Characteristics of people seeking consultation after progressing to severe dementia: A mixed-method analysis.

OBJECTIVES: This explores the characteristics of patients with worsening dementia who did not receive a specialized medical examination or care. METHODS: This study utilized a mixed methods analysis. Of the 2712 people who received the Mini Mental State of Examination (MMSE) at the Community Consultation Center for Citizens with MCI and Dementia between December 2007 and December 2019, 1413 people who scored 23 points or less were included. Participants were categorized into mild, moderate, and severe groups, based on their MMSE scores. Participants' characteristics-gender, age, presence or absence of an escort, demographics, family type, and presence or absence of a family doctor-were compared between the groups. To further understand the severe group's characteristics, clinical psychologists recorded consultation forms were categorized. RESULTS: More than 80% of the patients in each group had a family doctor. Moreover, all the severe groups had escorts, and the role of family members and supporters was important for the consultation. In the severe group, 29 patients had never received specialized medical care. Their characteristics were coded "non-existence" (fewer people or opportunities to notice their needs), "connection failure" (a lack of access or connections to consultations), and "evaluation failure" (not recognized as a problem requiring consultation). CONCLUSIONS: It is necessary to improve primary physician education, disseminate knowledge, and raise awareness about dementia, besides building and strengthening networks to alleviate the isolation of dementia patients and their families. The psychological aspects of family members' denial regarding their family members with dementia must be addressed through intervention.

Fibroblast growth factor receptor inhibitor erdafitinib promotes Mcl-1 degradation and synergistically induces apoptosis with Bcl-xL/Bcl-2 inhibitor in urothelial cancer cells.

Metastatic urothelial cancer is a lethal disease. Although recent advances in immunotherapies and targeted therapy against fibroblast growth factor receptor (FGFR)2/3 mutation (erdafitinib) have improved patient survival, there is still a critical need for novel therapeutic strategies for patients who do not benefit from these treatments. Evasion of apoptosis through amplifying anti-apoptotic Bcl-2 family proteins (Mcl-1, Bcl-xL, Bcl-2) is one mechanism responsible for treatment resistance in urothelial cancers, suggesting that targeting anti-apoptotic proteins may be a possible therapeutic strategy for urothelial cancers. Here, we showed that erdafitinib increased Mcl-1 degradation mainly through previously unknown mechanisms and synergized with a BH3 mimetic drug targeting Bcl-xL/Bcl-2 to induce apoptosis in FGFR wild-type urothelial cancer cells. Strikingly, clinical sequencing data showed amplification of MCL1 or BCL2L1 (encoding Bcl-xL) in subsets of FGFR mutation-negative bladder cancer tissues. In conclusion, these findings suggest that exploiting apoptosis pathways may be a promising treatment strategy for patients with FGFR wild-type metastatic urothelial cancer with Mcl-1 or Bcl-xL overexpression.

Photooxidation Reactions of Cyclometalated Palladium(II) and Platinum(II) Complexes.

New C,N,S-cyclometalated palladium(II) and platinum(II) complexes have been synthesized and their structural, electrochemical, and photochemical properties examined. The blue color of these complexes in solution changed to yellow under visible-light irradiation. By measurement of the absorption spectra for quantifying changes in color, isosbestic points for each complex clearly indicated the presence of only two species responsible for the change of color. X-ray analysis revealed that the visible-light-induced yellow species were S-oxygenated sulfinato complexes. Photosensitized generation of singlet oxygen (1O2) was confirmed by the direct detection of singlet oxygen luminescence at 1275 nm. The present cyclometalated palladium(II) and platinum(II) complexes are efficient photosensitizers of singlet oxygen, which rapidly reacts with coordinating sulfur atoms.

Measurement of telomere length in cells from pleural effusion: Asbestos exposure causes telomere shortening in pleural mesothelial cells.

We estimated the telomere lengths of neoplastic and non-neoplastic mesothelial cells and examined their correlation with asbestos exposure and the expression of markers of mesothelial malignancy. Cell blocks of pleural effusion obtained from 35 cases of non-neoplastic disease (NN), 12 cases of malignant mesothelioma (MM) and 12 cases of carcinomatous effusion due to lung adenocarcinoma (LA) were examined. Fifteen of the 35 NN cases had pleural plaques (NNpp+) suggestive of asbestos exposure, and the other 20 cases had no pleural plaques (NNpp-). Telomere length was measured using the tissue quantitative fluorescence in situ hybridization method, and expressed as normalized telomere-to-centromere ratio. NN cases had significantly longer telomeres than MM (P < 0.001) and LA (P < 0.001) cases. Telomeres in NNpp+ cases were slightly shorter than those of NNpp- cases (P = 0.047). MM and LA showed almost the same telomere length. NN cases with shorter telomeres tended to show aberrant expression of epithelial membrane antigen (EMA), CD146, glucose transporter 1 (GLUT1) and IGF-II messenger RNA-binding protein 3 (IMP3). These results suggest that telomere shortening and subsequent genetic instability play an important role in the development of MM. Measurement of telomere length of cells in pleural effusion might be helpful for earlier detection of MM.

Simeprevir (TMC435) once daily with peginterferon-α-2b and ribavirin in patients with genotype 1 hepatitis C virus infection: The CONCERTO-4 study.

AIM: The efficacy and safety of simeprevir in combination with peginterferon-α-2b and ribavirin (PEG IFN-α-2b/RBV) were investigated in patients infected with hepatitis C virus (HCV) genotype 1 who were treatment-naïve or had previously received interferon (IFN)-based therapy. METHODS: CONCERTO-4 (NCT01366638) was an open-label, non-comparative, multicenter study of once-daily simeprevir (TMC435) 100 mg in combination with PEG IFN-α-2b/RBV in treatment-naïve and -experienced patients (prior relapsers or non-responders to IFN-based therapy) with chronic HCV genotype 1 infection. Twelve-week combination treatment was followed by 24/48-week response-guided PEG IFN-α-2b/RBV therapy for treatment-naïve patients and prior relapsers, and 48-week PEG IFN-α-2b/RBV therapy for prior non-responders. Patients were followed for 72 weeks after treatment initiation. The proportions of patients with sustained viral response (SVR; undetectable HCV RNA) at treatment end and 12 weeks after the last treatment (SVR12) were among the major efficacy end-points. Safety, including adverse events (AE), was monitored. RESULTS: Of the 79 patients treated, the proportion achieving SVR12 was highest among treatment-naïve patients (91.7%) and prior relapsers (100%) versus 38.5% of prior non-responders. All treatment-naïve patients and prior non-responders who achieved SVR12 also achieved SVR at treatment end and 24 weeks after last dose; 96.6% of prior relapsers achieved both end-points. Most AE were of grade 1 or 2 severity. Grade 3 AE occurred in 17 patients, most frequently neutropenia (6.3%). CONCLUSION: Simeprevir combined with PEG IFN-α-2b/RBV was effective in patients infected with HCV genotype 1, both for initial treatment of naïve patients and for retreatment of patients in whom previous IFN-based therapy had failed.

The Restorative Effects of Eucommia ulmoides Oliver Leaf Extract on Vascular Function in Spontaneously Hypertensive Rats.

Eucommia ulmoides Oliv. leaf is a traditional Chinese antihypertensive and antidiabetic medicine. We examined the effects of chronic Eucommia leaf extract (ELE) administration on artery function and morphology in spontaneously hypertensive rats (SHRs). ELE was orally administered via normal diet ad libitum to six-week-old male SHRs at a concentration of 5% for seven weeks. Acetylcholine (ACh)-induced endothelium-dependent relaxation, sodium nitroprusside (SNP)-induced endothelium-independent relaxation, plasma nitric oxide (NO) levels, and media thickness were assessed. ELE significantly improved ACh-induced aortic endothelium-dependent relaxation but did not affect SNP-induced endothelium-independent relaxation in the SHRs, as compared to the animals receiving normal diet. Plasma NO levels and media thickness were significantly increased and decreased, respectively, in the ELE-treated SHRs. Therefore, long-term ELE administration may effectively improve vascular function by increasing plasma NO levels and bioavailability, and by preventing vascular hypertrophy in the SHR aorta.

Simeprevir with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial.

BACKGROUND & AIMS: In a Japanese Phase II study, the hepatitis C virus NS3/4A protease inhibitor simeprevir demonstrated potent antiviral activity and significantly improved sustained virologic response rates when added to peginterferon α-2a/ribavirin in treatment-naïve patients infected with hepatitis C virus genotype 1. METHODS: CONCERTO-1 was a Phase III, randomized, double-blind, placebo-controlled trial. Treatment-naïve adults (⩽ 70 years) with chronic hepatitis C virus genotype 1 infection (hepatitis C virus RNA ⩾ 5 log10 IU/ml) were randomized (2:1) to simeprevir 100mg once-daily with peginterferon α-2a/ribavirin for 12 weeks then response-guided therapy with peginterferon α-2a/ribavirin for 12 or 36 weeks, or to placebo with peginterferon α-2a/ribavirin for 12 weeks then peginterferon α-2a/ribavirin for 36 weeks. RESULTS: Overall, 183 patients were treated. Sustained virologic response 12 weeks after treatment end (primary efficacy endpoint) was achieved in 88.6% of simeprevir- and 61.7% of placebo-treated patients (p<0.0001 for stratum-adjusted between-group difference). Overall, 91.9% of simeprevir-treated patients met response-guided therapy criteria and completed treatment at week 24; sustained virologic response rate at 12 weeks in these patients was 92.0%. One simeprevir- (0.8%) and two placebo-treated patients (3.3%) experienced viral breakthrough; respective viral relapse rates were 7.6% and 30.6%. Overall adverse event profile in simeprevir-treated patients was comparable to that in patients who received peginterferon α-2a/ribavirin alone. CONCLUSIONS: Simeprevir once daily with peginterferon α-2a/ribavirin significantly improved sustained virologic response rate 12 weeks after treatment end in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection, with a shorter 24-week treatment duration in most patients.

Exploratory study to characterise the individual types of health literacy and beliefs and their associations with infection prevention behaviours amid the COVID-19 pandemic in Japan: a longitudinal study.

Background: During a global infectious disease pandemic such as the coronavirus disease 2019 (COVID-19), individuals' infection prevention/risk-taking behaviours are likely to differ depending on their health literacy and beliefs regarding the disease. To effectively promote infection prevention behaviours, it is necessary to enable information dissemination and risk communication that consider individuals' health literacy and beliefs. In this study, we exploratorily characterised segments based on individual health literacy and beliefs regarding COVID-19 among the Japanese during the early stage of the COVID-19 pandemic, and investigated whether infection prevention/risk-taking behaviours and fear of COVID-19 differed among these segments. Methods: In this study, we conducted two web-based longitudinal surveys in Japan (PHASE 1, 1-30 November 2020, 6,000 participants; PHASE 2, 1-31 December 2020, 3,800 participants). We characterised segments of the target population using cluster analysis on health literacy and beliefs regarding COVID-19 obtained in PHASE 1. We further investigated the associations between the clusters and infection prevention/risk-taking behaviours and fear of COVID-19, obtained from PHASE 2. Results: Five clusters were identified: 'Calm/hoax denial', 'Hoax affinity/threat denial', 'Minority/indifference', 'Over vigilance', and 'Optimism'. There were significant differences in infection prevention/risk-taking behaviours and fear of COVID-19 among the five clusters. The belief in susceptibility to infection, rather than affinity for hoaxes and conspiracy theories, was coherently associated with infection prevention/risk-taking behaviours and fear of infection across clusters. This study provides foundational knowledge for creating segment-specific public messages and developing interactive risk communication to encourage infection prevention behaviours.

Effect of laser engraving on shear bond strength of polyetheretherketone to indirect composite and denture-base resins.

Background/purpose: Polyetheretherketone (PEEK) is a highly sought-after thermoplastic due to its exceptional mechanical properties and biocompatibility. However, bonding PEEK to indirect composite resin (ICR) or denture-based resin (DBR) can be challenging. Laser engraving technology has shown potential to improve bonding for other materials; thus, this study aims to evaluate its effectiveness for PEEK. Materials and methods: The experiment involved preparing ingot-shaped PEEK samples, which were then categorized into four groups based on the treatment method employed: without treatment, air abrasion, sulfuric acid etching, and laser engraving (LS). Subsequently, the samples were bonded to ICR or DBR, and their shear bond strength (SBS) was tested with or without thermocycling using a universal testing machine. Furthermore, the failure mode was observed, with statistical analyses conducted to compare the results. Results: The grid-like microslit structure of LS group displayed the highest SBS for bonding PEEK to ICR or DBR (P < 0.05). During the bonding of PEEK to ICR, resin residue and penetration into the microslits were frequently observed in the LS group, indicating cohesive failure. However, when PEEK was bonded to DBR, mixture failure was frequently observed without thermocycling. After thermocycling, only the LS group showed cohesive failure, while the majority of specimens exhibited mixture failure. Conclusion: Laser engraving significantly improves the SBS between PEEK and both ICR and DBR. Furthermore, it was observed that resin had penetrated the microslits, indicating that laser engraving has great potential as a surface treatment method.

Determinants of Activity Phenotype in Patients with Chronic Obstructive Pulmonary Disease.

Introduction: Physical activity (PA) and sedentary behavior (SB) have attracted attention in chronic obstructive pulmonary disease (COPD), and there have been efforts to evaluate PA and SB separately. The factors associated with the characteristics of the four activity phenotypes defined by the durations of PA and SB are largely unknown. The aim of this study was to clarify the factors that could differentiate each activity phenotype. Materials and Methods: Study subjects were outpatients with stable COPD who were ≥40 years of age. We investigated the influence of 26 different factors on the activity phenotypes of COPD and extracted the factors that showed significant differences among the four activity phenotypes. Results: Two hundred sixteen patients were included in the analysis. Exercise capacity and dyspnea were determinants that distinguished the low PA groups from the high PA groups. The pulmonary function and desaturation during exercise were factors that distinguished the high PA with low SB group from the low PA with high SB group. BMI, grip strength, upper arm circumference and HbA1c were higher in the low PA and low SB group than in the low PA and high SB group. Conclusion: These factors could be the determinants discriminating activity phenotypes of patients with COPD.

Biosynthetic Gene Expression and Tissue Distribution of Diosgenin in Dioscorea japonica.

Diosgenin is an aglycone of dioscin, a major bioactive steroidal saponin found in plants, including Himalayan Paris (Paris polyphylla), fenugreek (Trigonella foenum-graecum), and yam (Dioscorea spp.). We have previously demonstrated that a species of natural yam, Dioscorea japonica, contains a promising bioactive compound diosgenin, which induces anti-carcinogenic and anti-hypertriacylglycerolemic activities. Here, we found for the first time that Japanese yam (D. japonica) bulbils are richer in diosgenin than the edible tubers (rhizomes) and leaves. LC-MS and imaging-MS analyses revealed that diosgenin accumulated in the peripheral region of D. japonica bulbils. Additionally, we performed RNA-seq analysis of D. japonica, and multiple sequence alignment identified D. japonica CYP90 (DjCYP90), the orthologous gene of CYP90G4 in P. polyphylla, CYP90B50 in T. foenum-graecum, CYP90G6 in Dioscorea zingiberensis, and CYP90G in Dioscorea villosa, which encodes a diosgenin biosynthetic rate-limiting enzyme. The expression levels of DjCYP90 were significantly upregulated in D. japonica bulbils than in its rhizomes and leaves. Since diosgenin is one of the most promising functional food factors executing several favorable bioactivities, D. japonica bulbils rich in diosgenin would be a beneficial natural resource.

Adjacent angle size correlates with diagnostic sensitivity of endobronchial ultrasonography with a guide sheath.

Background: An association exists among the diagnostic yield of transbronchial biopsy using endobronchial ultrasonography with a guide sheath (EBUS-GS-TBB) and several factors, such as simple within or adjacent endobronchial ultrasonography (EBUS) findings. Here, we aimed to investigate whether more detailed EBUS findings affect the diagnostic yield of lung cancer in EBUS-GS-TBB. Methods: We conducted this retrospective single-center cohort study, enrolling consecutive patients with lung cancer who underwent EBUS-GS-TBB. The primary outcome was examination of predictive factors affecting the diagnostic yield of lung cancer using EBUS-GS-TBB. The secondary outcome was a subgroup analysis of within and adjacent lesions. The adjacent angle was defined as the angle formed by the midpoint of the probe and the two points where the edge of the probe and shadow of the tumor intersected. Results: Of the 179 lesions investigated, 140 (78.2%) were diagnosed using EBUS-GS-TBB. The diagnostic yields of within and adjacent lesions were 91.6% and 51.7%, respectively. In the multivariable analysis, within lesions had significantly higher diagnostic yields than did the adjacent lesions (P<0.001). The adjacent angle was larger in lesions diagnosed using EBUS-GS-TBB than in undiagnosed lesions (P=0.003). In adjacent lesions, the diagnostic yields were 75.0% and 36.1% for lesions ≥180° and <180°, respectively. Conclusions: In adjacent lesions, the diagnostic yields differed significantly depending on the adjacent angle. Even if EBUS findings are adjacent, the operator should identify the branch of the bronchus with a greater adjacent angle. Future studies should investigate improvements in diagnostic yields via additional procedures for lesions with small adjacent angles.

Non-target GC-MS analyses of fecal VOCs in NASH-hepatocellular carcinoma model STAM mice.

The increased incidence of obesity in the global population has increased the risk of several chronic inflammation-related diseases, including non-alcoholic steatohepatitis (NASH)-hepatocellular carcinoma (HCC). The progression from NASH to HCC involves a virus-independent liver carcinogenic mechanism; however, we currently lack effective treatment and prevention strategies. Several reports have suggested that fecal volatile organic compounds (VOCs) are strongly associated with NASH-HCC; therefore, we explored the biomarkers involved in its pathogenesis and progression. Fecal samples collected from control and NASH-HCC model STAM mice were subjected to headspace autosampler gas chromatography-electron ionization-mass spectrometry. Non-target profiling analysis identified diacetyl (2,3-butandione) as a fecal VOC that characterizes STAM mice. Although fecal diacetyl levels were correlated with the HCC in STAM mice, diacetyl is known as a cytotoxic/tissue-damaging compound rather than genotoxic or mutagenic; therefore, we examined the effect of bioactivity associated with NASH progression. We observed that diacetyl induced several pro-inflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2, monocyte chemoattractant protein-1, and transforming growth factor-ß, in mouse macrophage RAW264.7 and Kupffer KPU5 cells. Additionally, we observed that diacetyl induced α-smooth muscle actin, one of the hallmarks of fibrosis, in an ex vivo cultured hepatic section, but not in in vitro hepatic stellate TWNT-1 cells. These results suggest that diacetyl would be a potential biomarker of fecal VOC in STAM mice, and its ability to trigger the macrophage-derived inflammation and fibrosis may partly contribute to NASH-HCC carcinogenesis.

Degradation of long-chain base 1-phosphate (LCBP) in Arabidopsis: functional characterization of LCBP phosphatase involved in the dehydration stress response.

Sphingolipid metabolites, long-chain base 1-phosphates (LCBPs), are involved in ABA signaling pathways. The LCBPs synthesized by long-chain base kinase are dephosphorylated by LCBP phosphatase or degraded by LCBP lyase. Here we show that the At3g58490 gene encodes AtSPP1, a functional LCBP phosphatase. Transient expression of green fluorescent protein fusion in suspension-cultured Arabidopsis cells showed that AtSPP1 is localized in the endoplasmic reticulum. The level of dihydrosphingosine 1-phosphate was increased in loss-of-function mutants (spp1) compared with wild-type (WT) plants, suggesting a role of AtSPP1 in regulating LCBP levels. The rate of decrease in fresh weight of detached aerial parts was significantly slower in spp1 mutants than in WT plants. A stomatal closure bioassay showed that the stomata of spp1 mutants were more sensitive than the WT to ABA, suggesting that AtSPP1 is involved in guard cell signaling. However, spp1 mutants showed decreased sensitivity to ABA with respect to primary root growth but not to seed germination. The response to fumonisin B(1) did not differ between the WT and spp1 mutant. A significant decrease in AtDPL1 (LCBP lyase) transcripts in spp1 mutants was observed. We conclude that AtSPP1 is a functional LCBP phosphatase that may play a role in stomatal responses through LCBP-mediated ABA signaling.

Validation of Simple Prediction Equations for Step Count in Japanese Patients with Chronic Obstructive Pulmonary Disease.

Physical activity is decreased in patients with chronic obstructive pulmonary disease, and decreased physical activity leads to a poor prognosis. To determine an individual's target step count from the measured step counts and predicted step counts, simple and detailed prediction equations for step count were developed. To verify the validity of the simple prediction equation, the validity of the simple equation was evaluated in a different cohort and the correlation between the step counts calculated by the simple equation and those by the detailed prediction equation were evaluated. When the step counts calculated by the simple prediction equation for all participants were compared with the measured step counts, a significant correlation was obtained among them, and the calculated values were found to be reproducible with the measured values in patients with a measured step count of <6500 by Bland−Altman plots. Furthermore, the values calculated by the simple prediction equation and those calculated by the detailed prediction equation showed a significant correlation. In conclusion, the simple prediction equation was considered reasonable.

Chemotherapy plus atezolizumab for a patient with small cell lung cancer undergoing haemodialysis: a case report and review of literature.

Little is known about the safety of chemotherapy plus atezolizumab for patients with extensive-stage small cell lung cancer (ES-SCLC) undergoing haemodialysis (HD). An 80-year-old male received carboplatin [area under the concentration-time curve (AUC) = 5 on day 1], etoposide (40 mg/m2 on days 1, 2, and 3), and atezolizumab (1200 mg/body on day 1) as the first-line therapy for ES-SCLC. He was undergoing HD thrice a week for seven years. HD was provided 16 h after carboplatin administration. During the first cycle, grade 4 neutropenia (neutrophil count: 74/µL) and leukopenia (white blood cell count: 680/µL) occurred. Therefore, chemotherapy was administered with a reduced dose of carboplatin (AUC = 4) and etoposide (30 mg/m2) from the second to fourth cycles. After four cycles, no severe non-haematological adverse events occurred, showing a remarkable response. We conclude that the carboplatin, etoposide, and atezolizumab combination can be safely administered to cancer patients undergoing HD.

Methylglyoxal binds to amines in honey matrix and 2'-methoxyacetophenone is released in gaseous form into the headspace on the heating of manuka honey.

Reports on the thermal stability of manuka honey in terms of food processing have been few. This study investigated changes in nine characteristic chemicals of manuka honey during heating. Among these, methylglyoxal (MGO) and 2'-methoxyacetophenone (MAP) were significantly decreased by heating at 90 °C. To elucidate the mechanism for this decrease, artificial honey was prepared from sugars and water with MAP or MGO and then heated. The decrease of MGO was enhanced with l-proline, lysine, or arginine derivatives, accompanied by formation of 2-acetyl-1-pyrroline, MGO-derived lysine dimer, or argpyrimidine, respectively, suggesting that an amino-carbonyl reaction is one pathway for the loss of MGO. The decrease of MAP in the artificial honey depended on the volume of headspace in a vessel. MAP from heated manuka honey was also detected in the gas phase, indicating that MAP was vaporized. Heating could thus reduce the beneficial and/or signature molecules in honey.

Prebiotic effect of fructo-oligosaccharides on the inner ear of DBA/2 J mice with early-onset progressive hearing loss.

Nutrition and dietary habits contribute to the onset and progression of sensorineural hearing loss (SNHL). Fructo-oligosaccharides (FOS) are non-digestible oligosaccharides and are known as prebiotics, which enhance short-chain fatty acid (SCFA) production and antioxidant activity. Although a substantial number of studies have shown that FOS play a role in the prevention of lifestyle-related diseases as prebiotics, little is known about the effects on the inner ear. The purpose of this study is to investigate the effect of FOS on gene expression and spiral ganglion neuron (SGN) protection in the inner ear of DBA/2 J mice, which is a model for early-onset progressive hearing loss. DBA/2 J mice were fed either control diet or FOS diet contained 10% (w/w) of FOS for 8 weeks. Analysis of mice fed the FOS diet revealed a change in intestinal flora including an inversion of the ratio of Bacteroidetes and Firmicutes, which was followed by a significant increase in SCFAs in the cecum and a decrease in an oxidative stress marker in the serum. In the inner ear, gene expression of neurotrophin, brain-derived neurotrophic factor (BDNF), its receptor, tyrosine kinase receptor b (Trkb), and the SCFA receptor, free fatty acid receptor 3 (FFAR3), were increased by FOS. In addition, the survival rate of SGNs in the inner ear was maintained in FOS-fed mice. Altogether, these results suggest that a compositional variation of the intestinal flora due to a prebiotic effect may be involved in the progression of SNHL.

Elevated levels of proinflammatory volatile metabolites in feces of high fat diet fed KK-Ay mice.

When the microfloral composition deteriorates, it triggers low-level chronic inflammation associated with several lifestyle-related diseases including obesity and diabetic mellitus. Fecal volatile organic compounds (VOCs) have been found to differ in gastrointestinal diseases as well as intestinal infection. In this study, to evaluate a potential association between the pathogenesis of lifestyle-related diseases and VOCs in the intestinal tract, fecal VOCs from obese/diabetic KK-Ay mice (KK) or controls (C57BL/6J mice; BL) fed a normal or high fat diet (NFD or HFD) were investigated using headspace sampler-GC-EI-MS. Principal component analysis (PCA) of fecal VOC profiles clearly separated the experimental groups depending on the mouse lineage (KK vs BL) and the diet type (NFD vs HFD). 16 s rRNA sequencing revealed that the PCA distribution of VOCs was in parallel with the microfloral composition. We identified that some volatile metabolites including n-alkanals (nonanal and octanal), acetone and phenol were significantly increased in the HFD and/or KK groups. Additionally, these volatile metabolites induced proinflammatory activity in the RAW264 murine macrophage cell line indicating these bioactive metabolites might trigger low-level chronic inflammation. These results suggest that proinflammatory VOCs detected in HFD-fed and/or diabetic model mice might be novel noninvasive diagnosis biomarkers for diabetes.

Synthesis of protein kinase Cdelta C1b domain by native chemical ligation methodology and characterization of its folding and ligand binding.

The C1b domain of protein kinase Cdelta (PKCdelta), a potent receptor for ligands such as diacylglycerol and phorbol esters, was synthesized by utilizing native chemical ligation. With this synthetic strategy, the domain was efficiently constructed and shown to have high affinity ligand binding and correct folding. The C1b domain has been utilized for the development of novel ligands for the control of phosphorylation by PKC family members. This strategy will pave the way for the efficient construction of C1b domains modified with fluorescent dyes, biotin, etc.