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At least 973 records · Page 54Linked to original sources
PubMed2000

Adventitial versus intimal liposome-mediated ex vivo transfection of canine saphenous vein grafts with endothelial nitric oxide synthase gene.

PURPOSE: Experiments were designed (1) to evaluate liposome-mediated endothelial constitutive nitric oxide synthase (ecNOS) transfection in vein grafts and (2) to compare intimal and adventitial routes of transfection. METHODS: Male mongrel dogs (N = 36) underwent bilateral femoral artery bypass grafting with the lateral saphenous vein. In each animal one vein was transfected with plasmid (pVR1012) containing the ecNOS gene, and another vein was transfected with plasmid alone (control). Gene transfer was performed from either the intimal surface (Group I, n = 18) or the adventitial surface (Group II, n = 18). In each group there were three transfection subgroups (n = 6 each): (a ) 10 microg/mL naked plasmid DNA, (b ) 10 microg/mL plasmid DNA + liposome (LipofectAMINE PLUS), and (c ) 100 microg/mL plasmid DNA + LipofectAMINE PLUS. Grafts were harvested on the third postoperative day, and the transfection was assessed with molecular techniques and enzyme assay for activity of NOS by conversion of tritiated l-arginine to tritiated l-citrulline. Proliferating cells were quantified with a digital analysis of histologic sections after nuclear antigen Ki-67 (MIB1) immunohistochemistry. RESULTS: Transgene was identified with polymerase chain reaction in all ecNOS-transfected grafts, regardless of transfection modality. However, significant transcription of the ecNOS transgene was observed only in Group IIc (mean ecNOS messenger RNA, 8.7+/-1.7 vs. 3.1+/-0.7 x 10(-2) attomole/microL, in transfected compared with control grafts, respectively, P =.01). NOS activity increased approximately twofold in this group (11.58+/-2.1 and 6.3+/-1.0 pmol tritiated l-citrulline per milligram protein per hour in transfected and control grafts, respectively, P = .05). Numbers of proliferating cells did not differ among ecNOS-transfected and control grafts in any transfection group. CONCLUSION: These results suggest that ecNOS transfection of vein grafts is feasible through intimal and adventitial routes with naked DNA or a liposomal vector. However, efficient transcription of the transgene is evident at postoperative day 3 only after adventitial transfection of 100 microg/mL of the gene.

Animals↗
PubMed2006

A probabilistic approach to protein backbone tracing in electron density maps.

One particularly time-consuming step in protein crystallography is interpreting the electron density map; that is, fitting a complete molecular model of the protein into a 3D image of the protein produced by the crystallographic process. In poor-quality electron density maps, the interpretation may require a significant amount of a crystallographer's time. Our work investigates automating the time-consuming initial backbone trace in poor-quality density maps. We describe ACMI (Automatic Crystallographic Map Interpreter), which uses a probabilistic model known as a Markov field to represent the protein. Residues of the protein are modeled as nodes in a graph, while edges model pairwise structural interactions. Modeling the protein in this manner allows the model to be flexible, considering an almost infinite number of possible conformations, while rejecting any that are physically impossible. Using an efficient algorithm for approximate inference--belief propagation--allows the most probable trace of the protein's backbone through the density map to be determined. We test ACMI on a set of ten protein density maps (at 2.5 to 4.0 A resolution), and compare our results to alternative approaches. At these resolutions, ACMI offers a more accurate backbone trace than current approaches.

Algorithms↗
PubMed2004

SPIDER: software for protein identification from sequence tags with de novo sequencing error.

For the identification of novel proteins using MS/MS, de novo sequencing software computes one or several possible amino acid sequences (called sequence tags) for each MS/MS spectrum. Those tags are then used to match, accounting amino acid mutations, the sequences in a protein database. If the de novo sequencing gives correct tags, the homologs of the proteins can be identified by this approach and software such as MS-BLAST is available for the matching. However, de novo sequencing very often gives only partially correct tags. The most common error is that a segment of amino acids is replaced by another segment with approximately the same masses. We developed a new efficient algorithm to match sequence tags with errors to database sequences for the purpose of protein and peptide identification. A software package, SPIDER, was developed and made available on Internet for free public use. This paper describes the algorithms and features of the SPIDER software.

Algorithms↗
PubMed1999

Role of the alpha2B-adrenergic receptor in the development of salt-induced hypertension.

Salt sensitivity is a common trait in patients with essential hypertension and seems to have both an inherited and an acquired component (eg, is influenced by aging and renal insufficiency). Experimental evidence suggests that salt loading induces hypertension via a neurogenic mechanism mediated by the alpha2-adrenergic receptors (alpha2-AR). To explore the alpha2-AR subtype involved in this mechanism, we studied 2 groups of mice genetically engineered to be deficient in one of the 3 alpha2-AR subtype genes (either alpha2B-AR +/- or alpha2C-AR -/- knockout mice) compared with their wild-type counterparts. The mice (n=10 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for up to 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intra-arterial BP recording. The alpha2B-AR-deficient mice had an attenuated BP response in this protocol (baseline 101.8+/-2.7 versus end point 109.9+/-2.8 mm Hg), whereas the BP of their wild-type counterparts went from a baseline 101.9+/-2.3 to an end point 141.4+/-7.1 mm Hg. The other 2 groups had BP increases of 44. 6+/-5.17 and 46.7+/-7.01 mm Hg, with no difference between the mice deficient in the alpha2C-AR gene subtype versus their wild-type counterparts. Body weight, renal remnant weight, and residual renal function were no different among groups. These data suggest that a full complement of alpha2B-AR genes is necessary to raise BP in response to dietary salt loading, whereas complete absence of the alpha2C-AR subtype does not preclude salt-induced BP elevation. It is unclear whether the mechanism(s) involved in this process are of central origin (inability to increase sympathetic outflow), vascular origin (inability to vasoconstrict), or renal origin (inability to retain excess salt and fluid).

Aging↗
PubMed1999

Activation of the brain angiotensin system by in vivo human angiotensin-converting enzyme gene transfer in rats.

The possibility of the brain-specific expression of a component of the renin-angiotensin system was evaluated in the present study. We used the hemagglutinating virus of Japan-liposome complex to transfect human angiotensin-converting enzyme (ACE) cDNA, driven by the cytomegalovirus enhancer and beta-actin promoter, into the lateral cerebroventricle of male Sprague-Dawley rats. We evaluated the time course of hemodynamics, the tissue levels of angiotensin (Ang) II and vasopressin, and ACE activity. Intracerebroventricular transfection of the human ACE gene increased both blood pressure and heart rate. Transfected rats exhibited higher concentrations of brain Ang II and increased brain ACE activity. This activation of the brain angiotensin system was accompanied by increased vasopressin production. The increases in blood pressure and heart rate were abolished by intracerebroventricular administration of an ACE inhibitor or Ang II type 1 receptor antagonist. The expression of the transgene was widely distributed in the periventricular cell layer, the cortex, the hypothalamic nuclei, and the brain stem. Expression in the neuronal cells persisted for up to 14 days. Thus, this hemagglutinating virus of Japan-liposome method is a highly efficient system for gene delivery and is extremely useful for functional gene transfection. This novel hypertensive model may enable characterization of the functions of the renin-angiotensin system in the brain and determination of its role in the pathogenesis of hypertension.

Angiotensin II↗
PubMed2006

Spatial normalization of array-CGH data.

BACKGROUND: Array-based comparative genomic hybridization (array-CGH) is a recently developed technique for analyzing changes in DNA copy number. As in all microarray analyses, normalization is required to correct for experimental artifacts while preserving the true biological signal. We investigated various sources of systematic variation in array-CGH data and identified two distinct types of spatial effect of no biological relevance as the predominant experimental artifacts: continuous spatial gradients and local spatial bias. Local spatial bias affects a large proportion of arrays, and has not previously been considered in array-CGH experiments. RESULTS: We show that existing normalization techniques do not correct these spatial effects properly. We therefore developed an automatic method for the spatial normalization of array-CGH data. This method makes it possible to delineate and to eliminate and/or correct areas affected by spatial bias. It is based on the combination of a spatial segmentation algorithm called NEM (Neighborhood Expectation Maximization) and spatial trend estimation. We defined quality criteria for array-CGH data, demonstrating significant improvements in data quality with our method for three data sets coming from two different platforms (198, 175 and 26 BAC-arrays). CONCLUSION: We have designed an automatic algorithm for the spatial normalization of BAC CGH-array data, preventing the misinterpretation of experimental artifacts as biologically relevant outliers in the genomic profile. This algorithm is implemented in the R package MANOR (Micro-Array NORmalization), which is described at http://bioinfo.curie.fr/projects/manor and available from the Bioconductor site http://www.bioconductor.org. It can also be tested on the CAPweb bioinformatics platform at http://bioinfo.curie.fr/CAPweb.

Algorithms↗