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Considering the desired energy density, safety and cost-effectiveness, rechargeable zinc-ion batteries (ZIBs) are regarded as one of the most promising energy storage units in next-generation energy systems. Nonetheless, the service life of the current ZIBs is significantly limited by rampant dendrite growth and severe parasitic reactions occurring on the anode side. To overcome these issues caused by poor interfacial ionic conduction and water erosion, we have developed a facile strategy to fabricate a uniform zinc borate layer at the zinc anode/electrolyte interface (ZnBO). Such protective layer integrates superhydrophobic-zincopholic properties, which can effectively eliminate the direct contact of water molecules on the anode, and homogenize the interfacial ionic transfer, thereby enhancing the cyclic stability of the zinc plating/stripping. As a result, the as-prepared ZnBO-coated anode exhibits extended lifespan of 1200 h at 1 mA cm -2 and demonstrates remarkable durability of 570 h at 20 mA cm -2 in Zn||Zn symmetric cells. Additionally, when coupled to an NH 4 V 4 O 10 (NVO) cathode, it also delivers a superior cyclability (203.5 mAh/g after 2000 cycles at 5 A/g, 89.3 % capacity retention) in coin full cells and a feasible capacity of 2.5 mAh at 1 A/g after 200 cycles in pouch full cells. This work offers a unique perspective on integrating hydrophobicity and zincophilicity at the anode/electrolyte interface through an artificial layer, thereby enhancing the cycle lifespan of ZIBs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Owing to the considerable capacity, high safety, and abundant zinc resources, zinc-ion batteries (ZIBs) have been garnering much attention. Nonetheless, the unsatisfactory cyclic lifespan and poor reversibility originate from side reactions and dendrite obstacles to their practical applications. In addition to inhibiting the corrosion of aqueous electrolytes, regulating planar deposition is a key strategy to enhance their long-term stability. Herein, an in situ conversion strategy is reported to construct a protective "dual-layer" structure (VZSe/V@Zn) on zinc metal, consisting of the VSe 2 -ZnSe outer layer with low lattice mismatch to Zn (002) plane, and corrosion-resistant nanometallic V inner layer. Such design integrates superior interfacial ionic/electronic transfer, corrosion resistance, and unique planar deposition regulation capability. The as-prepared VZSe/V@Zn demonstrates remarkable durability of 238 h at 50 mA cm -2 with a high depth of discharge (68.3% DOD) in the Zn||Zn symmetric cell. Even in the anode-free system, the as-prepared protective layer can extend the cycle life up to 2000 cycles, with an outstanding capacity retention of 93.1% and ultra-high average coulombic efficiency of 99.998%. This work delineates an effective strategy for fabricating lattice-matching protective layers, with profound implications for elucidating zinc deposition mechanisms and paving the way for the development of high-performance zinc batteries., (© 2024 Wiley‐VCH GmbH.)

Thermochromic smart windows are regarded as highly cost-effective and easily implementable strategies with zero energy input among the smart window technologies. They possess the capability to spontaneously adjust between transparent and opaque states according to the ambient temperatures, which is essential for energy-efficient buildings. Recently, thermochromic smart windows based on hydrogels with various chromic mechanisms have emerged to meet the increasing demand for energy-saving smart windows. This review provides an overview of recent advancements in hydrogel-based thermochromic smart windows, focusing on fabrication strategies, chromic mechanisms, and improvements in responsiveness, stability and energy-saving performance. Key developments include dual-responsiveness, tunable critical transition temperatures, freezing resistance, and integrations with radiative cooling/power generation technologies. Finally, we also offer a perspective on the future development of thermochromic smart windows utilizing hydrogels. We hope that this review will enhance the understanding of the chromic mechanism of thermochromic hydrogels, and bring new insights and inspirations on the further design and development of thermochromic hydrogels and derived smart windows.

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptor-α (PDGFRα), KIT, and RET that have been implicated in pathogenic angiogenesis, tumor growth, and cancer. The primary objective of this work was to evaluate, by establishing quantitative relationships, whether lenvatinib exposure and longitudinal serum biomarker data (VEGF, Ang-2, Tie-2, and FGF-23) are predictors for change in longitudinal tumor size which was assessed based on data from 558 patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving either lenvatinib or placebo treatment. Lenvatinib PK was best described by a 3-compartment model with simultaneous first- and zero-order absorption and linear elimination from the central compartment with significant covariates (body weight, albumin <30 g/dL, ALP>ULN, RR-DTC, RCC, HCC subjects, and concomitant CYP3A inhibitors). Except for body weight, none of the covariates have any clinically meaningful effect on exposure to lenvatinib. Longitudinal biomarker measurements over time were reasonably well defined by a PK/PD model with common EC 50 , E max , and a slope for disease progression for all biomarkers. Longitudinal tumor measurements over time were reasonably well defined by a tumor growth inhibition E max model, which in addition to lenvatinib exposure, included model-predicted relative changes from baseline over time for Tie-2 and Ang-2 as having significant association with tumor response. The developed PK/PD models pave the way for dose optimization and potential prediction of clinical response., (© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Site-targeted decoration of catalytic nanocrystals is essential for maximizing performance with minimal materials use. Here, we demonstrate successful, site-targeted decoration of palladium (Pd) nanocrystals with nickel (Ni) exclusively along crystal facet edges through the thermal decomposition of nickel carbonyl (Ni(CO) 4 ) vapor. Strong interactions between carbon monoxide and Pd facet for passivation or between Ni(CO) 4 and crystal facet edges resulted in selective Ni decoration at the nanocrystal edges. The Ni-decorated Pd nanocrystals exhibit superior catalytic performance for methane (CH 4 ) removal in an oxygen-rich lean-burn exhaust atmosphere, requiring 10 times less Ni decoration than conventional Pd-Ni composite catalysts prepared by the wet impregnation method. The site-targeted decoration of nanocrystals introduced in this work offers an efficient and resource-minimizing strategy for enhanced catalytic applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Solid-state nuclear track detectors (SSNTDs) are often used as ion detectors in laser-driven ion acceleration experiments and are considered to be the most reliable ion diagnostics since they are sensitive only to ions and measure ions one by one. However, ion pit analyses require tremendous time and effort in chemical etching, microscope scanning, and ion pit identification by eyes. From a laser-driven ion acceleration experiment, there are typically millions of microscopic images, and it is practically impossible to analyze all of them by hand. This research aims to improve the efficiency and automation of SSNTD analyses for laser-driven ion acceleration. We use two sets of data obtained from calibration experiments with a conventional accelerator where ions with known nuclides and energies are generated and from actual laser experiments using SSNTDs. After chemical etching and scanning the SSNTDs with an optical microscope, we use machine learning to distinguish the ion etch pits from noises. From the results of the calibration experiment, we confirm highly accurate etch-pit detection with machine learning. We are also able to detect etch pits with machine learning from the laser-driven ion acceleration experiment, which is much noisier than calibration experiments. By using machine learning, we successfully identify ion etch pits ∼105 from more than 10 000 microscopic images with a precision of ≳95%. A million microscopic images can be examined with a recent entry-level computer within a day with high precision. Machine learning tremendously reduces the time consumption on ion etch pit analyses detected on SSNTDs., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Nucleic acid therapeutics have been utilized for gene regulation, and their recent advancement has led to approval of novel drugs for liver-related disorders. However, systemic extrahepatic delivery remains challenging. Here, we report newly designed mannose-conjugated oligonucleotides for delivering oligonucleotides to macrophages by leveraging the mannose receptor, C-type 1 (MRC1, CD206), which is abundantly expressed in macrophages. We investigated the relationship between cellular uptake and multivalency (mono to tetra) of mannose ligands or linker length and selected a trivalent-mannose ligand. Trivalent-mannose (Man3)-conjugated siRNA induced concentration-dependent gene silencing in both human CD206-overexpressing cells and human macrophages in vitro. After subcutaneous injection into mice, we observed a high distribution of Man3-conjugated oligonucleotides in the liver and pancreata as well as cellular uptake into Kupffer cells and pancreatic macrophages. A single subcutaneous injection of Man3-conjugated siRNA (10 mg/kg) targeting β 2 -microglobulin (B2M) silenced B2m mRNA expression by ∼50% and decreased its protein levels in mouse pancreatic macrophages compared to those in saline-treated mice. Of note, multiple subcutaneous injections decreased B2m gene expression and B2M protein levels by ∼80% and ∼85%, respectively. These results show that mannose-conjugation with oligonucleotides is expected to help deliver oligonucleotides to macrophages and regulate gene expression in vivo, particularly in the pancreas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Blastocyst complementation is an intriguing way of generating humanized animals for organ preparation in regenerative medicine and establishing novel models for drug development. Confirming that complemented organs and cells work normally in chimeric animals is critical to demonstrating the feasibility of blastocyst complementation. Here, we generated thymus-complemented chimeric mice, assessed the efficacy of anti-PD-L1 antibody in tumor-bearing chimeric mice, and then investigated T-cell function. Thymus-complemented chimeric mice were generated by injecting C57BL/6 (B6) embryonic stem cells into Foxn1 nu/nu morulae or blastocysts. Flow cytometry data showed that the chimeric mouse thymic epithelial cells (TECs) were derived from the B6 cells. T cells appeared outside the thymi. Single-cell RNA-sequencing analysis revealed that the TEC gene-expression profile was comparable to that in B6 mice. Splenic T cells of chimeric mice responded very well to anti-CD3 stimulation in vitro; CD4 + and CD8 + T cells proliferated and produced IFNγ, IL-2, and granzyme B, as in B6 mice. Anti-PD-L1 antibody treatment inhibited MC38 tumor growth in chimeric mice. Moreover, in the chimeras, anti-PD-L1 antibody restored T-cell activation by significantly decreasing PD-1 expression on T cells and increasing IFNγ-producing T cells in the draining lymph nodes and tumors. T cells produced by complemented thymi thus functioned normally in vitro and in vivo. To successfully generate humanized animals by blastocyst complementation, both verification of the function and gene expression profiling of complemented organs/cells in interspecific chimeras will be important in the near future., (© 2022. The Author(s).)

Graphene is known as an atomically thin, transparent, highly electrically and thermally conductive, light-weight, and the strongest 2D material. We investigate disruptive application of graphene as a target of laser-driven ion acceleration. We develop large-area suspended graphene (LSG) and by transferring graphene layer by layer we control the thickness with precision down to a single atomic layer. Direct irradiations of the LSG targets generate MeV protons and carbons from sub-relativistic to relativistic laser intensities from low contrast to high contrast conditions without plasma mirror, evidently showing the durability of graphene., (© 2022. The Author(s).)

We present an experimental method to generate quasiperpendicular supercritical magnetized collisionless shocks. In our experiment, ambient nitrogen (N) plasma is at rest and well magnetized, and it has uniform mass density. The plasma is pushed by laser-driven ablation aluminum (Al) plasma. Streaked optical pyrometry and spatially resolved laser collective Thomson scattering clarify structures of plasma density and temperatures, which are compared with one-dimensional particle-in-cell simulations. It is indicated that just after the laser irradiation, the Al plasma is magnetized by a self-generated Biermann battery field, and the plasma slaps the incident N plasma. The compressed external field in the N plasma reflects N ions, leading to counterstreaming magnetized N flows. Namely, we identify the edge of the reflected N ions. Such interacting plasmas form a magnetized collisionless shock.

A new diagnosis method for the discriminative detection of laser-accelerated multi-MeV carbon ions from background oxygen ions utilizing solid-state nuclear track detectors (SSNTDs) is proposed. The idea is to combine two kinds of SSNTDs having different track registration sensitivities: Bisphenol A polycarbonate detects carbon and the heavier ions, and polyethylene terephthalate detects oxygen and the heavier ions. The method is calibrated with mono-energetic carbon and oxygen ion beams from the heavy ion accelerator. Based on the calibration data, the method is applied to identify carbon ions accelerated from multilayered graphene targets irradiated by a high-power laser, where the generation of high-energy high-purity carbon ions is expected. It is found that 93 ± 1% of the accelerated heavy ions with energies larger than 14 MeV are carbons. The results thus obtained support that carbon-rich heavy ion acceleration is achieved., (© 2021. The Author(s).)

PEGylation-modification with polyethylene glycol (PEG)-is useful for stabilizing lipid nanoparticles (LNPs). However, such PEGylation can prevent small interfering RNA (siRNA) encapsulated in LNPs from exerting its gene-silencing effects by disrupting the interaction of LNPs with target cells and by inducing the accelerated blood clearance phenomenon via anti-PEG IgM. PEG-lipids with short acyl chains can be used to address these issues because they are quickly shed from LNPs after administration; however, there are few reports on the relationships among PEG shedding rate, anti-PEG IgM production, and the gene-silencing activity of siRNA upon repeated LNP administration. Here, in mice, we found that LNPs conjugated to a fast-shedding PEG-lipid (short acyl chain) induced less anti-PEG IgM compared with LNPs conjugated to a slow-shedding PEG-lipid (long acyl chain). Moreover, pretreatment of mice with LNPs conjugated to the slow-shedding PEG-lipid caused loss of RNA interference activity after subsequent LNP administration because the payload siRNA was delivered primarily to Kupffer cells rather than to hepatocytes. Together, these findings imply that manipulating PEG shedding rate and anti-PEG antibody production is enormously important in the development of RNA interference-based therapeutics utilizing LNP technology., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Circulating tumor DNA (ctDNA) is an attractive source for liquid biopsy to understand molecular phenotypes of a tumor non-invasively, which is also expected to be both a diagnostic and prognostic marker. PIK3CA and KRAS are among the most frequently mutated genes in epithelial ovarian cancer (EOC). In addition, their hotspot mutations have already been identified and are ready for a highly sensitive analysis. Our aim is to clarify the significance of PIK3CA and KRAS mutations in the plasma of EOC patients as tumor-informed ctDNA., Materials and Methods: We screened 306 patients with ovarian tumors for somatic PIK3CA or KRAS mutations. A total of 85 EOC patients had somatic PIK3CA and/or KRAS mutations, and the corresponding mutations were subsequently analyzed using a droplet digital polymerase chain reaction in their plasma., Results: The detection rates for ctDNA were 27% in EOC patients. Advanced stage and positive peritoneal cytology were associated with higher frequency of ctDNA detection. Preoperative ctDNA detection was found to be an indicator of outcomes, and multivariate analysis revealed that ctDNA remained an independent risk factor for recurrence (p=0.010). Moreover, we assessed the mutation frequency in matched plasma before surgery and at recurrence from 17 patients, and found six patients had higher mutation rates in cell-free DNA at recurrence compared to that at primary diagnosis., Conclusion: The presence of ctDNA at diagnosis was an indicator for recurrence, which suggests potential tumor spread even when tumors were localized at the time of diagnosis.

Objectives: Circulating tumor DNA (ctDNA) has potential as a basis for understanding the molecular features of a tumor non-invasively and for use as a diagnostic, prognostic, and disease-monitoring marker. The aim of this study was to evaluate the clinical roles of ctDNA in patients with endometrial cancer., Methods: Since PIK3CA and KRAS are among the most common mutated genes in endometrial cancer, somatic mutations of these genes were investigated in tumor specimens and plasma collected before surgery, using droplet digital polymerase chain reaction (ddPCR). ctDNA was defined as positive when the corresponding mutation between somatic and plasma was also detected in plasma cell-free DNA (cfDNA). Relationships of the presence of ctDNA with clinicopathological features were examined., Results: Somatic PIK3CA and/or KRAS mutations were found in 68 (34%) of 199 patients with endometrial cancer. Ten (14.7%) of 68 patients had similar mutations in cfDNA. ctDNA detected in pre-operative plasma was correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.008), histology (p=0.028), and lymphovascular space invasion (p=0.002), and with shorter recurrence-free and overall survival (p=0.004 and p=0.010, respectively, by log-rank test)., Conclusion: Tumor-related ctDNA detected in plasma before surgery was associated with poorer oncologic outcome on univariate analysis in patients with endometrial cancer harboring PIK3CA or KRAS mutations., Competing Interests: Competing interests: KH received a grant from Eisai, (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

No report has yet examined the impact of oral hypofunction on physical frailty in relation to intra-relationships of physical frailty assessment items. The purpose of this study was to verify the potential of a clinical cascade between oral hypofunction and physical frailty, and especially to support the hypothesis that the influence of oral hypofunction on physical frailty is greater than the intra-relationships among elements of physical frailty and that sex differences significantly affect these relationships. The participants were 272 older adults (101 men and 171 women; mean age 75.1 ± 7.5 years). Maximum occlusal force (MOF) and oral dryness (OD), as indicators of oral hypofunction, and grip strength (GS) and walking speed (WS), as indicators of physical frailty, were measured. Mutual relationship of four variables was verified using covariance structure analysis. In men, three paths from MOF to WS and GS and from WS to GS were confirmed, and those from MOF to WS and from WS to GS were found to be significant (P < .01). In women, three paths from MOF to WS and GS and from WS to GS were also confirmed, as with the men, and those from MOF to WS and from MOF to GS were found to be significant (P < .01). Model adaptability was shown to be good for both men and women. The results suggest our hypothesis was verified, and it is expected that the early detection of oral hypofunction, that is MOF, may be important for assessing physical frailty, especially in women., (© 2019 John Wiley & Sons Ltd.)

A questionnaire survey was conducted to investigate eating behavior and the subjective symptoms of oral frailty, and to examine the relationship between them. A total of 744 subjects with ages over 65 years were included. The questionnaire comprised 18 question items indicating eating behavior and seven question items indicating oral frailty. All items were assessed according to 4 grades on a scale of 1 (not applicable) to 4 (applicable). The total score of oral frailty gradually increased with age. Regarding the scores for "eating recognition" and "eating habits", no changes were observed, however the scores for "eating action" demonstrated a decreasing tendency with age and the scores of ≥ 85 years age group was significantly lower than the 65-69, 70-74, and 75-79 years age groups. As a result of multiple regression analysis, among the significant independent variable, the scores of "I do not chew foods well" under the category of "eating action" showed the highest standard partial regression coefficients for dependent variable of symptoms of oral frailty. The significant association was found between the eating behavior and subjective symptoms of oral frailty, and this study suggests that the good chewing habit might be an important criterion for the prevention of oral frailty.

Background: Lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in the phase III Study of (E7080) LEnvatinib in differentiated Cancer of the Thyroid (SELECT) of patients with radioiodine-refractory differentiated thyroid cancer. This exploratory analysis investigated potential predictive biomarkers of lenvatinib efficacy and target engagement., Patients and Methods: Circulating cytokine/angiogenic factors (CAFs) in blood samples collected at baseline and throughout treatment were analysed from patients randomised to receive lenvatinib or placebo from August 5, 2011 to October 4, 2012. For CAF biomarker analyses, patients were dichotomised by baseline levels. Tumour tissues were analysed for BRAF and NRAS/KRAS/HRAS mutations., Results: Tumours and CAFs were analysed from 183/392 (47%) and 387/392 (99%) patients, respectively. Lenvatinib PFS benefit was maintained in all assessments. For lenvatinib-treated patients, interaction-term analyses revealed that low baseline Ang2 level was predictive of tumour shrinkage (P interaction  = 0.016) and PFS (P interaction  = 0.018). Vascular endothelial growth factor and fibroblast growth factor 23 (FGF23) were significantly upregulated with lenvatinib, and FGF23 upregulation on cycle 1/day 15 was associated with longer PFS. In mutation analyses, no significant differences in clinical outcomes were observed. BRAF WT may be a negative prognostic factor for PFS in placebo-treated patients with papillary thyroid cancer (P = 0.019)., Conclusion: The lenvatinib PFS benefit was maintained regardless of baseline CAF or BRAF/RAS status. Baseline Ang2 was predictive of PFS in a subgroup of lenvatinib-treated patients, indicating that Ang2 may be predictive of lenvatinib sensitivity. BRAF WT may be a poor prognostic factor in patients with radioiodine-refractory papillary thyroid cancer. Improved PFS associated with upregulated FGF23 suggests that lenvatinib-induced FGF receptor inhibition contributes to lenvatinib efficacy. Trial registration ID of the main study, SELECT: ClinicalTrials.gov: NCT01321554., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

E2012, a gamma secretase modulator without affecting Notch processing, aimed at Alzheimer's disease by reduction of amyloid β-42, induced cataract following repeated doses in the rat. Cataract appeared first at week 10-11 of treatment as a posterior subcapsular area with granular/punctate opaque or shiny dots along the suture line, characterized histologically as lenticular fiber degeneration, which eventually coalesced to form a triangular or circular opacity. It was associated with prolonged and sustained elevation of lenticular desmosterol (24-dehydrocholesterol), the final precursor of cholesterol, and decrease in lenticular cholesterol. In vitro studies to investigate the effect of E2012 on cholesterol metabolism demonstrated that E2012 inhibits 3β-hydroxysterol Δ24-reductase (DHCR24) at the final step in the cholesterol biosynthesis. In vivo lenticular concentration of E2012 after 13-week repeated dose with cataract was well above those where inhibition was observed in vitro. There was no cataract formation at doses where desmosterol did not accumulate in the lens. The elevation of desmosterol and decreased cholesterol levels were also seen in the liver and plasma and preceded those in the lens. These results demonstrate that E2012 induces cataract in the rat by inhibiting DHCR24 at the final step of cholesterol synthesis with associated elevation in desmosterol within the lens, preceded by desmosterol changes that would serve as a predictive safety biomarker for lenticular opacity.

Channels responsible for slowly activating delayed-rectifier potassium current (I(Ks)) are composed of KCNQ1 and KCNE1 subunits, and these channels play a role in the repolarization of cardiac action potentials. Recently, we showed that the antihyperlipidemic drug probucol, which induces QT prolongation, decreases the I(Ks) after 24-h treatment. In the present study, we investigated the effects of three cholesterol-lowering agents (probucol, an enhancer of cholesterol efflux; simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; and triparanol, a 3β-hydroxysterol-▵24-reductase inhibitor) on cholesterol synthesis, the KCNQ1 current (I KCNQ1), and the I(Ks) to clarify the differences in the modes of action of these agents on the I(Ks). Probucol did not inhibit cholesterol synthesis and had no effect on I KCNQ1, while I(Ks) decreased after 24-h treatment. Simvastatin inhibited cholesterol synthesis and decreased I KCNQ1 and I(Ks). Additionally, the activation kinetics of I(Ks) became faster, compared with that of control I(Ks). Triparanol inhibited cholesterol synthesis but did not reduce I KCNQ1 and I(Ks). However, the activation kinetics of I(Ks) became faster. Our data indicated that the mechanism by which probucol inhibits I(Ks) was not mediated by the inhibition of cholesterol synthesis but depended on an interaction with the KCNQ1/KCNE1 complex. Meanwhile, the reduction in cholesterol induced by simvastatin and triparanol is one of the mechanisms that affects the kinetics of I(ks).

A variety of internally N-alkylated N-confused porphyrins were prepared in a stepwise manner through the protection of the reactive peripheral nitrogen atom. NH-Tautomerism in N-confused porphyrins was found to be regulated by N-alkylation, which enabled us to obtain discrete information on two important NH-tautomers of an N-confused porphyrin.

Physiologically relevant assessment of delayed repolarization is necessary in drug development. In our preliminary experiments on the evaluation using a multielectrode recording system, we had found that the responsiveness of field potential duration (FPD), as QT-like intervals, to hERG channel blockers differed greatly from non-responders to excessive responders in human embryonic stem cell-derived cardiomyocyte clusters. Thus, we report a novel method of selecting clusters suitable for evaluating compounds for the assessment. Clusters were treated with cisapride, a hERG channel blocker, at 100nM, and selected with criteria of 5-20% of corrected FPD (FPDc) prolongation. Then, selected clusters were treated with reference compounds. FPDc was prolonged by blockade of the hERG channel (E-4031 and dl-sotalol) and KvLQT1 channel (chromanol 293B and HMR1556), and by activation of the sodium channel (veratridine) and calcium channel (Bay K8644). FPDc was shortened by calcium channel blockage (verapamil, nifedipine and diltiazem) and by K(ATP) channel activation (pinacidil). Class Ia antiarrhythmic drugs, quinidine and disopyramide, prolonged FPDc. Selected clusters are appropriate for assessing the effects of compounds on ion channels affecting QT intervals. This is the first report of the establishment of an assessment system of potential to influence QT interval, using pharmacologically selected clusters., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Size-monodispersed Fe65Co35 alloy clusters whose average sizes ranged from 7 to 12 nm were produced by a plasma-gas-condensation (PGC)-type cluster deposition apparatus. Fe65Co35 alloy cluster-assembled films were further prepared at room temperature by energetic cluster deposition method. Positively charged clusters in a cluster beam were accelerated electrically and deposited onto a negatively biased substrate together with neutral clusters from the same cluster source, leading to the formation of a high-density Fe65Co35 alloy cluster-assembled films with good soft magnetic properties. High frequency magnetic characteristics of these films were studied at room temperature using a high-frequency permeameter (RMF-3000, Ryowa). The real part (micro') of permeability for the Fe65Co35 alloy cluster-assembled films prepared at bias voltage V(a) = -20 kV has a large value of micro' = 135 at f = 1.5 GHz, and imaginary part (micro") of permeability has a maximum (micro" approximately 190) at about 2.5 GHz.

Graphite surfaces were irradiated by argon (Ar+) ions at 1 keV with a simultaneous cobalt (Co) supply at room temperature. Various kinds of carbon nanocomposites, such as nanocones with and without single nanofibers on their tops, nanorods and fish-scale-like nanoprotrusions, were formed depending on Co supply rates. It has been observed that with increasing the Co supply rate the formation of nanoprotrusions without nanofibers became prominent. Both nanofibers and nanoprotrusions were surely composed of carbon and Co, as confirmed by energy-dispersive X-ray analysis. The cobalt carbon nanocomposite fibers (CCNFs), -1.5 microm in average length, were grown on the top of the nanocones at the Co supply rate of 1.0 nm/min. The field electron emission characteristics of CCNFs thus grown indicated that there is an optimum parameter for the CCNF growth to achieve the better emission performance than that of pristine Ar(+)-induced carbon nanofibers.

The physical properties of Zn(1-x)Mn(x)O nanoparticles synthesized by thermal decomposition are extensively investigated by X-ray diffraction (XRD), Transmission Electron Microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Raman light scattering and Hysteresis measurements. XRD and XPS spectra reveal the absence of secondary phase in nanocrystalline ZnO doped with 5% or less Mn; and, later confirms that the valance state of Mn to be 2+ for all the samples. Raman spectra exhibit a peak at 660 cm(-1) which we attribute to the intrinsic lattice defects of ZnO with increasing Mn concentration. Overall, our results demonstrate that ferromagnetic properties can be realized while Mn-doped ZnO obtained in the nanocrystalline form.

A rhenium(I) complex of an N-heterocyclic carbene ligand embedded in an N-confused porphyrin core was serendipitously synthesized by the reaction of an inner-methylated N-confused porphyrin with Re(2)(CO)(10).

We have developed a new algorithm to estimate the surface air specific humidity over the ocean from AMSR-E data. It should be noted that remarkably reduced random errors of the estimated surface air specific humidity result from using the surface air specific humidity provided by reanalysis data. We validated our new algorithm using independent ship and buoy data. The bias, RMS error, and correlation coefficient of the products obtained using our algorithm for global buoys are 0.38 g/kg, 0.61 g/kg and 0.99, respectively. It should be noted that surface specific humidity having similar accuracy to the reanalysis data near in situ data could be derived from AMSR-E data by the present algorithm.

We investigated the antidiabetic effects of E3030, which is a potent dual activator of peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma, in an animal model of diabetes, C57BL/KsJ-db/db mice (db/db mice), and the lipidemic effects of E3030 in beagle dogs, whose PPARalpha and PPARgamma transactivation responses to E3030 were similar to those of humans. E3030 activated human PPARalpha, mouse PPARalpha, dog PPARalpha, human PPARgamma, mouse PPARgamma, and dog PPARgamma with EC(50) values of 65, 920, 87, 34, 73, and 34 nM, respectively, in the chimeric GAL4-PPAR receptor transactivation reporter assay. In db/db mice orally administered E3030 decreased blood glucose, triglyceride (TG), non-esterified fatty acids (NEFA), and insulin levels and increased blood adiponectin levels during a 14-day experimental period. Significant effects on blood glucose and adiponectin levels were observed at a dose of 3 mg/kg or greater. Furthermore, significant effects on blood TG, NEFA, and insulin levels were observed at doses of 1 mg/kg or more. An oral glucose tolerance test (OGTT) performed on Day 15 showed that E3030 at 3 mg/kg improved glucose tolerance in this model. Fourteen days of oral treatment with E3030 at a dose of 0.03 mg/kg or greater showed remarkable TG- and non high-density lipoprotein (non-HDL) cholesterol-lowering effects in beagle dogs. These results were similar to those observed for the PPARalpha agonist fenofibrate. E3030 also reduced apo C-III levels on Days 7 and 14, and elevated lipoprotein lipase (LPL) levels on Day 15. These results indicate that the TG- and non-HDL cholesterol-lowering actions of E3030 involve combined effects on reduction of apo C-III and elevation of LPL, resulting in increased lipolysis. The experimental results in animals suggest that E3030 has potential for use in the treatment of various aspects of metabolic dysfunction in type 2 diabetes, including dyslipidemia, hyperglycemia, hyperinsulinemia, and impaired glucose disposal.

Nonlinear-optical nanocomposite materials with a photonic crystal structure were fabricated using block copolymers and gold nanoparticles. By dispersing the gold nanoparticles into the selective microdomains of the block copolymers, we could achieve the enhancement of nonlinear optical properties as revealed by the Z-scan technique. The optical nonlinearities were enhanced by the local field effect and the effect of the periodic distribution of the microdomains filled with gold nanoparticles. Furthermore, the highest optical nonlinearity was achieved by matching the domain spacing of the copolymers with the frequency of the surface plasmon resonance peak of the gold.

Proteins containing the formin homology (FH) domains FH1 and FH2 are involved in cytokinesis or establishment of cell polarity in a variety of organisms. We have shown that the FH proteins Bni1p and Bnr1p are potential targets of the Rho family small GTP-binding proteins and bind to an actin-binding protein, profilin, at their proline-rich FH1 domains to regulate reorganization of the actin cytoskeleton in the yeast Saccharomyces cerevisiae. We found here that a novel Src homology 3 (SH3) domain-containing protein, encoded by YMR032w, interacted with Bnr1p in a GTP-Rho4p-dependent manner through the FH1 domain of Bnr1p and the SH3 domain of Ymr032wp. Ymr032wp weakly bound to Bni1p. Ymr032wp was homologous to cdc15p, which is involved in cytokinesis in Schizosaccharomyces pombe, and we named this gene HOF1 (homolog of cdc 15). Both Bnr1p and Hof1p were localized at the bud neck, and both the bnr1 and hof1 mutations showed synthetic lethal interactions with the bni1 mutation. The hof1 mutant cells showed phenotypes similar to those of the septin mutants, indicating that HOF1 is involved in cytokinesis. These results indicate that Bnr1p directly interacts with Hof1p as well as with profilin to regulate cytoskeletal functions in S. cerevisiae.

The RHO1 gene encodes a homologue of mammalian RhoA small G-protein in the yeast Saccharomyces cerevisiae. Rho1p is required for bud formation and is localized at a bud tip or a cytokinesis site. We have recently shown that Bni1p is a potential target of Rho1p. Bni1p shares the FH1 and FH2 domains with proteins involved in cytokinesis or establishment of cell polarity. In S. cerevisiae, there is an open reading frame (YIL159W) which encodes another protein having the FH1 and FH2 domains and we have named this gene BNR1 (BNI1 Related). Bnr1p interacts with another Rho family member, Rho4p, but not with Rho1p. Disruption of BNI1 or BNR1 does not show any deleterious effect on cell growth, but the bni1 bnr1 mutant shows a severe temperature-sensitive growth phenotype. Cells of the bni1 bnr1 mutant arrested at the restrictive temperature are deficient in bud emergence, exhibit a random distribution of cortical actin patches and often become multinucleate. These phenotypes are similar to those of the mutant of PFY1, which encodes profilin, an actin-binding protein. Moreover, yeast two-hybrid and biochemical studies demonstrate that Bni1p and Bnr1p interact directly with profilin at the FH1 domains. These results indicate that Bni1p and Bnr1p are potential targets of the Rho family members, interact with profilin and regulate the reorganization of actin cytoskeleton.

The RHO1 gene encodes a homolog of the mammalian RhoA small GTP-binding protein in the yeast Saccharomyces cerevisiae. Rho1p is localized at the growth site and is required for bud formation. The RHO1(G22S, D125N) mutation is a temperature-sensitive and dominant negative mutation of RHO1, and a multicopy suppressor of RHO1(G22S, D125N), ROM7, was isolated. Nucleotide sequencing of ROM7 revealed that it is identical to the BEM4 gene (GenBank accession number L27816), although its physiological function has not yet been reported. Disruption of BEM4 resulted in the cold- and temperature-sensitive growth phenotypes, and cells of the deltabem4 mutant showed abnormal morphology, suggesting that BEM4 is involved in the budding process. The temperature-sensitive growth phenotype was suppressed by overexpression of RHO1, ROM2, which encodes a Rho1p-specific GDP/GTP exchange factor, or PKC1, which encodes a target of Rho1p. Moreover, glucan synthase activity, which is activated by Rho1p, was significantly reduced in the deltabem4 mutant. Two-hybrid and biochemical experiments revealed that Bem4p directly interacts with the nucleotide-free form of Rho1p and, to lesser extents, with the GDP- and GTP-bound forms of Rho1p, although Bem4p showed neither GDP/GTP exchange factor, GDP dissociation inhibitor, nor GTPase-activating protein activity toward Rho1p. These results indicate that Bem4p is a novel protein directly interacting with Rho1p and is involved in the RHO1-mediated signaling pathway.

The RHO1 gene encodes a homolog of the mammalian RhoA small GTP binding protein in the yeast Saccharomyces cerevisiae. Rho1p is localized at the growth site and is required for bud formation. Multicopy suppressors of a temperature-sensitive, dominant negative mutant allele of RHO1, RHO1(G22S, D125N), were isolated and named ROM (RHO1 multicopy suppressor). Rom1p and Rom2p were found to contain a DH (Dbl homologous) domain and a PH (pleckstrin homologous) domain, both of which are conserved among the GDP/GTP exchange proteins (GEPs) for the Rho family small GTP binding proteins. Disruption of ROM2 resulted in a temperature-sensitive growth phenotype, whereas disruption of both ROM1 and ROM2 resulted in lethality. The phenotypes of deltarom1deltarom2 cells were similar to those of deltarho1 cells, including growth arrest with a small bud and cell lysis. Moreover, the temperature-sensitive growth phenotype of deltarom2 was suppressed by overexpression of RHO1 or RHO2, but not of CDC42. The glutathione-S-transferase (GST) fusion protein containing the DH domain of Rom2p showed the lipid-modified Rholp-specific GDP/GTP exchange activity which was sensitive to Rho GDP dissociation inhibitor. These results indicate that Rom1p and Rom2p are GEPs that activate Rho1p in S.cerevisiae.

We examined the bacteria isolated from urine of patients in our department from 1988 though 1989. A total of 809 strains were isolated from the outpatients. They were 241 strains of gram-positive bacteria (29.8%). E. coli (32.0%) was isolated most frequently, followed by Enterococcus spp. (9.9%), Proteus group (7.4%), S. epidermidis (6.2%), P. aeruginosa (5.1%) and others. A total of 412 strains were isolated from the inpatients. They consisted of 173 strains of gram-positive bacteria (42.0%). Enterococcus spp. (17.0%) was isolated most frequently, followed by P. aeruginosa (12.6%), S. epidermidis (9.7%), E. coli (7.3%), S. aureus (6.6%) and others. Fewer P. aeruginosa, S. marcescens and Proteus group were isolated from the outpatients and fewer S. marcescens, E. coli and K. pneumoniae from inpatients than previously. More S. aureus were isolated abruptly from the inpatients and more E. coli were isolated from the outpatients than previously. E. cloacae, S. epidermidis, S. aureus and Corynebacterium spp. all isolated from inpatients showed lower antimicrobial sensitivity than those isolated from the outpatients.

We studied the etiology, diagnosis and management of 201 cases of urinary extravasation reported in the Japanese literature along with our five cases. Most of them were caused by urolithiasis and malignant tumors. Four of our five cases also presented with a ureter stone; two being cured by spontaneous stone passage within several days and the others being treated by ureterolithotomy or nephrectomy. The other case involving a ureter tumor was treated by nephroureterectomy with partial cystectomy. The clinical manifestations of urinary extravasation were distinguished as spontaneous peripelvic extravasation and spontaneous rupture of the renal pelvis and ureter. Performing an accurate and differential diagnosis of these cases, however, was difficult. We therefore propose a set of clinical diagnostic criteria based on our findings of X-ray examination and the macroscopic appearance seen during surgical treatment. We review the 201 reported cases along with our five cases of urinary extravasation and discuss their diagnostic procedures and treatment approaches.

An unusual case of seminal vesicle cysts associated with adult polycystic kidney disease (APKD) is presented. The magnetic resonance (MR) appearance of this rare entity has not been described before. A brief review of the literature is included and the role of MR imaging is discussed.

Magnetic resonance (MR) features of five primary malignant mesenchymal neoplasms (plasmocytoma, leiomyosarcoma, undifferentiated sarcoma, epithelioid hemangioendothelioma, and angiosarcoma) of the liver were reported. All tumors were hypointense on T1-weighted images and hyperintense on T2-weighted images. No halo and intravenous extension were noted. A target appearance was revealed in epithelioid hemangioendothelioma. MR findings of angiosarcoma were essentially the same as those of cavernous hemangiomas (markedly hyperintense with hypointense linear septa on T2-weighted images). MR findings of these rare hepatic malignancies were nonspecific, although they were quite different from those of typical hepatocellular carcinomas. This study suggested that MR differentiation of primary hepatic mesenchymal tumors from other common benign and malignant neoplasms was difficult; however, the number of studied cases was limited.

A case of contralateral ureteral metastasis from renal cell carcinoma is reported. A 52-year-old man underwent left nephrectomy for renal cell carcinoma of November 20, 1986. He was clinically asymptomatic for 4 years 8 months after the operation. He was admitted on August 14, 1991, because of right loin pain. Right retrograde pyelography and percutaneous pyelography showed a filling defect in the right ureter at the level of L3. After the right ureter was explored, the tumor lesion of ureter was resected and end to end anastomosis of the ureter was performed. Histopathologic examination showed a metastatic clear cell carcinoma consistent with a renal primary. The contralateral ureteral metastasis from renal cell carcinoma is very rare and only 15 cases have been reported previously.

An atypical case of multilocular cystic hemangioma is presented. A 4.5 cm multilocular cystic mass was incidentally found in a 66-year-old healthy woman on ultrasound screening. CT, MR imaging, and angiography were performed: however, the features that are characteristic of cavernous hemangioma were not obtained. The final diagnosis could not be made until surgery.

A case report of primary osteosarcoma of the bladder is herein presented. A 75-year-old man presented with asymptomatic macrohematuria. Cystoscopic examination revealed a large tumor with a broad base arisen on the anterior wall. Pelvic computed tomographic scan showed multiple calcifications in the tumor itself. Total cystectomy and ileal conduit were performed. Histopathological diagnosis was osteosarcoma. The patient died 10 weeks after surgery. Metastasis to lung, heart, lymphnode, ureter and peritoneum were identified by autopsy. Primary osteosarcoma of the bladder is a rare tumor, only 25 cases have been reported previously. The prognosis of this tumor is very poor. Nineteen of these patients died within 6 months.

We report a case of metastatic bladder tumor from gastric carcinoma. A 55-year old male patient was referred to our urological clinic with a complaint of frequent urination and voiding pain. He had undergone total gastrectomy for poorly differentiated adenocarcinoma, signet-ring cell type, 9 months earlier. Computed tomographic scan revealed a thick bladder and rectum wall all around. Punch biopsies from vesical and rectal wall revealed metastatic adenocarcinoma, signet-ring cell type. There were no other metastatic sites. Systemic chemotherapy was done with a combination of mitomycin-C, 5-fluorouracil and cytosine arabinoside. This chemotherapy was effective and complete remission was obtained at bladder and rectum. Six months after chemotherapy, peritoneal recurrence developed and he died 9 months after chemotherapy. However no recurrence of bladder tumor was detected. This was a quite rare case of metastatic bladder tumor characterized by good response to systemic chemotherapy.

Dense accumulation of Lipiodol in hepatic segmental parenchyma was studied by computed tomography (CT) after transarterial chemoembolization (TACE) for hepatic tumor. Six patients showed dense accumulation of Lipiodol in hepatic segmental parenchyma on CT two weeks after TACE. Four of the six showed parenchymal accumulation of Lipiodol as dense as that in a tumor at three weeks after TACE. Therefore, it was considered that evaluation with CT should be performed after one month or more in order to differentiate between Lipiodol accumulation in tumors and that in non-neoplastic liver parenchyma.

Operations on inpatients during the 15-year period from 1975 to 1989 were analyzed statistically. A total of 3,791 operations were performed at our Department of Urology, including 717 operations on the kidney, 316 operations on the ureter, 583 operations on the bladder, 811 operations on the prostate, 136 operations on the urethra, 1,097 operations on the scrotum, 43 operations on the adrenal gland, 19 operations on the retroperitoneal space and 69 operations on other organs.

A case of giant müllerian duct cyst is reported. The patient was a 27-year-old male, complaining of microscopic hematuria. A giant cystic abdominal mass was palpable. After screening examination including ultrasound tomography, intravenous pyelography, computed tomography and magnetic resonance-imaging, müllerian duct cyst was suspected. Operation for this cyst was performed with median incision. The cyst measured 25 x 21 x 14 cm. The surface as smooth and consistency was soft. Included fluid was slightly turbid and yellowish measuring 2,200 ml. This was considered to be the largest müllerian duct cyst case reported in the Japanese literature.

Balloon dilation of the prostatic urethra was performed for the management of benign prostatic hypertrophy. The patients selected were mainly high risk patients who were poor surgical candidates for transurethral resection of the prostate. Ten patients between 61 and 87 years old with a mean age of 77.8 years were treated. Of the 10 patients 6 had urinary retention. The procedures were performed under spinal anesthesia, using 75 Fr dilation balloon for 10 minutes twice at 3 atmospheres. In a couple of months after treatments, 5 patients showed improvement in both uroflowmetry and clinical symptoms. Three patients revealed improvement of clinical symptoms only and 2 were in vain. One year after treatment, 3 out of 6 patients had persistent improvement. Balloon dilation of prostatic urethra was safe and showed promising effectiveness for high risk patients.

Direct communication between portal branches and the hepatic vein [macroscopic intra-hepatic portal-hepatic venous shunt (IPHVS)] is a rare entity. We have recently studied five patients with this condition. Magnetic resonance imaging (MRI) clearly demonstrated in each case the portal-hepatic venous shunt due to "flow void." Multiple diffuse shunts were present in one case and a solitary shunt was demonstrated in the others. The solitary shunt was either tubular, focally dilated or racemose in configuration. The MRI findings and clinical significance of this rare entity are discussed.

Iodized-oil CT in a patient with chronic liver disease revealed focal accumulation of iodized oil in an exophytic mass. Single photon emission CT (SPECT) with [99mTc]phytate showed the existence of functioning Kupffer cells, excluding hepatocellular carcinoma. Biopsy revealed a regenerating nodule. Positive iodized-oil CT does not always indicate hepatoma. In such cases, SPECT with [99mTc]phytate will help to make a correct diagnosis.