Long-term Clinical Outcomes Following Elective Stent Implantation for Unprotected Left Main Coronary Artery Disease

Background/PurposePercutaneous coronary intervention (PCI) has been increasingly adopted for unprotected left main coronary artery (LMCA) disease. The aim of this study was to evaluate the predictors of long-term clinical outcomes in patients after elective stent implantation for unprotected LMCA disease.MethodsA total of 122 patients with medically refractory angina who received coronary stenting for unprotected LMCA disease between August 1997 and December 2008 were included.ResultsDuring the follow-up period of 45 ± 35 months (range: 1–137 months), the incidence of repeated PCI and/or coronary artery bypass grafting (CABG), and cardiovascular and total mortality were 28% (34 patients), 20% (24 patients), and 25% (31 patients), respectively. Multivariate analysis revealed that young age [p = 0.02; hazard ratio (HR): 2.19, 95% confidence interval (CI): 1.11–4.30] and bare-metal stent (BMS) use (p = 0.02; HR: 5.35, 95% CI: 1.27–22.57) were the independent predictors of repeated PCI and/or CABG. Only lower left ventricular ejection fraction (LVEF) could predict both cardiovascular mortality (p = 0.003; HR: 4.25, 95% CI: 1.63–11.08) and total mortality (p = 0.002; HR: 3.95, 95% CI: 1.65–9.45). Lower LVEF (p = 0.001; HR: 0.31, 95% CI: 0.16–0.61) and small stent size (p = 0.01; HR: 5.95, 95% CI: 1.43–24.80) could predict the composite endpoint, including target vessel revascularization and total mortality.ConclusionWe showed that young age and BMS implantation could predict repeated PCI and/or CABG after stent implantation for unprotected LMCA disease. Only lower LVEF could predict both cardiovascular and total mortality. Lower LVEF and small stent size but not BMS implantation could predict composite target vessel revascularization/total mortality

14-3-3σ Regulates β-Catenin-Mediated Mouse Embryonic Stem Cell Proliferation by Sequestering GSK-3β

[[abstract]]Background: Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear. Methodology and Principal Findings: In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3σ isoform. Knockdown of 14-3-3σ with siRNA reduced embryonic stem cell proliferation, while only 14-3-3σ transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3σ was abrogated by β-catenin knockdown, we investigated the influence of 14-3-3σ overexpression on β-catenin/GSK-3β. 14-3-3σ bound GSK-3β and increased GSK-3β phosphorylation in a PI-3K/Akt-dependent manner. It disrupted β-catenin binding by the multiprotein destruction complex. 14-3-3σ overexpression attenuated β-catenin phosphorylation and rescued the decline of β-catenin induced by retinoid acid. Furthermore, 14-3-3σ enhanced Wnt3a-induced β-catenin level and GSK-3β phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3β/14-3-3σ binding. Significance:Our findings show for the first time that 14-3-3σ plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3β and enhancing Wnt-signaled GSK-3β inactivation. 14-3-3σ is a novel target for embryonic stem cell expansion

A Partial Structural and Functional Rescue of a Retinitis Pigmentosa Model with Compacted DNA Nanoparticles

Previously we have shown that compacted DNA nanoparticles can drive high levels of transgene expression after subretinal injection in the mouse eye. Here we delivered compacted DNA nanoparticles containing a therapeutic gene to the retinas of a mouse model of retinitis pigmentosa. Nanoparticles containing the wild-type retinal degeneration slow (Rds) gene were injected into the subretinal space of rds+/− mice on postnatal day 5. Gene expression was sustained for up to four months at levels up to four times higher than in controls injected with saline or naked DNA. The nanoparticles were taken up into virtually all photoreceptors and mediated significant structural and biochemical rescue of the disease without histological or functional evidence of toxicity. Electroretinogram recordings showed that nanoparticle-mediated gene transfer restored cone function to a near-normal level in contrast to transfer of naked plasmid DNA. Rod function was also improved. These findings demonstrate that compacted DNA nanoparticles represent a viable option for development of gene-based interventions for ocular diseases and obviate major barriers commonly encountered with non-viral based therapies

Cell-Specific DNA Methylation Patterns of Retina-Specific Genes

Many studies have demonstrated that epigenetic mechanisms are important in the regulation of gene expression during embryogenesis, gametogenesis, and other forms of tissue-specific gene regulation. We sought to explore the possible role of epigenetics, specifically DNA methylation, in the establishment and maintenance of cell type-restricted gene expression in the retina. To assess the relationship between DNA methylation status and expression level of retinal genes, bisulfite sequence analysis of the 1000 bp region around the transcription start sites (TSS) of representative rod and cone photoreceptor-specific genes and gene expression analysis were performed in the WERI and Y79 human retinoblastoma cell lines. Next, the homologous genes in mouse were bisulfite sequenced in the retina and in non-expressing tissues. Finally, bisulfite sequencing was performed on isolated photoreceptor and non-photoreceptor retinal cells isolated by laser capture microdissection. Differential methylation of rhodopsin (RHO), retinal binding protein 3 (RBP3, IRBP) cone opsin, short-wave-sensitive (OPN1SW), cone opsin, middle-wave-sensitive (OPN1MW), and cone opsin, long-wave-sensitive (OPN1LW) was found in the retinoblastoma cell lines that inversely correlated with gene expression levels. Similarly, we found tissue-specific hypomethylation of the promoter region of Rho and Rbp3 in mouse retina as compared to non-expressing tissues, and also observed hypomethylation of retinal-expressed microRNAs. The Rho and Rbp3 promoter regions were unmethylated in expressing photoreceptor cells and methylated in non-expressing, non-photoreceptor cells from the inner nuclear layer. A third regional hypomethylation pattern of photoreceptor-specific genes was seen in a subpopulation of non-expressing photoreceptors (Rho in cones from the Nrl −/− mouse and Opn1sw in rods). These results demonstrate that a number of photoreceptor-specific genes have cell-specific differential DNA methylation that correlates inversely with their expression level. Furthermore, these cell-specific patterns suggest that DNA methylation may play an important role in modulating photoreceptor gene expression in the developing mammalian retina

Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol

Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.Polyclonal activation of T cells, following injection of concanavalin A (ConA), in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST), induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD), a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b(+)Gr-1(+) MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naïve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1(-/-)) thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ∼2∶1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury.This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases

Pin1 and neurodegeneration: a new player for prion disorders?

Pin1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans conversion of phosphorylated proteins at serine or threonine residues which precede a proline. The peptidyl-prolyl isomerization induces a conformational change of the proteins involved in cell signaling process. Pin1 dysregulation has been associated with some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Proline-directed phosphorylation is a common regulator of these pathologies and a recent work showed that it is also involved in prion disorders. In fact, prion protein phosphorylation at the Ser-43-Pro motif induces prion protein conversion into a disease-associated form. Furthermore, phosphorylation at Ser-43-Pro has been observed to increase in the cerebral spinal fluid of sporadic Creutzfeldt-Jakob Disease patients. These findings provide new insights into the pathogenesis of prion disorders, suggesting Pin1 as a potential new player in the disease. In this paper, we review the mechanisms underlying Pin1 involvement in the aforementioned neurodegenerative pathologies focusing on the potential role of Pin1 in prion disorders

Experimental Analyses of Revised Fin Shapes for μ-P Remote Heat Exchanger

本論文實驗探討P4（Pentium4）RHE 散熱模組之熱管結合散熱鰭 片的散熱性能分析。在設定熱管熱傳導率，熱管相關尺寸，風扇性能 曲線，鰭片相關尺寸（如長度、間距、厚度）及片數、材質等條件下 分析散熱鰭片形狀參數，以期獲得RHE 較佳散熱效果。 本文所欲探討的散熱鰭片形狀共有A、B、C、D、E 組的形狀，其 中A 組為RHE 散熱鰭片43 片規則外形，B 組為RHE 新形散熱鰭片43 片，C 組為RHE 新形散熱鰭片31 片，D 組為RHE 新形散熱鰭片20 片， E 組為RHE 新形散熱鰭片10 片。 在散熱設計中，不論是利用自然對流或是強制對流，一般最終透 過散熱鰭片，將CPU 所產生的熱能，由周遭的空氣帶走。而整個傳 熱過程中，散熱鰭片與空氣間之熱傳效果，常是最具關鍵之設計所 在。故在五種不同外形散熱鰭片下尋找最佳散熱效果。 實驗分析發現，因改變外型下鰭片沒有足夠的熱擴散面積，間接 的降低RHE 的散熱效率。在改變RHE 散熱模組鰭片外形後，模組溫 度約上升2~4.6℃，散熱效率下降16.7~28.6％。The experiment of this thesis explores the cooling capability of the heat pipe of P4 (Pentium4) RHE thermal module in combination with cooling fins. Under the conditions of established heat pipe thermal conductivity rate, heat pipe-related size, fan capability curve, fin-related size (such as length, spacing, thickness, number of fins and material, We analyzed the cooling fin shape parameters, to achieve bester RHE cooling effect. The cooling fin shapes explored in this thesis have shapes of A, B, C, D, and E. Of which are 43 regularly shaped A RHE cooling fins, 43 new model B RHE cooling fins, 31 new model C RHE cooling fins, 20 new model D RHE cooling fins, and 10 new model E RHE cooling fins. III Cooling designs, regardless of free convection or forced convection, generally employ cooling fins to dissipate CPU heat to the air. The key in the design is usually the convection effect between cooling fins and the air. Therefore, the best cooling effect is sought among the five cooling fins with different shapes. Research analysis finds that a modified fin without sufficient thermal diffusion surface will indirectly lower the cooling efficiency of RHE. In the modified RHE thermal module fin shape, the temperature of the RHE thermal module increased between 2 to 4.6℃, the cooling efficiency decreased between 16.7 to 28.6%.V 誌謝···························································································I 中文摘要············································································· II 英文摘要············································································ III 目錄··················································································· V 表目錄··············································································· VIII 圖目錄··················································································IX 符號說明···········································································XII 第一章緒論························································································· 1 1-1 前言····························································································· 1 1-2 文獻回顧····················································································· 2 1-3 研究目的與動機········································································· 5 第二章實驗方法與設備·························································· 6 2-1 實驗方法····················································································· 6 2-2 實驗模型····················································································· 9 2-3 散熱鰭片··················································································· 11 2-4 熱管特性··················································································· 22 2-5 熱管的構造與作動原理·························································· 23 2-6 熱管性能之限制····································································· 24 2-6-1 飛散界線····································································· 24 2-6-2 音速界限····································································· 24 2-6-3 沸騰界限····································································· 25 2-6-4 毛細管構造界限························································· 25 2-6-5 黏性界限····································································· 25 2-7 熱管的使用與應用································································· 26 2-8 散熱膏···················································································· 27 2-9 冷卻風扇················································································ 27 2-9-1 鰭片與風扇之操作點理論分析·································· 29 2-10 實驗設備·············································································· 34 2-10-1 電源供應器································································ 35 2-10-2 熱電偶········································································ 36 2-10-3 溫度紀錄器································································ 37 2-10-4 熱阻抗量測機···························································· 37 2-10-5 HEAT FLUX·································································· 38 2-10-6 PRESS LOAD APPARATUS ············································ 39 2-11 溫度擷取裝置········································································ 40 2-11-1 紅外線熱像儀···························································· 40 2-12 實驗參數·············································································· 41 第三章實驗結果與討論·························································46 3-1 RHE 散熱鰭片43 片規則外形（A 組）與RHE 新形散熱鰭片 （B 組）、（C 组）、（D 組）、（E 組）結果比較與討論 ·······················································································46 第四章結論與建議·········································································· 48 4-1 結論························································································ 48 4-2 建議························································································ 49 參考文獻······························································································ 59 附錄······································································································· 6

Microstrip equivalent parasitics modeling of RFIC interconnects

We experimentally demonstrate a modeling methodology for inductive parasitics of RFIC interconnects. The method exploits the equivalence between a microstrip line and the cross section of a multi metal layer CMOS fabrication process. The proposed model is applied on an oscillator fabricated in a standard 0.18 mum mixed mode CMOS process. We compare the experimental results of the phase noise of the oscillator so fabricated with the simulation results using the microstrip equivalent model for the interconnects. The simulation and experimental results match very closely.© IEE