Search

Liver fibrosis is a reversible wound-healing process that is protective in the short term, but prolonged fibrotic responses lead to excessive accumulation of extracellular matrix components that suppresses hepatocyte regeneration, resulting in permanent liver damage. Upon liver damage, nonparenchymal cells including immune cells and hepatic stellate cells (HSCs) have crucial roles in the progression and regression of liver fibrosis. Here, we report differential roles of the glucocorticoid receptor (GR), acting in immune cells and HSCs, in liver fibrosis. In the carbon tetrachloride hepatotoxin-induced fibrosis model, both steroidal and nonsteroidal GR ligands suppressed expression of fibrotic genes and decreased extracellular matrix deposition but also inhibited immune cell infiltration and exacerbated liver injury. These counteracting effects of GR ligands were dissociated in mice with conditional GR knockout in immune cells (GRLysM) or HSC (GRhGFAP): the impacts of dexamethasone on immune cell infiltration and liver injury were totally blunted in GRLysM mice, whereas the suppression of fibrotic gene expression was diminished in GRhGFAP mice. The effect of GR activation in HSC was further confirmed in the LX-2 HSC cell line, in which antifibrotic effects were mediated by GR ligand inhibition of Sma and mad-related protein 3 (SMAD3) expression. We conclude that GR has differential roles in immune cells and HSCs to modulate liver injury and liver fibrosis. Specific activation of HSC-GR without alteration of GR activity in immune cells provides a potential therapeutic approach to treatment of hepatic fibrosis.

Recently computer-aided technology has been widely used in dentistry. DENTCA CAD/CAM denture system (DENTCA Inc.), one of CAD/CAM systems for fabricating complete denture, tries to collect and store all of a patient`s information at the first visit. This system aims to deliver denture at the second visit through utilizing the CAD/CAM software to access the stored data for designing the 3D denture model. The 3 dimensional (3D) denture will then be fabricated with 3D printer. Many case reports have evaluated clinical application of CAD/CAM system for fabricating complete dentures. This case report is about fabricating of complete dentures using DENTCA system and conventional method in same patient. With two cases, usefulness and limitation of DENTCA system could be evaluated.

// Dong Geon Kim 1, 2 , Kang Ho Kim 2 , Yun Jee Seo 2 , Heekyoung Yang 2, 3 , Eric G. Marcusson 6 , Eunju Son 2, 4 , Kyoungmin Lee 1, 2 , Jason K. Sa 1, 2 , Hye Won Lee 1, 2, 5 , Do-Hyun Nam 1, 2, 3 1 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea 2 Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea 3 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Urology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea 6 Providence Therapeutics, Calgary, Canada Correspondence to: Do-Hyun Nam, email: nsnam@skku.edu Keywords: anti-miR, glioblastoma, intratumoral injection, intraventricular injection, delivery efficiency Received: December 03, 2015 Accepted: March 28, 2016 Published: April 19, 2016 ABSTRACT Small non-coding RNAs called miRNAs are key regulators in various biological processes, including tumor initiation, propagation, and metastasis in glioblastoma as well as other cancers. Recent studies have shown the potential for oncogenic miRNAs as therapeutic targets in glioblastoma. However, the application of antisense oligomers, or anti-miRs, to the brain is limited due to the blood-brain barrier (BBB), when administered in the traditional systemic manner. To induce a therapeutic effect in glioblastoma, anti-miR therapy requires a robust and effective delivery system to overcome this obstacle. To bypass the BBB, different delivery administration methods for anti-miRs were evaluated. Stereotaxic surgery was performed to administer anti-Let-7 through intratumoral (ITu), intrathecal (ITh), and intraventricular (ICV) routes, and each method’s efficacy was determined by changes in the expression of anti-Let-7 target genes as well as by immunohistochemical analysis. ITu administration of anti-miRs led to a high rate of anti-miR delivery to tumors in the brain by both bolus and continuous administration. In addition, ICV administration, compared with ITu administration, showed a greater distribution of the miR across entire brain tissues. This study suggests that local administration methods are a promising strategy for anti-miR treatment and may overcome current limitations in the treatment of glioblastoma in preclinical animal models.

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection., Neonatal cholestasis is a result of elevated bile acid levels, and is associated with mutations in genes regulating bile acid homeostasis. Here the authors identify mutations in the bile acid sensing farnesoid X receptor in four individuals with neonatal cholestasis from two unrelated families.

In this study, we investigated the effects of increasing levels of palm kernel meal (PKM) in diets containing β-mannanase on growth performance, nutrient digestibility, and pork quality in growing-finishing pigs. One hundred twenty pigs [(Yorkshire × Landrace) × Duroc] with 29.68 ± 0.17 kg BW] were allotted to 5 dietary treatments with 4 pigs per pen and 6 replicates per treatment on the basis of sex and BW. These dietary treatments were: NC (negative control; corn-soybean meal-based diet), PC (positive control; basal diet + 0.10% β-mannanase), PKM6 (diet containing 6% PKM + 0.10% β-mannanase), PKM12 (diet containing 12% PKM + 0.10% β-mannanase), and PKM18 (diet containing 18% PKM + 0.10% β-mannanase). The BW was linearly decreased as the dietary inclusion level of PKM increased in early finishing phase (linear, P

Background & aims Despite advances in gene editing technologies, generation of tissue-specific knockout mice is time-consuming. We used CRISPR/Cas9-mediated genome editing to disrupt genes in livers of adult mice in just a few months, which we refer to as somatic liver knockouts. Methods In this system, Fah–/– mice are given hydrodynamic tail vein injections of plasmids carrying CRISPR/Cas9 designed to excise exons in Hpd; the Hpd-edited hepatocytes have a survival advantage in these mice. Plasmids that target Hpd and a separate gene of interest can therefore be used to rapidly generate mice with liver-specific deletion of nearly any gene product. Results We used this system to create mice with liver-specific knockout of argininosuccinate lyase, which develop hyperammonemia, observed in humans with mutations in this gene. We also created mice with liver-specific knockout of ATP binding cassette subfamily B member 11, which encodes the bile salt export pump. We found that these mice have a biochemical phenotype similar to that of Abcb11–/– mice. We then used this system to knock out expression of 5 different enzymes involved in drug metabolism within the same mouse. Conclusions This approach might be used to develop new models of liver diseases and study liver functions of genes that are required during development.

Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.

Application's memory footprints are growing exponentially due to an increase in their data set and additional software layer. Modern RDMA capable networks such as InfiniBand and Myrinet with low latency and high bandwidth provide us a new vision to utilize remote memory. Remote idle memory can be exploited to improvement performance of memory intensive applications on individual nodes. Network swapping will be faster than traditional swapping to local disk. In this paper, we design a remote memory system for remote memory utilization in InfiniBand clusters. We present the architecture, communication method and algorithm of InfiniBand Block Device (IBD), which is implemented as loadable kernel module for version 3.5.0-45 of the Linux kernel. Especially, we discuss design issues transfer pages to remote memory. Our experiments show that IBD can bring more performance gain for applications whose working sets are larger than the local memory on a node but smaller than idle memory available on the cluster.

The nuclear receptors farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP; NR0B2) play crucial roles in bile acid homeostasis. Global double knockout of FXR and SHP signaling (DKO) causes severe cholestasis and liver injury at early ages. Here, we report an unexpected beneficial impact on glucose and fatty acid metabolism in aged DKO mice, which show suppressed body weight gain and adiposity when maintained on normal chow. This phenotype was not observed in single Fxr or Shp knockouts. Liver-specific Fxr/Shp double knockout mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance, and accelerated fatty acid use. In both DKO and liver-specific Fxr/Shp double knockout livers, these metabolic phenotypes were associated with altered expression of fatty acid metabolism and autophagy-machinery genes. Loss of the hepatic FXR/SHP axis reprogrammed white and brown adipose tissue gene expression to boost fatty acid usage. Conclusion: Combined deletion of the hepatic FXR/SHP axis improves glucose/fatty acid homeostasis in aged mice, reversing the aging phenotype of body weight gain, increased adiposity, and glucose/insulin tolerance, suggesting a central role of this axis in whole-body energy homeostasis. (Hepatology 2017;66:498–509).

The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.

Background: The liver undergoes major changes in substrate utilization and metabolic output over the daily feeding and fasting cycle. These changes occur acutely in response to hormones such as insulin and glucagon, with rapid changes in signaling pathways mediated by protein phosphorylation and other post-translational modifications. They are also reflected in chronic alterations in gene expression in response to nutrient-sensitive transcription factors. Among these, the nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator activated receptor α (PPARα) provide an intriguing, coordinated response to maintain energy balance in the liver. FXR is activated in the fed state by bile acids returning to the liver, while PPARα is activated in the fasted state in response to the free fatty acids produced by adipocyte lipolysis or possibly other signals. Key Messages: Previous studies indicate that FXR and PPARα have opposing effects on each other's primary targets in key metabolic pathways including gluconeogenesis. Our more recent work shows that these 2 nuclear receptors coordinately regulate autophagy: FXR suppresses this pathway of nutrient and energy recovery, while PPARα activates it. Another recent study indicates that FXR activates the complement and coagulation pathway, while earlier studies identify this as a negative target of PPARα. Since secretion is a very energy- and nutrient-intensive process for hepatocytes, it is possible that FXR licenses it in the nutrient-rich fed state, while PPARα represses it to spare resources in the fasted state. Energy balance is a potential connection linking FXR and PPARα regulation of autophagy and secretion, 2 seemingly unrelated aspects of hepatocyte function. Conclusions: FXR and PPARα act coordinately to promote energy balance and homeostasis in the liver by regulating autophagy and potentially protein secretion. It is quite likely that their impact extends to additional pathways relevant to hepatic energy balance, and that these pathways will in turn interface with other well-known nutrient-responsive mechanisms of energy control.

Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors peroxisome proliferator-activated receptor-α (PPARα) and farnesoid X receptor (FXR) are activated in the fasted and fed liver, respectively. Here we show that both PPARα and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (Ppara(-/-), also known as Nr1c1(-/-)) mice, which are partially defective in the induction of autophagy by fasting. Pharmacological activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (Fxr(-/-), also known as Nr1h4(-/-)) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.

We present a hypervisor design that can be applied to any commercial 64-bit Android devices without support of set makers. We achieved the portability by using pure software virtualization while preserving high performance. The contribution of the design is to put the guest OS and the hypervisor together into a single address space which results in avoiding the address space compression problem and reducing major virtualization costs, using 32-bit compatible mode. The design using the single address space makes the hypervisor simple and run fast even with pure software technologies. Prototypical implementation of the design is composed of one kernel module and one user-level program managing virtual machines for Android OS. We have evaluated our design on a commercial mobile phone, Nexus 6P. Since any Android device allows inserting kernel modules and installing user programs on it, we think that our hypervisor can be utilized on any 64-bit ARM-based mobile phones.

Glioblastoma (GBM) is the most lethal and common type of primary brain tumor. Recent evidence suggests that a subpopulation of GBM cells (glioblastoma stem cells [GSCs]) is critical for tumor progression, invasion, and therapeutic resistance. We and others have demonstrated that MET, a receptor tyrosine kinase, positively regulates the stemness phenotype and radioresistance of GSCs. Here, we interrogated the downstream effector pathways of MET signaling in GSCs.We have established a series of GSCs and xenograft tumors derived from freshly dissociated specimens from patients with GBM and characterized a subpopulation enriched with MET activation (MET(high/+)). Through global expression profiling and subsequent pathways analysis, we identified signaling pathways that are enriched in MET(high/+) populations, one of which is Wnt/β-catenin signaling pathway. To determine molecular interaction and the biological consequences of MET and Wnt/β-catenin signaling, we used pharmacological and shRNA-mediated genetic inhibition and performed various molecular and cellular analyses, including flow cytometry, immunohistochemistry, and clonogenicity assays.We found that Wnt/β-catenin signaling is highly active in MET(high/+) cells, compared with bulk tumor cells. We also showed that Wnt/β-catenin signaling activities in GBM are directly modulated by the addition of ligand-mediated MET activation or MET inhibition. Furthermore, the ectopic expression of active-β-catenin (S37A and S45Y) rescued the phenotypic effects caused by MET inhibition.These data suggest that Wnt/β-catenin signaling is a key downstream effector of MET signaling and contributes to the maintenance of GSC and GBM malignancy.

Glioblastoma (GBM) patients have dismal median survival even with the most rigorous treatments currently available. Radiotherapy is the most effective non-surgical therapy for GBM patients; however, patients succumb due to tumor recurrence within a year. To develop a curative therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance in GBM. Towards this goal, we developed an in vivo orthotopic GBM model system that mimics the radiation response of human GBM, using both established-GBM cell line and patient-derived freshly dissociated GBM specimen. In-vivo ionizing radiation (IR) treatment prolonged the survival of mice with intracranical tumor derived from U373MG, but failed to prevent tumor recurrence. U373MG and GBM578 cells isolated after in-vivo IR (U373-IR and 578-IR) were more clonogenic and enriched with stem cell-like characteristics, compared with mock-treated control tumor cells. Transcriptomic analyses and quantitative real-time reverse-transcription PCR analyses using these matched GBM cells before and after radiation treatment revealed that Wnt pathways were preferentially activated in post-IR GBM cells. U373-IR cells and 578-IR were enriched with cells positive for both active β-catenin (ABC) and Sox2 population, and this subpopulation was further increased after additional in-vitro radiation treatment, suggesting that radiation resistance of GBM is mediated due, in part, to the activation of stem cell-associated pathways including Wnt. Finally, pharmacological and siRNA inhibition of Wnt pathway significantly decreased the survival and clonogenicity of GBM cells and reduced their ABC(+)/Sox2(+) population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.

Transparent conducting films having a hybrid structure of GZO/Metal/GZO were prepared on glass substrates by sequential deposition using DC magnetron sputtering. Silver, copper, aluminum and zinc thin films were used as the intermediate metal layers in the hybrid structure. The electrical and optical properties of hybrid transparent conducting films were investigated with varying the thickness of metal layer or GZO layers. With increasing the metal thickness, hybrid films showed a noticeable improvement of the electrical conductivity, which is mainly dependent on the electrical property of the metal layer. GZO(40 nm)/Ag(10 nm)/GZO(40 nm) film exhibits a resistivity of 5.2×10 Ω·cm with an optical transmittance of 82.8%. For the films with Zn interlayer, only marginal reduction in the resistivity was observed. Furthermore, unlike other metals, hybrid films with Zn interlayer showed a decrease in the resistivity with increasing the GZO thickness. The optimal thickness of GZO layer for anti-reflection effect at a given thickness of metal (10 nm) was found to be critically dependent on the refractive index of the metal. In addition, x-ray diffraction analysis showed that the insertion of Ag layer resulted in the improvement of crystallinity of GZO films, which is beneficial for the electrical and optical properties of hybrid-type transparent conducting films.

An investigation of the surface and the electrical properties of inductively-coupled plasma (ICP)etched N-face n-GaN is reported. Furthermore, a method for reducing the Ohmic contact resistance on plasma-damaged N-face n-GaN is proposed. The I−V characteristics show that the Cl2 flow rate used for the ICP etching has a strong influence on the Ohmic behavior of the etched N-face n-GaN. We also found that the surfaces of the ICP-etched N-face n-GaN were damaged by increasing the Cl2 flow rate, resulting in deteriorating Ohmic behavior. However, the plasma damage caused by the ICP etching could be removed by using a KOH etching process, which resulted in a decreased contact resistance.

Liver X receptor (LXR) is a ligand-activated transcription factor that plays important roles in cholesterol and lipid homeostasis. However, ligand-induced posttranslational modification of LXR is largely unknown. Here, we show that ligand-free LXRα is rapidly degraded by ubiquitination. Without ligand, LXRα interacts with an ubiquitin E3-ligase protein complex containing breast and ovarian cancer susceptibility 1 (BRCA1)-associated RING domain 1 (BARD1). Interestingly, LXR ligand represses ubiquitination and degradation of LXRα, and the interaction between LXRα and BARD1 is inhibited by LXR ligand. Consistently, T0901317, a synthetic LXR ligand, increased the level of LXRα protein in liver. Moreover, overexpression of BARD1/BRCA1 promoted the ubiquitination of LXRα and reduced the recruitment of LXRα to the target gene promoters, whereas BARD1 knockdown reversed such effects. Taken together, these data suggest that LXR ligand prevents LXRα from ubiquitination and degradation by detaching BARD1/BRCA1, which might be critical for the early step of transcriptional activation of ligand-stimulated LXRα through a stable binding of LXRα to the promoters of target genes.

Liver X receptor (LXR)α and LXRβ play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic β-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced β-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in β-cells as a possible cause of β-cell lipotoxicity, a key step in the development of type 2 diabetes.

We propose three different photoconductive antenna designs applicable as efficient THz receiver and investigate their detection properties. The experimental results showing different characteristics of spectral sensitivity and gain agree very well with the theoretical prediction.

In this unit, we describe two protocols for analyzing cell cycle status using flow cytometry. The first is based on the simultaneous analysis of proliferation specific marker (Ki-67) and cellular DNA content, which discriminates resting/quiescent cell populations (G0 cell) and quantifies cell cycle distribution (G1, S or G2/M, respectively). The second is based on differential staining of DNA and RNA through co-staining of Hoechst 33342 and Pyronin Y, which is also useful to identify G0 cells from G1 cells. Along with these methods for analyzing cell cycle status, we outline the basics of two additional methods for cell proliferation assays and recent updates of newly-developed fluorophores, which allows multiplex analysis of cell cycle status, cell proliferation and a gene of interest using flow cytometry.

Pyrite and other iron sulfides are readily oxidized by dissolved oxygen in aqueous phase, producing acidity and Fe(2+), which causes significant environmental problems. Applications of surface coating agents (Na2SiO3 and KH2PO4) were conducted at Boeun (Chungbuk, South Korea) outcrop site, and their efficiencies to inhibit the oxidation of sulfide minerals were monitored for a long-term period (449 days). The rock sample showed positive Net Acid Production Potential (NAPP = 20.23) and low Net Acid Generation pH (NAGpH = 2.42) values, suggesting that the rock sample was categorized in the potential acid-forming group. For the monitored time period (449 days), field study results showed that the application of Na2SiO3 effectively inhibited the pyrite oxidation as compared to KH2PO4. Na2SiO3 as a surface coating agent maintained pH 5-6 and reduced oxidation of pyrite surface up to 99.95 and 97.70 % indicated by Fe(2+) and SO4 (2-) release, respectively. The scanning electron microscope and energy-dispersive X-ray spectrometer analysis indicated that the morphology of rock surface was completely changed attributable to formation of iron silicate coating. The experimental results suggested that the treatment with Na2SiO3 was highly effective and it might be applicable on field for inhibition of iron sulfide oxidation.

A widely tunable multi-channel grating cavity laser is proposed and experimentally demonstrated. The device is implemented in Littman configuration with an echelle grating based on Rowland circle construction and realized by monolithically integrating all elements in an InP substrate. Lasing wavelength is selected by turning on an amplifier and the appropriate channel element in the array, and it is tuned by controlling light deflection electrically. The 6-channel device exhibits a tuning range of about 50 nm with a side mode suppression ratio of more than 30 dB. This is accomplished by adjusting the applied current of the dispersive element and phase control section.

All-optical wavelength conversion at 10 Gb s−1 is demonstrated in a Mach–Zehnder interferometric wavelength converter (MZI-WC) module with monolithically integrated SOA preamplifiers and tapered-edge multimode interference couplers (TMMIs). A conventional buried-type 1 × 2 MMI coupler exhibits a minimal excess loss of 0.43 dB and a reflectivity of 5.1 × 10−4 (LMMI = 172 µm, WMMI = 12 µm). We adapt the 1 × 2 TMMI in the MZI-WC to improve back-reflection and poor uniformity, which is a major problem of conventional MMI and Y-branch. A good performance of the MZI-WC monolithically integrated with TMMI and SOA preamplifiers at 10 Gb s−1 is obtained with clear eye patterns, and a power penalty below 1.5 dB at a 10−9 bit error rate over the whole C band (45 nm span) is obtained. The dynamic input power range is enhanced up to 11.3 dB by adjusting only the injection current of the SOA preamplifier.

Specific cell type differentiation is driven by programmed regulation of gene expression, which is the result of coordinated modulation of the transcription machinery and chromatin-remodeling factors. We present evidence here that the down-regulation of histone deacetylases is an important process during adipocyte differentiation. In 3T3-L1 cells, histone hyperacetylation was selectively induced at the promoter regions of adipogenic genes during adipocyte differentiation. Interestingly, this was accompanied by a dramatic decrease in the expression level of several histone deacetylases including HDAC1, -2, and -5 and a reduction in overall histone deacetylase enzyme activity. Inhibition of histone deacetylase activity using sodium butyrate resulted in stimulation of adipogenic gene expression and adipocyte differentiation. Consistently, HDAC1 knock-down promoted adipogenesis whereas HDAC1 overexpression attenuated adipocyte differentiation in 3T3-L1 cells. Together, these results suggest that the regulation of not only adipogenic transcription factors, but also chromatin-modifying enzymes is crucial for the execution of bona fide adipogenesis.

Adipocyte determination- and differentiation-dependent factor 1 (ADD1) plays important roles in lipid metabolism and insulin-dependent gene expression. Because insulin stimulates carbohydrate and lipid synthesis, it would be important to decipher how the transcriptional activity of ADD1/SREBP1c is regulated in the insulin signaling pathway. In this study, we demonstrated that glycogen synthase kinase (GSK)-3 negatively regulates the transcriptional activity of ADD1/SREBP1c. GSK3 inhibitors enhanced a transcriptional activity of ADD1/SREBP1c and expression of ADD1/SREBP1c target genes including fatty acid synthase (FAS), acetyl-CoA carboxylase 1 (ACC1), and steroyl-CoA desaturase 1 (SCD1) in adipocytes and hepatocytes. In contrast, overexpression of GSK3beta down-regulated the transcriptional activity of ADD1/SREBP1c. GSK3 inhibitor-mediated ADD1/SREBP1c target gene activation did not require de novo protein synthesis, implying that GSK3 might affect transcriptional activity of ADD1/SREBP1c at the level of post-translational modification. Additionally, we demonstrated that GSK3 efficiently phosphorylated ADD1/SREBP1c in vitro and in vivo. Therefore, these data suggest that GSK3 inactivation is crucial to confer stimulated transcriptional activity of ADD1/SREBP1c for insulin-dependent gene expression, which would coordinate lipid and glucose metabolism.

We propose a filter-free wavelength conversion using a Mach-Zehnder interferometer with monolithically integrated 2×2 multimode interference semiconductor optical amplifiers (MMI-SOAs). The device has been optimized by considering a non-homogeneous carrier distribution due to the self-imaging properties of the MMI-SOA. Static measurements show an extinction ratio of up to 18 dB and an input signal rejection ratio of up to 20 dB. Keywords: Wavelength conversion, semiconductor optical amplifier, March-Zehnder interferometer, cross-phase modulation.

We demonstrated monolithic integration of a continuous wave probe source consisting of a loss-coupled distributed feedback laser diode (DFB LD) and a Mach–Zehnder interferometric wavelength converter. The integrated device was fabricated using a modified buried ridge stripe (BRS) structure with an undoped InP clad layer on the top of a passive waveguide to reduce high propagation loss. A propagation loss in the passive waveguide as low as 5.29 ± 0.92 dB cm−1 was achieved. For the first time, wavelength conversion at 10 Gb s−1 was achieved with an extinction ratio of 7 dB and a power penalty of 2.8 dB at a 10−9 bit error rate. The proposed BRS structure is very useful for fabrication of photonic integrated circuits consisting of monolithic integration of active and passive waveguides.

SUMMARY The Virtual Interface Architecture (VIA) is an industrystandard user-level communication architecture for system area networks. The VIA provides a protected, directly-accessible interface to a network hardware, removing the operating system from the critical communication path. In this paper, we design and implement a user-level Sockets layer over VIA, named SOVIA (Sockets Over VIA). Our objective is to use the SOVIA layer to accelerate the existing Sockets-based applications with a reasonable effort and to provide a portable and high-performance communication library based on VIA to application developers. SOVIA realizes comparable performance to native VIA, showing a minimum one-way latency of 10.5 µs and a peak bandwidth of 814 Mbps on Giganet’s cLAN. We have shown the functional compatibility with the existing Sockets API by porting File Transfer Protocol (FTP) and Remote Procedure Call (RPC) applications over the SOVIA layer. Compared to the Giganet’s LAN Emulation (LANE) driver which emulates TCP/IP inside the kernel, SOVIA easily doubles the file transfer bandwidth in FTP and reduces the latency of calling an empty remote procedure by 77% in RPC applications. Copyright c � 2003 John Wiley & Sons, Ltd.

We confirmed the potential of an aluminum nitride (AlN) substrate to be used as a bonding material for the high current operation of vertical light-emitting diodes (VLEDs). For the electrical connection to the top and bottom of the AlN substrate, via-holes were formed by laser drilling and then filled with Ag, which plays a role in improving the thermal dissipation from the VLEDs. The forward voltage of the fabricated AlN-bonded VLEDs was 3.54 V at 350 mA, which is similar to that of the Si-bonded VLEDs. It was also found that the light output power of the AlN-bonded VLEDs increased steadily with increasing injection current up to 1 A, while that of the Si-bonded VLEDs started to decrease at around 850 mA. In addition, the thermal resistance of the AlN-bonded VLEDs was significantly reduced, as compared with that of the Si-bonded VLEDs and conventional LEDs, under the same package conditions.

Highly reflective and thermally stable indium-tin-oxide (ITO)-Ag-Pt p-type reflectors for use in high-performance GaN-based light-emitting diodes (LEDs) have been investigated. The specific contact resistance of the ITO-Ag-Pt contacts was found to be 7.2 t10-5Omegamiddotcm2. The ITO-Ag-Pt contacts showed a higher reflectance after thermal annealing (82% at 460 nm), while the reflectance of the ITO-Ag contacts was reduced from 81% to 65%. In addition, surface agglomeration was drastically decreased, indicating that the Pt layer efficiently prevents the surface agglomeration of the Ag layer. The vertical LEDs (VLEDs) fabricated with the ITO-Ag-Pt contacts had a 17% higher output power (at 20 mA) than the VLEDs fabricated with the ITO-Ag contacts.

A widely tunable grating cavity laser based on the Rowland circle construction for a concave grating is proposed and demonstrated. The device is implemented by employing multichannel array structure in a Littman configuration and fabricated by integrating all elements in an InP substrate. Only one channel is turned on at a time, with coarse tuning realized by selecting the appropriate element in the channel array and fine tuning by controlling the beam deflection provided by dispersive element. An overall tuning range of 50 nm with a sidemode suppression ratio of more than 30 dB has been achieved for the six-channel device

A multiwavelength grating cavity laser is reported using a novel design for a multichannel light source based on an etched diffraction grating. Following the design, the compact eight-channel device capable of fine-tuning has been realized by monolithically integrating semiconductor optical amplifiers, various passive waveguides, and deeply etched grating, providing high butt-coupling efficiency, and low waveguide losses. As a result, the sidemode suppression ratio in excess of 45 dB over all channels was achieved.

A novel grating cavity tunable laser is proposed and experimentally demonstrated. It is realized by monolithically integrating a semiconductor optical amplifier, a dispersive element, a phase-control section, and an etched diffraction grating in a single chip. Tuning operation is based on electrically controlled beam deflection provided by dispersive element and phase matching by phase-control section. With the electrical control, the wavelength tuning of 8.5 nm with a sidemode suppression ratio of about 35 dB has been successfully achieved.

Tunable external-cavity lasers with low power variation over a broad tuning range are demonstrated using asymmetric multiple quantum-wells with a wide and flat gain. For a 2.8-/spl mu/m-wide ridge waveguide laser of cavity length 380 /spl mu/m, when used in a grating external cavity and with an antireflection coating on one facet of laser diode chip, the power variation of less than -1 dB is obtained over a range of 80 nm. This extremely low power variation is a direct result of the spectrally flat gain.

Despite advances in its treatment, CNS lymphoma remains a devastating disease. Taking advantage of the tumour-tropic properties of neural stem cells (NSCs) is a novel therapeutic strategy. To apply this strategy to the treatment of CNS lymphoma, we investigated the role of NSCs expressing carboxyl esterase (HB1.F3.CE), which activates irinotecan.In order to find in vitro bystander effects of engineered NSCs, we performed cell viability assays. In vivo, the HB1.F3.CE cells were injected into the brain of mice with orthotopic CNS lymphoma. Mice were then treated with irinotecan by systemic administration.The HB1.F3.CE cells significantly inhibited the growth of Raji cells with irinotecan treatment. In vivo, the HB1.F3.CE cells migrated into the tumour and significantly reduced tumour volume. In addition, survival of mice was prolonged by treatment with HB1.F3.CE and irinotecan.Transplantation of human NSCs encoding CE into brain, combined with irinotecan therapy, may be an effective treatment regimen for CNS lymphoma.

Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis.

A simple method has been developed for splitting a chromosome in Saccharomyces cerevisiae into two replicating halves. Haploid yeast cells of an ura3 mutant were transformed with a linear molecule bearing an S. cerevisiae DNA fragment for targeted integration into a chromosome, the URA3 and CEN4 DNA sequences of S. cerevisiae , and a pair of inverted repeats (IRs) of the terminal 0.7 kbp of Tetrahymena ribosomal DNA (Tr). The integrated IRs of Tr ends of the molecule at a site on a chromosome in an ura3 mutant cell of S. cerevisiae subsequently resolved and the chromosome was split into two monocentric chromosomes in the Ura + transformant. Using this procedure, chromosomes XI, VIII, and II were each split into two halves, at the GCN3 , YHR088 , and VPS15 loci, respectively. Occurrence of the split chromosomes was confirmed by examination of their electrophoretic karyotypes. Some of the clones with the split chromosomes proliferated more quickly than the parental strain.

We propose and demonstrate a novel tunable external-cavity laser diode that simultaneously achieves rapid tuning rate and wide tuning range by electrical control. This contains new-type integrated laser diode, collimating lens, and diffraction grating mirror. The integrated laser diode consists of Fabry-Pe/spl acute/rot laser diode and waveguide-type deflector, which can deflect the beam passing through the waveguide. By control of the current in the deflector region, maximum wavelength variation of 8.6 nm and sidemode suppression ratio of >35 dB were obtained.

This paper proposes a fast Operating System (OS) Switcher for ARM-based Consumer Electronics (CE) such as Smart Phones, Tablets and IPTVs. The OS switcher enables users to utilize multiple OSes on single H/W device without security problem from interference among OSes. The OS switcher is notably faster than the multi-boot approach and can preserve the previous working states. The OS switcher does not burden any run time overhead compared to virtualization and can be easily applied to the new product. We implemented the OS switcher in the bootloader layer without any modification of OS.

Wavelength conversion is demonstrated for the first time at 10 Gb/s in a Mach-Zehnder interferometric wavelength converter monolithically integrated with a CW probe source of a loss-coupled distributed feedback (DFB) laser diode. The integrated device was fabricated using a buried ridge stripe (BRS) structure with an undoped InP clad layer on the top of a passive waveguide to reduce high propagation loss. Good performance at 10 Gb/s was obtained with an extinction ratio of 7 dB and a power penalty of 2.8 dB at a 10-9 bit error rate.