Tokushima Prefecture, Japan during the period 2012-2013. We obtained anthropometric data and information on lifestyle characteristics using a self-administered questionnaire. Dietary intake was assessed using a food frequency questionnaire, and dietary diversity was determined using the Quantitative Index for Dietary Diversity (QUANTIDD). The characteristics of lifestyle and health awareness according to quartiles of the QUANTIDD score were assessed using the chi-square test and a general linear model. The higher the QUANTIDD score was, the larger were the proportions of participants who knew the appropriate amount of dietary intake and participants who referred to nutritional component information when choosing and / or buying food. Among participants with higher QUANTIDD scores, the proportion of participants who considered their current diet was good was high in women, whereas the proportion of participants who wanted to improve their diet in the future was high in men. Those results indicate that higher dietary diversity was related to better characteristics of lifestyle and awareness of health. J. Med. Invest. 67 : 255-264, August, 2020.

The affinity of a synthetic polymer nanoparticle (NP) to a target biomacromolecule is determined by the association and dissociation rate constants ( k on , k off ) of the interaction. The individual rates and their sensitivity to local environmental influences are important factors for the on-demand capture and release a target biomacromolecule. Positively charged NPs for small interfering RNA (siRNA) delivery is a case in point. The knockdown efficacy of siRNA can be strongly influenced by the binding kinetics to the NP. Here, we show that k on and k off of siRNA to NPs can be individually engineered by tuning the chemical structure and composition of the NP. N -Isopropylacrylamide-based NPs functionalized with hydrophobic and amine monomers were used. k off decreased by increasing the amount of amine groups in the NP, whereas k on did not change. Importantly, NPs showing a low k off at pH 5.5 together with a high k off at pH 7.4 showed high knockdown efficiency when NP/siRNA complexes were packaged in lipid nanoparticles. These results provide direct evidence for the premise that the efficacy of an siRNA delivery vector is linked with the strong affinity to the siRNA in the endosome and low affinity in the cytoplasm.

The coordination chemistry of our recently isolated bis(diphenylphosphinyl)-functionalized dipyrido-annulated NHC (N-heterocyclic carbene), dpa P2 -NHC, towards copper(i) and silver(i) has been studied. Based on dpa P2 -NHC, two dinuclear silver and copper complexes [2, (Ag 2 L 2 ) and 3, (Cu 2 L 2 )], two tetranuclear copper complexes {4, [Cu 4 L 2 (NCMe) 2 ] and 6, (Cu 4 LBr 4 )} and a pentanuclear copper complex [5, (Cu 5 L 2 Br 3 )] exhibiting strong intramolecular metal-metal interactions were achieved and characterized. All the complexes exhibited dynamic behavior in solution, in which the NMR coalescence of 2 was well resolved at low temperature (below 208 K) and dissociation for 2 was observed according to the calculated Eyring plot. Ag 2 L 2 (2) shows a similar coordination sphere to that of our previously reported gold complex Au 2 L 2 ; Cu 2 L 2 (3) features a rare μ 2 -bridging carbene and a terminal carbene; Cu 4 LBr 4 (6) is neutral and monomeric, in which four copper atoms were rigidly fixed by the tridentate dpa P2 -NHC ligand and bromide anions. All the complexes (2-6) were luminescent at room temperature, in which 4-6 provided phosphorescence at 77 K. Based on the comparison of the emission bands with dpa P2 -NHC, we conclude that the electronic transitions of 2-6 can be attributed to the ligand-centered (LC) transitions.

Many of the reports summarizing neurological disorders in cats considered only a limited disease group(s). There is only one large-scale survey on neurological disorders in cats based on the histopathological viewpoint. We described the localizations and frequencies of neurological diseases in a large population of cats that were referred to the Kyoto Animal Referral Medical Center between 2009 and 2016. We attempted to determine the localization of lesions at the time of the examination in each case and to classify the disease etiologies of these 276 cats with neurological disorders retrospectively. There were 174 cases with lesions in the brain region, 14 cases with lesions in the cervical cord region, 34 cases with lesions in the thoracolumbar cord region, and 54 cases with lesions in the peripheral neuromuscular region. High morbidity rates were observed in cases of idiopathic epilepsy and intracranial tumor in the brain region, spinal cord infarction in the cervical cord region, spinal cord infarction and spinal cord tumor in the thoracolumbar cord region, and peripheral vestibular dysfunction arising from otitis media/interna in the peripheral neuromuscular region. It was suggested that there is a higher number of brain diseases than spinal cord and peripheral neuromuscular diseases in cats. Idiopathic and neoplastic diseases were common in the brain region, vascular diseases were common in the spinal cord region, and infectious diseases were common in the peripheral neuromuscular region.

Vertebrate sex development consists largely of two processes: "sex determination," the initial bifurcation of sexual identity, and "sex differentiation," which subsequently facilitates maleness or femaleness according to the sex determination signal. Steroid hormones promote multiple types of sexual dimorphism in eutherian mammals and avians [1-3], in which they are indispensable for proper sex differentiation. By contrast, in many poikilothermic vertebrates, steroid hormones have been proposed to be key players in sex determination as well as sex differentiation [4-8]. This hypothesis was introduced more than 50 years ago but has never been rigorously tested due to difficulties in discriminating the roles of steroids in sex determination and differentiation. We found that a missense SNP in the gene encoding the steroidogenic enzyme 17β-hydroxysteroid dehydrogenase 1 (Hsd17b1) was perfectly associated with ZZ/ZW sex determination in Seriola fishes. Biochemical analyses revealed that a glutamate residue present specifically in Z-type HSD17B1 attenuated interconversion between 17-keto and 17β-hydroxy steroids relative to the allelic product from the W chromosome, which harbors glycine at that position, by disrupting the hydrogen bond network between the steroid and the enzyme's catalytic residues. Hsd17b1 mRNA is constitutively expressed in undifferentiated and differentiating gonads of both genotypic sexes, whereas W-type mRNA is expressed only in genotypic females. Meanwhile, Cyp19a1 is predominantly expressed in differentiating ovary. We conclude that the combination of Hsd17b1 alleles determines sex by modulating endogenous estrogen levels in Seriola species. These findings strongly support the long-standing hypothesis on steroids in sex determination., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The highly malignant phenotype of oral squamous cell carcinoma (OSCC), including the presence of nodal and distant metastasis, reduces patient survival. High-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is involved in advanced malignant phenotypes and poor prognosis in several human cancers. However, its biological role in OSCC remains to be elucidated. The purpose of this study was to determine the clinical significance and role of HMGA2 in the malignant potential of OSCC. We first investigated the expression pattern of HMGA2 and its clinical relevance in 110 OSCC specimens using immunohistochemical staining. In addition, we examined the effects HMGA2 on the regulation of vascular endothelial growth factor (VEGF)-A, VEGF-C, and fibroblast growth factor (FGF)-2, which are related to angiogenesis, in vitro. High expression of HMGA2 was significantly correlated with distant metastasis and poor prognosis. Further, HMGA2 depletion in OSCC cells reduced the expression of angiogenesis genes. In OSCC tissues with high HMGA2 expression, angiogenesis genes were increased and a high proportion of blood vessels was observed. These findings suggest that HMGA2 plays a significant role in the regulation of angiogenesis and might be a potential biomarker to predict distant metastasis and prognosis in OSCC.

Phosphine-functionalized N-heterocyclic carbene (NHC) ligands are known to complex group 11 metal centers to form multinuclear complexes with photoluminescence properties. This study reports a structurally rigid ortho-substituted dipyrido-annulated NHC with T-shape coordination geometry and its di- and tetranuclear gold(I) complexes. The free ligand as well as all metal complexes are found luminescent at room temperature and phosphorescent at 77 K. Although metal d 10 -d 10 interactions are evident based on their solid-state structures, their effect on the photoemission is limited, most likely due to the weak coordination of the ligand to the metal centers in solution.

Background: The epidermal growth factor receptor (EGFR) is a therapeutic target for patients with non-small cell lung cancer (NSCLC). Cetuximab is an anti-EGFR monoclonal antibody that inhibits EGFR signaling and proliferation of colorectal cancer and head and neck cancers. Since only few NSCLC patients benefit from cetuximab therapy, we evaluated a novel combination treatment using cetuximab and EGFR small interfering RNA (siRNA) to strongly suppress EGFR signaling and searched for a biomarker in NSCLC cell lines harboring wild-type EGFR ., Methods: Alterations in EGFR and its downstream genes in five NSCLC cell lines (A549, Lu99, 86-2, Sq19 and Ma10) were assessed through sequencing. The protein expression levels of these molecules were assessed through western blotting. The effect of combination treatment was determined through cell proliferation assay, caspase-3/7 assay, invasion assay, and migration assay., Results: All cell lines were harboring wild-type EGFR , whereas KRAS , PTEN , TP53 and TP53 were mutated in A549 and Lu99; Lu99 and Sq19; Lu99, 86-2, Sq19 and Ma10; and A549, 86-2, and Sq19 cell lines, respectively. PTEN was not expressed in Sq19, and LKB1 was not expressed in both A549 and Sq19. TP53 was not expressed in both A549 and Lu99. The combination of cetuximab and EGFR siRNA significantly suppressed cell proliferation in 86-2, Sq19 and Ma10, which express wild-type KRAS . It induced apoptosis in A549, 86-2 and Ma10 cells, which express wild type PTEN . The combination treatment had no effect either on cell invasion nor migration in all cell lines., Conclusion: EGFR targeted therapy using the combination of cetuximab and EGFR siRNA is effective in NSCLC cell lines harboring wild-type EGFR . Wild-type KRAS may act as a potential biomarker for response to combination treatment by the induction of apoptosis in cells with wild-type PTEN .

Scdachitin is a polymethoxyflavone (5,7,4'-trihydroxy-6,8,3-trimethoxyflavone) that is found in the peel of Citrus sudachi . We examined the effect of sudachitin on immune response in ovalbumin-immunized BALB/c mice. Treatment with sudachitin increased ovalbumin-specific IL-4 and IL-10 productions. In addition, mice that received sudachitin showed higher levels of ovalbumin-specific IgE, IgG1 and IgG l production than did control mice. The antibody response to the thymus-independent antigen 2,4,6-trinitrophenyl Ficoll was not different in the control and sudachitin groups, suggesting that sudachitin does not directly stimulate antibody production. An in vitro study showed that treatment of sudachitin enhanced the ability of antigen presentation in bone marrow-derived dendritic cells. Furthermore, CD11c + cells that had been treated with sudachitin showed increased expression of co-stimulatory molecules. The results indicate that sudachitin regulates immune function both in vivo and in vitro ., Competing Interests: No potential conflicts of interest were disclosed.

Structurally characterized hexacoordinate organophosphorus compounds remain rare due to their highly reactive nature and thermal instability. Herein we report the first synthesis of a pair of O-facial and O-meridional hexacoordinate oxaphosphates ( 5B and 5D ) obtained from the O-apical and O-equatorial β-hydroxyalkylphosphoranes 3 and 4 . This was achieved by using the bulky C 2 F 5 -groups on the ortho-substituted aryl backbone. Calculations of the relative energies of possible isomers indicate 5B and 5D are thermodynamic products. Although the mechanisms of their formation and the determining factor of stereo-selectivity are still unclear, their isolation and structure conformation contributes to a formulation of a viable strategy for diastereoselective synthesis of heteroleptic hexacoordinate organophosphates.

In mammals with binocular vision, retinal ganglion cell (RGC) axons from each eye project to eye-specific domains in the contralateral and ipsilateral dorsal lateral geniculate nucleus (dLGN), underpinning disparity-based stereopsis. Although domain-specific axon guidance cues that discriminate contralateral and ipsilateral RGC axons have long been postulated as a key mechanism for development of the eye-specific retinogeniculate projection, the molecular nature of such cues has remained elusive. Here, we show that the extracellular glycoprotein Nell2 (neural epidermal growth factor-like-like 2) is expressed in the dorsomedial region of the dLGN, which ipsilateral RGC axons terminate in and contralateral axons avoid. In Nell2 mutant mice, contralateral RGC axons abnormally invaded the ipsilateral domain of the dLGN, and ipsilateral axons terminated in partially fragmented patches, forming a mosaic pattern of contralateral and ipsilateral axon-termination zones. In vitro , Nell2 exerted inhibitory effects on contralateral, but not ipsilateral, RGC axons. These results provide evidence that Nell2 acts as a domain-specific positional label in the dLGN that discriminates contralateral and ipsilateral RGC axons, and that it plays essential roles in the establishment of the eye-specific retinogeniculate projection., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)