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PubMed1989

Organic solids produced from simple C/H/O/N ices by charged particles: applications to the outer solar system.

CH4, CO, and CO2 are all potential one-carbon molecular repositories in primitive icy objects. These molecules are all found in the Comet Halley coma, and are probable but, (except for CH4 detected on Triton and Pluto) undetected subsurface constituents in icy outer solar system objects. We have investigated the effects of charged particle irradiation by cold plasma discharge upon surfaces of H2O:CH4 clathrate having a 200:1 ratio, as well as upon ices composed of H2O plus C2H6 or C2H2 (sometimes plus NH3) which are also plausible constituents. These materials color and darken noticeably after a dose 10(9) - 10(10) erg cm-2, which is deposited rapidly (< or = 10(4) yr.) in solar system environments. The chromophore is a yellowish to tan organic material (a tholin) which we have studied by UV-VIS reflection and transmission, and IR transmission spectroscopy. Its yield, -1 C keV-1, implies substantial production of organic solids by the action of cosmic rays and radionuclides in cometary crusts and interiors, as well as rapid production in satellite surfaces. This material shows alkane bands which Chyba and Sagan have shown to well match the Halley infrared emission spectrum near 3.4 microns, and also bands due to aldehyde, alcohol and perhaps alkene/aromatic functional groups. We compare the IR spectral properties of these tholins with the spectra of others produced by irradiation of gases and ices containing simple hydrocarbons.

Cosmic Radiation↗

PubMed1991

Integrated genetic databases in the study of neuropsychiatric diseases: inborn errors of cerebral metabolic pathways?

1. Genetic databases are an expanding and readily accessible repository of information on the mapping and sequencing of the human genome, and that of other model organisms. The integration and application of this information to neuropsychiatric disease is illustrated using neuroendocrine and neuropharmacologic data, computerized and other genetic databases. 2. This computer-assisted integrated approach to knowledge structures permits the rapid generation of hypotheses, the prompt identification of candidate gene loci, an explanation for genetic heterogeneity, and strategies for the use of potential linked markers. 3. Results using this integrated search strategy demonstrate that over 30 candidate loci for neuropsychiatric disease have currently been mapped in man (spread over 14 chromosomes in the human genome), and that at least 6 homologous loci have been mapped in mouse. 4. Using a metabolic pathway approach, it can be shown that the best current candidate gene locus for a subtype of schizophrenia located on chromosome 5q11-13 (HGML10 # SCZD1 and OMIM #181510) is in the serotonergic pathway, i.e. a receptor for 5-hydroxytryptamine (subtype 1A; HGML10 #HTR1A) which also maps in the same chromosomal region. 5. Parallels are suggested between inborn errors of metabolic pathways in the somatic endocrine system (using insulin-dependent diabetes mellitus as a paradigm) and the neurotransmitter and hormonal systems within the brain. 6. A subset of neuropsychiatric disorders may thus be viewed as inborn errors of cerebral metabolic pathways primarily affecting the biogenic amine pathways.

Animals↗

PubMed1993

Artificial intelligence approach in analysis of DNA sequences.

We present an approach for designing a knowledge-based system, called Sequence Acquisition In Context (SAIC), that will be able to cooperate with a biologist in the analysis of DNA sequences. The main task of the system is the acquisition of the expert knowledge that the biologist uses for solving ambiguities from gel autoradiograms, with the aim of re-using it later for solving similar ambiguities. The various types of expert knowledge constitute what we call the contextual knowledge of the sequence analysis. Contextual knowledge deals with the unavoidable problems that are common in the study of the living material (eg noise on data, difficulties of observations). Indeed, the analysis of DNA sequences from autoradiograms belongs to an emerging and promising area of investigation, namely reasoning with images. The SAIC project is developed in a theoretical framework that is shared with other applications. Not all tasks have the same importance in each application. We use this observation for designing an intelligent assistant system with three applications. In the SAIC project, we focus on knowledge acquisition, human-computer interaction and explanation. The project will benefit research in the two other applications. We also discuss our SAIC project in the context of large international projects that aim to re-use and share knowledge in a repository.

Artificial Intelligence↗

PubMed1995

An analysis of thymic function and the possible role of the thymus in stem cell production.

The thymus is considered to be essentially an organ of the immune system, its purpose being to supply T cells. The role of the T cell is to regulate the immune reaction which it does by liberating lymphokines. The lymphokine function of the T cells was not deciphered in vivo, but in explanted T cells, and it is debatable if explanted cells behave in the same way as their counterparts in the intact animal, so the liberated lymphokines may not represent nature's intent. Adding to the disquiet are those biological properties of the thymus which are difficult to explain on an immunological basis, in particular why the thymus is essential in the child but not in the adult. Thus, there is room for a different approach to the role of the thymus. There is sound evidence that the thymus plays a part in somatic growth and differentiation, and one explanation is that the thymus provides the stem cells for somatic growth. A stem cell role is supported by studies on mastopoiesis and eosinophilopoiesis, and also supported by the way embryonic organs grow after their initial development. From the arguments put forward, the hypothesis is put that the role of the thymus is to store and propagate the stem cells required for the organ growth which takes place subsequent to their initial development. If the thymus is a repository for stem cells, the varied aspects of thymic behaviour, including its role in immunity, can be explained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Cloned infectious complementary DNA of the poliovirus Sabin 1 genome: biochemical and biological properties of the recovered virus.

A complete cDNA copy of the genome of the attenuated type 1 poliovirus vaccine (Sabin 1) strain was constructed and inserted into the EcoRI site of the plasmid pBR325. When cultured mammalian cells were transfected with this recombinant plasmid, 20 to 50 poliovirus plaques per 10 micrograms plasmid DNA were observed. Fingerprints of the RNA of the recovered virus showed no changes when compared with those of the parental virus genome, an observation indicating that the primary structure of the cloned cDNA is a reflection of authentic poliovirus RNA. The recovered virus had the same properties as those of the Sabin 1 strain in regard to antigenicity, sensitivity to temperature, and dependency on bicarbonate concentration. These results suggest that the virus obtained by DNA transfection is indistinguishable from the Sabin 1 strain. The recombinant plasmid could therefore be used as a stable repository of the virus and as inoculum for the oral polio live vaccine.

Animals↗

PubMed1992

Humanized animal viruses with special reference to the primate adaptation of morbillivirus.

This review article discusses the evolution of human viruses with special reference to paramyxoviruses. This family of viruses causes epidemics representing the dissemination of infection from one acutely infected host to the next. Since there is no repository for human paramyxoviruses in animals or in the form of persistent infections in man, the history of epidemics afflicting human civilization is short, presumably not exceeding 4000-5000 years. Evolutionary relationships can be deduced for comparison of nucleotide sequences of genes or even complete genomes. The present paramyxovirus genus will probably in the future be divided into two separate genera. In the genus morbillivirus, two pairs of more closely related virus types can be distinguished: canine and phocid viruses, and rinder-pest and measles viruses, respectively. It is speculated that recombination events may have occurred in the evolution of the morbillivirus archetype.

Animals↗

PubMedDate not supplied

Transient storage of a nuclear matrix protein along intermediate-type filaments during mitosis: a novel function of cytoplasmic intermediate filaments.

We recently identified a nuclear matrix protein, named NMP125 for its molecular weight (M(r) 125 kDa). On the basis of immunofluorescence analysis with monoclonal anti-NMP125 antibodies of differentially extracted cells in situ, including detergents, DNase I, RNase A, and high/low ionic strength conditions, it is concluded that NMP125 is a component of a chromatin- and histone-depleted nuclear substructure, operationally defined as nuclear matrix in interphase cells. The protein revealed evolutionary conservation in man, rat, chicken, and Xenopus, at least at the level of immunological crossreactivity. The subcellular distribution of NMP125 is cell-cycle-dependent; in interphase cells NMP125 is confined to a nuclear substructure with a granular aspect, whereas after nuclear envelope breakdown, it is freed into the cytoplasm. However, most of the protein remains attached to a cytoskeletal ligand that we have identified as the intermediate-type filament vimentin. In late mitotic stages the protein forms punctuate aggregates of relatively large size, which get passively closer to the newly formed telophase nuclei together with the reorganized vimentin around the nuclei in late telophase. From the morphological point of view, although static in nature, a dynamic cell-cycle-dependent distribution of NMP125 is found, revealing dissociation and spreading throughout the cytoplasm in metaphase, binding to vimentin filaments, cytoplasmic aggregation, and transport to nuclei in telophase. The transient affinity of the nuclear protein NMP125 to vimentin filaments during mitosis together with a passive cytoplasmic dislocation of the vimentin/NMP125 conjugate toward the telophase nuclei could represent a novel and dynamic function of cytoplasmic intermediate filaments, implicating a transient repository and passive shift of nuclear proteins during mitosis.

Animals↗

PubMed2006

Strategies for comparing gene expression profiles from different microarray platforms: application to a case-control experiment.

Meta-analysis of microarray data is increasingly important, considering both the availability of multiple platforms using disparate technologies and the accumulation in public repositories of data sets from different laboratories. We addressed the issue of comparing gene expression profiles from two microarray platforms by devising a standardized investigative strategy. We tested this procedure by studying MDA-MB-231 cells, which undergo apoptosis on treatment with resveratrol. Gene expression profiles were obtained using high-density, short-oligonucleotide, single-color microarray platforms: GeneChip (Affymetrix) and CodeLink (Amersham). Interplatform analyses were carried out on 8414 common transcripts represented on both platforms, as identified by LocusLink ID, representing 70.8% and 88.6% of annotated GeneChip and CodeLink features, respectively. We identified 105 differentially expressed genes (DEGs) on CodeLink and 42 DEGs on GeneChip. Among them, only 9 DEGs were commonly identified by both platforms. Multiple analyses (BLAST alignment of probes with target sequences, gene ontology, literature mining, and quantitative real-time PCR) permitted us to investigate the factors contributing to the generation of platform-dependent results in single-color microarray experiments. An effective approach to cross-platform comparison involves microarrays of similar technologies, samples prepared by identical methods, and a standardized battery of bioinformatic and statistical analyses.

Breast Neoplasms↗

PubMed2004

Coordinated series of studies to evaluate characteristics and mechanisms of acute coronary syndromes in high-risk patients randomly assigned to enoxaparin or unfractionated heparin: design and rationale of the SYNERGY Library.

Clinical trials and accompanying substudies in patients with acute coronary syndromes (ACS) have over the last several years yielded a wealth of knowledge about the pathophysiology and management of this high-risk condition. The Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a large-scale, randomized, controlled trial evaluating the effect of enoxaparin and unfractionated heparin on death and myocardial infarction in high-risk patients presenting with non-ST-segment elevation ACS. The SYNERGY Library has been designed as a coordinated series of investigations with simultaneous data acquisition on the same cohort of approximately 500 SYNERGY patients at 60 centers in North America. Specifically, electrocardiograms, coronary arteriograms, inflammatory markers, coagulation studies, and genetic samples will be collected and processed at core laboratory facilities, and the results will be stored in a central repository. This novel strategy for substudy investigation is unprecedented in cardiovascular clinical trials. The goal is to gain significant understanding about this patient population, discover new principles of pathophysiology, identify novel pharmacologic targets, and streamline further drug development. It is hoped that the SYNERGY Library will serve as a model for future substudy design to maximize academic insight within the framework of a large-scale, multicenter trial.

Angina, Unstable↗

PubMed2006

Genetic variations in CC chemokine receptors and hypertension.

BACKGROUND: CC-chemokine receptor 5 (CCR5) is a co-receptor for human immunodeficiency virus type 1 (HIV-1) infection. Homozygosity for a 32-base pair (bp) deletion (Delta32) in the CCR5 gene confers resistance to HIV-1. Previous studies found an increased prevalence of hypertension among CCR5-Delta32 homozygotes and among carriers of a polymorphism (CCR2-64I) found on the gene that codes a closely related chemokine receptor. The present study was carried out to verify these associations. METHODS: Subjects in this cross-sectional study were selected from the Global Repository at Genomics Collaborative, which includes patients and healthy control subjects enrolled at multiple clinical sites in the United States and other nations. The current study includes 2842 subjects with hypertension and 2893 nonhypertensive control subjects from white populations in the United States and Poland. Case and control subjects were frequency matched by age, gender, and birthplace. All subjects were genotyped for CCR5-Delta32 and CCR2-64I polymorphisms by established Taqman assays. RESULTS: The CCR5-Delta32 genotype was not found to be associated with hypertension (CCR5-Delta32 heterozygosity: odds ratio [OR] 0.99, 95% confidence interval [CI] 0.87 to 1.14; CCR5-Delta32 homozygosity: OR 1.07, 95% CI 0.68 to 1.67) among these subjects. There was also no association between CCR2-64I genotype and hypertension (CCR2-64I heterozygosity: OR 0.96, 95% CI 0.83 to 1.10; CCR2-64I homozygosity: OR 1.18, 95% CI 0.73 to 1.92). These results changed little after adjustment for potential confounding variables. CONCLUSION: The results of the present study, which is much larger than previously published studies, provide no evidence that either CCR5-Delta32 or CCR2-64I is associated with hypertension.

Adult↗

PubMed2006

Types of medication errors in North Carolina nursing homes: a target for quality improvement.

BACKGROUND: Medication errors are an important problem in nursing homes, but little is known about the types of medications involved in errors in this setting. Gaining a better understanding of the types of medications commonly involved in medication errors in nursing homes would be an important step toward quality improvement. OBJECTIVES: This study sought to describe the types of medication errors most frequently reported to a statewide repository by North Carolina nursing homes. We also examined whether nursing homes reporting an error involving a drug on the updated Beers list of medications considered potentially inappropriate for use in the elderly were likely to report a greater number of medication errors or more harmful medication errors compared with nursing homes that did not report such an error. METHODS: Medication errors were defined as preventable events that had the potential to cause/lead to or actually caused/led to inappropriate medication use or patient harm. We analyzed summary reports of medication errors submitted to the State of North Carolina by licensed nursing homes for the 9-month period from January 1, 2004, to September 30, 2004, using a Web-based reporting system. Drugs commonly involved in medication errors were summarized for all nursing homes in the state. Errors involving medications on the updated Beers list also were identified. Nursing homes were profiled and compared according to the type of medication error and whether the error reached the patient and/or caused harm. RESULTS: Among the 384 licensed nursing homes included in our analysis, 9272 medication errors were reported. The specific medication involved was documented for 5986 of these errors. The medications most commonly involved in an error were lorazepam (457 errors [8%]), warfarin (349 [6%]), insulin (332 [6%]), hydrocodone and hydrocodone combinations (233 [4%]), furosemide (173 [3%]), and the fentanyl patch (150 [3%]). The medication errors disproportionately included central nervous system agents (16%) and analgesics (11%). Medications considered potentially inappropriate in the elderly were frequently involved in the reported errors (10% of all reported errors), with the greatest number of such errors associated with lorazepam (457 [8%]), alprazolam (130 [2%]), and digoxin (74 [1%]). Nursing homes reporting potentially inappropriate drugs among their 10 most common medication errors also reported a significantly greater mean number of errors compared with nursing homes that did not report such errors (26.9 vs 17.6, respectively; P < 0.001), as well as a significantly greater number of errors that reached the patient (6148 vs 1393; P < 0.001). CONCLUSION: Based on the experience in North Carolina, quality improvement efforts in nursing homes should focus on the medications commonly involved in errors and should continue to discourage or closely monitor the use of medications considered potentially inappropriate in the elderly.

Adverse Drug Reaction Reporting Systems↗

PubMed2005

Sorption of Cesium on smectite-rich clays from the Bohemian Massif (Czech Republic) and their mixtures with sand.

Sorption is an important process for the transport of radionuclides through backfill materials in a radioactive waste underground repository. Within this study, sorption of Cs on selected Czech clay materials and their mixtures with sand was investigated by batch tests. The experiments were performed under oxic conditions at 25 degrees C. Synthetic groundwater as a liquid phase and unconditioned clays (as they were provided by their producer) were used to reach the natural conditions as close as possible. Distribution ratios (Rds) of Cs for all selected clays rise with increase of the clay fraction in clay/sand mixtures in agreement with previous works studying sorption behaviour of such mixtures. The rise of Rds is from 10(2) cm3 g(-1) for mixtures with 80% of sand to 10(3) cm3 g(-1) for pure clays. There are significant differences between natural and technologically modified clays.

Adsorption↗

PubMed2005

Simulation of radionuclides 99Tc and 243Am migration in compacted bentonite.

The distribution coefficients of radionuclides derived from batch experiments are used to evaluate the migration behavior of radionuclides (99)Tc and (243)Am in compacted bentonite after different times. The effects of times, dispersion coefficient, distribution coefficient and pore water velocity on the concentration distribution of (99)Tc and (243)Am in the environment are also calculated from the theoretical migration equation. (99)Tc is poorly sorbed to bentonite and moves quickly into the environment. Migration of radionuclide increases with increasing dispersion coefficient and decreasing distribution coefficient. The effects of water velocity on the migration of Tc and Am are obvious. Most (243)Am is retained in the first several meters, and 20 m of the backfill-compacted bentonites are sufficient to prevent the migration of radionuclide Am from the repository to the environment.

Journal Article↗

PubMed2006

The uncertainties associated with the application of batch technique for distribution coefficients determination--a case study of cesium adsorption on four different bentonites.

The uncertainties associated with the batch method used often as adsorption data source for performance assessments of radioactive waste repositories have been analyzed and evaluated. The adsorption of cesium on four different bentonites (two Na- and two Ca-bentonites) using a radiotracer ((137)Cs) technique has been studied to evaluate experimental uncertainties and compare their effects on calculated distribution coefficients (K(d)s). Three main factors influencing uncertainty of K(d) at given conditions were identified-the radiotracer operation (mainly tracer addition to experimental systems), the phase separations efficiency and the mineralogical heterogeneity of samples. It was found that the determination of quantitative contributions of the last two factors to the uncertainty of K(d) is difficult, depending on input material and conditions. The centrifugation and ultrafiltration method has been tested for removing colloids in sample solutions, but the results obtained were disputable. The mineral heterogeneity (complex mineral composition) effect has been identified mainly in kinetics of cesium adsorption where three different trends were described. This has important influence on the time-scale of the experiment's planning and equilibrium time estimation or identification. It has been concluded that experimental procedure may represent important uncertainty source of calculated K(d). In performance assessment studies, this uncertainty of K(d) given by the appropriate experimental procedure should be taken into account and properly evaluated.

Journal Article↗

PubMed2025

Identification and external validation of a prognostic signature based on myeloid-derived suppressor cells-related LncRNAs to evaluate survival prognosis and treatment efficacy in invasive breast carcinoma.

BACKGROUND: Originating in the hematopoietic tissue, myeloid-derived suppressor cells (MDSCs) significantly contribute to tumor-related immunological processes. However, their relationship with long noncoding RNAs (lncRNAs) and breast cancer remains incompletely understood. In this study, we introduced MDSCs-associated lncRNAs as novel prognostic biomarkers to assess outcomes in patients with invasive breast carcinoma (BRCA). METHODS: Information regarding BRCA cases, including clinical and genomic details, was obtained from the TCGA repository. Predictive indicators were discovered, and their reliability underwent thorough verification. A clinically useful nomogram was developed following application-based validation. Additional investigations encompassed functional analysis, TMB assessment, TME profiling, immunotherapy efficacy forecasting, and drug sensitivity testing along with target identification. Long non-coding RNA expression was measured using reverse transcription quantitative PCR. RESULTS: A risk stratification model incorporating eight MDSCs-related lncRNAs effectively predicted patient outcomes. Kaplan-Meier (K-M) survival analysis clearly indicated a much worse prognosis among patients classified as high-risk (p < 0.001). The nomogram accurately forecasted overall survival (OS). Analysis of functional enrichment revealed that pathways associated with epithelial cells showed activity among patients at higher risk. Characterization of the tumor microenvironment showed increased immune cell presence in those classified as low-risk. Conversely, individuals with greater risk displayed higher tumor mutational burden. TIDE and IPS analyses indicated superior immunotherapy responsiveness in the low-risk BRCA subgroup. Among 47 drugs with notable IC50 variations, Ribociclib, PD173074, KU-55933, NU7441, and nutlin-3a exhibited lower IC50 values within the low-risk group, whereas Lapatinib demonstrated greater efficacy among the high-risk group. Moreover, 10 potential therapeutic agents and their targets were predicted for high-risk patients. RT-qPCR validation confirmed the robustness of the model. CONCLUSIONS: We successfully verified a new model of molecular markers of MDSCs-related lncRNAs, offering critical insights for predicting outcomes and guiding therapeutic decisions in BRCA cases.

Bioinformatics↗

PubMed2005

Anticancer metal compounds in NCI's tumor-screening database: putative mode of action.

Clustering analysis of tumor cell cytotoxicity profiles for the National Cancer Institute (NCI)'s open compound repository has been used to catalog over 1100 metal or metalloid containing compounds with potential anticancer activity. The molecular features and corresponding reactivity of these compounds have been analyzed in terms of properties of their metals, their associated organic components (ligands) and their capacity to inhibit tumor cell growth. Cytotoxic responses are influenced by both the identity of the metal and the properties of its coordination ligand, with clear associations between structural similarities and cytotoxicity. Assignments of mechanisms of action (MOAs) for these compounds could be segregated into four broad response classes according to preference for binding to biological sulfhydryl groups, chelation, generation of reactive oxygen species (ROS), and production of lipophilic ions. Correlations between specific cytotoxic responses and differential gene expression profiles within the NCI's tumor cell panel serve as a validation for candidate biological targets and putative MOA classes. In addition, specific sensitivity toward subsets of metal containing agents has been found for certain tumor cell panels. Taken together, our results expand the knowledge base available for evaluating, designing and developing new metal-based anticancer drugs that may provide the basis for target-specific therapeutics.

Antineoplastic Agents↗

PubMed2005

Exploration of soil bacterial communities for their potential as bioresource.

Soil is a repository of diverse microorganisms, which has frequently been used to isolate and exploit microbes for industrial, environmental and agricultural applications. Knowledge about the structure and dynamics of bacterial communities in soil has been limited as only a small fraction of bacterial diversity is accessible to culture methods. Traditional enrichment techniques and the pure culture approach for microbiological studies have offered only a narrow portal for examining the soil microbial flora due to their limited selectivity. Therefore, the morphological and nutritional criteria used to describe bacterial community failed to provide a natural taxonomic order according to evolutionary relationship. Molecular methods under an emerging discipline of biology "molecular microbial ecology" are now helping in getting these constraints removed to some extent. Nucleic acid extraction from soil is the first crucial step in the application of most of the molecular techniques, which have largely been dominated by diverse variations of PCR. Due to its rapidity, sensitivity and specificity, PCR-based finger printing techniques have proved extremely useful in assessing the changes in microbial community structure. Such techniques can yield complex community profiles and can also provide useful phylogenetic information. Fluorescent in situ hybridization (FISH) can be used to evaluate the distribution and function of bacterial population in situ. DNA microarray techniques have also been developed and being frequently used for the evaluation of ecological role and phylogenetic affiliations of bacterial populations in the soil.

Bacteria↗

PubMed2005

A statistical analysis of the TRANSFAC database.

Transcription factors are key regulatory elements that control gene expression. The TRANSFAC database represents the largest repository for experimentally derived transcription factor binding sites (TFBS). Understanding TFBS, which are typically conserved during evolution, helps us identify genomic regions related to human health and disease, and regions that might be predictive of patient outcomes. Here we present a statistical analysis of all TFBS in the TRANSFAC database. Our analysis suggests that current definition of TFBS core regions in TRANSFAC should be re-examined so as to capture a more precise notion of "cores." We offer insight into more appropriate definitions of TFBS consensus sequences and core regions. These revised definitions provide a better understanding of the nature of transcription factor-DNA binding and assist with developing algorithms for de novo TFBS discovery as well as finding novel variants of known TFBS.

Algorithms↗