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At least 325 records · Page 18Linked to original sources
PubMed1999

Structural and functional integrity of precision-cut liver slices in xenobiotic metabolism: a comparison of the dynamic organ and multiwell plate culture procedures.

1. Objectives were two-fold: (1) to compare the viability of precision-cut liver slices in two culture systems, namely the dynamic organ and the multiwell plate; and (2) to evaluate whether increasing the number of slices per incubation results in a proportional increase in the extent of metabolism. 2. With both culturing systems, the major products of 7-ethoxycoumarin metabolism were the sulphate and glucuronide conjugates of 7-hydroxycoumarin with very low levels of the free compound. When the multiwell plate procedure was used, metabolism increased linearly for at least 10 h, whereas it tended to plateau after 6 h in the dynamic organ culture system. At preincubations > 10 h, significantly more metabolism of 7-ethoxycoumarin was seen in the slices cultured using the multiwell system compared with the dynamic organ system. 3. Morphological evaluation employing light and electron microscopy revealed that liver slices incubated using the multiwell system were structurally better preserved compared with those incubated using the dynamic organ system. 4. Using the multiwell system, increasing the number of slices per incubation from one to two resulted in only a modest increase in the metabolism of 7-ethoxycoumarin. The rate of metabolism of this substrate was much higher with one liver slice when expressed per mg homogenate protein. 5. It is concluded that (1) the multiwell plate culture system for culturing slices is superior to the dynamic organ system in studying the metabolism of xenobiotics following long-term incubations, (2) increasing the number of slices per incubation does not result in a corresponding increase in the rate of metabolism, and (3) in both culture systems optimal viability appears to be within 24 h of incubation.

Animals↗
PubMed2005

Biological master games: using biologists' reasoning to guide algorithm development for integrated functional genomics.

We review some powerful new algorithms that build on the intuitive biological interpretation techniques for statistical analysis of functional genomics experiments. Although they were originally designed for transcriptomics, we argue that these algorithms are applicable to any type of -omics study (transcriptomics, proteomics, metabolomics). Rank Products (RP), a strictly non-parametric test statistic to detect differentially regulated elements (genes, proteins, metabolites) in genome-wide screens. RP is particularly powerful for noisy data and low numbers of replicates and makes full use of the availability of a large number of parallel measurements that is typical of modern large-scale experiments. Iterative Group Analysis (iGA), a statistical method that makes the transition from regulated single elements to significant classes of elements, and thus provides an automatic functional annotation of an experiment. Graph-based iGA (GiGA), an extension of iGA that combines experimental data with a broad variety of biological annotations to highlight physiologically relevant regions in a given "evidence graph" (e.g., metabolic networks, signaling pathway diagrams, protein interaction maps). The sequential application of these techniques yields an increasingly abstract interpretation of experimental data that is at the same time quantitative, statistically rigorous, and biologically significant. The results can be used either as helpful tools to guide data visualization and exploration, or as the input for downstream computational applications in a systems biology framework.

Algorithms↗
PubMed1998

Analysis of the impact of intracellular reactive oxygen species generation on the structural and functional integrity of human spermatozoa: lipid peroxidation, DNA fragmentation and effectiveness of antioxidants.

Exposure of human spermatozoa to nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the dose dependent generation of reactive oxygen species (ROS) which, at a critical level of intensity, induced lipid peroxidation, DNA damage and a dramatic decline of sperm motility. This system was then used as a model for screening the ability of different antioxidants to combat oxidative stress created through the excessive intracellular generation of toxic oxygen products of metabolism. A variety of antioxidants that has previously been shown to be protective against extracellularly derived oxidants (e.g. superoxide dismutase, catalase, vitamin E, hypotaurine) were ineffective in this system. Albumin, however, could provide complete protection against NADPH induced oxidative stress via mechanisms that did not involve the suppression of the lipid peroxidation cascade but rather the inactivation of lipid peroxides generated during this process. Albumin did not protect against DNA damage induced by NADPH but was extremely effective at preventing DNA fragmentation arising from the suppression of glutathione peroxidase activity with mercaptosuccinate. These studies emphasize that the design of clinically effective antioxidant treatments will depend, critically, upon the source of the oxidative stress. For cases involving excessive intracellular ROS generation, albumin appears to be an important means of neutralizing lipid peroxide-mediated damage to the sperm plasma membrane and DNA.

Antioxidants↗
PubMed2003

Integrated functional and bioinformatics approach for the identification and experimental verification of RNA signals: application to HIV-1 INS.

Regulation of gene expression involves sequence elements in nucleic acids. In promoters, multiple sequence elements cooperate as functional modules, which in combination determine overall promoter activity. We previously developed computational tools based on this hierarchical structure for in silico promoter analysis. Here we address the functional organization of post-transcriptional control elements, using the HIV-1 genome as a model. Numerous mutagenesis studies demonstrate that expression of HIV structural proteins is restricted by inhibitory sequences (INS) in HIV mRNAs in the absence of the HIV-1 Rev protein. However, previous attempts to detect conserved sequence patterns of HIV-1 INS have failed. We defined four distinct sequence patterns for inhibitory motifs (weight matrices), which identified 22 out of the 25 known INS as well as several new candidate INS regions contained in numerous HIV-1 strains. The conservation of INS motifs within the HIV genome was not due to overall sequence conservation. The functionality of two candidate INS regions was analyzed with a new assay that measures the effect of non-coding mRNA sequences on production of red fluorescent reporter protein. Both new INS regions showed inhibitory activity in sense but not in antisense orientation. Inhibitory activity increased by combining both INS regions in the same mRNA. Inhibitory activity of known and new INS regions was overcome by co-expression of the HIV-1 Rev protein.

Computational Biology↗
PubMed1991

Requirement of innervation for maintenance of structural and functional integrity in the rat prostate.

The rat prostate is innervated by pelvic and hypogastric nerves through a single pelvic ganglion, removal of which would result in complete denervation of the prostatic complex. The present study was conducted to investigate the effect of denervation on the rat prostate. Adult Sprague-Dawley rats of 300 g in body weight were divided into two groups. Bilateral pelvic ganglion denervation was performed in one group of animals; the other group received a sham operation. Three weeks later, animals were killed; and the ventral prostates were removed, weighed, and subjected to routine procedures for light and electron microscopy. The average weight, total protein content, and total content of acid phosphatase of the ventral prostates in the denervated group were significantly less than those in the control group. Total DNA content per prostate, however, was not significantly different between the two groups. Results of histological examination indicated that the prostates from control animals showed normal morphology, whereas those from the denervated animals showed reduced cell height and enlarged vacuoles surrounding the nuclei. Inspection of electron micrographs revealed that the prostates from denervated animals, compared with those of controls, showed a reduced ratio of cell height:cell width, which is associated with a reduced number of microvilli and secretory granules. These results indicate that denervation in the prostate is associated with a lower prostatic weight, decreased cell height, and reduced secretory activity.

Acid Phosphatase↗
PubMed2001

Methodological and technical issues for integrating functional magnetic resonance imaging data in a neuronavigational system.

OBJECTIVE: The aim of this article was to analyze the technical and methodological issues resulting from the use of functional magnetic resonance image (fMRI) data in a frameless stereotactic device for brain tumor or pain surgery (chronic motor cortex stimulation). METHODS: A total of 32 candidates, 26 for brain tumor surgery and six chronic motor cortex stimulation, were studied by fMRI scanning (61 procedures) and intraoperative cortical brain mapping under general anesthesia. The fMRI data obtained were analyzed with the Statistical Parametric Mapping 99 software, with an initial analysis threshold corresponding to P < 0.001. Subsequently, the fMRI data were registered in a frameless stereotactic neuronavigational device and correlated to brain mapping. RESULTS: Correspondence between fMRI-activated areas and cortical mapping in primary motor areas was good in 28 patients (87%), although fMRI-activated areas were highly dependent on the choice of paradigms and analysis thresholds. Primary sensory- and secondary motor-activated areas were not correlated to cortical brain mapping. Functional mislocalization as a result of insufficient correction of the echo-planar distortion was identified in four patients (13%). Analysis thresholds (from P < 0.0001 to P < 10(-12)) more restrictive than the initial threshold (P < 0.001) had to be used in 25 of the 28 patients studied, so that fMRI motor data could be matched to cortical mapping spatial data. These analysis thresholds were not predictable preoperatively. Maximal tumor resection was accomplished in all patients with brain tumors. Chronic motor cortex electrode placement was successful in each patient (significant pain relief >50% on the visual analog pain scale). CONCLUSION: In brain tumor surgery, fMRI data are helpful in surgical planning and guiding intraoperative brain mapping. The registration of fMRI data in anatomic slices or in the frameless stereotactic neuronavigational device, however, remained a potential source of functional mislocalization. Electrode placement for chronic motor cortex stimulation is a good indication to use fMRI data registered in a neuronavigational system and could replace somatosensory evoked potentials in detection of the central sulcus.

Adolescent↗
PubMed2025

The Annotated Blueprint: Integrated Functional Genomic Resources for a model Tetraploid Wheat Triticum turgidum cv. Kronos.

Triticum turgidum cv. Kronos is a tetraploid wheat cultivar that underpins one of the richest community platforms for functional genomics. Over the past decade, about 3,000 exome- and promoter-capture datasets, linked to mutagenized seed stocks, and transcriptomic and phenotypic resources have accumulated, yet the absence of a reference genome has constrained their impact. Here, we present a chromosome-scale reference genome of Kronos with high-confidence annotations, including manual curation of over 1,000 disease resistance (NLR) genes. This reference revealed previously hidden NLR diversity and clarified their genomic organization at chromosomal ends. Re-analysis of exome- and promoter-capture datasets enabled high-resolution mutation discovery in genes and regulatory regions that were previously inaccessible, uncovering the full standing variation present in Kronos mutant lines. We further re-curated transcriptomic and small RNA datasets, generating improved, genome-wide maps of microRNAs and phasiRNAs important for wheat development. Collectively, these resources elevate Kronos to reference quality and establish it as a versatile platform for functional and translational wheat research.

Journal Article↗