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A fundamental understanding of the design of polymer ligands of proximal enzymes is essential for the precise targeting of cancer cells, but it is still in its infancy. In this study, we systematically investigated the contribution of the chain length, ligand density, and ligand ratio of proximal enzyme-targeted polymers to the efficacy, synergy, and selectivity for the inhibition of cancer cell proliferation. The results revealed that employing a moderate chain length as a scaffold allowed for an intrinsically high efficacy and synergy of proximal enzyme-targeted polymers, in contrast to single enzyme-targeted polymers that prefer longer chain length for efficacy. The synergy obtained in proximal enzyme targeting was not provided by the combination of the corresponding small molecules. Moreover, the maturation of the synergistic efficacy of the proximal enzyme-targeted polymers also improved selectivity. This study proposes a rational design for polymer inhibitors and/or ligands for cancer cells with a high efficacy and selectivity.

The indispensability of a base in Suzuki-Miyaura coupling (SMC) employing organoboronic acids/esters is well recognized, which occasionally induces competitive protodeborylation in organoboron reagents. This phenomenon is particularly pronounced in fluorine-substituted aryl and heteroaryl boron compounds. Here, we show that direct SMC of naphthalene-1,8-diaminato (dan)-substituted aryl boron compounds, Ar-B(dan), characterized by its remarkable stability toward protodeborylation due to their diminished boron-Lewis acidity, occurs utilizing a weak base in conjunction with a palladium/copper cooperative catalyst system. The approach delineated in this study enables the efficient incorporation of various perfluoroaryl- and heteroaryl-B(dan) reagents, while maintaining high functional group tolerance. Furthermore, the inherent inertness of the B(dan) moiety allowed sequential cross-coupling, where other metallic moieties chemoselectively undergo the reaction, thus leading to the concise, protection-free synthesis of oligoarenes. Our results provide a potent approach to a delicate dilemma between a protodeborylation-resistant property and SMC activity intimately linked to boron-Lewis acidity., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

SiO x electrodes are promising for high-energy-density lithium-ion batteries (LIBs) due to their ability to mitigate volume expansion-induced degradation. Here, we investigate the surface dynamics of SiO x thin-film electrodes cycled in different carbonate-based electrolytes using a combination of ex situ X-ray photoelectron spectroscopy (XPS) and operando synchrotron X-ray reflectivity analyses. The thin-film geometry allows us to probe the depth-dependent chemical composition and electron density from surface to current collector through the solid electrolyte interphase (SEI), the active material, and the thickness evolution during cycling. Results reveal that SiO x lithiation initiates below 0.4 V vs Li + /Li and indicate a close relationship between SEI formation and SiO x electrode lithiation, likely due to the high resistivity of SiO x . We find similar chemical compositions for the SEI in FEC-containing and FEC-free electrolytes but observe a reduced thickness in the former case. In both cases, the SEI thickness decreases during delithiation due to the removal or dissolution of some carbonate species. These findings give insights into the (de)lithiation of SiO x , in particular, during the formation stage, and the effect of the presence of FEC in the electrolyte on the evolution of the SEI during cycling.

Background: Endurance is an important capacity to sustain healthy lifestyles. Aged garlic extract (AGE) has been reported to exert an endurance-enhancing effect in clinical and animal studies, although little is known about its active ingredients and mechanism of action., Objectives: This study investigated the potential effect of S-1-propenylcysteine (S1PC), a characteristic sulfur amino acid in AGE, on the swimming endurance of mice, and examined its mechanism of action by a metabolomics-based approach., Methods: Male Institute of Cancer Research (ICR) mice (6 wk old) were orally administered either water (control) or S1PC (6.5 mg/kg/d) for 2 wk. The swimming duration to exhaustion was measured at 24 h after the final administration. Nontargeted metabolomic analysis was conducted on the plasma samples obtained from mice after 40-min submaximal swimming bouts. Subsequently, the enzyme activity of carnitine acyltransferase-1 (CPT-1) and the content of malonyl-coenzyme A (CoA), acetyl-CoA, and adenosine triphosphate (ATP) were quantified in heart, skeletal muscles, and liver of mice., Results: The duration time of swimming was substantially increased in the S1PC-treated mice as compared with the control group. Metabolomic analysis revealed significant alterations in the plasma concentration of the metabolites involved in fatty acid metabolism, in particular medium- or long-chain acylcarnitines in the mice treated with S1PC. Moreover, the administration of S1PC significantly enhanced the CPT-1 activity with the concomitant decrease in the malonyl-CoA content in the heart and skeletal muscles. These effects of S1PC were accompanied by the elevation of the acetyl-CoA and ATP levels to enhance the energy production in those tissues., Conclusions: S1PC is a key constituent responsible for the endurance-enhancing effect of AGE. This study suggests that S1PC helps provide energy during endurance exercise by increasing fatty acid metabolism via CPT-1 activation in the heart and skeletal muscles., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine the associations between dietary diversity and risk of dyslipidemia in Japanese workers., Methods: The cross-sectional study included 1399 participants aged 20-63 years and the longitudinal study included 751 participants aged 20-60 years in 2012-2013 (baseline) who participated at least once from 2013 to 2017 with cumulative participation times of 4.9 times. Dietary intake was assessed using a food frequency questionnaire, and dietary diversity score (DDS) was determined using the Quantitative Index for Dietary Diversity. Dyslipidemia was diagnosed when at least one of the following conditions was met: hypertriglyceridemia, high LDL-cholesterol, low HDL-cholesterol, high non-HDL-cholesterol, and a history of dyslipidemia. Multivariable logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for dyslipidemia with control of confounding factors in cross-sectional analysis. Generalized estimating equations were used for calculating the ORs (95% CI) for dyslipidemia in the follow-up period according to the DDS at baseline with control of confounding factors in longitudinal analysis., Results: Cross-sectional analysis showed that the highest DDS reduced the odds of dyslipidemia in men (OR [95% CI] in Tertile 3: 0.67 [0.48-0.95], p value = 0.023). In longitudinal analysis, a moderate DDS reduced the risk of dyslipidemia (OR [95% CI] in Tertile 2: 0.21 [0.07-0.60], p value = 0.003) in women., Conclusions: The results of cross-sectional analysis in this study suggest that the higher diversity of diet might reduce the presence of dyslipidemia in men and the results of longitudinal analysis suggest that a moderate DDS might reduce the risk of dyslipidemia in women. Further studies are needed since the results of cross-sectional and longitudinal analyses in this study were inconsistent., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Organometallic reagents such as organolithium and Grignard reagents have long been esteemed in chemical synthesis for their exceptional reactivity. In contrast, the application of their sodium and potassium counterparts has been comparatively sluggish, notwithstanding their augmented reactivity stemming from their heightened ionic character. This inertia persists due to the constrained accessibility of these heavy alkali metal reagents. In this study, our focus was directed towards devising a convenient and pragmatic approach for fabricating heavy alkali metal-based reagents, particularly those grounded in potassium. Herein, we present a novel, direct method for generating stannylpotassium (Sn-K) reagents through the simple combination of readily available silylstannanes and t -BuOK. Subsequently, the generated Sn-K reagents were effectively harnessed for stannylative substitution of aryl halides, furnishing an array of arylstannanes straightforwardly under transition metal-free conditions. This application distinctly underscores the potential utility of highly reactive Sn-K species, hitherto sparingly tapped into within the realm of synthetic organic chemistry. Furthermore, our investigation confirms that Sn-K reagents manifest notably superior reactivity compared with their well-established stannyllithium (Sn-Li) counterparts. This heightened reactivity can be ascribed to the increasing ionic character of Sn-K, which was supported by computational experiments., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Purpose: To clarify the association between dietary diversity and inflammatory status in Japanese workers., Methods: Of 1,460 men and women aged 20-64 years in 2010 (baseline), those who were followed-up at least once between 2011 and 2018 were included in this study; 1,433 participants and 745 participants were included in the cross-sectional and longitudinal analyses, respectively. Dietary intake was assessed using a food frequency questionnaire at baseline, and the dietary diversity score was determined using the Quantitative Index for Dietary Diversity (QUANTIDD). High-sensitivity C-reactive protein (hs-CRP) was taken to indicate inflammatory status at the baseline and follow-up surveys. In the cross-sectional analysis using baseline data, a generalized linear model was used to calculate adjusted means and 95% confidence intervals (CIs) for hs-CRP according to the QUANTIDD score. In the longitudinal analysis, generalized estimating equations were used to calculate the adjusted mean (95% CI) for hs-CRP in follow-up according to the QUANTIDD score at baseline., Results: In the cross-sectional analysis, the hs-CRP concentration in male participants was significantly lower in those who had a high QUANTIDD score (adjusted mean [95% CI]: 0.074 [0.009-0.140] mg/dL in the lower group vs. 0.038 [-0.029-0.105] mg/dL in the higher group, p-value = 0.034). In the longitudinal analysis, the hs-CRP concentration of male participants also tended to be lower in those with higher QUANTIDD scores (p-value = 0.103). In both the cross-sectional and longitudinal analyses in women, there was no significant difference between the lower and higher QUANTIDD score groups., Conclusion: These findings suggest that, in male Japanese workers, higher dietary diversity might be important for maintaining a low inflammatory status., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Antimicrobial treatment disrupts human microbiota. The effects of lascufloxacin (LSFX), a new fluoroquinolone, on human microbiota remains unknown. Therefore, in this study, we aimed to evaluate the effects of LSFX administration on the gut and salivary microbiota of healthy participants and those with pneumonia., Methods: LSFX (75 mg, once a day, orally) was administered to healthy adults (healthy group) and adult patients with pneumonia (pneumonia group), and fecal and saliva samples were collected at five time points (Days 0, 3, 7, 14, and 28). Using the collected samples, α- and β-diversity indices, as well as bacterial composition of the gut microbiota and salivary microbiota were analyzed using next-generation sequencing., Results: In the healthy group, α-diversity indices of the gut and salivary microbiota were reduced and the lowest values on Day 3. For the gut microbiota, the Chao1 index (richness) recovered on Day 28, whereas the Shannon index (evenness) did not. In the salivary microbiota, the Chao1 and Shannon indices did not recover within the 28 day period. The β-diversity indices changed after LSFX administration and subsequently recovered on Day 28. After LSFX administration, the abundance of the Lachnospiraceae family decreased in the gut microbiota, and the abundance of Granulicatella, Streptococcus, Prevotella, Absconditabacteriales(SR1), and Saccharimonadales decreased in the salivary microbiota. In the pneumonia group, the α-diversity indices were lowest on Day 14 after LSFX administration., Conclusions: We elucidated that LSFX administration differentially affected the gut and salivary microbiota; however, the richness and beta diversity recovered within 28 days., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

An Arabidopsis sterol mutant, smt2 smt3 , defective in sterolmethyltransferase2 (SMT2), exhibits severe growth abnormalities. The loss of C-24 ethyl sterols, maintaining the biosynthesis of C-24 methyl sterols and brassinosteroids, suggests specific roles of C-24 ethyl sterols. We characterized the subcellular localizations of fluorescent protein-fused sterol biosynthetic enzymes, such as SMT2-GFP, and found these enzymes in the endoplasmic reticulum during interphase and identified their movement to the division plane during cytokinesis. The mobilization of endoplasmic reticulum-localized SMT2-GFP was independent of the polarized transport of cytokinetic vesicles to the division plane. In smt2 smt3 , SMT2-GFP moved to the abnormal division plane, and unclear cell plate ends were surrounded by hazy structures from SMT2-GFP fluorescent signals and unincorporated cellulose debris. Unusual cortical microtubule organization and impaired cytoskeletal function accompanied the failure to determine the cortical division site and division plane formation. These results indicated that both endoplasmic reticulum membrane remodeling and cytokinetic vesicle transport during cytokinesis were impaired, resulting in the defects of cell wall generation. The cell wall integrity was compromised in the daughter cells, preventing the correct determination of the subsequent cell division site. We discuss the possible roles of C-24 ethyl sterols in the interaction between the cytoskeletal network and the plasma membrane.

Most hydrogels have poor mechanical properties, severely limiting their potential applications, and numerous approaches have been introduced to fabricate more robust and durable examples. However, these systems consist of nonbiodegradable polymers which limit their application in tissue engineering. Herein, we focus on the fabrication and investigate the influence of hydrophobic segments on ionic cross-linking properties for the construction of a tough, biodegradable hydrogel. A biodegradable, poly(γ-glutamic acid) polymer conjugated with a hydrophobic amino acid, l-phenylalanine ethyl ester (Phe), together with an ionic cross-linking group, alendronic acid (Aln) resulting in γ-PGA-Aln-Phe, was initially synthesized. Rheological assessments through time sweep oscillation testing revealed that the presence of hydrophobic domains accelerated gelation. Comparing gels with and without hydrophobic domains, the compressive strength of γ-PGA-Aln-Phe was found to be six times higher and exhibited longer stability properties in ethylenediaminetetraacetic acid solution, lasting for up to a month. Significantly, the contribution of the hydrophobic domains to the mechanical strength and stability of ionic cross-linking properties of the gel was found to be the dominant factor for the fabrication of a tough hydrogel. As a result, this study provides a new strategy for mechanical enhancement and preserves ionic cross-linked sites by the addition of hydrophobic domains. The development of tough, biodegradable hydrogels reported herein will open up new possibilities for applications in the field of biomaterials.

[Purpose] Virtual reality (VR) rehabilitation has become popular in the medical field. VR-guided exercises (VR-ge) have demonstrated positive effects on gait and trunk control. Trunk muscle activation, particularly that of the transversus abdominis (TrA), is responsible for these improvements. However, the difference in muscle activation between VR and real space remains unclear. Therefore, this study aimed to clarify the differences in trunk muscle activation during exercise therapy performed in VR and real space. [Participants and Methods] A total of 22 healthy male volunteers were divided into two equal groups: VR-ge and Control exercise (C-e) groups. Both groups performed reaching exercises in a seated position. Ultrasound imaging was used to measure the thicknesses of the right external oblique, internal oblique, and TrA muscles, both at rest and during the reaching exercises performed in six different directions. [Results] No significant differences were observed in TrA muscle thickness changes between the groups before the intervention. However, after the intervention, the VR-ge group showed significantly greater TrA muscle thickness changes during reaching compared to that of the C-e group. [Conclusion] VR-ge increased TrA activation during reaching compared to exercising in real space., Competing Interests: Masahiko Hara is a director of mediVR Inc., in which he holds private equity. Masashi Kitano is full-time employee of mediVR Inc., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Silylation of aryl and alkenyl triflates is found to occur readily with silylboronic esters as a silicon source under copper catalysis. The silyl moieties are exclusively installed into the organic frameworks through the preferential generation of a silylcopper species, wherein base-mediated direct borylation is totally suppressed. The combined use of tri- n -butylphosphine and 4,4'-diphenyl-2,2'-bipyridine as a ligand combination turned out to be indispensable for achieving the high catalytic activity.

Physical therapy for mobilization after a hip fracture is effective in improving muscle strength and balance training of the lower extremities; however, effective interventions targeting the trunk muscles remain to be established. The efficacy of virtual reality (VR)-based exercise therapy has been recently reported. This case report demonstrates the effectiveness of VR-based intervention in improving the gait of a female patient in her 90s with a femoral neck fracture who had difficulty in independent gait postoperatively due to trunk dysfunction. The patient had undergone bipolar hip hemiarthroplasty for a right femoral neck fracture sustained via a fall at home. Standard physical therapy, including range of motion exercises, resistance training, and gait training, was commenced gradually the day after surgery. An improvement in lower extremity pain was reported at the two-month follow-up visit but without any improvement in the gait ability. Trunk flexion was observed during gait, and the patient had difficulty in independent gait and walking without upper limb support. Withdrawal and reversal designs (BAB) were employed, and each period lasted one week. Standard physiotherapy supplemented with trunk reach training in a seated position using VR equipment was commenced subsequently. An improvement in the maximum anterior pelvic tilt angle and sitting and standing postures, increased hip extension range of motion and step length during gait, and decreased gait speed were observed during the intervention phase. These results highlight the importance of physiotherapy interventions targeting the trunk muscle and the effectiveness of VR-guided trunk training in patients with femoral neck fractures., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Ethics Committee of Morinomiya University of Medical Sciences issued approval 2022-160. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kawanishi et al.)

The Lewis basicity of a μ 3 -oxo ligand for (μ 3 -O)[Rh(cod)] 3 (μ 4 -O)M (cod = 1,5-cyclooctadiene) complexes was controllable by metal species on the μ 4 -oxo ligand locating at the opposite site of the μ 3 -oxo ligand. Coordination of the μ 3 -oxo ligand of [(μ 3 -O){Rh(cod)} 3 (μ 4 -O){Au(PPh 3 )}][BF 4 ] (1) to [Au(PPh 3 )] + indicated sufficient Lewis basicity of the μ 3 -oxo ligand in 1 to form [{(Ph 3 P)Au}(μ 3 -O){Rh(cod)} 3 (μ 4 -O){Au(PPh 3 )}][BF 4 ] (2). In contrast, the addition of Li + to 1 induced elimination of the originally coordinated [Au(PPh 3 )] + due to the weak Lewis basicity of the μ 3 -oxo ligand for (μ 3 -O){Rh(cod)} 3 (μ 4 -O)Li(THF) 3 , in which a pentanuclear species, [{(Ph 3 P)Au}(μ 3 -O){Rh(cod)} 3 (μ 4 -O){Li(THF) 3 }][BF 4 ] (3), was assumed to be generated in situ before the dissociation of [Au(PPh 3 )] + .

The cycloaddition of nitrile oxides with ethynyl-B(dan) (dan=naphthalene-1,8-diaminato) allowed the facile preparation of diverse isoxazolyl-B(dan) compounds, all of which displayed excellent protodeborylation-resistant properties. The dan-installation on the boron center proves vital to the high stability of the products as well as the perfect regioselectivity arising from hydrogen bond-directed orientation in the cycloaddition. The diminished boron-Lewis acidity of ethynyl-B(dan) also renders it amenable to azide-alkyne cycloaddition, Larock indole synthesis and related heteroannulations. The obtained boron-containing triazole, indoles, benzofuran and indenone exhibit sufficient resistance toward protodeborylation. Despite the commonly accepted transmetalation-inactive property derived from the diminished Lewis acidity, the synthesized heteroaryl-B(dan) compound was still found to be convertible to the oligoarene via sequential Suzuki-Miyaura coupling., (© 2023 Wiley-VCH GmbH.)

Objective: To evaluate change in higher-level functional capacity of older Japanese individuals during the COVID-19 pandemic., Methods: Four hundred older Japanese individuals completed an online questionnaire in early May 2021. Participants were asked retrospectively about their higher-level functional capacity and lifestyle before and during the COVID-19 pandemic. Higher-level functional capacity was determined as total score on the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC). Total TMIG-IC score ranges from 0 to 13. A decline in higher-level functional capacity was defined as a decrease in TMIG-IC score of more than 2 points during the COVID-19 pandemic. Changes in higher-level functional capacity during the COVID-19 pandemic were assessed by paired t-test and a general linear model., Results: Decreased TMIG-IC scores were found in 43 (21.5%) men and 61 (30.5%) women. Among those with higher-level functional capacity, scores for total TMIG-IC and Social Role decreased significantly in both sexes (all p<0.005)., Conclusion: The findings suggest an association of the COVID-19 pandemic with a decrease in higher-level functional capacity, especially in Social Role, among older adults living in Japan. J. Med. Invest. 71 : 66-74, February, 2024.

Immune checkpoint therapy has been shown to be an effective therapy for many types of tumors. Much attention has been paid to the development of an effector target would be helpful for immune checkpoint therapy. Genistein has been shown to have an anti-tumor effect both in vitro and in vivo . In this study, we examined the effect of genistein on immune checkpoint blockade therapy against B16F1 melanoma tumors. Mice treated with genistein or anti-programmed death (PD)-1 antibody showed a significant decrease in tumor growth. However, treatment with genistein had no effect on or attenuated the efficacy of immune checkpoint therapy. The percentages of T cell receptor (TCR)β + CD4 + and TCRβ + CD8 + cells and the concentrations of interferon-γ and tumor necrosis factor-α in tumor tissue were not different among the experimental groups. A significant difference was also not found in microbe composition. Interestingly, a high expression level of PD-ligand (L)1 closely reflected the outcome of therapy by genistein or anti-PD-1 antibody. The study showed that a combination of genistein treatment does not improve the effect of immune blockade therapy. It also showed that a high PD-L1 expression level in tumors is a good prediction maker for the outcome of tumor therapy., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2024 JCBN.)

The formation of Lewis pairs is an important chemical concept. Recently, the complexation of Lewis acidic tris(pentafluorophenyl)borane with Lewis basic moieties and subsequent reduction has emerged as a fascinating strategy for designing novel reactions and structures. The impact of the complexation and subsequent reduction of antiaromatic systems bearing Lewis base moieties has been investigated. We found how Lewis adduct formation stabilizes an antiaromatic system consisting of 9,10-dicyanoanthracene and tris(pentafluorophenyl)borane by using synthesis, X-ray crystallography, spectroscopic analysis, and quantum chemical calculations., (© 2023 Wiley-VCH GmbH.)

Background: Primary angiosarcomas of the breast are rare and highly aggressive. We herein report a rare case of multiple angiosarcomas detected concurrently in both breasts., Case Presentation: A 49-year-old woman visited a doctor after noticing a lump in her right breast. At that time, mammography and ultrasonography revealed no abnormal findings in either breast. She was referred to our hospital 5 months later, because screening mammography had revealed a focal asymmetric density in her right breast. Ultrasonography showed ill-defined hyper- and hypo-echoic lesions in both breasts. Magnetic resonance imaging disclosed five heterogeneously enhanced masses (5.8 cm in maximum diameter) in the right breast and six enhanced masses (approximately 1-3 cm in diameter) in the left breast. Histological examination of core needle biopsies revealed proliferation of irregularly shaped vascular channels lined by atypical endothelial cells throughout the adipose tissue and lobules of the breasts, leading to a diagnosis of well-differentiated angiosarcoma. The lesions were assumed to be primary angiosarcomas, because she had neither a history of breast surgery nor of radiation therapy. She underwent bilateral mastectomies and postoperative chest wall irradiation. Computed tomography 11 weeks after the surgery revealed multiple, small, subcutaneous nodules in the chest wall that were suspected of being angiosarcoma metastases. We started chemotherapy (weekly paclitaxel 80 mg/m 2 ), which achieved shrinkage of these nodules within 2 months., Conclusions: Early diagnosis, immediate initiation of local and systemic therapies, and intensive follow-up are important in improving the prognosis of angiosarcomas., (© 2023. The Author(s).)

Synthetic strategies to access high-valent iridium complexes usually require use of π donating ligands bearing electronegative atoms (e. g. amide or oxide) or σ donating electropositive atoms (e. g. boryl or hydride). Besides the η 5 -(methyl)cyclopentadienyl derivatives, high-valent η 1 carbon-ligated iridium complexes are challenging to synthesize. To meet this challenge, this work reports the oxidation behavior of an all-carbon-ligated anionic bis(CCC-pincer) Ir III complex. Being both σ and π donating, the diaryl dipyrido-annulated N-heterocyclic carbene (dpa-NHC) Ir III complex allowed a stepwise 4e - oxidation sequence. The first 2e - oxidation led to an oxidative coupling of two adjacent aryl groups, resulting in formation of a cationic chiral Ir III complex bearing a CCCC-tetradentate ligand. A further 2e - oxidation allowed isolation of a high-valent tricationic complex with a triplet ground state. These results close a synthetic gap for carbon-ligated iridium complexes and demonstrate the electronic tuning potential of organic π ligands for unusual electronic properties., (© 2023 Wiley-VCH GmbH.)

Periodontal disease is one of the most common dental health problems in dogs. Clinical studies in humans have shown that aged garlic extract (AGE), which contains stable and water-soluble sulfur-containing bioactive compounds, improves the symptoms of periodontal diseases. Our previous study demonstrated that oral administration of AGE in healthy Beagle dogs at 90 mg/kg/day for 12 weeks had no adverse effects such as hemolytic anemia, which is well known to occur as a result of ingestion of Allium species, including onions and garlic, in dogs. However, the therapeutic potential of AGE in canine periodontal disease remains unclear. Accordingly, we investigated the therapeutic effects of AGE in Beagle dogs with mild gingivitis. Feeding 18 mg/kg/day of AGE for 8 weeks resulted in the improvement of gingival index score, level of volatile sulfur compounds in exhaled air, and enzyme activity of periodontal pathogens without any adverse effects on clinical signs and hematological and serum biochemical parameters. Moreover, AGE increased the concentration of salivary cathelicidin, an antimicrobial peptide that contributes to the oral innate immune response. These results suggest that AGE could be a potential therapeutic agent for canine gingivitis., Competing Interests: HN, MU, MT, MN, TM, and HJ were employed by Wakunaga Pharmaceutical Co., Ltd. The authors declare that this study received funding from Wakunaga Pharmaceutical Co., Ltd. The funder had the following involvement in the study: providing the AGE for the study. 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 to publish this manuscript., (Copyright © 2023 Takahashi, Nango, Ushijima, Takashima, Nakamoto, Matsutomo, Jikihara, Arakawa, Maki, Yabuki, Endo and Yamato.)

The case is of a 66-year-old woman who visited a general practitioner with a chief complaint of cough. She was referred to the Internal Medicine Department of our hospital because an abnormal shadow was found in her chest X-ray examination. A CT scan suspected her to have a metastatic lung tumor, and gastric cancer was diagnosed on primary site search. The patient was started on G-SOX therapy. After 2 courses, she experienced massive hematemesis and was referred to the hospital. A CT scan revealed arterial bleeding into the stomach. She went into cardiac arrest shortly afterward, and cardiopulmonary resuscitation was started. Hemostasis was obtained by interventional radiology(IVR). Upper gastrointestinal endoscopy performed after hemostasis showed the tumor to be necrotic and shrunk. Bleeding from advanced gastric cancer is common; however, bleeding due to the effects of chemotherapy have been reported. We report a case of massive bleeding and cardiopulmonary arrest during chemotherapy.

An enzyme-fueled transient volume phase transition (TVPT) of hydrogels under out-of-equilibrium conditions is reported. The approach takes inspiration from the metabolic cycle, comprising nutrient intake and anabolism/catabolism followed by waste excretion. The incorporation of methacrylic acid and acrylated trypsin in a polymeric hydrogel allowed the TVPT of the gel to be fueled by lysozyme. With the intake of lysozyme as fuel, the construction/destruction of electrostatic cross-linkages induced transient shrinkage/swelling of the gel accompanied by the depletion of lysozyme activity. The system's transient response could be flexibly programmed by adjusting not only the fuel concentration but the chemical composition of materials. The lysozyme-fueled TVPT of the gel could be exploited to transient changes in the mechanical properties of the gel. Our work opens a route toward a new class of stimuli-responsive hydrogels for biomedical applications.

Direct, transition metal-free B(dan)-installation into organic frameworks has been developed. Heteroaryl-H bonds were transformable into the respective heteroaryl-B(dan) bonds through deprotonation. The resulting heteroaryl-B(dan) compounds, which are otherwise difficult to access, can undergo the direct Suzuki-Miyaura coupling. The method was demonstrated to apply to a silicon nucleophile, giving Lewis acidity-diminished stable silyl-B(dan) and -B(aam) in one pot.

Objective: The ayu or sweetfish Plecoglossus altivelis is ray-finned fish that is widely distributed in East Asia. The genome size of ayu was estimated at approximately 420 Mb. Previously, we reported on ayu draft genome assembly by whole-genome shotgun using Illumina short reads and PacBio long reads; however, the assembly was not to chromosome level. Therefore, to improve the draft genome sequence of ayu to chromosome level, we performed in situ Hi-C sequencing as a source of linkage information., Results: The ayu genome assembly yielded 28 large scaffolds that corresponded to the karyotype of ayu (n = 28). The resulting ayu genome assembly has a N50 scaffold length of 17.0 Mb, improved from 4.3 Mb. The high-quality reference genome will be helpful for phylogenetic research on bony fishes and for breeding programs in ayu aquaculture., (© 2023. The Author(s).)

In cancer therapy, a drug delivery system (DDS) has been widely studied to achieve selective drug accumulation at the tumor site. However, DDS still has a major drawback in that it requires multistep processes for intracellular delivery, resulting in low efficiency of drug delivery. To overcome this problem, we recently reported a molecular block (MB) that disrupts cancer cell membranes in the cancer microenvironment using deoxycholic acid (DCA). However, the MB showed considerable cytotoxicity even at neutral pH, possibly due to the structural hydrophobic property of DCA. Herein, we focused on selecting the most suitable bile acid for an MB that possessed high responsiveness to the cancer microenvironment without cytotoxicity at neutral pH. Cell viabilities of the free bile acids such as DCA, chenodeoxycholic acid (CDCA), cholic acid (CA), and ursodeoxycholic acid (UDCA) were evaluated at neutral pH (pH = 7.4) and a cancer acidic environment (pH = 6.3-6.5). The half-maximal inhibition concentration (IC 50 ) value of UDCA at pH = 7.4 showed an approximately 7.5-fold higher IC 50 value than that at pH = 6.3, whereas the other bile acids yielded less than a 4-fold IC 50 value difference between the same pHs. Biocompatible poly(vinyl alcohol) (PVA) was functionalized with UDCA (PVA-UDCA) for the synthesis of higher responsiveness to the cancer microenvironment without cytotoxicity at neutral pH. Importantly, 56% pancreatic cancer cell death was observed at pH = 6.5, whereas only 10% was detected at neutral pH by the PVA-UDCA treatment. However, PVA-DCA indicated almost the same cancer cell death property, independent of pH conditions. These results suggest PVA-UDCA shows great potential for a new class of MB.

Radioresistance is a major obstacle to the successful treatment of oral squamous cell carcinoma (OSCC). To help overcome this issue, we have developed clinically relevant radioresistant (CRR) cell lines generated by irradiating parental cells over time, which are useful for OSCC research. In the present study, we conducted gene expression analysis using CRR cells and their parental lines to investigate the regulation of radioresistance in OSCC cells. Based on gene expression changes over time in CRR cells and parental lines subjected to irradiation, forkhead box M1 (FOXM1) was selected for further analysis in terms of its expression in OSCC cell lines, including CRR cell lines and clinical specimens. We suppressed or upregulated the expression of FOXM1 in OSCC cell lines, including CRR cell lines, and examined radiosensitivity, DNA damage, and cell viability under various conditions. The molecular network regulating radiotolerance was also investigated, especially the redox pathway, and the radiosensitizing effect of FOXM1 inhibitors was examined as a potential therapeutic application. We found that FOXM1 was not expressed in normal human keratinocytes but was expressed in several OSCC cell lines. The expression of FOXM1 was upregulated in CRR cells compared with that detected in the parental cell lines. In a xenograft model and clinical specimens, FOXM1 expression was upregulated in cells that survived irradiation. FOXM1-specific small interfering RNA (siRNA) treatment increased radiosensitivity, whereas FOXM1 overexpression decreased radiosensitivity, and DNA damage was altered significantly under both conditions, as well as the levels of redox-related molecules and reactive oxygen species production. Treatment with the FOXM1 inhibitor thiostrepton had a radiosensitizing effect and overcame radiotolerance in CRR cells. According to these results, the FOXM1-mediated regulation of reactive oxygen species could be a novel therapeutic target for the treatment of radioresistant OSCC; thus, treatment strategies targeting this axis might overcome radioresistance in this disease., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Rapid antigen tests are widely used to diagnose influenza. However, despite their simplicity and short turnover time, the sensitivity of these tests is relatively low, and molecular tests with greater sensitivity are being sought. In this study, we developed and clinically evaluated a protocol for the rapid multiplex testing of influenza A and B, using a rapid real-time PCR system, GeneSoC ® , that is based on microfluidic thermal cycling technology., Methods: The specificity of the developed assay was validated using cultured viral strains of influenza A/B, human metapneumovirus, and respiratory syncytial virus. Analytical sensitivity was evaluated using serially diluted RNA synthesized via in vitro transcription and nasopharyngeal swab samples collected from consecutive patients seeking medical attention for a combination of upper respiratory and general symptoms. Cross-validation of GeneSoC ® based on comparisons with conventional real-time RT-PCR and rapid antigen tests was performed by parallel testing of influenza-positive clinical specimens., Results: The GeneSoC ® assay detected the target sequences of influenza A and B at minimum concentrations of 38 and 65 copies/µL in reaction, respectively. For the analysis of clinical specimens, the positive, negative, and overall agreement between GeneSoC ® RT-PCR and a conventional real-time RT-PCR was in all cases 100%, whereas for the comparison between GeneSoC ® RT-PCR and the rapid antigen test, the agreements for positive, negative, and overall findings were 100%, 90.9%, and 95.7%, respectively. The mean time for completing GeneSoC ® RT-PCR was 16 min 29 s (95% confidence interval, 16 min 18 s to 16 min 39 s)., Conclusion: The microfluidic real-time PCR system, GeneSoC ® , has an analytical performance comparable to that of conventional real-time RT-PCR with rapid turnover time, and represents a promising alternative to rapid antigen tests for diagnosing influenza A and B., Competing Interests: Conflict of interest: H. Chikumi was provided the study materials (GeneSoC® chips), and is participating in the other joint research project of which theme is different from this study with Kyorin Pharmaceutical Co., Ltd. Kryoin Pharmaceutical Co., Ltd. had no role in the conduct of the study, data collection, data interpretation or preparation of the report., (©2023 Tottori University Medical Press.)

Starting from tetrakis(trimethylsilyl)cyclobutadiene and an amidinate-supported silylene of the Roesky-type, a sequence of addition and reduction cleanly gives the elusive silapyramidane via an isolable cyclobutene intermediate with an exocyclic Si═C bond. The silapyramidane features an unusually shielded 29 Si NMR resonance at -448.3 ppm for the apex silicon atom. Treatment with Fe 2 (CO) 9 results in the formation of the corresponding silapyramidane-iron complex. Silapyramidane also reacts with the cyclobutadiene starting material to cleanly afford a fluorescent spirobis(silole).

To stabilize S N 2 transition state-like penta-coordinate carbon species, triaryl-substituted cationic carbon compounds bearing a moderately flexible 7-6-7-ring skeleton with sulfur donors were synthesized and characterized. Electronic effects of para substituents (R=Cl, F, H, CH 3 , SMe, OMe) of the two equatorial aryl groups bound to the cationic central carbon were investigated systematically along with a planar bidentate thioxanthene derivative. X-ray analysis on their solid-state structures showed that the parent (R=H), chloro-, fluoro- and methyl-derivatives were tetracoordinate carbon (sulfonium) structures, while the p-MeO and thioxanthenyl system were pentacoordinate carbocation structures. The Hammett substituent constants for the para substituents (σ p + ) correlates well with the bonding in these compounds. The methylthio-derivative with intermediate Hammett substituent constants (p-MeS; σ p + =-0.60) showed a tetracooridnate solid-state structure, though solution UV-Vis properties suggested the presence of a penta-coordinate structure. These findings amount to the first unambiguous solution evidence of the hypervalent apical 3c-4e interactions in pentacoordinate carbon compounds., (© 2022 Wiley-VCH GmbH.)

Lewis acidity of organoboronates [B(pin), B(neop), B(cat), B(eg), B(nad)] and organoboronamides [B(dan), B(aam), B(mdan)] has been found to be unifiedly evaluated by computed ammonia affinity (AA), while other methods [LUMO energies, global electrophilicity index (GEI), fluoride ion affinity (FIA)] were only partially applicable. The relationships between the AA values and such structural characters including the B-X bond lengths, the X-B-X angles, and the changes in the B-X bond lengths in the formation of the ammonia adducts were also described., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This study assessed the validity of dietary balance scores (DBSs) by investigating the association between DBSs and nutrient adequacy (NA) in two Japanese populations. The participants were 65 community-dwelling Japanese from Tokushima Prefecture and 2,330 community-dwelling Japanese from Aichi Prefecture. Based on food frequency questionnaires or 3-day dietary records, we obtained 18 food groups. The NA score integrates nine beneficial nutrients and two nutrients that should be limited. We calculated four different DBSs: DBS1 consisted of five food groups (score range:0?20), DBS2 consisted of nine food groups (score range:0?36), DBS3 consisted of eight food groups (score range:0?32), and DBS4 consisted of 10 food groups (score range:0?40). Both the Spearman rank correlation coefficient with NA and the area under the receiver operating characteristic curve (AUC-ROC) for the nine beneficial nutrients were then estimated to test the performance of each DBS in predicting nutrient intake. The results showed that DBS1 and DBS4 were positively correlated with NA, while the AUC-ROC showed that DBS4 could moderately discriminate individuals with adequate intake levels of all nine nutrients. These findings suggest DBSs (especially DBS4) are useful in assessing dietary balance in middle-aged and older community-dwelling Japanese. J. Med. Invest. 70 : 377-387, August, 2023.

Background: Recent studies indicate that the timing of introduction of potentially allergenic food is crucial for the development of food allergy in children. This cross-sectional study aimed to clarify the reality of allergen food intake in a general population of young children in Japan., Methods: A questionnaire survey of caregivers was conducted at health checkups for 1.5-year (18-month)-old and 3-year-old children in the fall of 2020. The caregivers were asked about (1) the presence/absence of allergic disease symptoms based on the ISAAC questionnaire, and (2) foods that caregivers avoided giving their children. Ordinal logistic regression analyses were periformed to determine factors associated with food avoidance., Results: Questionnaires were distributed to 1720 caregivers, and 1603 (93%) responded. The responders consisted of 771 and 832 caregivers who participated in 1.5-year-old and 3-year-old checkups, respectively. The prevalence of allergic diseases was comparable to recent epidemiological studies in Japan, indicating that the population may be representative. At 1.5 years old, more than 50% of the children were not exposed to peanuts, tree nuts, fish eggs, shellfish, and buckwheat. At 3 years old, the avoidance rates of the foods had decreased but were still between 18.8% and 32.0%. On the other hand, the avoidance rates of chicken egg and cow's milk, the top 2 common allergenic foods in Japan, were much lower at 2.8% and 1.5% at 1.5 years, and they decreased to 1.4% and 0.7% at 3 years old, respectively. Ordinal logistic analysis showed that avoidance of chicken egg, cow's milk, and wheat was associated with food allergy diagnosis and chicken egg avoidance with eczema, but avoidance of other foods showed no associations with any risk factors for food allergy., Conclusion: Caregivers avoided giving various foods, independent of allergy risk factors, to their young children. Since delayed introduction of an allergenic food has been reported to increase the risk of developing an allergy to the food, the results warrant future investigation of the development of food allergies in relation to current eating habits and recommendations.

We examined the effects of polymethoxyflavonoids (PMFs) on T helper (Th) 17 cell differentiation in vitro and in vivo. Five different PMFs including nobiletin (NOB), sudachitin (SUD), demethoxysudachitin, heptamethoxyflavone and natsudaidain were used for the in vitro study, and effects of those flavonoids on Th17 responses were investigated. NOB and heptamethoxyflavone significantly suppressed the proliferation response, but SUD, demethoxysudachitin and natsudaidain did not suppress the proliferation response. All of the five flavonoids decreased IL-17A production. Mice with experimentally induced autoimmune encephalomyelitis were used as an in vivo Th17 differentiation model. We focused on two flavonoids, NOB and SUD, and examined the effects of those flavonoids. NOB significantly suppressed Th17 cell proliferation and cytokine responses, but SUD only decreased proliferation responses. The results suggest that the suppressive effect of NOB on Th17 response in vivo is stronger than that of SUD. J. Med. Invest. 70 : 166-170, February, 2023.

Since conventional molecular targeted drugs often result in side effects, the development of novel molecular targeted drugs with both high efficacy and selectivity is desired. Simultaneous inhibition of metabolically and spatiotemporally related proteins/enzymes is a promising strategy for improving therapeutic interventions in cancer treatment. Herein, we report a poly-α-l-glutamate-based polymer inhibitor that simultaneously targets proximal transmembrane enzymes under hypoxia, namely, carbonic anhydrase IX (CAIX) and zinc-dependent metalloproteinases. A polymer incorporating two types of inhibitors more effectively inhibited the proliferation and migration of human breast cancer cells than a combination of two polymers functionalized exclusively with either inhibitor. Synergistic inhibition of cancer cells would occur owing to the hetero-multivalent interactions of the polymer with proximate enzymes on the cancer cell membrane. Our results highlight the potential of polymer-based cancer therapeutics.

This study investigated the association between caudal vena cava (CVC) size and circulatory dynamics in dogs using computed tomography (CT) under general anesthesia. The subjects were 104 dogs who had undergone CT under general anesthesia in the past. The ratio of short diameter of the CVC to aortic diameter (CVC S /Ao) and the ratio of long to short diameter of the CVC (CVC L /CVC S ) in the thorax and abdomen, respectively, were calculated using factors such as mean blood pressure (MBP), shock index (SI), anemia, hypoproteinemia, presence of intra-abdominal mass, and cardiac disease. There was a significant but negligible negative correlation between CVC S /Ao and MBP. In contrast, no significant correlation was found between CVC size and SI. The low MBP group had significantly higher CVC S /Ao of the thorax than the normal MBP group. The group with intra-abdominal mass had significantly lower CVC S /Ao of the abdomen than the group without intra-abdominal mass. The group with cardiac disease had significantly lower CVC L /CVC S of the thorax than the group without cardiac disease. In multiple regression analysis, low MBP, cardiac disease, intra-abdominal mass, and anemia were significant factors for CVC S /Ao of the thorax, CVC L /CVC S of the thorax, CVC S /Ao of the abdomen, and CVC L /CVC S of the abdomen, respectively. In conclusion, CVC size assessment using CT in dogs under general anesthesia is influenced by various factors.

There is no standard clinically adaptable criterion for assessing plantar sensation for pre- and post-intervention comparisons. Studies using Semmes-Weinstein monofilaments (SWMs) to investigate intervention effects on plantar sensation vary in procedure and do not consider measurement errors. This study aimed to develop a simple criterion using SWMs to assess plantar sensation, determine the measurement error range, and identify areas of low error. Six examiners assessed 87 healthy young adults in Experiment 1, while two examiners assessed 10 participants in Experiment 2. Filaments were graded from 1 to 20 based on increasing diameter. The smallest grade that could be perceived for three sequential stimuli was used as the criterion (smallest perceivable grade, SPG). The SPG was significantly smaller at the hallux and larger at the heel than at other sites. There were no significant differences between the SPG of the repeated tests performed by the same versus different examiners. The interquartile range of the differences was <±3 at all sites. Thus, our criteria were reliable in evaluating the effects of plantar sensation interventions, especially at the heel and the middle of the metatarsal heads and could contribute to the development of more effective treatments for plantar sensations.

Left ventricular dilatation (LVD) and left ventricular hypertrophy (LVH) are risk factors for heart failure, and their detection improves heart failure screening. This study aimed to investigate the ability of deep learning to detect LVD and LVH from a 12-lead electrocardiogram (ECG). Using ECG and echocardiographic data, we developed deep learning and machine learning models to detect LVD and LVH. We also examined conventional ECG criteria for the diagnosis of LVH. We calculated the area under the receiver operating characteristic (AUROC) curve, sensitivity, specificity, and accuracy of each model and compared the performance of the models. We analyzed data for 18,954 patients (mean age (standard deviation): 64.2 (16.5) years, men: 56.7%). For the detection of LVD, the value (95% confidence interval) of the AUROC was 0.810 (0.801-0.819) for the deep learning model, and this was significantly higher than that of the logistic regression and random forest methods (P < 0.001). The AUROCs for the logistic regression and random forest methods (machine learning models) were 0.770 (0.761-0.779) and 0.757 (0.747-0.767), respectively. For the detection of LVH, the AUROC was 0.784 (0.777-0.791) for the deep learning model, and this was significantly higher than that of the logistic regression and random forest methods and conventional ECG criteria (P < 0.001). The AUROCs for the logistic regression and random forest methods were 0.758 (0.751-0.765) and 0.716 (0.708-0.724), respectively. This study suggests that deep learning is a useful method to detect LVD and LVH from 12-lead ECGs.

Japanese flounder ( Paralichthys olivaceus ) is an important marine fish species of both fisheries and aquaculture in Northeast Asia. The commercial interest for all-female progenies due to several sex-related traits has prompted basic research on the mechanisms of sex determination in this species. By conducting a linkage analysis of the sex-determining locus, we initially identified 12 microsatellite markers linked to sex in 11 scaffolds, whose localization was restricted to a specific region of linkage group 9. Sequence analysis of this region identified 181 genes based on the UniProt database annotations. Among them, the amh gene was considered a potential candidate for sex determination because this gene is known to have taken over the role of sex determination in many teleosts. An in-depth sequence analysis of both the coding and non-coding regions of amh in XX and XY individuals detected nine SNPs linked with maleness. However, because these substitutions were synonymous, the upstream and downstream regions of amh were also investigated and a male-specific variant with deletions in the promoter region was detected. This truncated Y-specific amh variant was named amhy , and the amh shared by both sexes was named amhx . The association analysis using both females and males of the genotypic sex inferred by the presence/absence of amhy found complete association with phenotypic sex and genotype. Gene expression analysis in larvae derived from a single-pair progeny by quantitative real-time PCR detected amhy transcripts in the larval trunks between 20 and 100 days after hatching only in XY larvae. Localization of amhy by in situ hybridization was detected in presumptive Sertoli cells of XY gonads. Expression of amhx was almost undetectable in both XX and XY genotypes. Loss of Amh function by CRISPR-Cas9 induced male-to-female sex reversal, indicating that this gene was necessary for the masculinization of XY individuals. In conclusion, the complete linkage of amhy with males, its early expression in XY gonads before testicular differentiation, and the induction of sex reversal by loss-of-function mutation support the view that amhy is the sex-determining gene in this species., Competing Interests: The 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., (Copyright © 2022 Hattori, Kumazawa, Nakamoto, Nakano, Yamaguchi, Kitano, Yamamoto, Fuji and Sakamoto.)

A metabolic cycle-inspired hydrogel which exhibits the biomacromolecule-fueled transient volume phase transition is reported. This hydrogel has the affinity and digestive capacity for a fuel α-poly-L-lysine by incorporating acrylic acid and trypsin. The hydrogel captured fuel and transiently shrank owing to the construction of electrostatic cross-linkages. This process was inherently connected with the digestion of these cross-linkages and the release of oligo-lysine as waste, which induced the reswelling of the hydrogel at equilibrium. The transient volume change of the hydrogel realized the fuel-stimulated transient release of a payload. This study provides a strategy for engineering materials with biomacromolecule-fueled dynamic functions under the out-of-equilibrium condition., (© 2022 Wiley-VCH GmbH.)

Oligomannose-type glycans on glycoproteins play an important role in the endoplasmic reticulum (ER)-protein quality control. Mannose trimming of the glycans triggers the ER-associated protein degradation pathway. In mammals, ER mannosyl-oligosaccharide 1,2-α-mannosidase 1 and three ER degradation -enhancing α-mannosidase-like proteins (EDEMs) are responsible for mannose trimming. However, the exact role of EDEMs as α-mannosidases in ERAD remains unclear. Here, we performed the biochemical characterization of EDEM3 using synthetic oligomannose-type glycan substrates. In vitro assays revealed that EDEM3 can convert an asparagine-linked M9 glycan to M8 and M7 glycans in contrast to glycine-linked M9 glycan, and the activity is enhanced in the presence of ERp46, a known partner protein of EDEM3. Our study provides novel insights into the enzymatic properties of EDEM3 and the use of artificial glycan substrates as tools to study ERAD mechanisms., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In Japan, the Positive List (PL) system was introduced (Enforcement: June 1, 2020) in the regulative field of Food Apparatus, Containers, and Packaging (ACP) by the recent amendment of the Food Sanitation Act. Under this situation, continuous requests for the risk assessments from the Ministry of Health, Labour and Welfare (MHLW) to the Food Safety Commission of Japan (FSCJ) will be expected. To enhance fairness and transparency and to clarify the data required for the risk assessment, the FSCJ established its "Guidelines for the Risk Assessment of Food Apparatus, Containers, and Packaging" on May 28, 2019. The Guidelines apply to new Food Contact Materials or Substances (FCMs) after enforcement of the PL system (June 1, 2020). The subject material is synthetic resins, because the PL system was first introduced to them in Japan. In general, the substances that are migrated from ACP are not intended to migrate into foods, and their technological effects on foods are not expected. It can be supposed that the migration of these substances is generally very limited. Therefore, as adopted in the USA and the EU, the Guidelines also adopt the tiered approach for the toxicological data requirement that depend on the estimated migration levels (Tier of Dietary Concentration (Tier of DC)) on the subject substance. The greater the exposure to the substance through migration, the more toxicity test results will be needed. The risk assessment steps by the tiered approach in the Guidelines are (1) migration assessment, (2) toxicity assessment, (3) exposure assessment, and (4) risk characterization. These steps are aimed to harmonize with the general 4 steps of risk assessments: hazard identification, hazard characterization, exposure assessment, and risk characterization. In this review, we will introduce the overview of the Guidelines and details of the above 4 steps., (©2022 Food Safety Commission, Cabinet Office, Government of Japan.)

Stabilization of low oxidation gold anions as aurate or auride by organic ligands has long been a synthetic challenge, owing to the proneness of low-valent gold centres to cluster. Despite being the most electronegative metal, isolable gold(I) aurate complexes have only been obtained from a few σ-withdrawing organo- and organo-main group ligands. Stabilization of highly-reduced gold complexes by π-modulating redox active ligands has only been achieved by cyclic (amino)(alkyl)carbene (CAAC), which is limited to 1e - -reduction to form neutral gold(0) complexes. This work reports a simple modular synthesis of a boron, nitrogen-containing heterocyclic carbene ( Cl BNC) at a gold(I) center through metal-assisted coupling between azadiboriridine and isocyanides. The anionic electrophilic Cl BNC ligand in the gold(I) complex [( Cl BNC)AuPMe 3 ] (3a and 3b) allows a 2e - -reduction to form the first η 1 -carbene aurate complex [(BNC)AuPMe 3 ]Li(DME) (5a, DME = dimethoxyethane). Single crystal crystallographic analysis and computational studies of these complexes revealed a highly π-withdrawing character of the neutral 4π B,N-heterocyclic carbene (BNC) moiety and a 6π weakly aromatic character with π-donating properties to the gold(I) fragment in its reduced form, showcasing the first cyclic carbene ligand that allows electronic tunability between π-withdrawing (Fischer-type)- and π-donating (Schrock-type) properties.

The chick retina has long been an important model system in developmental neurobiology, with advantages including its large size, rapid development, and accessibility for visualization and experimental manipulations. However, its major technical limitation had been the lack of robust loss-of-function approaches for gene function analyses. This protocol describes a methodology of gene silencing in the developing chick retina that involves transgenic expression of artificial microRNAs (miRNAs) by using the Tol2 transposon system. In this approach, a Tol2 transposon plasmid that contains an expression cassette for the EmGFP (emerald green fluorescent protein) marker and artificial pre-miRNA sequences against a target gene is introduced into the embryonic chick retina with a Tol2 transposase expression construct by in ovo electroporation. In the transfected retinal cells, the transposase catalyzes the excision of the expression cassette from the transposon vector and its integration into host chromosomes, leading to the stable expression of miRNAs and the EmGFP protein. In our previous study, we have demonstrated that the expression of Nel, a glycoprotein that exerts multiple functions in neural development, can be significantly suppressed in the developing chick retina by using this technique. Our results indicate that this methodology induces a stable and robust suppression of gene expression and thus provides an efficient loss-of-function approach for studies of retinal development.

A new dimethyl(phenyl)silylborane having a naphthalene-1,8-diaminato (dan) substituent on the boron center, PhMe 2 Si-B(dan), was synthesized. Owing to the diminished boron Lewis acidity, it is highly stable toward air. Synthetic application of the silylborane to catalytic silylboration and silylation of alkynes is also described.

Improving the efficiency and selectivity of drug delivery systems (DDS) is still a major challenge in cancer therapy. Recently, the low transport efficiency of anticancer drugs using a nanocarrier due to the elimination of the carriers from the blood circulation and the blocking by tumor stromal tissues surrounding cancer cells has been reported. Furthermore, multiple steps are required for their intracellular delivery. We recently reported a cancer microenvironment-targeting therapy termed molecular block (MB) which induced cancer cell death by a pH-driven self-aggregation and cell membrane disruption at tumor microenvironment. The MB were designed to disperse as nanoscale assemblies in the bloodstream for efficient circulation and penetration through the stromal tissues. When the MBs reach the tumor site, they self-assembled in microscale aggregates on the cancer cell surfaces in response to the cancer microenvironment and induced cancer cell death. However, in vivo study in mice showed that the MB could not efficiently accumulate at the tumor site because slight hydrophobic aggregations in the bloodstream might potentially be the reason for the off-target accumulation. In this study, we optimize the hydrophilic-hydrophobic balance of MB for avoiding the off-target accumulation and for gaining higher sensitivity to the cancer microenvironment at weak acid condition. Copper-free click reaction with propiolic acid was used to reduce the hydrophobicity of the main chain and obtain higher responsive MB at cancer microenvironment for rapid cell killing. The optimized MB can be considered as a promising approach for an improved cancer cell targeting.