Search

Aims/Introduction Diabetes mellitus is a major risk factor for the development of cardiovascular diseases. Heart failure with preserved ejection fraction is characterized by left ventricular diastolic dysfunction (LVDD). It has been reported that excess cortisol found in patients with Cushing's syndrome was associated with the development of LVDD. However, the relationship between cortisol concentration and LVDD in patients with diabetes mellitus has not been addressed. Materials and Methods We enrolled 109 patients with diabetes mellitus and 104 patients without diabetes mellitus who had undergone echocardiographic examination at Kyushu University Hospital, Fukuoka, Japan, between November 2016 and March 2019. Left ventricular function was evaluated and the ratio of early diastolic velocity from transmitral inflow to early diastolic velocity (E/eʹ) was used as an index of diastolic function. Plasma cortisol concentrations, glycemic control, lipid profiles, treatment with antidiabetic drugs and other clinical characteristics were evaluated, and their associations with E/eʹ were determined using univariate and multivariate analyses. Results Multivariate linear regression analysis showed that log E/eʹ was positively correlated with age (P = 0.017), log systolic blood pressure (P = 0.004) and cortisol (P = 0.037), and negatively correlated with estimated glomerular filtration rate (P = 0.016) and the use of sodium–glucose cotransporter 2 inhibitors (P = 0.042) in patients with diabetes mellitus. Multivariate analysis showed that cortisol was positively correlated with age (P = 0.016) and glycated hemoglobin (P = 0.011). There was no association between E/eʹ and cortisol in patients without diabetes mellitus. Conclusions Increased cortisol levels might increase the risk of developing LVDD in diabetes mellitus patients.

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.

The ruthenium(II)-catalyzed regioselective annulation of N-(7-azaindole)amides with 1,3-diynes has been demonstrated. Bioactive N-amino-7-azaindole has been used as a new bidentate directing group to furnish an array of 3-alkynylated isoquinolones. Furthermore, the developed protocol works efficiently for both aryl- and heteroaryl-substituted amides producing a range of pharmacologically useful 7-azaindole-based isoquinolones with a wide range of functionality.

BACKGROUND: Posterior capsule opacification (PCO) often occurs after cataract surgery. Metformin has been known to have an ability to inhibit fibrosis. This study aimed to investigate the effects of metformin on cell contractility, collagen deposition and degradation in human lens epithelial cells (HLEC) of cataract patients. METHODS: HLEC were isolated from the anterior lens capsule of patients undergoing cataract surgery. The HLEC culture was carried out using explant culture technique. The in vitro PCO model was created by scratching technique on HLEC cultures. The treatment groups were given 0.1, 0.5 and 1 mM metformin, respectively, while the control group were given 10% fetal bovine serum (FBS). On the 7th day after scratching technique, the collagen deposition, collagen degradation and cell contractility were evaluated. RESULTS: Collagen deposition in HLEC was significantly reduced after given 0.1 mM, 0.5 mM and 1 mM metformin (17.92±6.16 mg/mL, 12.92±4.31 mg/mL, 11.25±5.30 mg/mL, respectively), compared to the control group (31.46±7.52 μg/mL, p =0.002). Collagen degradation significantly was increased in the 0.1 mM, 0.5 mM and 1 mM metformin groups (4.77±9.27 mg/mL, 6.59±1.16 mg/mL, 6.35±1.90 mg/mL, respectively) compared to the control group (2.21±2.78 μg/mL, p=0.002). While, collagen contractility in HLEC was significantly reduced in 0.1mM, 0.5mM and 1 mM metformin groups (16.39±3.89%, 13.89±2.59%, 11.93±2.44%, respectively), compared to the control group (44.25±4.95%, p =0.000). CONCLUSION: Metformin reduced collagen deposition and contractility, but increased collagen degradation in HLEC of cataract patients through mechanism of extracellular matrix remodeling. KEYWORDS: metformin, human lens epithelial cell, fibrosis

Interleukin-6 is a pleiotropic cytokine that plays a pathogenic role in type 1 diabetes. Therefore, anti-interleukin-6 receptor antibody, tocilizumab, used for the treatment of rheumatoid arthritis, is considered a candidate for immune intervention in type 1 diabetes. Here, we report the case of a 73-year-old woman (HLA-DR9-DQ3 homozygote) with well-controlled rheumatoid arthritis who developed type 1 diabetes while receiving tocilizumab treatment. At 57 years-of-age, the patient was diagnosed with rheumatoid arthritis, for which she underwent tocilizumab therapy that enabled complete suppression of her joint inflammation. A total of 17 months after starting tocilizumab therapy, she noticed polydipsia, polyuria, general fatigue and weight reduction (-2 kg/month), and was diagnosed with type 1 diabetes with diabetic ketoacidosis based on an arterial pH of 7.26, serum ketone body of 7,437 μmol/L, blood glucose level of 925 mg/dL, glycated hemoglobin of 13.2% and the presence of anti-islet autoantibodies. This case report shows valuable insight regarding the effect of anti-interleukin-6 receptor antibody therapy on type 1 diabetes prevention.

A ruthenium(II)-catalyzed cross dehydrogenative annulation of N-(7-azaindole)benzamides with maleimides has been demonstrated. Herein, we have explored the use of N-amino-7-azaindole as a new bidentate directing group for dehydrogenative [4 + 2] annulation. This method works efficiently, affording a variety of pharmacologically useful 7-azaindole-based isoquinolones and showing a wide functional group tolerance.

Coronavirus disease 2019 (COVID‐19) is globally rampant, and to curb the growing burden of this disease, in‐depth knowledge about its pathophysiology is needed. This was an observational study conducted at a single center to investigate serum cytokine and chemokine levels of COVID‐19 patients, based on disease severity. We included 72 consecutive COVID‐19 patients admitted to our hospital from March 21 to August 31, 2020. Patients were divided into Mild‐Moderate I (mild) and Moderate II‐Severe (severe) groups based on the COVID‐19 severity classification developed by the Ministry of Health, Labor and Welfare (MHLW) of Japan. We compared the patient characteristics as well as the serum cytokine and chemokine levels on the day of admission between the two groups. Our findings indicated that the severe group had significantly higher levels of serum fibrinogen, d‐dimer, lactate dehydrogenase, C‐reactive protein, ferritin, Krebs von den Lungen‐6, surfactant protein (SP)‐D, and SP‐A than the mild group. Strikingly, the levels of interleukin (IL)‐28A/interferon (IFN)‐λ2 were significantly lower in the severe group than in the mild group. We believe that reduced levels of type III interferons (IFN‐λs) and alterations in the levels of other cytokines and chemokines may impact the severity of the disease.

A new approach to cyclophane-based supramolecular mechanophores is presented. We report a mechanically responsive cyclic motif that contains two fluorescent 1,6-bis(phenylethynyl)pyrene moieties that are capable of forming intramolecular excimers. The emission spectra of dilute solutions of this cyclophane and a polyurethane elastomer into which a small amount of the mechanophore (0.08 wt %) had been covalently integrated are dominated by excimer emission. Films of the cyclophane-containing polyurethane also display a considerable portion of excimer emission, but upon deformation, the fluorescence becomes monomer-dominated and a perceptible change from cyan to blue is observed. The response is instant, reversible, and consistent with a mechanically induced change of the molecular conformation of the mechanophore so that the excimer-promoting interactions between the luminophores are suppressed. In-depth investigations show a correlation between the applied strain and the emission color, which can conveniently be expressed by the ratio of monomer to excimer emission intensity. The current study suggests that cyclophanes can be utilized to develop various supramolecular mechanophores that detect and visualize weak forces occurring in polymeric materials or generated by living tissues.

A highly deformable hydrogel, viologen pendant poly-L-lysine-based glutaraldehyde cross-linked hydrogel (PLLV-GA-gel), was characterized using surface-enhanced Raman scattering (SERS) signals under...

Sarcopenia is common in patients with chronic obstructive pulmonary disease (COPD). Serum creatinine/cystatin C (Cr/CysC) ratio has attracted attention as a surrogate marker for sarcopenia but has not been adequately studied in patients with COPD. Thus, the purpose of this study was to investigate the validity of serum Cr/CysC ratio as a predictor of sarcopenia, evaluate a statistical cut-off value, and assess the relationship between Cr/CysC ratio and clinical factors.In this prospective observational study, we enrolled 234 male outpatients with COPD. We determined the relevance of serum Cr/CysC ratio as a surrogate maker for sarcopenia by comparing it with various biomarkers and prospectively investigated the relationship of Cr/CysC ratio with the annual exacerbation rate.Serum Cr/CysC was significantly correlated with handgrip strength (r = 0.53, P 0.01) and muscle mass (r = 0.44, P 0.01). The area under the curve for sarcopenia was significantly larger for serum Cr/CysC ratio than for other biomarkers (Cr/CysC: 0.87, CysC: 0.63, Cr: 0.61, albumin: 0.57). Multivariate analysis showed no significant difference in the frequency of acute exacerbations between patients in the low- and high-Cr/CysC group, defined by the cutoff value 0.71; however, the frequency of severe acute exacerbations was significantly higher in the low-Cr/CysC group.Serum Cr/CysC ratio can be used accurately, inexpensively, and easily to evaluate sarcopenia in male patients with COPD. Our study shows that patients with Cr/CysC below 0.71 have poor physical clinical factors and are at high risk of severe acute COPD exacerbations.

Background Carbon monoxide causes electrical, functional, and morphological changes in the heart. It is unclear, however, whether the indicators of myocardial damage can predict the patient’s prognosis after carbon monoxide poisoning. This retrospective study aimed to investigate the relationship between the carboxyhemoglobin level and electrocardiographic (ECG) changes and whether the ECG changes and troponin I levels are related to the patient’s prognosis after carbon monoxide poisoning. Methods Carboxyhemoglobin, troponin I, and ECG parameters were measured in 70 patients with carbon monoxide poisoning. The QT and RR intervals were measured for each ECG lead in all patients, and the corrected QT interval and corrected QT dispersion were calculated. Results The correlation between the maximum corrected QT interval and the carboxyhemoglobin level was significant (P = 0.0072, R2 = 0.1017), as were the relationships between QT dispersion and carboxyhemoglobin (P R2 = 0.2358) and the corrected QT dispersion and carboxyhemoglobin (P R2 = 0.2613). The multivariate logistic analysis showed that the significant predictors of sequential disability were corrected QT dispersion (P = 0.0042), and troponin I level (P = 0.0021). Conclusions Patients’ prognosis following carbon monoxide poisoning can be predicted based on corrected QT dispersion and the troponin I level. Patients with myocardial damage should be monitored not only for their cardiovascular outcome but also for their neurological outcome and their prognosis.

An investigation into the methanol extracts obtained from the stems of Dodonaea viscosa led to the isolation of one nor-clerodane diterpene (1) and two labdane diterpenes (2, 3), as well as 17 known compounds (4-20). The structures of these compounds were elucidated based on chemical and spectral evidence. The stereochemical structure of the nor-clerodane diterpene was confirmed via its circular dichroism spectrum and calculated electronic circular dichroism spectrum. Isolated compounds were evaluated for their inhibitory effects on collagenase and tyrosinase. Since 5,7,4'-trihydroxy-3'-(4-hydroxy-3-methylbutyl)-5'-(3-methylbut-2-enyl)-3,6-dimethoxyflavone (9) showed collagenase inhibitory activity and scopoletin (12) had significant tyrosinase inhibitory activity, they were considered to be good candidates for cosmetic agents.

BackgroundThe use of pyronaridine-artesunate (PA) has been associated with scarce transaminitis in patients. This analysis aimed to evaluate the hepatic safety profile of repeated treatment with PA versus artemether–lumefantrine (AL) in patients with consecutive uncomplicated malaria episodes in Bobo-Dioulasso, Burkina Faso.MethodsThis study analysed data from a clinical trial conducted from 2012 to 2015, in which participants with uncomplicated malaria were assigned to either PA or AL arms and followed up to 42 days. Subsequent malaria episodes within a 2-years follow up period were also treated with the same ACT initially allocated. Transaminases (AST/ALT), alkaline phosphatase (ALP), total and direct bilirubin were measured at days 0 (baseline), 3, 7, 28 and on some unscheduled days if required. The proportions of non-clinical hepatic adverse events (AEs) following first and repeated treatments with PA and AL were compared within study arms. The association of these AEs with retreatment in each arm was also determined using a logistic regression model.ResultsA total of 1379 malaria episodes were included in the intention to treat analysis with 60% of all cases occurring in the AL arm. Overall, 179 non-clinical hepatic AEs were recorded in the AL arm versus 145 in the PA arm. Elevated ALT was noted in 3.05% of treated malaria episodes, elevated AST 3.34%, elevated ALP 1.81%, and elevated total and direct bilirubin in 7.90% and 7.40% respectively. Retreated participants were less likely to experience elevated ALT and AST than first episode treated participants in both arms. One case of Hy’s law condition was recorded in a first treated participant of the PA arm. Participants from the retreatment group were 76% and 84% less likely to have elevated ALT and AST, respectively, in the AL arm and 68% less likely to present elevated ALT in the PA arm. In contrast, they were almost 2 times more likely to experience elevated total bilirubin in both arms.ConclusionsPyronaridine-artesunate and artemether–lumefantrine showed similar hepatic safety when used repeatedly in participants with uncomplicated malaria. Pyronaridine-artesunate represents therefore a suitable alternative to the current first line anti-malarial drugs in use in endemic areas.Trial registrationPan African Clinical Trials Registry. PACTR201105000286876

Redox-active ionic liquids (RAILs) are gaining attention as a material that can create a wide range of functions. We herein propose a charge-transfer (CT) RAIL by mixing two RAILs, specifically a carbazole-based ionic liquid ([CzC4ImC1][TFSI]) as a donor and a viologen-based ionic liquid ([C4VC7][TFSI]2) as an acceptor. We investigated the effect of CT interaction on the physicochemical properties of the CT ionic liquid (CT-IL) using the results of temperature-dependent measurements of UV-vis absorption, viscosity, and ionic conductivity as well as cyclic voltammograms. We employed the Walden analysis and the Grunberg–Nissan model to elucidate the effect of the CT interaction on the viscosity and ionic conductivity. The CT interaction reduces the viscosity by reducing the electrostatic attraction between the dicationic viologen and TFSI anion. It also reduces the ionic conductivity by the CT association of the dicationic viologen and carbazole. The electrochemically reversible responses of the viologens in [C4VC7][TFSI]2 and CT-IL are consistent with the Nernstian and the interacting two-redox site models. Notably, the transport and electrochemical properties are modulated by CT interaction, leading to unique features that are not present in individual component ILs. The inclusion of CT interaction in RAILs thus provides a powerful means to expand the scope of functionalized ionic liquids., A redox-active ionic liquid (RAIL) consisting of a carbazole and viologen shows charge transfer (CT) interaction. The physicochemical properties are modulated by the CT interaction by comparison with the individual RAILs.

Cyclophanes featuring luminophores are considered promising candidates as thermal or mechanical stimuli-responsive luminescent materials. The mechanism of the changes in the photophysical properties on the crystal–crystal or crystal–amorphous phase transitions can be easily clarified, owing to the crystal structure of the cyclophanes. However, in the case where flexible aliphatic chains are introduced to the target cyclophane, the procurement of the crystals suitable for single-crystal X-ray analysis is challenging. Conversely, the introduction of significantly shorter linkers between large π-conjugated groups leads to difficulties in compound purification, resulting in incorrect photophysical properties, particularly in the solid state. Herein, we report the crystal structure of a 1,6-bis(phenylethynyl)pyrene-based cyclophane and mechanoresponsive luminescence. The cyclophane has a naphthalene group as another aromatic group, and the two different π-conjugated groups are bridged by tetraethylene glycol linkers. Single-crystal X-ray analysis revealed that the pyrene and naphthalene moieties form intramolecular π-stacked structures in the crystals, and intermolecular excimer formation of the luminophores was not observed. The arrangement of the isolated luminophore results in light-blue emission with a well-resolved vibronic structure in the fluorescence spectrum. Mechanical grinding induces a phase transition from crystal to amorphous, which was confirmed by the powder X-ray diffraction measurements, and the emission colour turns green. The photoluminescence spectroscopy and emission lifetime measurements clarified that the green emission is ascribed to intermolecular excimer formation. Subsequent thermal treatment recovers the initial light-blue-emissive crystalline state. The crystalline phase is thermodynamically stable, whereas the amorphous state is thermodynamically metastable.

A bionic concept originating from the mechanism of gastric mucosa protecting a gastric wall from corrosion by gastric acid is creatively proposed, with the intention of finding a new way to reduce the corrosion of insulation coatings in liquid metal blankets. A compatible fluid barrier that mimics the function of gastric mucosa is used to prevent the flowing liquid metal from contacting the inner wall of a loop pipeline. The design of the bionic structure and the control of the barrier fluid are the most critical and difficult. A single-channel simulation is performed using Computational Fluid Dynamics (CFD) analysis to evaluate the effect of a compatible fluid barrier on separating the liquid lithium and insulation coating. The results show that the compatible fluid barrier can completely cover the inner wall of the pipeline within which the liquid metal is flowing, indicating that the bionic design can eliminate the corrosion of insulation coatings with flowing liquid lithium. Based on this, a compatible fluid barrier is investigated with multiple conditions, including the coverage area and film thickness, by changing the velocity ratio of the lithium to the barrier fluid, the shape of the inlet port, and the curvature radius of the bend pipes. In addition, an S-shaped pipe is confirmed to be completely corrosion free. This bionic concept is aimed at all corrosive liquid metals, and this work only starts with the extreme case of pure lithium. This work is expected to provide a preliminary feasibility basis for anti-corrosion design for a pipeline with dual fluids.

Achieving multiple mechanoresponsive luminescence-related functions from a single molecule remains challenging. Here, we demonstrate that both two-step mechanoresponsive luminescence and the release of small guest molecules are achieved by a 9,10-bis(phenylethynyl)anthracene-based cyclophane. When gently crushed, the yellow-emissive crystal of the cyclophane exhibits a hypsochromic shift of the emission band, because of alterations in molecular packing at the surface. Subsequent grinding results in a bathochromic shift of the emission band due to excimer formation accompanying the transition from the crystalline state to an amorphous state. Another pseudopolymorph of the cyclophane exhibits the release of chloroform from its crystal structure in response to mechanical stimuli, accompanied by a photoluminescent color change from yellow-green to yellow. These results reveal that luminescent cyclophanes are promising candidates for creating sophisticated mechanoresponsive luminescent materials.

FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1–4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1–4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3–50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1–4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing.Significance:Preclinical characterization of futibatinib, an irreversible FGFR1–4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors.

Suicide gene therapy using gene-directed enzyme prodrug therapy (GDEPT) is based on delivering a gene-encoded enzyme to cells that converts a nontoxic prodrug into its toxic metabolite. The bystander effect is thought to compensate for inefficiencies in delivery and expression because the produced toxic metabolite can spread to adjacent non-expressing cells. The purpose of this study was to assess the significance of bystander effect in GDEPT over the long term in vivo. We performed experiments using mixtures of yeast cytosine deaminase (yCD) expressing and empty vector (EV) containing cells. First, the bystander effect was assessed in various ratios of colon cancer cell lines RKO with yCD/EV in 2D and 3D culture. Next, tumors raised from RKO with yCD/EV in mice were treated with the prodrug 5-fluorocytosine (5-FC) for 42 days to assess bystander effect in vivo. Cell types constituting relapsed tumors were determined by 5-FC treatment and PCR. We were able to demonstrate bystander effect in both 2D and 3D. In mice, tumors initially regressed, but they all eventually recurred including those produced from 80% yCD expressing cells. Cells explanted from the recurrent tumors demonstrated that suicide gene expressing cells had been selected against during in vivo treatment with 5-FC. We conclude that gene therapy of malignant tumors in patients using the yCD/5-FC system will require targeting well over 80% of the malignant cells, and therefore will likely require improved bystander effect or repeated treatment.

Guinea’s reference ranges for biological parameters rely on those of Caucasian values. Variability in reference ranges according to the context is well-documented. We conducted this study for the purpose of future malaria clinical trials that assess the efficacy and safety of malaria drugs. A repeated cross-sectional study was carried out, in an apparently healthy cohort population. Surveys took place in Maferinyah rural community, which is located at 75 km from the capital. The 2.5thand 97.5thpercentiles were determined nonparametrically and stood for reference intervals. Reference values were determined separately for males and females according to ranges of age (6-10 years of age; 11-15 years of age; 16-45 years of age). Differences between genders were tested using the Mann-Whitney test, while the Friedman test was performed to test differences within each gender group according to the seasons. A total of 450 volunteers were enrolled. The median age was 13. Males 16-45 years of age had significantly higher hematologic and biochemical values compared to a female of the same age (for hematological parameters: Mean Cell Hemoglobin Concentration MCHCp≤0.001, Plateletsp≤0.001, monocytesp=0.0305, eosinophilsp=0.0225; for biochemical parameters: Aspartate aminotransferase ASTp≤0.001, Alanine Aminotransferase ALTp≤0.001, creatininep≤0.001). We noticed significant seasonal variations for all the biochemical parameters and some hematologic parameters (Mean Corpuscular Hemoglobin MCH, MCHC, Mean Cell volume). This is the first study establishing hematologic and biochemical parameters in Guinea. These findings provide a useful guide for the clinical researchers and care providers. Studies on large scale and in different settings would be also desirable.

Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα1 mRNA expression and hydroxyproline content, all of which were significantly attenuated by trehalose. In addition, CG challenges induced a marked peritoneal accumulation of α-SMA+ myofibroblasts that was reduced by trehalose. The number of Wt1+ α-SMA+ cells in the peritoneum increased following CG challenges, suggesting that a part of α-SMA+ myofibroblasts were derived from peritoneal mesothelial cells (PMCs). The number of Wt1+ α-SMA+ cells was also suppressed by trehalose. Additionally, trehalose attenuated the increase of α-SMA and ColIα1 mRNA expression induced by TGF-β1 through Snail protein degradation, which was dependent on autophagy in PMCs. These results suggest that trehalose might be a novel therapeutic agent for PF through the induction of autophagy and the suppression of mesothelial-to-mesenchymal transition in PMCs.

We explored the electrowetting behavior of a hydrofluoroester solvent, Novec 7100 (Novec), as a liquid droplet on a Au(111) electrode in water (0.05 M KClO4). Comparison with the electrowetting of hexadecane (HD) highlighted the significance of the lower adhesion energy and static friction energy of Novec than those of HD. The electrode potential-dependent contact angle θ of a Novec droplet showed little hysteresis. When potentials were set by means of potential steps, a Novec droplet increased its θ at more positive potentials than the potential of zero charge (pzc) of the Au(111) electrode. We found that the key factor of the electrowetting behavior for Novec is its low adhesion energy and static friction energy. The static friction energy of the oils to the Au(111) electrode surface was evaluated by a comparative analysis of the potential dependence of the interfacial tension at the solid/water interface, ΔγS/W–E curve, calculated from electrochemical surface charge data and the experimental cos θ–E curve: 2.6 mN/m for HD and 0.95 mN/m for Novec. When Br– was added in the aqueous solution to allow its adsorption on the Au surface surrounding a Novec droplet, the potential of maximum cos θ was shifted to negative. Overall, although the Novec droplet showed a narrower range of θ change than a HD droplet, the Novec droplet seldom got stuck to the surface as far as potential step was used, reflecting the narrower plateau region of θ near the pzc. Also, the specific adsorption of a coexistent anion was a significant factor of θ. This work has featured the significance of a slippy droplet on an electrode surface, giving an impact on the technology of microfluid transportation control by electric potentials., Langmuir, 36(33), pp.9685–9692; 2020

Corn fibre xylan (CX) shows high resistance to enzymatic hydrolysis due to its densely decorated side chains. To find enzymes capable of hydrolyzing CX, we isolated a bacterial strain (named H2C) from soil, by enrichment culture using non-starch polysaccharides of corn as the sole carbon source. Analysis based on the 16S rRNA sequence placed strain H2C within genus Paenibacillus. Enzymes were purified from supernatant of culture broth of strain H2C based on solubilizing activities toward CX. Four enzymes, Xyn5A, Xyn10B, Xyn11A, and Xyn30A, were successfully identified, which belong to glycoside hydrolase (GH) families, 5, 10, 11, and 30, respectively. Phylogenetic analysis classified Xyn5A in subfamily 35 of GH family 5, a subfamily of unknown function. Their activities toward beechwood xylan and/or wheat arabinoxylan indicated that these enzymes are β-1,4-xylanases. They showed high solubilizing activities toward a feed material, corn dried distiller’s grains with solubles, compared to five previously characterized xylanases. Abbreviations : CX: corn fibre xylan; DDGS: corn dried distiller’s grains with solubles

Neuromuscular junctions (NMJs) are cholinergic synapses characterized by ultrastructural specializations, including the presynaptic active zones, the acetylcholine (ACh) release sites of the motor nerve terminal, and the postsynaptic junctional folds of muscle membrane, where ACh receptors (AChRs) cluster for efficient neuromuscular transmission. The formation and maintenance of NMJs are governed by the muscle-specific receptor tyrosine kinase MuSK. We had previously demonstrated that the muscle cytoplasmic protein Dok-7 is an essential activator of MuSK, and its activation and NMJ formation are enhanced in the Dok-7 transgenic (Tg) mice, in which Dok-7 is specifically overexpressed in skeletal muscle. Although Dok-7 Tg mice develop abnormally large NMJs but show normal motor function, the forced expression of Dok-7 in the muscle improves impaired motor activity in mouse models of neuromuscular disorders with NMJ defects. However, the effect of Dok-7 overexpression in skeletal muscle on ultrastructure and neuromuscular transmission of NMJs is yet to be studied. Here, we investigated the structural and electrophysiological properties of NMJs in the diaphragm muscle of 8-week-old Dok-7 Tg mice. The areas of the presynaptic motor nerve terminals and postsynaptic muscle membrane of NMJs were 2.7 and 4.3 times greater in Dok-7 Tg mice than in WT mice, respectively. Electrophysiological analyses revealed that neuromuscular transmission via NMJs in Dok-7 Tg mice was significantly enhanced but not proportionally with the increased size of the synaptic contact. Consistent with this, the densities of active zones and synaptic vesicles (ACh carriers) in the presynaptic motor nerve terminals were reduced. In addition, the density and size of postsynaptic junctional folds in the muscle membrane were also reduced. Moreover, terminal Schwann cells exhibited significantly greater penetration of their processes into the synaptic clefts, which connect the pre- and post-synaptic specializations. Together, our findings demonstrate that transgenic overexpression of Dok-7 in the skeletal muscle enhances neuromuscular transmission with significant enlargement and ultrastructural alterations of NMJs, the latter of which might prevent toxic overactivation of AChRs at the abnormally enlarged NMJs.

Objective: Hypothyroidism is not commonly considered a cause of hyperkalemia. We previously reported that hyperkalemia was observed mainly in elderly patients treated with renin-angiotensin-aldosterone system (RAS) inhibitors when levothyroxine treatment was withdrawn for the thyroidectomized patients with thyroid carcinoma to undergo radioactive iodine treatment. Here, we investigated whether acute hypothyroidism causes hyperkalemia in patients who were not treated with RAS inhibitors. We also investigated factors influencing potassium metabolism in hypothyroid patients. Methods: We conducted a single-center, prospective cohort study of 46 Japanese patients with thyroid carcinoma undergoing levothyroxine withdrawal prior to radioiodine therapy. All patients were normokalemic before levothyroxine withdrawal. Blood samples were analyzed 3 times: before, and at 3 and 4 weeks after levothyroxine withdrawal. We investigated factors that may be associated with the elevation of serum potassium levels from a euthyroid state to a hypothyroid state. Results: None of the patients developed symptomatic hyperkalemia. The mean serum potassium level was significantly higher at 4 weeks after levothyroxine withdrawal compared to baseline. The serum sodium levels, the estimated glomerular filtration rate (eGFR), and the plasma renin activity (PRA) decreased significantly as hypothyroidism advanced. In contrast, the plasma levels of adrenocorticotropic hormone, cortisol, aldosterone, and antidiuretic hormone were not changed, while serum thyroid hormone decreased. At 4 weeks after their levothyroxine withdrawal, the patients' serum potassium values were significantly correlated with the eGFR and the PRA. Conclusion: Acute hypothyroidism can cause a significant increase in the serum potassium level, which may be associated with a decreased eGFR and decreased circulating RAS. Abbreviations: ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; ATPase = adenosine triphosphatase; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; K+ = potassium; Na+ = sodium; PRA = plasma renin activity; RAS = renin-angiotensin-aldosterone system; T4 = thyroxine; TSH = thyroid-stimulating hormone

Luminescent materials that change their photophysical properties and molecular arrangement in response to external stimuli have attracted attention because of the potential application in sensors, memory, security inks, and informational displays. The combination of external stimuli-responsive luminescence with the release of volatile molecules would give more sophisticated photofunctional materials. Herein we discuss a 9,10-bis(phenylethynyl)anthracene derivative that formed green-emissive crystals containing one-dimensional toluene channels. Amide groups of the compounds formed linear hydrogen-bonds in the crystals. Thermal treatment resulted in a phase transition to another crystalline state with the release of the guest toluene molecules. However, little alteration in the photoluminescent properties occurred during the transition. Mechanical stimuli led to the release of volatile molecules along with an emission colour change with a transition from the crystalline to an amorphous phase. Infrared spectroscopy showed that linear hydrogen bonds remained after a thermal treatment-induced phase transition, whereas mechanical stimuli disturbed them.

Introducing a cyclic structure to luminophores is a promising approach for achieving external stimuli-responsive luminescence. This is because luminescent cyclophanes containing flexible linkers tend to form several molecular assembled states. However, previously reported cyclophanes exhibiting thermoresponsive and/or mechanoresponsive luminescence have not given crystals suitable for single crystal X-ray structure analysis because of the flexible cyclic molecular structures. Such analysis is important because solved crystal structures can show unambiguous correlation between the arrangement of luminophores and photophysical properties. Here, we report the crystal structure of a cyclophane featuring a 9,10-bis(phenylethynyl)anthracene group and the thermoresponsive luminescence. The cyclophane was designed with shorter flexible oligo(ethyleneglycol) chains used as linkers bridging the luminophore and another aromatic group. The two different π-conjugated groups were orthogonally arranged in the individual molecule, and the luminophores partially overlapped between adjacent molecules. The cyclophane showed a supercooled nematic phase at room temperature upon cooling. Thermal treatment for the kinetically trapped state led to a transition to another crystalline state and, consequently, a change in photoluminescence colour. Emission spectroscopic studies and emission lifetime measurements revealed that the luminophores formed excimers in the supercooled nematic phase, whereas no excimer formation was observed for the crystalline phases.

Soybean seeds contain phytochemicals such as polyamines and isoflavones, which have been identified as functional components mediating health benefits in association with the consumption of soy foods. While a clear picture of the spatial distribution of these components within the seed is lacking, such information would be important to enhance or reduce their concentration in respective foods through processing. Thus, the objective of the present study was to visualize the most relevant components with respect to their distribution in soybean seeds. Mature soybean seeds were subject to atmospheric‐pressure scanning‐microprobe matrix‐assisted laser desorption/ionization (AP‐SMALDI) combined with a Fourier‐transform orbital trapping mass spectrometer to generate high‐resolution chemical images of phytochemical distribution. Based on seed cross sections, differential distributions of functional components were found between soybean cotyledon and germ (shoot, hypocotyl, root) regions. Spermidine and spermine were present in higher concentrations in the germ rather than in cotyledons with highest concentrations in root and shoot meristem tissues. Differential concentrations of spermidine and other components between the germ and cotyledon regions were confirmed by seed fractioning. In contrast to polyamines spermidine and spermine, the different types of daidzein, glycitein, and genistein isoflavones were all visualized in root parenchyma tissue exclusively. Overall, mass spectrometry imaging of soybean seeds revealed clear insights into the differential distribution of functional phytochemicals. Based on their distribution and depending on specific needs, spermidine and isoflavones can either be enriched or reduced during food processing by separating cotyledon and germ fractions., Spermidine is mediating various health effects through the induction of intracellular autophagy. In soybean, spermidine concentration is highest in the germ region of the embryo (shoot and root meristem tissues) as revealed by mass spectrometry imaging. Thus, separation of soybean germs during processing and food production can generate raw materials for the development of food supplements enriched in spermidine.

To explore the effect of the presence of a self-assembled monolayer (SAM) of an alkyl thiol derivative as an underlayer of a Nafion film, redox reaction of methyl viologen (MV) at the Au/SAM/Nafion (1 µm-thick) interface was characterized using the results of the voltammetric and electroreflectance measurements. The perfluorinated SAM slowed the kinetics of the interfacial electron transfer process compared to a Au/Nafion electrode, whereas 1-dodecanethiol SAM accelerated it. However, both the SAMs decreased the voltammetric current by half. Importance of the approach to underlay a SAM was discussed.

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.

Vibrio has a polar flagellum driven by sodium ions for swimming. The force-generating stator unit consists of PomA and PomB. PomA contains four-transmembrane regions and a cytoplasmic domain of approximately 100 residues which interacts with the rotor protein, FliG, to be important for the force generation of rotation. The three-dimensional structure of the stator shows that the cytosolic interface (CI) helix of PomA is located parallel to the inner membrane. In this study, we investigated the function of CI helix and its role as stator. Systematic proline mutagenesis showed that residues K64, F66, and M67 were important for this function. The mutant stators did not assemble around the rotor. Moreover, the growth defect caused by PomB plug deletion was suppressed by these mutations. We speculate that the mutations affect the structure of the helices extending from TM3 and TM4 and reduce the structural stability of the stator complex. This study suggests that the helices parallel to the inner membrane play important roles in various processes, such as the hoop-like function in securing the stability of the stator complex and the ion conduction pathway, which may lead to the elucidation of the ion permeation and assembly mechanism of the stator.ImportanceBacteria have a motor embedded in the membrane to rotate flagella as screw for swimming. The motor is composed rotor and stator complexes. The interaction between the rotor and stator converts the electrochemical potential gradient across the membrane into motor torque. The stator functions as an ion channel and is composed of two membrane proteins, MotA and MotB for proton or PomA and PomB for sodium ion. Based on the structural data of stator, we systematically introduce the proline replacement mutations and found that the cytosolic interface (CI) helix which is located parallel to the inner membrane between the second and third transmembrane (TM) segments, performs a hoop-like function in securing the stability of the stator complex and the ion conduction pathway. The results of this study provide novel insights into the energy conversion mechanism of the flagellar motor and the general mechanism of the ion channel function.

Due to the high energy demands and characteristic morphology, retinal photoreceptor cells require a specialized lipid metabolism for survival and function. Accordingly, dysregulation of lipid metabolism leads to the photoreceptor cell death and retinal degeneration. Mice with a frameshift mutation of lysophosphatidylcholine acyltransferase 1 (Lpcat1), which produces saturated phosphatidylcholine (PC) composed of two saturated fatty acids, has been reported to cause spontaneous retinal degeneration (rd11 mice). In this study, we performed a detailed characterization of LPCAT1 in the retina and found that genetic deletion of Lpcat1 induces light-independent and photoreceptor-specific apoptosis in mice. Lipidomic analyses of the retina and isolated photoreceptor outer segment (OS) suggested that loss of Lpcat1 decreases saturated PC production and affects the proper cellular fatty acid flux, presumably by altering saturated fatty acyl-CoA availabilities. Furthermore, we demonstrated that Lpcat1 deletion increased mitochondrial reactive oxygen species (ROS) levels in photoreceptor cells, but not in other retinal cells without affecting the OS structure and trafficking of OS-localized proteins. These results suggest that the LPCAT1-dependent production of saturated PC is critical for metabolic adaptation during photoreceptor maturation. Our findings highlight the therapeutic potential of saturated fatty acid metabolism in photoreceptor cell degeneration-related retinal diseases.

Pancreatic cancer cells (PCCs) are surrounded by an abundant stroma, which is produced by pancreatic stellate cells (PSCs). PSCs promote tumor cell proliferation and invasion. The objective of the current study was to identify compounds that suppress PSC activation. Gene expression profiles of cancer-derived fibroblasts and normal fibroblasts were used, and the pathway analysis suggested altered pathways that were chosen for validation. It was found that the 'neuroactive ligand-receptor interaction' pathway from the Kyoto Encyclopedia of Genes and Genomes pathway analysis was one of the altered pathways. Several compounds related with this pathway were chosen, and changes in PSC activity were investigated using fluorescence staining of lipid droplets, reverse transcription-quantitative PCR, western blotting, and invasion and migration assays. Among these candidates, duloxetine, a serotonin-noradrenaline reuptake inhibitor, was found to suppress PSC activation and disrupt tumor-stromal interaction. Thus, duloxetine may be a potential drug for suppressing PSC activation and pancreatic cancer growth.

Background: Artemether-lumefantrine is a highly effective artemisinin-based combination therapy that was adopted in Mali as first-line treatment for uncomplicated Plasmodium falciparum malaria. This study was designed to measure the efficacy of artemether-lumefantrine and to assess the selection of the P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multi-drug resistance 1 (pfmdr1) genotypes that have been associated with drug resistance. Methods: A 28-day follow-up efficacy trial of artemether-lumefantrine was conducted in patients aged 6 months and older suffering from uncomplicated falciparum malaria in four different Malian areas during the 2009 malaria transmission season. The polymorphic genetic markers MSP2, MSP1, and Ca1 were used to distinguish between recrudescence and reinfection. Reinfection and recrudescence were then grouped as recurrent infections and analyzed together by PCR-restriction fragment length polymorphism (RFLP) to identify candidate markers for artemether-lumefantrine tolerance in the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multi-drug resistance 1 (pfmdr1) gene. Results: Clinical outcomes in 326 patients (96.7%) were analyzed and the 28-day uncorrected adequate clinical and parasitological response (ACPR) rate was 73.9%. The total PCR-corrected 28-day ACPR was 97.2%. The pfcrt 76T and pfmdr1 86Y population prevalence decreased from 49.3% and 11.0% at baseline (n = 337) to 38.8% and 0% in patients with recurrent infection (n = 85), p = 0.001), respectively. Conclusion: Parasite populations exposed to artemether-lumefantrine in this study were selected toward chloroquine-sensitivity and showed a promising trend that may warrant future targeted reintroduction of chloroquine or/and amodiaquine.

We are proposing to connect a supercritical CO2 gas turbine (SCOT) power generator to the Operational Recovery of Separated Hydrogen and Heat Inquiry-2 (Oroshhi-2) nuclear fusion primary mo...

In 2013–2014, the FliNaK/LiPb twin-loop system Operational Recovery Of Separated Hydrogen and Heat Inquiry-2 (Oroshhi-2) was constructed at National Institute for Fusion Science as a liquid blanket...

We report a new application of N-amino-7-azaindole as a new bidentate-directing group for [Ru(p-cymene)Cl2]2-catalyzed C(sp2)-H alkenylation/annulation of N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamides with internal alkynes to afford N-isoquinolono-7-azaindole via the formation of C-C and C-N bonds. The reaction shows a wide range of substrate scope with different symmetrical and unsymmetrical alkynes, affording the desired product in good to excellent yields. In the case of unsymmetrical alkynes, a highly regioselective product was obtained, which was confirmed by single-crystal X-ray crystallography. A new ruthenium-4-methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide complex was isolated, and its structure was confirmed by single-crystal X-ray crystallography.

The accumulation of fibroblasts is a critical step in the development of fibrosis, and lysophosphatidic acid (LPA) promotes fibrosis by regulating multiple fibroblast functions. Autotaxin (ATX) is a key LPA-producing enzyme, and we hypothesized that ATX contributes to the development of renal interstitial fibrosis through LPA-mediated effects on fibroblast functions. In a mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO), the levels of renal ATX protein and activity increased with the progression of fibrosis in ligated kidneys, despite concurrent reductions in renal ATX mRNA. UUO enhanced vascular permeability in the renal interstitium, and ATX protein localized to areas of vascular leak, suggesting that vascular leak allowed ATX to enter the renal interstitium. In vitro studies showed that ATX induces the migration and proliferation of renal fibroblasts and enhances the vascular permeability of endothelial monolayers. Finally, pharmacological inhibition of ATX partially attenuated renal interstitial fibrosis. These results suggest that during the development of renal fibrosis, ATX accumulates in the renal interstitium and drives fibroblast accumulation and promotes renal interstitial vascular leak, thereby partially contributing to the pathogenesis of renal interstitial fibrosis. Taken together, ATX inhibition may have the potential to be a novel therapeutic strategy to combat renal interstitial fibrosis.

The impacts of chemical stability of inert-matrix-fuel (IMF) on the material attractiveness for states and non-state actors were evaluated in an open transuranic fuel cycle employing high temperature gas cooled reactors. The methodology for material attractiveness evaluation was developed to assess material attractiveness for states and treat IMF which is chemically inert for nitric acid solution. The material attractiveness was relatively assessed with physical properties of material in each of three discrete phases in the development of a nuclear explosive device. The material attractiveness assessment for non-state actors revealed that the non-irradiated TRISO fuel particle and IMF kernel for high temperature gas cooled reactors and the non-irradiated mixed oxide fuel (MOX) powder for MOX light water reactors were the most vulnerable targets in each fuel cycles. The TRISO fuel particle and IMF kernel would have less material attractiveness than the MOX powder because of their greater processing time and complexity. The material attractiveness assessment for states aiming concealed diversion revealed that the TRISO fuel particle and IMF kernel have less material attractiveness than the MOX powder, and are regarded as irradiated uranium fuel grade in the material attractiveness.