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RATIONAL: Vascular smooth muscle cells (VSMCs) switching from a contractile/differentiated to a synthetic/dedifferentiated phenotype has an essential role in atherosclerosis, postangioplastic restenosis and hypertension. However, ...
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RATIONAL: Vascular smooth muscle cells (VSMCs) switching from a contractile/differentiated to a synthetic/dedifferentiated phenotype has an essential role in atherosclerosis, postangioplastic restenosis and hypertension. However, how normal VSMCs maintain the differentiated state is less understood. OBJECTIVE: We aimed to indentify the effect of cartilage oligomeric matrix protein (COMP), a normal vascular extracellular matrix, on modulation of VSMCs phenotype. METHODS AND RESULTS: We demonstrated that COMP was associated positively with the expression of VSMC differentiation marker genes during phenotype transition. Knockdown of COMP by small interfering (si)RNA favored dedifferentiation. Conversely, adenoviral overexpression of COMP markedly suppressed platelet-derived growth factor-BB-elicited VSMC dedifferentiation, characterized by altered VSMC morphology, actin fiber organization, focal adhesion assembly, and the expression of phenotype-dependent markers. Whereas alpha(7) integrin coimmunoprecipitated with COMP in normal rat VSMCs and vessels, neutralizing antibody or siRNA against alpha(7) integrin inhibited VSMC adhesion to COMP, which indicated that alpha(7)beta(1) integrin is a potential receptor for COMP. As well, blocking or interference by siRNA of alpha(7) integrin completely abolished the effect of COMP on conserving the contractile phenotype. In accordance, ectopic adenoviral overexpression of COMP greatly retarded VSMC phenotype switching, rescued contractility of carotid artery ring, and inhibited neointima formation in balloon-injured rats. CONCLUSIONS: Our data suggest that COMP is essential for maintaining a VSMC contractile phenotype and the protective effects of COMP are mainly mediated through interaction with alpha(7)beta(1) integrin. Investigations to identify the factors affecting the expression and integrity of COMP may provide a novel therapeutic target for vascular disorders.
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In flowering plants, the accumulation of small deletions through unequal homologous recombination (UR) and illegitimate recombination (IR) is proposed to be the major process counteracting genome expansion, which is caused primari...
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In flowering plants, the accumulation of small deletions through unequal homologous recombination (UR) and illegitimate recombination (IR) is proposed to be the major process counteracting genome expansion, which is caused primarily by the periodic amplification of long terminal repeat retrotransposons (LTR-RTs). However, the full suite of evolutionary forces that govern the gain or loss of transposable elements (TEs) and their distribution within a genome remains unclear. Here, we investigated the distribution and structural variation of LTR-RTs in relation to the rates of local genetic recombination (GR) and gene densities in the rice (Oryza sativa) genome. Our data revealed a positive correlation between GR rates and gene densities and negative correlations between LTR-RT densities and both GR and gene densities. The data also indicate a tendency for LTR-RT elements and fragments to be shorter in regions with higher GR rates; the size reduction of LTR-RTs appears to be achieved primarily through solo LTR formation by UR. Comparison of indica and japonica rice revealed patterns and frequencies of LTR-RT gain and loss within different evolutionary timeframes. Different LTR-RT families exhibited variable distribution patterns and structural changes, but overall LTR-RT compositions and genes were organized according to the GR gradients of the genome. Further investigation of non-LTR-RTs and DNA transposons revealed a negative correlation between gene densities and the abundance of DNA transposons and a weak correlation between GR rates and the abundance of long interspersed nuclear elements (LINEs)/short interspersed nuclear elements (SINEs). Together, these observations suggest that GR and gene density play important roles in shaping the dynamic structure of the rice genome.
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Upconversion luminescence (UCL) imaging is expected to play a significant role in future photoluminescence imaging since it shows advantages of sharp emission lines, long lifetimes, superior photostability and no blinking. To furt...
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Upconversion luminescence (UCL) imaging is expected to play a significant role in future photoluminescence imaging since it shows advantages of sharp emission lines, long lifetimes, superior photostability and no blinking. To further improve penetration depth, herein, near-infrared to near-infrared (NIR-to-NIR) UCL and magnetic properties were combined into a nanoparticle, and NIR-to-NIR UCL and MRI dual-modal bioimaging in vivo of whole-body animal were developed. Hydrophilic and carboxylic acid-functionalized Tm(3+)/Er(3+)/Yb(3+) co-doped NaGdF(4) upconversion nanophosphors (AA-NPs) were synthesized and showed both NIR-to-visible and NIR-to-NIR luminescence under excitation of 980 nm. Collecting the signal of the upconversion emission from AA-NPs in the visible and NIR range, all UCL imaging of cells, tissues and whole-body animals with different penetration depth showed high contrast. Moreover, AA-NPs showed a high relaxivity of 5.60 s(-1) (mM)(-1) and were successfully applied as contrast agents for magnetic resonance imaging (MRI) in vivo. By means of the combination of UCL imaging and MRI, the distribution of AA-NPs in living animals was studied, and the results indicated that these particles mainly accumulate in the liver and spleen without undesirable stay in the lungs. Therefore, the concept of UCL and MR dual-modality imaging in vivo of whole-body animals using Tm(3+)/Er(3+)/Yb(3+) co-doped NaGdF(4) with NIR-to-NIR upconversion luminescent and magnetic resonance properties can serve as a platform technology for the next-generation of probes for bioimaging in vivo.
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BACKGROUND & AIMS: High-frequency gastric electrical stimulation (GES) is a relatively new treatment for medically refractory gastroparesis. There have been a number of clinical studies based on the use of a high-frequency stimulator (Enterra, Medtronic, Minneapolis, MN). A meta-analysis was performed to evaluate evidence for improved clinical outcome with this device. METHODS: A literature search of major medical databases was performed for the period January 1992 to August 2008. Clinical studies involving an implanted high-frequency GES device were included and reported a range of clinical outcomes. Studies of external, temporary, and/or low-frequency GES were excluded. RESULTS: Of 13 included studies, 12 lacked controls and only one was blinded and randomized. Following GES, patients reported improvements in total symptom severity score (3/13 studies, mean difference 6.52 [confidence interval--CI: 1.32, 11.73]; P = 0.01), vomiting severity score (4/13, 1.45 [CI: 0.99, 1.91]; P < 0.0001), nausea severity score (4/13, 1.69 [CI: 1.26, 2.12]; P < 0.0001), SF-36 physical composite score (4/13, 8.05 [CI: 5.01, 11.10]; P < 0.0001), SF-36 mental composite score (4/13, 8.16 [CI: 4.85, 11.47]; P < 0.0001), requirement for enteral or parenteral nutrition (8/13, OR 5.53 [CI: 2.75, 11.13]; P < 0.001), and 4-h gastric emptying (5/13, 12.7% [CI: 9.8, 15.6]; P < 0.0001). Weight gain did not reach significance (3/13, 3.68 kg [CI: -0.23, 7.58]; P = 0.07). The device removal or reimplantation rate was 8.3%. CONCLUSIONS: Results show substantial benefits for high-frequency GES in the treatment of gastroparesis. However, caution is necessary in interpreting the results, primarily because of the limitations of uncontrolled studies. Further controlled studies are required to confirm the clinical benefits of high-frequency GES....
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BACKGROUND & AIMS: High-frequency gastric electrical stimulation (GES) is a relatively new treatment for medically refractory gastroparesis. There have been a number of clinical studies based on the use of a high-frequency stimulator (Enterra, Medtronic, Minneapolis, MN). A meta-analysis was performed to evaluate evidence for improved clinical outcome with this device. METHODS: A literature search of major medical databases was performed for the period January 1992 to August 2008. Clinical studies involving an implanted high-frequency GES device were included and reported a range of clinical outcomes. Studies of external, temporary, and/or low-frequency GES were excluded. RESULTS: Of 13 included studies, 12 lacked controls and only one was blinded and randomized. Following GES, patients reported improvements in total symptom severity score (3/13 studies, mean difference 6.52 [confidence interval--CI: 1.32, 11.73]; P = 0.01), vomiting severity score (4/13, 1.45 [CI: 0.99, 1.91]; P < 0.0001), nausea severity score (4/13, 1.69 [CI: 1.26, 2.12]; P < 0.0001), SF-36 physical composite score (4/13, 8.05 [CI: 5.01, 11.10]; P < 0.0001), SF-36 mental composite score (4/13, 8.16 [CI: 4.85, 11.47]; P < 0.0001), requirement for enteral or parenteral nutrition (8/13, OR 5.53 [CI: 2.75, 11.13]; P < 0.001), and 4-h gastric emptying (5/13, 12.7% [CI: 9.8, 15.6]; P < 0.0001). Weight gain did not reach significance (3/13, 3.68 kg [CI: -0.23, 7.58]; P = 0.07). The device removal or reimplantation rate was 8.3%. CONCLUSIONS: Results show substantial benefits for high-frequency GES in the treatment of gastroparesis. However, caution is necessary in interpreting the results, primarily because of the limitations of uncontrolled studies. Further controlled studies are required to confirm the clinical benefits of high-frequency GES.
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Insertional mutagenesis leading to insurgence of leukemia has been shown as a consequence of retroviral (RV)-mediated gene transfer in animal models and in clinical trials of gene therapy for X-linked severe combined immunodeficie...
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Insertional mutagenesis leading to insurgence of leukemia has been shown as a consequence of retroviral (RV)-mediated gene transfer in animal models and in clinical trials of gene therapy for X-linked severe combined immunodeficiency. Aberrant expression of oncogenes neighboring the gamma-RV vector insertion site via induction by the enhancer element of the viral long terminal repeats (LTRs) is thought to have played a role in leukemogenesis. Consequently, RV vectors devoid of LTR enhancer elements could prove as safer tools for gene transfer. To test this hypothesis, we evaluated the immortalization ability of two RV vectors: one carrying the full-length Moloney leukemia virus (MLV) LTR and one with the same LTR in which the enhancer element was deleted [MLV self-inactivating (SIN)]. Unexpectedly, transduction with MLV SIN resulted in an only slightly and not significant decreased immortalization frequency of primary bone marrow (BM) cultures (about 37%) compared to transduction with MLV (about 48%). Similar to MLV, immortalization by MLV SIN is likely caused by insertional activation of oncogenes including Evi1, Mds1, Mef2c, and Hoxa7. Our results indicate that the MLV SIN, devoid of the LTR enhancer element, was still able to immortalize BM cells by activating nearby gene expression, indicating the need of an accurate selection of the internal promoter to obtain safer SIN RV vectors.
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Panax notoginseng (Sanqi) is a cardiovascular herb containing ginsenosides that are believed to be responsible for the therapeutic effects of Sanqi. The aim of this study was to evaluate rat exposure to ginsenosides after oral adm...
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Panax notoginseng (Sanqi) is a cardiovascular herb containing ginsenosides that are believed to be responsible for the therapeutic effects of Sanqi. The aim of this study was to evaluate rat exposure to ginsenosides after oral administration of Sanqi extract and to identify the key factors affecting their absorption and disposition. Ginsenosides were administered to rats, either in the form of Sanqi extract or as pure chemicals. The ginsenosides Ra(3), Rb(1), Rd, Re, Rg(1), and notoginsenoside R(1) were the major saponins present in the herbal extract. Systemic exposure to ginsenosides Ra(3), Rb(1), and Rd after oral administration of the extract was significantly greater than that to the other compounds. Considerable colonic deglycosylation of the ginsenosides occurred, but the plasma levels of deglycosylated metabolites were low in rats. Poor membrane permeability and active biliary excretion are the two primary factors limiting systemic exposure to most ginsenosides and their deglycosylated metabolites. In contrast with other ginsenosides, biliary excretion of ginsenosides Ra(3) and Rb(1) was passive. Meanwhile, the active biliary excretion of ginsenoside Rd was significantly slower than that of other saponins. Slow biliary excretion, inefficient metabolism, and slow renal excretion resulted in long-circulating and thus relatively high exposure levels for these three ginsenosides. For these reasons, plasma ginsenosides Ra(3), Rb(1), and Rd were identified as pharmacokinetic markers for indicating rat systemic exposure to Sanqi extract. This is a systematic investigation of the absorption and disposition of ginsenosides from an herb, the information gained from which is important for linking Sanqi administration to its medicinal effects.
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Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) convey fast synaptic transmission in the CNS and mediate various forms of hippocampal plasticity. Disruption of glutamate receptor type 1 (GluR1), a membe...
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Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) convey fast synaptic transmission in the CNS and mediate various forms of hippocampal plasticity. Disruption of glutamate receptor type 1 (GluR1), a member of the AMPAR family, causes synaptic alterations and learning/memory deficits in mice. To gain mechanistic insight into the synaptic and behavioral changes associated with GluR1 deletion, hippocampal genome-wide expression profiling was conducted using groups of GluR1 knockout (KO) mice and their wild-type littermates. Regulation of 38 genes was found to be altered more than 30% (P < 0.01, n = 8), and seven of these genes were studied with additional quantitative experiments. A large portion of the altered genes encoded molecules involved in calcium signaling, including calcium channel components, calcium-binding proteins and calcium-calmodulin-dependent protein kinase II subunits. At the protein level, we further evaluated some genes in the calcium pathway that were altered in GluR1 KO mice. Protein levels of two key molecules in the calcium pathway - GluR, ionotropic, N-methyl-d-aspartate-1 and calcium/calmodulin-dependent protein kinase II alpha - showed similar changes to those observed in mRNA levels. These findings raise the possibility that calcium signaling and other plasticity molecules may contribute to the hippocampal plasticity and behavioral deficits observed in GluR1 KO mice.
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A gallium focused ion beam has been used to create discrete pits on a SrTiO_3 (100) surface with the idea that these pits will serve as the nucleation sites for subsequent Cu_2O nanodot growth. The concentration of gallium within ...
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A gallium focused ion beam has been used to create discrete pits on a SrTiO_3 (100) surface with the idea that these pits will serve as the nucleation sites for subsequent Cu_2O nanodot growth. The concentration of gallium within these pits has been analysed using a high-resolution Auger system immediately after pit formation and also following wet chemical etching and thermal annealing of the surface. The geometry of the pits has been determined following etching and annealing using atomic force microscopy (AIM). Growth of Cu_2O nanodots on the patterned surfaces has been performed for different processing and Ga dose conditions. Growth of Cu_2O nanodots within the pits is the primary mode of dot formation. In several samples, dot growth within pits appears to occur by a two-step process with pits filling before initiation of a second, distinct phase of nanodot growth above the plane of the original SrTiO_3 surface.
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WHAT IS ALREADY KNOWN ABOUT THE SUBJECT: * Concomitant use of different drugs may yield excessive risk for adverse drug reactions and it is a challenging task to do surveillance on the safety profile of the interaction between dif...
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WHAT IS ALREADY KNOWN ABOUT THE SUBJECT: * Concomitant use of different drugs may yield excessive risk for adverse drug reactions and it is a challenging task to do surveillance on the safety profile of the interaction between different drugs. * Currently, several methods are used by pharmacoepidemiologists and statisticians to detect possible drug-drug interactions in spontaneous reporting systems. * However, with the increasing number of reports in the system, there is a growing need for a computerized system that could facilitate the process of data arrangement and detection of drug interaction. WHAT THIS STUDY ADDS: * We had already developed a computerized system to detect adverse drug reaction signals due to single drugs. * After the development of this system, interaction between different drugs could also be detected automatically and intelligently. AIMS: In spontaneous reporting systems (SRS), there is a growing need for the automated detection of adverse drug reactions (ADRs) resulting from drug-drug interactions. In addition, special attention is also needed for systems facilitating automated data preprocessing. In our study, we set up a computerized system to signal possible drug-drug interactions by which data acquisition and signal detection could be carried out automatically and the process of data preprocessing could also be facilitated. METHODS: This system was developed with Microsoft Visual Basic 6.0 and Microsoft Access was used as the database. Crude ADR reports submitted to Shanghai SRS from January 2007 to December 2008 were included in this study. The logistic regression method, the Omega shrinkage measure method, an additive model and a multiplicative model were used for automatic detection of drug-drug interactions where two drugs were used concomitantly. RESULTS: A total of 33 897 crude ADR reports were acquired from the SRS automatically. The 10 drug combinations most frequently reported were found and the 10 most suspicious drug-drug ADR combinations for each method were detected automatically after the performance of the system. CONCLUSIONS: Since the detection of drug-drug interaction depends upon the skills and memory of the professionals involved, is time consuming and the number of reports is increasing, this system might be a promising tool for the automated detection of possible drug-drug interactions in SRS.
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BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated disorder in which destruction of platelets is accelerated by anti-platelet autoimmune antibodies. B-cell-activating factor (BAFF) and a proliferation-inducing ligand ...
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BACKGROUND: Immune thrombocytopenia (ITP) is an immune-mediated disorder in which destruction of platelets is accelerated by anti-platelet autoimmune antibodies. B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL), essential factors for B cell survival are elevated in systemic autoimmune diseases and correlated with clinical findings. High expression of BAFF has been shown in patients with ITP, but the status of APRIL in ITP is still unknown. OBJECTIVE: To determine the expression of APRIL and it receptors, B-cell maturation antigen (BCMA) and trans-membrane activator and calcium modulator and cyclophilin ligand interactor (TACI), in patients with ITP, and evaluate the correlation between plasma APRIL levels and platelet accounts or other clinical parameters. METHODS: Plasma samples from 57 patients with ITP, and 30 normal healthy subjects were assayed for APRIL plasma concentration by enzyme linked immunosorbent assay. Real-time quantitative polymerase chain reaction was performed to determine the mRNA expression of APRIL and its receptors (BCMA and TACI) in peripheral blood mononuclear cells (PBMNCs) in 25 normal controls and 34 untreated ITP patients with active disease. RESULTS: The APRIL levels in the plasma samples from patients with ITP were significantly higher than those from healthy controls (p = 0.000). PBMNCs may be a source of the excess APRIL. Treated patients with normal platelet count have relatively normal plasma APRIL (p = 0.599). Plasma APRIL levels in active patients were significantly correlated with platelet counts (r = -0.387 and p = 0.024). CONCLUSION: APRIL is over expressed in untreated active ITP patients and might be a pathogenic factor of this disorder.
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