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BACKGROUND Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. METHODS Data from 11,498 men and women aged 35-69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10-8) were selected from the GWAS catalog, and seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). RESULTS We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. CONCLUSIONS The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking.

Simultaneous measurements of the circulating testosterone (TS) and dehydroepiandrosterone sulfate (DHEAS) are deemed to be helpful for the assessment of men's health. Liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) is the most reliable methodology for this purpose; however, it has room for improvement in analysis throughput. In this study, a quadruplicate of the Girard reagents was used to develop an LC/ESI-MS/MS method capable of quantifying TS and DHEAS in four different serum samples in a single run. The four serum samples were separately pretreated, derivatized with one of four Girard reagents, and then combined. The LC/ESI-MS/MS analysis of the combined sample provided the androgen concentrations of four serum samples in parallel. The method had practical measuring ranges, in which good precision and accuracy, as well as negligible matrix effects were verified. The speed-up capability of the developed method was evaluated through the analysis of ten batches of serum samples (total 40 samples); the method saved a 60% post-pretreatment analysis time compared to the non-derivatization method for 40 samples.

Selective transformation of C-F bonds remains a significant goal in organic chemistry, but C-F insertion of a one-carbon-atom unit has never been established. Herein we report the BF3-catalyzed formal insertion of diazo esters as one-carbon-atom sources into C-F bonds to accomplish one-carbon elongation of benzylic fluorides. A DFT calculation study revealed that the BF3 catalyst could contribute to both C-F bond cleavage and re-formation. This elongation provided α-fluoro-α,β-diaryl esters with a high level of diastereoselectivity. Various benzylic fluorides and diazo esters were applicable. The synthetic utility of this method was demonstrated by the synthesis of a fluoro analogue of a compound that is used as a transient receptor and potential canonical channel inhibitor.

We attempted to develop an efficient method for producing isomaltose, a disaccharide consisting of an α-(1→6)-linkage, from starch by combining enzymes of known activity. We found that the combination of 1,4-α-glucan 6-α-glucosyltransferase from Bacillus globisporus N75 and isopullulanase from Aspergillus brasiliensis ATCC 9642 led to the efficient synthesis of isomaltose. Inclusion of isoamylase and cyclomaltodextrin glucanotransferase resulted in increased efficiency, with production yields exceeding 70%. Furthermore, we considered that isomaltooligosaccharides could be synthesized from starch by combining 1,4-α-glucan 6-α-glucosyltransferase from Paenibacillus sp. PP710 and isopullulanase. In reactions that additionally utilized isoamylase and α-amylase, the total concentration of product, which included a series of isomaltooligosaccharides from isomaltose to isomaltodecaose, was 131 m m, and the ratio of 6-linked glucopyranosyl bonds to all bonds was 91.7% at a substrate concentration of 10%. The development of these manufacturing methods will accelerate the industrial production of isomaltose and isomaltooligosaccharides.

A σ-π extended aryldisilane, comprising a thienopyrazine group as an acceptor fragment and phenothiazine groups as the donor moiety, has been prepared through the introduction of two Si-Si bridges (compound 1). X-ray diffraction analysis determined the crystal structure of 1, and experimental and theoretical approaches investigated its optical properties. Solvatochromic studies revealed the dual emission of 1 in all solvents tested. Compound 1 also exhibited fluorescence in the solid state upon excitation with a hand-held UV lamp, as well as mechanochromic luminescent properties. The packing mode in the crystal structure, variation of phenothiazine conformation, morphological changes between crystalline and amorphous phases are the major factors showing reversible fluorescence under external stimuli. A theoretical conformer study found that 1 exists in distinct conformational groups differing in Gibbs free energy by less than 3 kcal mol-1 . The conformer in the crystalline state of 1 can promote the complete separation of the HOMO and LUMO between the phenothiazine donor and the thienopyrazine acceptor, linked by the disilane linker. HOMO-LUMO energy transition in the crystalline state is forbidden due to the lack of frontier orbital overlap. Crystalline state emission showed LUMO → HOMO-1 transition (locally excited (LE) state). In the amorphous state, the partial presence of quasi-axial conformers allows intramolecular charge-transfer type emission via energy transfer from dominant quasi-equatorial conformers. The strategy proposed in this work provides important guidance for developing stimuli-responsive materials with controlled excited states.

Phenolic compounds are abundant in nature and have multiple beneficial effects on human health due to their antioxidant, anti-inflammatory, antithrombotic, antiallergenic, anticancer, and antiatherosclerotic properties. For this reason, phenolics are becoming relevant functional ingredients for several industries, mainly the food industry, derived from food consumer exigencies and regulations. However, the use of their beneficial properties still presents some limitations, such as chemical instability under environmental and processing conditions, which leads to structural changes and compromises their biological activities. They also present poor water solubility and sensitivity to pH changes, decreasing their bioavailability in the organism. The technologies for extraction and stabilization of these compounds have evolved rapidly in the development of different delivery systems to encapsulate sensitive active molecules. Biopolymeric nanoparticles are biodegradable polymer-based colloidal systems with sizes ranging from 1 to 1000 nm, and different techniques can be carried out to develop them. These systems have emerged as a green and effective alternative to improve stability, bioavailability, and biological effects of phenolic compounds. This comprehensive review aims to present an overview of recent advances in encapsulation processes of phenolic compounds within biopolymer nanoparticles as delivery systems and the impact on their physicochemical properties and biological effects after encapsulation. © 2021 Society of Chemical Industry.

The superconducting magnetic separation was examined to reduce the volume of cesium contaminated soil by the Fukushima Daiichi nuclear power plant accident. By using superconducting high gradient magnetic separation, silt and clay with high radioactive concentration due to the large particle surface area per unit mass can be further separated into high-dose 2:1 type and low-dose 1:1 type clay minerals selectively. Here, we examined filter conditions to improve the magnetic separation performance in farmland soil that is rich in organic matter. The results of magnetic separation of uncontaminated soil suggested that the separation selectivity of 1:1 and 2:1 type clay minerals was larger with the filters with smaller wire diameter. On the other hand, it was found that it was difficult to magnetically separate 0–20 μm particles even with the filters with small wire diameter and high selectivity. To solve this problem, magnetic separation was performed under the same conditions on actual contaminated soil that was highly classified into 0–20 μm and 20–75 μm particles. As the result, it was found that the radioactivity can be further reduced by removed high-dose 0–20 μm particles and targeting the 20–75 μm particles.

Aims/Introduction We recently reported the beneficial effect of the combination of sodium–glucose cotransporter 2 inhibitor and dipeptidyl peptidase‐4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. Materials and Methods The CALMER study was a multicenter, open‐label, prospective, randomized, parallel‐group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. Results All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2–82.7%, P

Various molecular‐targeting drugs have markedly improved the treatment of patients with breast cancer. As yet, therapies for triple‐negative breast cancer are mainly cytotoxic agents. To investigate the novel therapy for triple‐negative breast cancer, we herein examined the effects of a new combination therapy comprising a RAF/MEK inhibitor CH5126766, also known as VS‐6766, which we originally discovered, and eribulin. The combination of CH5126766 and eribulin potently inhibited cell growth in the triple‐negative breast cancer cell lines tested. The underlying mechanism in the efficacy of this combination treatment in vitro and in vivo was due to enhanced apoptosis through the suppression of survivin and Bcl‐2 family proteins. We also showed the suppressed expression of programmed cell death ligand 1 (PD‐L1) in combination therapy in vivo. We found that combination therapy with eribulin and CH5126766 for triple‐negative breast cancer inhibited cell growth by apoptosis and raised a possibility that immune responses through suppression of PD‐L1 might partially contribute to inhibition of tumor growth, indicating the potential of this combination as a novel strategy for triple‐negative breast cancer., We showed that combination therapy with eribulin and CH5126766 for triple‐negative breast cancer inhibited cell growth by apoptosis and raised a possibility that immune responses, through suppression of programmed death ligand 1, might partially contribute to inhibition of tumor growth, indicating the potential of this combination as a novel strategy for triple‐negative breast cancer.

Developing highly active and durable electro-catalysts, consisting of earth-abundant elements, for oxygen evolution reaction (OER) is pivotal for large-scale water splitting for hydrogen production. Herein, we report that the commercially available FeNiCo alloy can be converted to a highly active electrocatalyst for OER by galvanostatic anodizing in a fluoride-containing ethylene glycol electrolyte. Anodizing of the alloy develops a porous film consisting of the (FeNiCo)F-2 phase, which is readily converted to a highly active porous oxyhydroxide during anodic polarization in a KOH electrolyte. The anodized alloy exhibits high activity and high durability for OER with an overpotential as low as 0.26 V at a current density of 10 mA cm(-2). The present study demonstrates that a simple and cost-effective anodizing process can be used to form a highly active OER electrode from a low-cost, practical, iron-based alloy. In addition, we found that fluorides containing Fe, Ni, and Co are excellent precursors for the formation of oxyhydroxides exhibiting high OER activity and durability.

The progression of diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, involves mineralocorticoid receptor (MR) activation. We previously identified crosstalk between the small guanosine triphosphatase (GTPase) RAS-related C3 botulinus toxin substrate 1 (Rac1) and MR, but the role of Rac1-MR pathway activation in the progression of DKD is not clear. We performed uninephrectomy on type 2 diabetic mouse models, db/db (UNx-high salt [HS] db/db ), and their lean control, db/m (UNx-HS db/m ), at 4-week postpartum, and fed them a high-salt diet for 10 weeks. To evaluate the involvement of the Rac1-MR pathway in the DKD progression, we investigated the effects of the nonsteroidal MR antagonist, finerenone, and the Rac1 inhibitor, NSC23766, on blood pressure and glomerular injury in UNx-HS db/db mice. UNx-HS db/db mice with hyperaldosteronism showed hypertension and hypokalemia with increased cleaved α-epithelial sodium channel expressions and massive albuminuria, accompanied by glomerular injury with nodular lesions, which is a characteristic finding in human diabetic nephropathy. Expressions of active Rac1 and serum-and glucocorticoid-induced protein kinase 1 (Sgk1), a downstream molecule of MR signaling, in the renal cortex and isolated glomeruli, significantly elevated in UNx-HS db/db mice, associated with intense staining of active Rac1 in glomerular podocytes, but both hypertension and renal injury were ameliorated by NSC23766 and finerenone, associated with Sgk1 inhibition, suggesting that Rac1-MR activation contributes to hypertension and podocyte injury. In conclusion, salt-induced activation of Rac1-MR pathway in distal tubules and glomeruli is involved in DKD progression through hypertension and glomerular injury, respectively. This finding highlights MR antagonism along with Rac1 inhibition as a novel strategy for DKD treatment.

Background and Aim We aimed to identify clinical features that suggest that coronavirus disease 2019 (COVID‐19) should be a differential diagnosis in patients presenting with a chief complaint of fever and abnormal liver function. Methods We retrospectively studied the presence or absence of abnormal liver function in 216 patients diagnosed with mild–moderate severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection between February and September 2020. Results Abnormal liver function was observed in 51 patients with mild–moderate COVID‐19. The median peak aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were 57.5, 75.5, and 332.5 U/L, respectively. The median number of days from symptom onset to peak AST, ALT, and LDH were 8.5, 9, and 8.5, respectively. The median peak LDH/AST ratio was 9.0. Low lymphocyte‐to‐white blood cell ratio and elevated LDH were found to be independent contributing factors for intensive care unit (ICU) admission on a multivariate analysis. Conclusions AST‐predominant AST/ALT/LDH elevation peaking 8–9 days after symptom onset and not accompanied by elevated alkaline phosphatase or gamma‐glutamyl transferase may be a useful clinical feature for differentiating COVID‐19 from other diseases. Since the median LDH/AST ratio was 9.0, it seems that the abnormal liver function caused by SARS‐CoV‐2 is an indirect damage to liver cells due to elevated cytokine levels caused by liver‐infiltrating lymphocytes. SARS‐CoV‐2 infection should be considered in patients presenting with a chief complaint of fever and liver injury; those with a high lymphocyte‐to‐white blood cell ratio or and a high LDH/AST ratio may be admitted to the ICU., Aspartate aminotransferase (AST)‐predominant AST/alanine aminotransferase/lactate dehydrogenase (LDH) elevation peaking 8–9 days after symptom onset and not accompanied by elevated alkaline phosphatase or gamma‐glutamyl transferase may be a useful clinical feature for differentiating coronavirus disease 2019 from other diseases. Since the median LDH/AST ratio was 9.0, it seems that the abnormal liver function caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is an indirect damage to liver cells due to elevated cytokine levels caused by liver‐infiltrating lymphocytes. SARS‐CoV‐2 infection should be considered in patients presenting with a chief complaint of fever and liver injury.

Homologation of alkyl acetates, alkyl ethers, acetals, and ketals was accomplished via formal insertion of diazo esters into carbon–carbon σ-bonds. The combined Lewis acid InI3 with Me3SiBr catalyzed the homologation of alkyl acetates and alkyl ethers. That of acetals and ketals was catalyzed solely by the use of InBr3. The key point of the homologation mechanism is that the indium-based Lewis acids have the appropriate amount of Lewis acidity to achieve both the abstraction and release of leaving groups. The abstraction of a leaving group by an indium-based Lewis acid and the electrophilic addition of carbocation or oxonium intermediates to diazo esters followed by the rearrangement of carbon substituents provide the corresponding cation intermediates. Finally, the leaving group that is captured by the Lewis acid bonds with cation intermediates to furnish the homologated products.

One of the earliest maturation steps in cardiomyocytes (CMs) is the sarcomere protein isoform switch between TNNI1 and TNNI3 (fetal and neonatal/adult troponin I). Here, we generate human induced pluripotent stem cells (hiPSCs) carrying a TNNI1[EmGFP] and TNNI3[mCherry] double reporter to monitor and isolate mature sub-populations during cardiac differentiation. Extensive drug screening identifies two compounds, an estrogen-related receptor gamma (ERRγ) agonist and an S-phase kinase-associated protein 2 inhibitor, that enhances cardiac maturation and a significant change to TNNI3 expression. Expression, morphological, functional, and molecular analyses indicate that hiPSC-CMs treated with the ERRγ agonist show a larger cell size, longer sarcomere length, the presence of transverse tubules, and enhanced metabolic function and contractile and electrical properties. Here, we show that ERRγ-treated hiPSC-CMs have a mature cellular property consistent with neonatal CMs and are useful for disease modeling and regenerative medicine., ヒトのiPS細胞から新生児レベルまで成熟した心筋細胞を作製する. 京都大学プレスリリース. 2021-06-21., Lowering the cost of heart cell therapies. 京都大学プレスリリース. 2021-06-21.

We revealed the effects of the substituents in ligands on properties of Phebox-aluminum complexes. The substituents at the 4-position of Phebox ligands effectively influenced the Lewis acidity via ...

Methyl erythritol phosphate (MEP) is the metabolite found in the MEP pathway for isoprenoid biosynthesis, which is known to be utilized by plants, algae, and bacteria. In this study, an unprecedented observation was found in the oleaginous yeast Yarrowia lipolytica, in which one of the chromatographic peaks was annotated as MEP when cultivated in the nitrogen limiting condition. This finding raised an interesting hypothesis of whether Y. lipolytica utilizes the MEP pathway for isoprenoid biosynthesis or not, because there is no report of yeast harboring the MEP pathway. Three independent approaches were used to investigate the existence of the MEP pathway in Y. lipolytica; the spiking of the authentic standard, the MEP pathway inhibitor, and the 13C labeling incorporation analysis. The study suggested that the mevalonate and MEP pathways co-exist in Y. lipolytica and the nitrogen limiting condition triggers the utilization of the MEP pathway in Y. lipolytica.

Glucanotransferases that can synthesize cyclo-{→6)-α-d-Glcp-(1→6)-α-d-Glcp-(1→6)-α-d-Glcp-(1→6)-α-d-Glcp-(1→} (CI4) from dextran were purified to homogeneity from the culture supernatant of Agreia sp. D1110 and Microbacterium trichothecenolyticum D2006. The molecular mass of both enzymes was estimated to be 86 kDa by SDS-PAGE. The glucanotransferase, named CI4-forming enzyme, from Agreia sp. exhibited the highest activity at pH 6.0 and 40 °C. The enzyme was stable on the pH range of 4.6-9.9 and up to 40 °C. On the other hand, the enzyme from M. trichothecenolyticum exhibited the highest activity at pH 5.7 and 40 °C. The enzyme was stable on the pH range of 5.0-6.9 and up to 35 °C. Both enzymes catalyzed 4 reactions, namely, intramolecular α-1,6-transglycosylation (cyclization), intermolecular α-1,6-transglycosylation, hydrolysis of CI4, and coupling reaction. Furthermore, the CI4-forming enzyme produced CI4 from α-1,6-linked glucan synthesized from starch by 6-α-glucosyltransferase. These findings will enable the production of CI4 from starch.

Scorpion venom contains a variety of biologically active peptides. Among them, neurotoxins are major components in the venom, but it also contains peptides that show antimicrobial activity. Previously, we identified three insecticidal peptides from the venom of the Liocheles australasiae scorpion, but activities and structures of other venom components remained unknown. In this study, we performed a transcriptome analysis of the venom gland of the scorpion L. australasiae to gain a comprehensive understanding of its venom components. The result shows that potassium channel toxin-like peptides were the most diverse, whereas only a limited number of sodium channel toxin-like peptides were observed. In addition to these neurotoxin-like peptides, many non-disulfide-bridged peptides were identified, suggesting that these components have some critical roles in the L. australasiae venom. In this study, we also isolated a component with antiviral activity against hepatitis C virus using a bioassay-guided fractionation approach. By integrating mass spectrometric and transcriptomic data, we successfully identified LaPLA2-1 as an anti-HCV component. LaPLA2-1 is a phospholipase A2 having a heterodimeric structure that is N-glycosylated at the N-terminal region. Since the antiviral activity of LaPLA2-1 was inhibited by a PLA2 inhibitor, the enzymatic activity of LaPLA2-1 is likely to be involved in its antiviral activity.

Isolated silica concretions in calcareous sediments have unique shapes and distinct sharp boundaries and are considered to form by diagenesis of biogenic siliceous grains. However, the details and rates of syngenetic formation of these spherical concretions are still not fully clear. Here we present a model for concretion growth by diffusion, with chemical buffering involving decomposition of organic matter leading to a pH change in the pore-water and preservation of residual bitumen cores in the concretions. The model is compatible with some pervasive silica precipitation. Based on the observed elemental distributions, C, N, S, bulk carbon isotope and carbon preference index (CPI) measurements of the silica-enriched concretions, bitumen cores and surrounding calcareous rocks, the rate of diffusive concretion growth during early diagenesis is shown using a diffusion-growth diagram. This approach reveals that ellipsoidal SiO2 concretions with a diameter of a few cm formed rapidly and the precipitated silica preserved the bitumen cores. Our work provides a generalized chemical buffering model involving organic matter that can explain the rapid syngenetic growth of other types of silica accumulation in calcareous sediments.

In this study, we developed an analytical method using LC-MS/MS for the simultaneous determination of five bile acids (BAs) that have been recently reported as candidate diagnostic biomarkers for Alzheimer's disease (AD) or AD related factors in the brain. The measurement of BAs in the brains of healthy mice led to the determination of candidate diagnostic markers for AD, such as cholic acid and deoxycholic acid, and other bile acids, such as chenodeoxycholic acid noted for the ameliorating effect on the symptoms of AD. Significant positive correlations were observed between the brain and plasma concentrations of four BAs in healthy young mice. These results indicate that the BA level in the brain may be estimated by the corresponding BA level in the plasma. Thus, our study suggested that the proposed method for the analysis of the five bile acids would aid in the diagnosis of AD or in studies that use AD model mice.

The adsorption and photocatalytic degradation of Ethyl methylphosphonate (EMPA) on powdery TiO2 film has experimentally investigated using attenuated total reflection-infrared Fourier transform spectroscopy (ATR-FTIR) in ambient condition. Characteristic IR frequency as P-O-C vibration mode as EtO was observed by EMPA adsorbed at the surface of TiO2. By TiO2 photocatalysis, the adsorbed EMPA was decomposed to methyl phosphonic acid and phosphoric acid. The increment of IR intensity of which is assigned to Ti–O-P-O-Ti of EMPA was accompanied with increasing the IR peak intensity assigned to MPA. About that, we suggest that the appearance of the Ti–O-P-O-Ti of EMPA by the TiO2 photocatalysis is regarded as acceleration of the hydrolysis of EMPA by the surface OH groups of TiO2. The plausible adsorption structure and the photocatalytic reaction mechanism of EMPA at the surface of TiO2 photocatalyst were elucidated.

The international issue to be addressed towards realizing a low-carbon society is to reduce the amount of carbon-based underground reserves such as coal, petroleum, and coke, and strongly encouraged to use carbon neutral biomass-derived resources. Woodceramics is a hybrid porous carbon material composed of wood-based biomass and phenolic resin, characterized by high far-infrared emissivity and large specific surface area. Woodceramics has been studied as heating elements and humidity and gas sensors, etc. If this is applied to the inner walls of aging and grain drying furnaces for vegetables and fruits, both ripening and drying are greatly promoted and fossil fuels used in boilers can be significantly reduced. In fact, it can produce black garlic with far infrared rays using a woodceramics brick efficiently. Furthermore, as a substitute for phenolic resin, if plant-based liquefied materials from cashew nut shell oil can be prepared and can be used for manufacturing woodceramics, then all carbon neutral circulating woodceramics made from wood-based biomass is possible to manufacture. On the other hand, woodplastics is a composite material that can be made of wooden materials and plastics, and able to expect the effective use of wood-based biomass and waste plastics.

Water electrolysis driven by renewable energy can produce clean hydrogen, but its efficiency remains low, in part because of slow kinetics at the anode for the oxygen evolution reaction (OER). Learning from the most active catalysts for the OER, iridium oxides, would be the key to the development and establishment of design guidelines for active and stable OER catalysts. This article reviews in situ or operando spectroscopic and advanced computational studies in the past decade concerning the OER over iridium oxide for both the oxidation of water molecules and hydroxide ions. By collectively reviewing the reported findings, we illustrate the plausible OER catalytic cycles including the dissolution of iridium during the reaction, which at the same time disclosed discrepancies in the proposed mechanisms. Such discrepancies are thought to originate from variations in the experimental conditions employed in those studies, calling for comprehensive and systematic in situ or operando studies in the future. Toward the end, we discuss a recent approach for improving the activity and stability of OER catalysts.

We synthesized novel hypervalent iodines possessing cationic heterocyclic moieties nearby the iodine(III) center. The novel hypervalent iodines exhibited a totally different regioselectivity from common PhI(OAc)2 during the sulfonyloxylactonization of 2-vinylbenzoic acids. The noncovalent interactions between the sulfonyloxy groups and the cationic heterocyclic moieties resulted in a significant change in the regioselectivity, which was revealed by the observation of intermediates and density functional theory studies including noncovalent interaction analysis.

We report the first example of a chiral BDH-TTP radical-cation salt. Chirality is induced in the structure via the use of a chiral spiroboronate anion where three stereocentres are present, one on each chiral ligand and one on the boron centre. Despite starting from a labile racemic mixture of BS and BR enantiomers, only one enantiomer is present in the crystal lattice. The anions pack in a novel double anion layer which is the thickest anion layer found in a BDH-TTP salt. This material is chiral and shows metallic behaviour down to at least 4.2 K.

Water electrolysis driven by electrical power generated from renewable energy sources will play a pivotal role in future sustainable societies, which requires adaptation of various reaction conditions as well as electrolyte identities. Regardless, the anodic half-reaction of the oxygen evolution reaction (OER) is considered a kinetic bottleneck. This study provides quantitative description of the OER kinetics based on rigorous microkinetic analyses including Tafel analysis, isotope effects and temperature dependence using an IrOx electrocatalyst in unbuffered solution at varying pH levels. The diffusional constraints of H+/OH− determine three distinctive kinetic regimes in the pH-potential-current relationships: below pH 5, between pH 5 and 10, and above pH 10 at appreciable current densities on the order of 1 mA cm−2. When shifting from alkaline to acidic solution, the complete consumption of local OH− near the electrode surface switches the OER proceeding as the oxidation of OH− to that of the water molecule at pH ~ 11 irrespective of the electrode identity. At pH 5–10, the diffusional constraints of H+ generated via oxidation reaction yield an environment with pH ~ 4 near the electrode surface even prior to the OER, resulting in a bulk pH-independent region for the OER performance. Under this unbuffered near-neutral-pH condition, the isotope effect was diminished for the OER catalysis, which is consistent with the rate-determining step (rds) being the sole electron-transfer step via the formation of O-O bonds, decoupled from proton transfer. This reaction mechanism is distinct from that under more acidic conditions (pH

We developed the regioselective anti-carbometalation of alkynyl sulfides via the use of InBr3 and organosilicon nucleophiles to give β-mercaptoalkenylindium compounds. The structure of β-mercaptoal...

Human adrenomedullin (AM) functions as a circulating hormone and as a local paracrine mediator with multiple biological activities. We investigated the metabolism of AM by examining its fragmentation in human serum. Adrenomedullin was rapidly cleaved in human serum, but was relatively stable in plasma. We showed that AM was rapidly digested by thrombin in serum, with AM(13-44) as the main product. On the basis of these data, we prepared AM analogs in which Arg-44 was replaced by Ala, Lys, and D-Arg, respectively. These analogs were resistant to thrombin and showed comparable biological activity to native AM. Furthermore, the bioavailabilities of these peptides were improved after subcutaneous administration in rats. These AM analogs may be promising drug candidates for clinical applications.

Many microbial secondary metabolites are produced by multienzyme complexes comprising nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). The ketosynthase (KS) domains of polyketide synthase normally catalyze the decarboxylative Claisen condensation of acyl and malonyl blocks to extend the polyketide chain. However, the terminal KS domain in tenuazonic acid synthetase 1 (TAS1) from the fungus Pyricularia oryzae conducts substrate cyclization. Here, we report on the unique features of the KS domain in TAS1. We observed that this domain is monomeric, not dimeric as is typical for KSs. Analysis of a 1.68-Å resolution crystal structure suggests that the substrate cyclization is triggered via proton abstraction from the active methylene moiety in the substrate by a catalytic His-322 residue. Additionally, we show that TAS1 KS promiscuously accepts aminoacyl substrates and that this promiscuity can be increased by a single amino acid substitution in the substrate-binding pocket of the enzyme. These findings provide insight into a KS domain that accepts the amino acid–containing substrate in an NRPS–PKS hybrid enzyme and provide hints to the substrate cyclization mechanism performed by the KS domain in the biosynthesis of the mycotoxin tenuazonic acid.

Fibrillins (FBNs) form mesh‐like structures of microfibrils in various elastic tissues. RECK and FBN1 are co‐expressed in many human tissues, suggesting a functional relationship. We found that dermal FBN1 fibers show atypical morphology in mice with reduced RECK expression (RECK‐Hypo mice). Dermal FBN1 fibers in mice‐lacking membrane‐type 1‐matrix metalloproteinase (MT1‐MMP) show a similar atypical morphology, despite the current notion that MT1‐MMP (a membrane‐bound protease) and RECK (a membrane‐bound protease inhibitor) have opposing functions. Our experiments using dermal fibroblasts indicated that RECK promotes pro‐MT1‐MMP activation, increases cell‐associated gelatinase/collagenase activity, and decreases diffusible gelatinase/collagenase activity, while MT1‐MMP stabilizes RECK in these cells. Experiments using purified proteins indicate that RECK and its binding partner ADAMTS10 keep the proteolytic activity of MT1‐MMP within a certain range. These findings suggest that RECK, ADAMTS10, and MT1‐MMP cooperate to support the formation of robust FBN1 fibers., Fibrillin‐1 fibers in the skin of mice with reduced RECK or membrane‐type 1‐matrix metalloproteinase (MT1‐MMP) deficiency show atypical morphology. Our experiments in vitro indicated that RECK, ADAMTS10, and MT1‐MMP cooperate to support the formation of robust fibrillin‐1 fibers.

This study aimed to investigate the design S-N curve on the basis of the hot spot stress (HSS) approach considering proper thickness effect for welded aluminum joints. The effect of the main plate thickness is examined by using the results of fatigue tests in this study and references of fatigue data of previous literature. The fatigue tests are performed on 5083-O welded joint specimens with four kinds of main plate thicknesses, namely 12 mm, 16 mm, 20 mm, and 25 mm. The main plate thicknesses of the fatigue data of the references ranged from 2.8 to 25 mm. We clarify the relationship between fatigue strength and main plate thickness, and propose hot spot design S-N curve for welded aluminum joints with thickness of less than 25 mm based on the research of the thickness effect. Fatigue tests of large-scale model are carried out to test the validity of the proposed design S-N curve for welded structures.

The behavior of point defects was visualized in lightly and heavily boron (B)-doped Czochralski-silicon (CZ-Si) crystals by employing a special growth technique, namely, rapidly cooling a growing crystal after it is detached from the Si melt. In the case of crystal growth with a high pulling rate, an anomalous oxygen precipitation (AOP) region dominated by vacancies appeared, whereas in the case of crystal growth with a low pulling rate, a dislocation loop region dominated by self-interstitials appeared. In the crystals cooled rapidly after halting growth for several hours, self-interstitials flowed into the AOP region and dislocation loop regions formed and expanded, while the AOP region shrunk due to diffusion of excess vacancies to the crystal surface and void regions. These transient changes in the point defect distribution were reproduced using a point defect simulator. Defect regions related to self-interstitials could not be confirmed in the heavily B-doped crystals with resistivities of 10 mΩcm or less, where the void- and oxidation-induced stacking fault (OSF)-ring regions disappeared completely at the center of the crystal. These results show that the behaviors of point defects in heavily doped CZ-Si crystals with various impurities are important research subjects in relation to future advanced power applications.

The CYP11B2 enzyme is the terminal enzyme in the biosynthesis of aldosterone. Immunohistochemistry using antibodies against CYP11B2 defines cells of the adrenal ZG that synthesize aldosterone. CYP11B2 expression is normally stimulated by angiotensin II, but becomes autonomous in primary hyperaldosteronism, in most cases driven by recently discovered somatic mutations of ion channels or pumps. Cells expressing CYP11B2 in young normal humans form a continuous band beneath the adrenal capsule; in older individuals they form discrete clusters, aldosterone-producing cell clusters (APCC), surrounded by non-aldosterone producing cells in the outer layer of the adrenal gland. Aldosterone-producing adenomas may exhibit a uniform or heterogeneous expression of CYP11B2. APCC frequently persist in the adrenal with an aldosterone-producing adenoma suggesting autonomous CYP11B2 expression in these cells as well. This was confirmed by finding known mutations that drive aldosterone production in adenomas in the APCC of clinically normal people. Unilateral aldosteronism may also be due to multiple CYP11B2-expressing nodules of various sizes or a continuous band of hyperplastic ZG cells expressing CYP11B2. Use of CYP11B2 antibodies to identify areas for sequencing has greatly facilitated the detection of aldosterone-driving mutations.

Enhanced degradation of tryptophan (Trp) and thus decreased plasma Trp levels are common in several types of cancers. Although it is well known that Trp catabolism is induced in the tumor microenvironment by the enzymes expressed in cancer cells, immune cells, or both, few studies have examined systemic Trp catabolism in cancer pathophysiology. The present study aimed to evaluate Trp catabolism in both tumor and peripheral tissues using tumor‐engrafted Copenhagen rats that were s.c. inoculated with AT‐2 rat prostate cancer cells negative for expression of Trp catabolic enzymes. Liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) metabolomics showed significantly decreased plasma Trp levels in AT‐2 engrafted rats, accompanied by increased kynurenine/Trp ratios in spleen and thymus and serotonin levels in liver and thymus. Quantitative PCR and enzymatic activity assays showed indoleamine‐2, 3‐dioxygenase, an inducible enzyme that catalyzes Trp to kynurenine, was increased in tumor tissues, whereas tryptophan‐2,3‐dioxygenase, a major Trp catabolic enzyme that regulates systemic level of Trp, tended to be increased in the liver of AT‐2 engrafted rats. Furthermore, tryptophan hydroxylase‐1 (TPH1), an enzyme that catalyzes the reaction of Trp to serotonin, was significantly increased in liver and spleen of AT‐2 engrafted rats. Further histochemical analysis revealed that the induction of TPH1 in the liver could be attributed to infiltration of mast cells. A similar phenomenon was observed with nonneoplastic liver samples from colorectal cancer patients. These results suggested that Trp catabolism toward serotonin synthesis might be induced in peripheral remote tissues in cancer, which could have a pathophysiological effect on cancer., Our study reported for the first time that L‐tryptophan catabolic enzymes, tryptophan‐2, 3‐dioxygenase (TDO) and/or tryptophan hydroxylase‐1 (TPH1), are induced in remote tissues, liver and spleen, of tumor burden model. Similar TPH1 induction in remote liver tissues was observed with nonneoplastic liver samples from some of the colorectal cancer patients. Our findings suggest that Trp catabolism can be induced not only in tumor microenvironment but also in peripheral remote tisssues in cancer.

The regioselective anti-carboindation of ynamides by using InBr3 and silylated nucleophiles was developed to synthesize (Z)-β-(carbonylamino)alkenylindiums. The X-ray crystallographic analysis of an alkenylindium suggested that the reaction proceeded in an anti-addition fashion. In contrast to reported syn-carbometalations of ynamides by using organometallics, a cooperation of InBr3 and silylated nucleophiles to ynamides achieved an anti-addition, which was supported by DFT calculations. The scope of substrates included various ynamides and silylated nucleophiles, such as silyl ketene acetals and silyl ketene imines. The transformation of synthesized alkenylindiums by iodination, radical coupling, and Pd-catalyzed cross-coupling successfully afforded trisubstituted enamines with high regio- and stereoselectivities.

Organogallium and ‐indium compounds are useful reagents in organic synthesis because of their moderate stability, efficient reactivity and high chemoselectivity. Carbogallation and ‐indation of a carbon‐carbon multiple bond achieves the simultaneous formation of carbon‐carbon and carbon‐metal bonds. Heterogallation and ‐indation construct carbon‐heteroatom and carbon‐metal bonds. Therefore, these reaction systems represent a significant synthetic method for organogalliums and ‐indiums. Many chemists have attempted to apply various types of unsaturated compounds such as alkynes, alkenes, and allenes to these reaction systems. This minireview provides an overview of carboindation and ‐gallation as well as heteroindation and ‐gallation., Organogallium and ‐indium compounds are useful reagents in organic synthesis due their moderate stability. Carbogallation and ‐indation of carbon‐carbon multiple‐bonds achieves simultaneous formation of carbon‐carbon and carbon‐metal bonds. And, heterogallation and ‐indation are used to construct carbon‐heteroatom and carbon‐metal bonds. So, these reaction systems represent significant synthetic methods for the use of organogalliums and ‐indiums. Various unsaturated compounds, such as alkynes, alkenes, and allenes are applicable to these reaction systems to access to organogalliums and ‐indiums with diverse functionalities.

Objective To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). Methods Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators’ discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. Results All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to Conclusion These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. Trial registration JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.