Search

Supplementary Figures S1-S7 from p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

Single-crystal gallium nitride (GaN) thin films were grown using a graphene mask via multiple epitaxial lateral overgrowth (multiple-ELOG). During the growth process, the graphene mask self-decomposed to enable the emergence of a GaN film with a thickness of several hundred nanometres. This is in contrast to selective area growth of GaN using an SiO2 mask leading to the well known hexagonal-pyramid shape under the same growth conditions. The multiple-ELOG GaN had a single-crystalline wurtzite structure corresponding to the crystallinity of the GaN template, which was confirmed with electron backscatter diffraction measurements. An X-ray diffraction rocking curve of the asymmetric 102 reflection showed that the FWHM for the multiple-ELOG GaN decreased to 405 from 540′′ for the underlying GaN template. From these results, the self-decomposition of the graphene mask during ELOG was experimentally proven to be affected by the GaN decomposition rather than the high-temperature/H2 growth conditions.

The sensitivity of infrared (IR) imagers can be significantly improved by reducing the size of photodetectors down to the diffraction limit. Emerging low-dimensional material enable submicron photodetectors, which can be diffraction limited and lead to significant sensitivity improvement in the critical short-wave IR band. However, reaching this limit requires pixel sizes smaller than the metal bumps needed for hybridization to silicon readout chips. Such tiny fragile pixels are susceptible to damages due to the mechanical pressure applied during flip-chip bonding, degrading the number of functional camera pixels. Herein, we systematically characterize the influence of the detector size on the imager pixel yield. We then introduce strategies for improving the yield of sub-micron pixels from less than half of total pixels to more than 3/4 of them. While we used a top-down fabrication for our detectors, the developed method is also applicable to bottom-up fabrication methods to make highly sensitive IR cameras based on emerging low-dimensional material such as catalyst-assisted nanowires.

Metformin is one of the most effective therapies for treating type 2 diabetes and has been shown to also attenuate aging and age-related disorders. In this study, we explored the relationship between metformin and DNA damage repair in ionizing radiation (IR)-induced damage of human aortic endothelial cells (HAECs). Metformin treatment suppressed IR-induced senescence phenotypes, such as increased senescent-associated β-galactosidase (SA β-gal) activity and decreased tube formation and proliferation. Moreover, metformin increased BRCA1-associated RING domain protein 1 (BARD1) and RAD51 expression in both aging and IR-exposed cells. Metformin-treated cells exhibited higher levels of the BRCA1-BARD1-RAD51 complex during irradiation, even in the presence of compound C, an AMP-activated protein kinase inhibitor. BARD1 knockdown confirmed its critical role in metformin-mediated inhibition of endothelial senescence. Metformin increased blood vessel sprouting and decreased SA β-gal activity in mouse aortas. Collectively, our findings provide new insights into how metformin can prevent endothelial cell senescence by promoting BARD1-related DNA damage repair, suggesting that metformin may be an effective anti-aging agent and a promising therapeutic for protecting against radiation-induced cardiotoxicity.

Background: this study aimed to conduct a biological assessment of the potential exposure to carcinogenic substances in current semiconductor workers. Methods: A cross-sectional study was conducted on 306 semiconductor workers. The assessed biomarkers were as follows: (benzene) urine S-phenylmercapturic, trans,trans-muconic acid, blood benzene; (trichloroethylene) urine trichloroacetic acid; (2-ethoxyethanol) 2-ethoxyacetic acid; (arsine) urine arsenic3+, arsenic5+, monomethylarsonic, dimethylarsinic acid, arsenobetaine; (shift work) 6-hydroxymelatonin; (smoking) cotinine, and (radiation). The detection rate of these materials is defined as more than the biological exposure index (BEI) or the previous reference value. Results: Some workers exposed to trans,trans-muconic acid, trichloroacetic acid, and arsenic5+ showed high BEI levels. Generally, there was no difference according to job categories, and workers were suspected to be exposed to other sources. The melatonin concentration tended to decrease when working at night, and cotinine was identified as an excellent surrogate marker for smoking. In the case of radiation exposure, there was no significant difference in the number of stable chromosome translocation in 19 semiconductor workers. Their estimated radiation exposure level was below the limit of detection (LOD) or near the LOD level. Conclusion: In this study, most carcinogens were below the BEI level, but verification through re-measurement was needed for workers who were identified to have a high BEI level. For continuous monitoring, a prospective cohort is necessary to deal with the healthy worker effect and assess additional materials.

In this study, we proposed a strategy to fabricate vertically stacked subpixel (VSS) micro-light-emitting diodes (μ-LEDs) for future ultrahigh-resolution microdisplays. At first, to vertically stack the LED with different colors, we successfully adopted a bonding-interface-engineered monolithic integration method using SiO2/SiNx distributed Bragg reflectors (DBRs). It was found that an intermediate DBR structure could be used as the bonding layer and color filter, which could reflect and transmit desired wavelengths through the bonding interface. Furthermore, the optically pumped μ-LED array with a pitch of 0.4 μm corresponding to the ultrahigh-resolution of 63 500 PPI could be successfully fabricated using a typical semiconductor process, including electron-beam lithography. Compared with the pick-and-place strategy (limited by machine alignment accuracy), the proposed strategy leads to the fabrication of significantly improved high-density μ-LEDs. Finally, we systematically investigated the effects of surface traps using time-resolved photoluminescence (TRPL) and two-dimensional simulations. The obtained results clearly demonstrated that performance improvements could be possible by employing optimal passivation techniques by diminishing the pixel size for fabricating low-power and highly efficient microdisplays.

In recent years, research into implementing microdisplays for use in virtual reality and augmented reality has been actively conducted worldwide. Specifically, inorganic light-emitting diodes (LED)...

Monolithic 3-D integration has emerged as a promising technological solution for traditional transistor scaling limitations and interconnection bottleneck. The challenge we must overcome is a processing temperature limit for top side devices in order to ensure proper performance of bottom side devices. To solve this problem, we developed a low temperature III–V and Ge layer stacking process using wafer bonding and epitaxial lift-off, since these materials can be processed at a low temperature and provide extended opportunity/functionality (sensor, display, analog, RF, etc.) via heterogeneous integration. In this paper, we discuss technology for integrating III–V and Ge materials and its applicability to CMOS, thin film photodiodes, mid-infrared photonics platforms, and MicroLED display integration for creating the ultimate 3-D chip of the future.

The cardiotoxicity of various anticancer therapies, including radiotherapy, can lead to cardiovascular complications. These complications can range from damaging cardiac tissues within the irradiation field to increasing the long-term risks of developing heart failure, coronary artery disease, and myocardial infarction. We analyzed radiation-induced metabolites capable of mediating critical biological processes, such as inflammation, senescence, and apoptosis. Previously, by applying QTOF-MASS analysis to irradiated human fibroblasts, we identified that metabolite sets of lysophosphatidylcholine (LPC) were increased in these cells. In this study, radiation-induced LPC accumulation in human aortic endothelial cells (HAECs) increased reactive oxygen species (ROS) production and senescence-associated-beta-galactosidase staining, in addition to decreasing their tube-forming ability. Knockdown of lipoprotein-associated phospholipase A2 (Lp-PLA2) with small interfering RNA (siRNA) inhibited the increased LPC production induced by radiation, and reduced the radiation-induced cell damage produced by ROS and oxidized low-density lipoprotein (LDL). Lp-PLA2 depletion abolished the induction of proinflammatory factors, such as interleukin 1β, tumor necrosis factor-alpha, matrix metalloproteinase 2, and matrix metalloproteinase 9, as well as adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and E-selection. Likewise, we showed that Lp-PLA2 expression was upregulated in the vasculature of irradiated rat, resulting in increased LPC production and LDL oxidation. Our data demonstrate that radiation-induced LPC production is a potential risk factor for cardiotoxicity that is mediated by Lp-PLA2 activity, suggesting that LPC and Lp-PLA2 offer potential diagnostic and therapeutic approaches to cardiovascular damage during radiotherapy.

We introduce political tournament “participation/inclusion” games. Dominant strategies determine whether players choose to compete by enhancing economic performance. Unique Nash equilibria competitors win (only) inclusion as promotion candidates. We find empirical justification for such equilibria in Chinese province heads' periodic political tournaments/elections for promotion to the Communist Party politburo and government positions. We document pervasive tournament-synchronized corporate decision-making cyclicality. Firms enhance economic performance by increasing investments, taxes, and employment before elections. Cyclicality is dominantly driven by privately-owned enterprises, is weaker in economically/politically weak(strong) provinces. Political promotions, however, are not sensitive to corporate investments enhanced before tournaments but to long-run investments.

Procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD3), a membrane-bound homodimeric enzyme, hydroxylates lysyl residues in collagen-like peptides; however, its role in lung cancer is unknown. This study aimed to investigate the role of PLOD3 as a pro-metastatic factor and to elucidate the underlying mechanism. First, we experimentally confirmed the release of PLOD3 in circulation in animal models, rendering it a potential serum biomarker for lung cancer in humans. Thereafter, we investigated the effects of PLOD3 overexpression and downregulation on cancer cell invasion and migration in vitro and in vivo, using human lung cancer cell lines and a mouse tumor xenograft model, respectively. Further, PLOD3 levels were determined in lung tissue samples from lung cancer patients. Functional analyses revealed that PLOD3 interacts with STAT3, thereby expressing matrix metalloproteinases (MMP-2 and MMP-9) and with urokinase plasminogen activator (uPA) to enhance tumor metastasis. PLOD3 and the STAT3 pathway were significantly correlated in the metastatic foci of lung cancer patients; PLOD3–STAT3 levels were highly correlated with a poor prognosis. These results indicate that PLOD3 promotes lung cancer metastasis in a RAS-MAP kinase pathway-independent manner. Therefore, secreted PLOD3 serves as a potent inducer of lung cancer metastasis and a potential therapeutic target to enhance survival in lung cancer.

Excess exposure to ionizing radiation generates reactive oxygen species and increases the cellular inflammatory response by modifying various metabolic pathways. However, an investigation of metabolic perturbations and organ-specific responses based on the amount of radiation during the acute phase has not been conducted. In this study, high-resolution magic-angle-spinning (HR-MAS) NMR and solution NMR-based metabolic profiling were used to investigate dose-dependent metabolic changes in multiple organs and tissues--including the jejunum, spleen, liver, and plasma--of rats exposed to X-ray radiation. The organs, tissues, and blood samples were obtained 24, 48, and 72 h after exposure to low-dose (2 Gy) and high-dose (6 Gy) X-ray radiation and subjected to metabolite profiling and multivariate analyses. The results showed the time course of the metabolic responses, and many significant changes were detected in the high-dose compared with the low-dose group. Metabolites with antioxidant properties showed acute responses in the jejunum and spleen after radiation exposure. The levels of metabolites related to lipid and protein metabolism were decreased in the jejunum. In addition, amino acid levels increased consistently at all post-irradiation time points as a consequence of activated protein breakdown. Consistent with these changes, plasma levels of tricarboxylic acid cycle intermediate metabolites decreased. The liver did not appear to undergo remarkable metabolic changes after radiation exposure. These results may provide insight into the major metabolic perturbations and mechanisms of the biological systems in response to pathophysiological damage caused by X-ray radiation.

We employed a rat model system as a first step toward studying the influence of ionizing radiation on the parameters of the metabolite markers in the liver of rats exposed to X-ray at the dose of 6 Gy. We applied whole-body X-ray irradiation to the rat, and profiled metabolites by 2D nuclear magnetic resonance (NMR) spectroscopy to sort out candidate molecules that can be used to deduce the information needed. We identified 32 metabolites from rat liver extracts. Statistical analysis suggested that samples with or without X-ray irradiation and samples harvested 24 or 72 h after irradiation could approximately be divided into four quadrants of the principal component space. Combinatorial use of signals from characteristic metabolites could differentiate X-ray-irradiated samples from controls and, furthermore, samples collected 24 h after irradiation from those after 72 h. We hope that this work would form a base for treating radiation-poisoned patients in the future.

Human embryonic stem cell-derived mesenchymal stem cells (hE-MSCs) have greater proliferative capacity than other human mesenchymal stem cells (hMSCs), suggesting that they may have wider applications in regenerative cellular therapy. In this study, to uncover the anti-senescence mechanism in hE-MSCs, we compared hE-MSCs with adult bone marrow (hBM-MSCs) and found that hepatocyte growth factor (HGF) was more abundantly expressed in hE-MSCs than in hBM-MSCs and that it induced the transcription of RAD51 and facilitated its SUMOylation at K70. RAD51 induction/modification by HGF not only increased telomere length but also increased mtDNA replication, leading to increased ATP generation. Moreover, HGF-treated hBM-MSCs showed significantly better therapeutic efficacy than naive hBM-MSCs. Together, the data suggest that the RAD51-mediated effects of HGF prevent hMSC senescence by promoting telomere lengthening and inducing mtDNA replication and function, which opens the prospect of developing novel therapies for liver disease.

Monolithic 3D (M3D) integration has attracted lots of attentions to continue equivalent scaling by vertically stacking transistors [1]. It allows the reduction of the interconnect delay, resulting in reduction of the power consumption of the chip, which is the attractive driving force for M3D integration. Moreover, with M3D, many other components such as digital, analog, MEMS, sensors, etc. can be heterogeneously integrated together in a single chip to provide enhanced functionality (Fig. 1). In this context, M3D concept can have additional benefit by integrating two or more different materials [2]. Heterogeneous integration of different materials combined with M3D is more powerful, because each processes with different materials don't have to share same process step and sequence, allowing us more flexible process design and it naturally has many benefits from their advantageous physical properties.

In general, to realize full color, inorganic light-emitting diodes (LEDs) are diced from respective red-green-blue (RGB) wafers consisting of inorganic crystalline semiconductors. Although this conventional method can realize full color, it is limited when applied to microdisplays requiring high resolution. Designing a structure emitting various colors by integrating both AlGaInP-based and InGaN-based LEDs onto one substrate could be a solution to achieve full color with high resolution. Herein, we introduce adhesive bonding and a chemical wet etching process to monolithically integrate two materials with different bandgap energies for green and red light emission. We successfully transferred AlGaInP-based red LED film onto InGaN-based green LEDs without any cracks or void areas and then separated the green and red subpixel LEDs in a lateral direction; the dual color LEDs integrated by the bonding technique were tunable from the green to red color regions (530–630 nm) as intended. In addition, we studied vertically stacked subpixel LEDs by deeply analyzing their light absorption and the interaction between the top and bottom pixels to achieve ultra-high resolution.

Funding: FCT - Fundacao para a Ciencia e Tecnologia (UID/ECO/00124/2013 ) and POR Lisboa (LISBOA-01-0145-FEDER-007722) Existing literature emphasizes skills-based explanations for executive-firm matching, namely in the context of financial expertise. In contrast, our paper argues that informational concerns may also be relevant. We model a public firm with a project opportunity of uncertain quality, where long-run shareholders choose between hiring an operational manager or a financial expert. These managers are equally myopic, however financial experts are also privy to stock-market beliefs. Financial experts invest sub-optimally due to catering incentives, while operational managers tend to engage in signaling-driven overinvestment. We show that operational managers are preferred for low-NPV projects or when stock markets are well informed. authorsversion published

Mesenchymal stem cells (MSCs), which are multipotent and have self-renewal ability, support the regeneration of damaged normal tissue. A number of external stimuli promote migration of MSCs into peripheral blood and support their participation in wound healing. In an attempt to harness the potential beneficial effects of such external stimuli, we exposed human MSCs (hMSCs) to one such stimulus—low-dose ionizing radiation (LDIR)—and examined their biological properties. To this end, we evaluated differences in proliferation, cell cycle, DNA damage, expression of surface markers (CD29, CD34, CD90, and CD105), and differentiation potential of hMSCs before and after irradiation with γ-rays generated using a 137CS irradiator. At doses less than 50 mGy, LDIR had no significant effect on the viability or apoptosis of hMSCs. Interestingly, 10 mGy of LDIR increased hMSC viability by 8% (p

The surface of biodegradable chitosan nanofibers was functionalized with pristine amine groups and used for immobilization of substance-P, which mediates pain perception and regulates wound healing, inflammation, and angiogenesis. The objectives of this study were to develop substance-P immobilized chitosan nanofibers and to evaluate the biological effects of the immobilized substance-P. Under the same conditions, the amount of substance-P covalently immobilized on chitosan nanofibers was 72.5 ± 16.9 ng compared to 7.3 ± 2.2 ng in passively absorbed samples. Substance-P on chitosan nanofibers released slowly and promoted greater proliferation (∼1.4-fold) of human mesenchymal stem cells than pristine samples after 7 days in culture.

Nitrogen flow rate is one of the important growth parameters for the growth of group-III nitride nanowires in plasma-assisted molecular beam epitaxy. However, nitrogen flow rate has received less attention compared to the group-III metal fluxes since its effects are not as prominent as that of the metal fluxes. In this study, we investigated the effects of nitrogen flow rate on the morphology and composition of AlGaN nanowires. Reducing the nitrogen flow rate improved the structural uniformity and increased the Al composition. We present a composition change model and show that excess nitrogen suppresses Ga desorption by recombining the Ga atoms, thereby causing a change in the composition of AlGaN. It was confirmed that the influence of the nitrogen flow rate on the Al composition varied with the growth temperature. These results provide insights into the role of nitrogen flow rate on the growth of AlGaN nanowires and suggest that more sophisticated growth control is possible by considering the nitrogen flow rate.

We report hybrid n-ZnO/i-InGaN/p-GaN solar cells in which the n-GaN layer of n-GaN/i-InGaN/p-GaN solar cell was replaced with n-type ZnO. In this study, inverted structures were used for hybrid ZnO/nitride solar cells where p-type GaN was first grown on sapphire substrate, followed by i-InGaN and n-ZnO layers. The as-fabricated device showed high series resistance and low energy conversion efficiency due to the formation of damaged p-GaN region during dry etching. On the other hand, formation of microrods on the p-GaN eased the removal of the damaged p-GaN resulting in significantly lowered series resistance and enhanced energy conversion efficiency. (a) n-ZnO/i-InGaN/p-GaN solar cell structure without microrods, (b) n-ZnO/i-InGaN/p-GaN solar cell structure with microrods, and (c) magnified image of the dashed box on (b).

Three in vitro dose calibration curves for biodosimetry such as dicentric chromosome assay, fluorescence in situ hybridization (FISH) assay for translocation, and micronuclei (MNs) in binucleated cell assay were established after exposure to ionizing radiation. Peripheral blood lymphocyte samples obtained from healthy donors were irradiated with 60Co source at a dose rate of 0.5 Gy/min to doses of 0.1–6 Gy. The results from three in vitro dose calibration curves for biodosimetry were analyzed to understand the relationship among biodosimetry assay techniques. Our comparison demonstrates that there is a very strong positive correlation among the dicentric assay, FISH, and MNs analysis, and these three biodosimetry assays strongly support the in vitro dose reconstruction and the emergency preparedness of public or occupational radiation overexposure.

Clinical irradiation therapy for cancer could increase the risk of localized wound complications. This study was conducted to evaluate the potential use of a chitosan microparticle-pluronic F127 (CSMP-PF) hydrogel complex containing bioactive molecules, substance P and transforming growth factor-β1, to regeneratively repair skin damaged by local ionizing radiation (IR). The BALB/c/bkl mice were locally irradiated to their limbs with a single 40 Gy dose of Co-60 γ rays to induce a skin injury. The morphological characteristics of the chitosan microparticles were analysed by scanning electron microscopy. The amounts of bioactive molecules taken up and released by the CSMP-PF hydrogel complex were measured. Haematoxylin and eosin staining of IR-damaged skin showed acanthosis and hyperkeratosis in the epidermis; and damage to hair follicles/skin appendages and adipose tissue, as well as panniculus carnosus, in the dermis. Injection of the CSMP-PF hydrogel complex into IR-damaged skin resulted in skin repair, suggesting that the complex has potential for use in the regenerative repair of IR-damaged skin.

In this study, we have fabricated a blue-green color-tunable monolithic InGaN/GaN LED having a multi-junction structure with three terminals. The device has an n-p-n structure consisting of a green and a blue active region, i.e., an n-GaN / blue-MQW / p-GaN / green-MQW / n-GaN / Alsub2/subOsub3/substructure with three terminals for independently controlling the two active regions. To realize this LED structure, a typical LED consisting of layers of n-GaN, blue MQW, and p-GaN is regrown on a conventional green LED by using a metal organic chemical vapor deposition (MOCVD) method. We explain detailed mechanisms of three operation modes which are the green, blue, and cyan mode. Moreover, we discuss optical properties of the device.

The 3-dimensional (3D) printing technologies, referred to as additive manufacturing (AM) or rapid prototyping (RP), have acquired reputation over the past few years for art, architectural modeling, lightweight machines, and tissue engineering applications. Among these applications, tissue engineering field using 3D printing has attracted the attention from many researchers. 3D bioprinting has an advantage in the manufacture of a scaffold for tissue engineering applications, because of rapid-fabrication, high-precision, and customized-production, etc. In this review, we will introduce the principles and the current state of the 3D bioprinting methods. Focusing on some of studies that are being current application for biomedical and tissue engineering fields using printed 3D scaffolds.

Although much is known about interleukin (IL)-1β and its role as a key mediator of cartilage destruction in osteoarthritis, only limited information is available on IL-1β signaling in chondrocyte dedifferentiation. Here, we have characterized the molecular mechanisms leading to the dedifferentiation of primary cultured articular chondrocytes by IL-1β treatment. IL-1β or lipopolysaccharide, but not phorbol 12-myristate 13-acetate, retinoic acid, or epidermal growth factor, induced nicotinamide phosphoribosyltransferase (NAMPT) expression, showing the association of inflammatory cytokines with NAMPT regulation. SIRT1, in turn, was activated NAMPT-dependently, without any alteration in the expression level. Activation or inhibition of SIRT1 oppositevely regulates IL-1β-mediated chondrocyte dedifferentiation, suggesting this protein as a key regulator of chondrocytes phenotype. SIRT1 activation promotes induction of ERK and p38 kinase activities, but not JNK, in response to IL-1β. Subsequently, ERK and p38 kinase activated by SIRT1 also induce SIRT1 activation, forming a positive feedback loop to sustain downstream signaling of these kinases. Moreover, we found that the SIRT1-ERK complex, but not SIRT1-p38, is engaged in IL-1β-induced chondrocyte dedifferentiation via a Sox-9-mediated mechanism. JNK is activated by IL-1β and modulates dedifferentiation of chondrocytes, but this pathway is independent on NAMPT-SIRT1 signaling. Based on these findings, we propose that IL-1β induces dedifferentiation of articular chondrocytes by up-regulation of SIRT1 activity enhanced by both NAMPT and ERK signaling.

The Ras-related small GTP-binding protein RhoB is rapidly induced in response to genotoxic stresses caused by ionizing radiation. It is known that UV-induced RhoB expression results from the binding of activating transcription factor 2 (ATF2) via NF-Y to the inverted CCAAT box (-23) of the RhoB promoter. Here, we show that the association of c-Jun with the distal CCAAT box (-72) is primarily involved in UV-induced RhoB expression and p38 MAPK regulated RhoB induction through the distal CCAAT box. UV-induced RhoB expression and apoptosis were markedly attenuated by pretreatment with the p38 MAPK inhibitor. siRNA knockdown of RhoB, ATF2 and c-Jun resulted in decreased RhoB expression and eventually restored the growth of UV-irradiated Jurkat cells. In the reporter assay using luciferase under the RhoB promoter, inhibition of RhoB promoter activity by the p38 inhibitor and knockdown of c-Jun using siRNA occurred through the distal CCAAT box. Immunoprecipitation and DNA affinity protein binding assays revealed the association of c-Jun and p300 via NF-YA and the dissociation of histone deacetylase 1 (HDAC1) via c-Jun recruitment to the CCAAT boxes of the RhoB promoter. These results suggest that the activation of p38 MAPK primarily contributes to UV-induced RhoB expression by recruiting the c-Jun and p300 proteins to the distal CCAAT box of the RhoB promoter in Jurkat cells.

Female C57BL/6 mice were exposed to a single dose of protons or 60Co gamma rays at 20 mGy and 2 Gy, which represent the recommended limit for annual occupational exposure and the daily fractional dose for patients undergoing radiotherapy, respectively. A control group was not exposed to radiation. The number of peripheral blood, bone marrow, and spleen cells was assessed 24 h after radiation to investigate the marrow suppression. The number of lymphocytes and neutrophils in peripheral blood was significantly lower in mice exposed to the higher dose of radiation than in the nonirradiated mice. However, at a low dose of radiation, there were no discernable hematological effects. The frequency of micronuclei in bone marrow cells was increased only after the high dose of gamma radiation. Radiation-induced intestinal apoptosis was measured using terminal deoxynucleotide transferase labeling assay. The magnitude of damage was greater after gamma irradiation than after proton irradiation at the same dose. Among ...

The Ras-related small GTP-binding protein RhoB is known to be a pro-apoptotic protein and immediate-early inducible by genotoxic stresses. In addition, JNK activation is known to function in gamma-radiation-induced apoptosis. However, it is unclear how JNK activation and gamma-radiation-dependent RhoB induction are related. Here we verified the relationship between JNK activation and RhoB induction. RhoB induction by gamma-radiation occurred at the transcriptional level and transcriptional activation of RhoB was concomitant with an increase in RhoB protein. gamma-Radiation-induced RhoB expression was markedly attenuated by pretreatment with a JNK-specific inhibitor, SP600125, but not by a p38 MAPK inhibitor, SB203580. Inhibition of JNK caused a decrease in early apoptotic cell death that correlated with RhoB expression. However, PI3K inhibition had no significant effects, indicating that the AKT survival pathway was not involved. The siRNA knockdown of JNK resulted in a decrease in RhoB expression and the siRNA knockdown of RhoB restored cell growth even in the gamma-irradiated cells. These results suggest that RhoB regulation involves the JNK pathway and contributes to the early apoptotic response of Jurkat T cells to gamma-radiation.

An immediate challenge in the post-genomic era is to assign a biological functions to proteins unraveled by genome analysis. This report is based on studies conducted using Schizosaccharomyces pombe, a simple model organism, and presents various vector systems as tools for high-throughput functional analysis of human genes. We constructed S. pombe expression vectors for efficient cloning of genes via the Gateway system. We modified the pREP and pSLF series vectors, which are widely used for gene expression in S. pombe. The vectors constructed have a uniform backbone of S. pombe autonomously replicating sequence (ARS) elements with different selective markers, namely, urw4 (+) and Saccharomyces cerevisiae LEU2 complementing leul. These vectors contain 3 different strengths of the inducible promoter nmtl, which affect the expression levels of the cloned open reading frames (ORFs). Further, target proteins can be fused with an N-terminal or C-terminal tag such as triple hemagglutinin (3x HA), enhanced green fluorescent protein (EGFP), or Discosoma red fluorescent protein (DsRed). We tested the feasibility of the constructed vectors by using 3 human genes, namely, RAB18, SCC-112, and PTEN. Proper expression of tagged RAB18 was confirmed by western blot analysis. Further, localization of RAB18, SCC112, and PTEN was demonstrated. The constructed vectors can be utilized for high-throughput functional analysis of heterologous genes.

Functional suppression of spindle checkpoint protein activity results in apoptotic cell death arising from mitotic failure, including defective spindle formation, chromosome missegregation, and premature mitotic exit. The recently identified p31comet protein acts as a spindle checkpoint silencer via communication with the transient Mad2 complex. In the present study, we found that p31comet overexpression led to two distinct phenotypic changes, cellular apoptosis and senescence. Because of a paucity of direct molecular link of spindle checkpoint to cellular senescence, however, the present report focuses on the relationship between abnormal spindle checkpoint formation and p31comet-induced senescence by using susceptible tumor cell lines. p31comet-induced senescence was accompanied by mitotic catastrophe with massive nuclear and chromosomal abnormalities. The progression of the senescence was completely inhibited by the depletion of p21Waf1/Cip1 and partly inhibited by the depletion of the tumor suppressor protein p53. Notably, p21Waf1/Cip1 depletion caused a dramatic phenotypic conversion of p31comet-induced senescence into cell death through mitotic catastrophe, indicating that p21Waf1/Cip1 is a major mediator of p31comet-induced cellular senescence. In contrast to wild-type p31comet, overexpression of a p31 mutant lacking the Mad2 binding region did not cause senescence. Moreover, depletion of Mad2 by small interfering RNA induced senescence. Here, we show that p31comet induces tumor cell senescence by mediating p21Waf1/Cip1 accumulation and Mad2 disruption and that these effects are dependent on a direct interaction of p31comet with Mad2. Our results could be used to control tumor growth. (Mol Cancer Res 2009;7(3):371–82)

This paper provides evidence of the market segmentation of stock and options. We find that informed out-of-the money (OTM) option trading measure, which is publicly available, predicts the returns of underlying stock and its at-the-money (ATM) options, but not the returns of OTM options. Specifically, higher OTM put-call trading volume ratio predicts negative returns of stock and ATM calls while predicting positive returns of ATM puts. The results are robust in large stock and not driven by short-selling costs. Using the OTM put-call volume ratio, we propose an implementable investment strategy that offers 20 bp weekly risk-adjusted stock returns (i.e., about 10% annually). Our findings support the segmentation between stock and option markets and between the option contracts in the same class.

Using bid-level data from a large U.S. peer-to-peer lending platform, we document that an average lender has strong herding tendencies: capital flow to a listing increases exponentially as the listing attracts more capital. However, loans funded in explosive bidding auctions do not show superior performance, suggesting that herding does not improve capital allocation efficiency. Rather, herders amplify the effect of random early bidding on the listing's funding success and skew capital allocation in the cross-section of listings. In particular, all else equal, listings started at times of exogenously lower lender activity on the platform are less likely to be funded. In investor heterogeneity analysis, we find that propensity to follow or lead is a persistent investor characteristic and that leaders realize better performance. Overall, this study highlights an important non-fundamental factor of capital allocation in transparent credit markets.

Excess exposure to ionizing radiation generates reactive oxygen species and increases the cellular inflammatory response by modifying various metabolic pathways. However, an investigation of metabolic perturbations and organ-specific responses based on the amount of radiation during the acute phase has not been conducted. In this study, high-resolution magic-angle-spinning (HR-MAS) NMR and solution NMR-based metabolic profiling were used to investigate dose-dependent metabolic changes in multiple organs and tissues--including the jejunum, spleen, liver, and plasma--of rats exposed to X-ray radiation. The organs, tissues, and blood samples were obtained 24, 48, and 72 h after exposure to low-dose (2 Gy) and high-dose (6 Gy) X-ray radiation and subjected to metabolite profiling and multivariate analyses. The results showed the time course of the metabolic responses, and many significant changes were detected in the high-dose compared with the low-dose group. Metabolites with antioxidant properties showed acute responses in the jejunum and spleen after radiation exposure. The levels of metabolites related to lipid and protein metabolism were decreased in the jejunum. In addition, amino acid levels increased consistently at all post-irradiation time points as a consequence of activated protein breakdown. Consistent with these changes, plasma levels of tricarboxylic acid cycle intermediate metabolites decreased. The liver did not appear to undergo remarkable metabolic changes after radiation exposure. These results may provide insight into the major metabolic perturbations and mechanisms of the biological systems in response to pathophysiological damage caused by X-ray radiation.