We study the optimal retirement and consumption/investment choice of an infinitely‐lived economic agent with a time‐separable von Neumann–Morgenstern utility. A particular aspect of our problem is ...that the agent has a retirement option. Before retirement the agent receives labor income but suffers a utility loss from labor. By retiring, he avoids the utility loss but gives up labor income. We show that the agent retires optimally if his wealth exceeds a certain critical level. We also show that the agent consumes less and invests more in risky assets when he has an option to retire than he would in the absence of such an option.
An explicit solution can be provided by solving a free boundary value problem. In particular, the critical wealth level and the optimal consumption and portfolio policy are provided in explicit forms.
Screening a compound library of quinolinone derivatives identified compound 11a as a new P2X7 receptor antagonist. To optimize its activity, we assessed structure-activity relationships (SAR) at ...three different positions, R1, R2 and R3, of the quinolinone scaffold. SAR analysis suggested that a carboxylic acid ethyl ester group at the R1 position, an adamantyl carboxamide group at R2 and a 4-methoxy substitution at the R3 position are the best substituents for the antagonism of P2X7R activity. However, because most of the quinolinone derivatives showed low inhibitory effects in an IL-1β ELISA assay, the core structure was further modified to a quinoline skeleton with chloride or substituted phenyl groups. The optimized antagonists with the quinoline scaffold included 2-chloro-5-adamantyl-quinoline derivative (16c) and 2-(4-hydroxymethylphenyl)-5-adamantyl-quinoline derivative (17k), with IC50 values of 4 and 3 nM, respectively. In contrast to the quinolinone derivatives, the antagonistic effects of the quinoline compounds (16c and 17k) were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1β, from LPS/IFN-γ/BzATP-stimulated THP-1 cells (IC50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.
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•Quinoline derivatives were developed as P2X7 receptor antagonists.•We performed the introduction of various substituents at the R3 position of the quinoline structure.•Compounds 16c, 17b−c and 17h−k showed potent antagonistic effects (EtBr IC50 = 3–18 nM).•Also, compounds 16c, 17b−c and 17h−k exhibited highly potent functional activities (IL-1β IC50 = 7–33 nM).•16c has an acceptable in vitro anti-cancer activities against the glioblastoma cells, in which P2X7Rs are overexpressed.
PURPOSEA critical indicator of the overall survival of patients with high-grade glioma is the successful isolation of tumor mesenchymal stem-like cells (tMSLCs), which play important roles in glioma ...progression. However, attempts to isolate tMSLCs from surgical specimens have not always been successful, and the reasons for this remain unclear. Considering that the amount of surgical high-grade glioma specimens varies, we hypothesized that larger surgical specimens would be better for tMSLC isolation. MATERIALS AND METHODSWe assessed 51 fresh, high-grade glioma specimens and divided them into two groups according to the success or failure of tMSLC isolation. The success of tMSLC isolation was confirmed by plastic adherence, presenting antigens, tri-lineage differentiation, and non-tumorigenicity. Differences in characteristics between the two groups were tested using independent two sample t-tests, chi-square tests, or Kaplan-Meier survival analysis. RESULTSThe mean specimen weights of the groups differed from each other (tMSLC-negative group: 469.9±341.9 mg, tMSLC positive group: 546.7±618.9 mg), but the difference was not statistically significant. The optimal cut-off value of specimen weight was 180 mg, and the area under the curve value was 0.599. CONCLUSIONOur results suggested a minimum criterion for specimen collection, and found that the specimen amount was not deeply related to tMSLC detection. Collectively, our findings imply that the ability to isolate tMSLCs is determined by factors other than the specimen amount.
Receptor tyrosine kinase Mer (MerTK) has been shown to be highly expressed in Glioblastoma multiforme (GBM) in comparison to its healthy counterpart and is implicated in brain tumorigenesis. ...Clarifying the underlying mechanism of MerTK induced invasiveness would result in novel strategies to improve patient's response to chemotherapeutics. In vitro and in vivo assays were performed to examine the functional role of cancer stem sell (CSC) maintenance in MerTK associated invasiveness. In this article, we demonstrate that apart from GBM cells, MerTK is also upregulated in GBM stem-like cells and associated with an increased infiltrative potential of brain tumors in vivo. Silencing of MerTK suppressed the self-renewal of patient-derived GBM stem-like cells. The signaling mechanisms by which MerTK contributes to CSC maintenance have largely been obscure. Molecular analyses revealed that high expression of the signal transducer and activator of transcription 3 (STAT3)- Kirsten rat sarcoma viral oncogene homolog (KRAS) and proto-oncogene tyrosine-protein kinase SRC axis supports MerTK-induced CSC maintenance in GBM spheroids. Furthermore, a short-hairpin RNA-mediated MerTK knockdown effectively blocked invasiveness and N-cadherin expression in mouse xenografts. Collectively, our results uncover a critical function of MerTK in CSC maintenance. Considering the low basal level of MerTK expression in healthy brain cells, evaluation of MerTK as a therapeutic target should advance the research into better therapeutics for GBM.
Abstract The increasing demand for electric vehicles necessitates the development of cost‐effective, mass‐producible, long‐lasting, and highly conductive batteries. Making this kind of battery is ...exceedingly tricky. This study introduces an innovative fabrication technique utilizing a laser‐induced graphene (LIG) approach on commercial Kapton film to create hexagonal pores. These pores form vertical conduction paths for electron and ion transportation during lithiation and delithiation, significantly enhancing conductivity. The nongraphitized portion of the Kapton film makes it a binder‐less, free‐standing electrode, providing mechanical stability. Various analytical techniques, including scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), Raman spectroscopy, and atomic force microscopy (AFM) are utilized to confirm the transformation of a 3D porous graphene sheet from a commercial Kapton film. Cross‐sectional SEM images verify the vertical connections. The specific capacity of 581 mAh g −1 is maintained until the end, with 99% coulombic efficiency at 0.1C. This simple manufacturing method paves the pathway for future LIG‐based, cost‐effective, lightweight, mass‐producible, long‐lasting, vertically conductive electrodes for lithium‐ion batteries.
Optical clearing has emerged as a powerful tool for volume imaging. Although volume imaging with immunostaining have been successful in many protocols, yet obtaining homogeneously stained thick ...samples remains challenging. Here, we propose a method for label-free imaging of brain slices by enhancing the regional heterogeneity of the optical properties using the tissue clearing principle. We used FxClear, a method for delipidation of brain tissue, to retain a larger proportion of lipids at the white matter (WM). Furthermore, the embedding media affected the contrasts for the lipid-rich or extracellular matrix-rich areas, depending on their chemical properties. Thus, we tailored clearing conditions for the enhancement of the refractive indices (RIs) differences between gray and WM, or several pathological features. RI differences can be imaged using conventional light microscopy or optical coherence tomography. We propose that our protocol is simple, reliable, and flexible for label-free imaging, easily implementable to routine histology laboratory.
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•Label-free imaging via enhancing RI differences in optically cleared brain•Recognition of lipid- or ECM-rich regions using tailored protocols•Easy and affordable protocols using conventional optics
Physiology; Techniques in Neuroscience; Biology Experimental Methods
Studies have investigated biguanide-derived agents for the treatment of cancers and have reported their effects against tumorspheres (TSs). The purpose of this study was determining the effects of ...HL156A, a newly designed biguanide with improved pharmacokinetics, on glioblastoma TSs (GMB TSs) and assess the feasibility of this drug as a new line of therapy against glioblastoma, alone or combined with a conventional therapeutic agent, temozolomide(TMZ). The effects of HL156A, alone and combined with TMZ, on the stemness and invasive properties of GBM TSs and survival of orthotopic xenograft animals were assessed. HL156A, combined with TMZ, inhibited the stemness of GBM TSs, proven by neurosphere formation assay and marker expression. Three-dimensional collagen matrix invasion assays provided evidence that combined treatment inhibited invasive properties, compared with control and TMZ-alone treatment groups. TMZ alone and combined treatment repressed the expression of epithelial-mesenchymal transition-related genes. A gene ontology comparison of TMZ and combination-treatment groups revealed altered expression of genes encoding proteins involved in cellular adhesion and migration. Combined treatment with HL156A and TMZ showed survival benefits in an orthotopic xenograft mouse model. The inhibitory effect of combination treatment on the stemness and invasive properties of GBM TSs suggest the potential usage of this regimen as a novel strategy for the treatment of GBM.
Keratin is an important protein used in wound healing and tissue recovery. In this study, keratin was modified chemically with iodoacetic acid (IAA) to enhance its solubility in organic solvent. ...Poly(hydroxybutylate-
co
-hydroxyvalerate) (PHBV) and modified keratin were dissolved in hexafluoroisopropanol (HFIP) and electrospun to produce nanofibrous mats. The resulting mats were surface-characterized by ATR-FTIR, field-emission scanning electron microscopy (FE-SEM) and electron spectroscopy for chemical analysis (ESCA). The pure
m
-keratin mat was cross-linked with glutaraldehyde vapor to make it insoluble in water. The biodegradation test
in vitro
showed that the mats could be biodegraded by PHB depolymerase and trypsin aqueous solution. The results of the cell adhesion experiment showed that the NIH 3T3 cells adhered more to the PHBV/
m
-keratin nanofibrous mats than the PHBV film. The BrdU assay showed that the keratin and PHBV/
m
-keratin nanofibrous mats could accelerate the proliferation of fibroblast cells compared to the PHBV nanofibrous mats.
To compare gene expression profiles of placentas from preeclamptic and normal pregnancies.
We performed microarray experiments to analyze genome-wide expression profiling for 10 placentas from ...pregnant women with preeclampsia and 10 placentas from women who experienced noncomplicated pregnancies (CON), and to identify dysregulated signaling pathways as well as genes in preeclampsia. RT-PCR, real-time RT-PCR and/or immunofluorescence analyses were performed to validate the data obtained from microarray experiments.
Unsupervised hierarchical clustering showed heterogeneity of preeclampsia at the molecular levels, whereas expression profiles of preeclampsia are distinctly different from those of CON. A list of genes which are differentially expressed between preeclampsia and CON included well known preeclampsia markers, such as Flt-1, leptin, HTRA1 and SIGLEC6. Gene Set Enrichment Analysis, a pathway-oriented analysis method for expression profiles, provided evidence that a number of biological activities including pathways that regulate actin cytoskeleton, TGFβ signaling, oxidative phosphorylation, and proteasome activity were aberrantly either up-regulated or down-regulated in preeclampsia. RT-PCR and real-time-RT-PCR for genes contributing these biological pathways (gene sets) enriched in either CON or preeclampsia reinforced that these biological processes were systemically dysregulated in preeclampsia.
Genome-wide expression profiles of preeclampsia showed heterogeneous characteristics of preeclampsia at the molecular levels. Dysregulation of genes and biological pathways could contribute to abnormal behavior of preeclmapsia. Our results will help further understand underlying mechanisms by which preeclampsia affects placental physiology.
The isolation from brain tumors of tumor mesenchymal stem-like cells (tMSLCs) suggests that these cells play a role in creating a microenvironment for tumor initiation and progression. The clinical ...characteristics of patients with primary glioblastoma (pGBM) positive for tMSLCs have not been determined. This study analyzed samples from 82 patients with pGBM who had undergone tumor removal, pathological diagnosis, and isolation of tMSLC from April 2009 to October 2014. Survival, extent of resection, molecular markers, and tMSLC culture results were statistically evaluated. Median overall survival was 18.6 months, 15.0 months in tMSLC-positive patients and 29.5 months in tMSLC-negative patients (P=0.014). Multivariate cox regression model showed isolation of tMSLC (OR = 2.5, 95% CI = 1.1~5.6, P=0.021) showed poor outcome while larger extent of resection (OR = 0.5, 95% CI = 0.2~0.8, P=0.011) has association with better outcome. The presence of tMSLCs isolated from the specimen of pGBM is associated with the survival of patient.
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