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PubMed1998

Matrix-assisted laser desorption/ionization mass spectrometry of acidic glycoconjugates facilitated by the use of spermine as a co-matrix.

Negative-ion matrix-assisted laser desorption/ionization mass spectra of sialyated glycoconjugates were acquired employing 2,5-dihydroxybenzoic acid (DHB) in conjunction with spermine as a co-matrix. The addition of spermine to DHB permitted an improved crystal formation as well as a higher analyte solubility. Moreover, DHB/spermine appears to minimize alkali adduct formation, thus allowing the sample analysis without desalting. The combined matrix permitted the analysis of complex sialylated and sialylated/fucosylated structures down to the femotomole range. The ability to use such a matrix also facilitates determination of the sialic acid linkages (in combination with a specific enzyme cleavage). The matrix also appears suitable for studies on gangliosides.

Animals↗
PubMed2005

Metabotropic glutamate receptors in the basal ganglia motor circuit.

In recent years there have been tremendous advances in our understanding of the circuitry of the basal ganglia and our ability to predict the behavioural effects of specific cellular changes in this circuit on voluntary movement. These advances, combined with a new understanding of the rich distribution and diverse physiological roles of metabotropic glutamate receptors in the basal ganglia, indicate that these receptors might have a key role in motor control and raise the exciting possibility that they might provide therapeutic targets for the treatment of Parkinson's disease and related disorders.

Animals↗
PubMed2006

NMR study of the electron transfer complex of plant ferredoxin and sulfite reductase: mapping the interaction sites of ferredoxin.

Plant ferredoxin serves as the physiological electron donor for sulfite reductase, which catalyzes the reduction of sulfite to sulfide. Ferredoxin and sulfite reductase form an electrostatically stabilized 1:1 complex for the intermolecular electron transfer. The protein-protein interaction between these proteins from maize leaves was analyzed by nuclear magnetic resonance spectroscopy. Chemical shift perturbation and cross-saturation experiments successfully mapped the location of two major interaction sites of ferredoxin: region 1 including Glu-29, Glu-30, and Asp-34 and region 2 including Glu-92, Glu-93, and Glu-94. The importance of these two acidic patches for interaction with sulfite reductase was confirmed by site-specific mutation of acidic ferredoxin residues in regions 1 and 2, separately and in combination, by which the ability of mutant ferredoxins to transfer electrons and bind to sulfite reductase was additively lowered. Taken together, this study gives a clear illustration of the molecular interaction between ferredoxin and sulfite reductase. We also present data showing that this interaction surface of ferredoxin significantly differs from that when ferredoxin-NADP(+) reductase is the interaction partner.

Aspartic Acid↗
PubMed2004

Field evaluation of methods for determining the obstructed section of branches of industrial ventilation systems.

This study proposes and evaluates the effectiveness of three methods in determining the location of obstructions and alterations in the branches of industrial ventilation systems. Three branch-screening methods (reference ratio, static pressure ratio, and power loss coefficient methods) were adapted to determine if obstructions lay in four distinct areas of a branch. The areas were the hood, middle, and end sections, with the middle and end sections combined to form the fourth area. These methods were evaluated for their ability to detect obstructions in each specific section and also for their ability to detect obstructions in sections after the branch was surveyed for obstructions using a screening method. The results of this study indicate that each method is very useful in determining the presence and location of an obstruction in every section of the branch except the hood section. Each method performed poorly when determining obstructions in the hood section. However, because of the ability of the methods to detect obstructions in the other three sections, the process of elimination can be used with confidence to determine obstructions in the hood.

Environmental Monitoring↗
PubMed1986

Long-term care patient assessment. Evaluation of a methods effect.

Evaluation of a long-term care patient classification instrument in use in the Veterans Administration revealed that the levels of functional ability used in such instruments can influence their abilities to explain use of nursing time and reliability between raters. Specifically, a three-level scale that combines patients who require supervision with those who require help does not explain use of LPN and nurse's aide personal care time as well as does a four-level scale or a three-level scale that combines patients who require supervision with those who are independent. These findings should be considered in designing and applying patient assessment instruments.

Disease↗
PubMed2002

T cells from newborn humans are fully capable of developing into cytotoxic T lymphocyte effector cells in adoptive hosts.

BACKGROUND: The finding of reduced incidence of graft-versus-host disease (GVHD) associated with cord blood transplantation, compared to unrelated allogeneic bone marrow, could be related to the lower number of T cells infused in the cord blood (CB) inoculum or it might represent an intrinsic property of CB T cells. We investigated the in vivo function of human cord blood mononuclear cells (CBMC) after their adoptive transfer into lethally irradiated BALB/c radioprotected with severe combined immunodeficiency (SCID) mouse bone marrow. METHODS: The ability of human CBMC to engraft and produce antigen-specific alloreactive cytotoxic T lymphocytes (CTLs) and antibodies was determined by FACS, 51Chromium-release assay, and ELISA. RESULTS: Recipients of human CBMC showed engraftment of high levels of both CD14+ and CD3+ cells. Human cells recovered from the peritoneal cavity of chimeric mice, 1 week after immunization with irradiated allogeneic cells, showed adult-level human CTL response against the immunizing cells, without further stimulation in vitro. In contrast, immunization with the tetanus (TT) antigen did not lead to the generation of anti-TT immunoglobulins (Ig) in the cord blood chimera. Furthermore, whereas the addition of purified adult T cells to the cord blood inoculum resulted in the enhancement of human Ig production of both IgG and IgM subclasses, it could not induce antigen-specific antibodies after immunization. CONCLUSION: This report demonstrates in mice for the first time the generation of classical human alloreactive CTLs, derived from cord blood cells. The alloreactivity exhibited by the cord blood mononuclear cells is not different from that displayed by cells originating from adult blood. Any reduction in the observed GVHD associated with cord blood transplants might therefore represent a quantitative difference in the total number of T cells infused.

Adoptive Transfer↗
PubMed2002

A novel indolocarbazole, ICP-1, abrogates DNA damage-induced cell cycle arrest and enhances cytotoxicity: similarities and differences to the cell cycle checkpoint abrogator UCN-01.

DNA damaging agents such as cisplatin arrest cell cycle progression at either G1, S, or G2 phase, although the G1 arrest is only seen in cells expressing the wild-type p53 tumor suppressor protein. We have reported that 7-hydroxystaurosporine (UCN-01) overcomes S and G2 phase arrest and enhances the cytotoxicity of cisplatin. Abrogation of arrest appears to be selective for cells defective in p53 and therefore provides a potential, tumor-targeted therapy. Unfortunately, UCN-01 binds avidly to human plasma proteins, limiting access to the tumor. A screen of related indolocarbazoles identified analogues with both beneficial and undesirable properties. This led to a synthetic program to develop a novel analogue rationally designed to overcome the obstacles observed with the other analogues. We report the synthesis and analysis of a novel analogue, ICP-1. This analogue abrogated S and G2 phase arrest and enhanced cytotoxicity induced by cisplatin only in p53 defective cells. ICP-1 also abrogated arrest and enhanced cell killing induced by the topoisomerase I inhibitor SN38. Analysis of proteins that regulate cell cycle arrest suggest both drugs inhibit checkpoint kinases Chk1 and/or Chk2. In contrast to UCN-01, checkpoint abrogation by ICP-1 was only slightly inhibited by human plasma. UCN-01 and ICP-1 differed significantly in other regards. UCN-01 potently enhanced the activity of 1-beta-D-arabinofuranosylcytosine in both p53 wild-type and mutant cells, whereas ICP-1 was inactive in this combination. This property of UCN-01 was independent of its ability to inhibit protein kinase C because more specific inhibitors of protein kinase C failed to enhance cell killing induced by 1-beta-D-arabinofuranosylcytosine. High concentrations of UCN-01 also inhibit C-TAK1 that results in S phase-arrested cells directly entering mitosis, but this property was not observed with ICP-1. Hence, ICP-1 appears to be a more selective inhibitor of the S and G2 cell cycle checkpoint than previously studied analogues and is worthy of study in preclinical tumor models.

Alkaloids↗
PubMed1983

[Characteristics of Proteus, Klebsiella, Enterobacter and Citrobacter strains isolated in urological infections].

The comparative study of more than 300 Proteus, Klebsiella, Enterobacter and Citrobacter strains isolated from patients with urological infections and parenteral infections of other localization, as well as from the feces of healthy persons has been carried out. The strains causing inflammatory processes in the urinary tract have been shown to possess no strict specificity. The ability of opportunistic enterobacteria to cause urinary tract lesions is their polydeterminant property ensured by the combination of different factors. A number of characteristics which can be considered as the markers of "nephritogenic" strains have been revealed. Thus, among Proteus mirabilis strains the largest percentage is constituted by strains fermenting sucrose and producing hemolysin. The urological pathogenicity of "nephritogenic" strains belonging to the genera Proteus, Klebsiella and Enterobacter has been found to be linked with their resistance to complement and their capacity for producing substances increasing capillary permeability. In C. freundii strains differences in O serogroups and a number of markers (the fermentation of raffinose, the formation of hemolysin and permeability factor) have been revealed. These data may be useful for the prognosis and evaluation of the course of urological infections.

Animals↗
PubMed2003

Detection and quantification of Plectosphaerella cucumerina, a potential biological control agent of potato cyst nematodes, by using conventional PCR, real-time PCR, selective media, and baiting.

Potato cyst nematodes (PCN) are serious pests in commercial potato production, causing yield losses valued at approximately $300 million in the European Community. The nematophagous fungus Plectosphaerella cucumerina has demonstrated its potential as a biological control agent against PCN populations by reducing field populations by up to 60% in trials. The use of biological control agents in the field requires the development of specific techniques to monitor the release, population size, spread or decline, and pathogenicity against its host. A range of methods have therefore been developed to monitor P. cucumerina. A species-specific PCR primer set (PcCF1-PcCR1) was designed that was able to detect the presence of P. cucumerina in soil, root, and nematode samples. PCR was combined with a bait method to identify P. cucumerina from infected nematode eggs, confirming the parasitic ability of the fungus. A selective medium was adapted to isolate the fungus from root and soil samples and was used to quantify the fungus from field sites. A second P. cucumerina-specific primer set (PcRTF1-PcRTR1) and a Taqman probe (PcRTP1) were designed for real-time PCR quantification of the fungus and provided a very sensitive means of detecting the fungus from soil. PCR, bait, and culture methods were combined to investigate the presence and abundance of P. cucumerina from two field sites in the United Kingdom where PCN populations were naturally declining. All methods enabled differences in the activity of P. cucumerina to be detected, and the results demonstrated the importance of using a combination of methods to investigate population size and activity of fungi.

Animals↗
PubMed1994

Individual effects of the DR11-variable beta-chain residues 67, 71, and 86 upon DR(alpha,beta 1*1101)-restricted, peptide-specific T cell proliferation.

The four members of the HLA-DR11 family of class II molecules vary only by three or fewer amino acids via dimorphisms among DR beta-chain residues 67, 71, and 86. However, they differ markedly in their abilities to induce proliferation of DR(alpha,beta 1*1101)-restricted, peptide-specific T cell clones. To dissect which DR11-variable residues, individually and in combination, mediate these functional differences, we used as APC transfectants expressing DR molecules with one of all possible permutations of DR11-variable sequences, including the four DR11 family members, and four additional DR11 variant mutants. The abilities of the wild-type or mutant molecules to present two distinct influenza peptide Ags, HA307-19 and HA128-45, to T cells was assessed in in vitro T cell proliferation assays. Of the naturally dimorphic DR11 positions, residue beta 71 variation significantly influenced the ability of DR11 molecules to present both peptides to DR(alpha,beta 1*1101)-restricted T cells. Residue beta 86 variation had relatively less influence than reported in several other DR and peptide systems. Residue beta 67 variation usually appeared irrelevant to T cell proliferation, but in two mutants led to unexpected T cell proliferation independent of nominal peptide Ag. Peptide binding, assessed by flow cytometry, was not found to be altered by any mutations that disrupted DR(alpha,beta 1*1101)-like presentation. These data indicate that residue beta 71 exerts a central role in influencing the functional differences among DR11 molecules, whereas the widely studied dimorphism of residue beta 86 is not as generally influential in DR11 as in other alleles.

Alleles↗
PubMed2000

Nuclear receptor-DNA binding specificity: A COMBINE and Free-Wilson QSAR analysis.

Specific binding of transcription factors to DNA is crucial for gene regulation. We derived models for the binding specificity of transcription factors of the nuclear receptor family to DNA using two QSAR methods: a Free-Wilson-like method and COMparative BINding Energy (COMBINE) analysis. The analysis is based on experimental data for the interaction of 20 mutant glucocorticoid receptor DNA-binding domains with 16 different response elements in a total of 320 complexes (Zilliacus, J.; Wright, A. P.; Carlstedt-Duke, J.; Nilsson, L.; Gustafsson, J. A. Proteins 1995, 21, 57-67). The predictive abilities of the models obtained by the two methods are similar. The COMBINE analysis indicates that the most important properties for determining binding specificity for this dataset are the changes upon binding of the solvation free energies of the bases that are mutated in the dataset and the electrostatic interactions of the mutated nucleotides with certain charged amino acids. Further important descriptors are the changes of solvation free energy and surface area of the side chain of the mutated residue. It is clear, however, that there are additional features important for the specificity of binding that are not included in the models, such as differences in interfacial hydration of the complexes.

Algorithms↗
PubMed1996

Production of cytokines by rat immunocytoma clonal variants: a new type of intratumor heterogeneity.

A long-term tissue culture line of highly metastatic IR202 immunocytoma of LOU rats, and five of its clones (B4, C2, C4, C5, D3) was examined for their ability to produce cytokines. A combination of cytokine detection bioassays was employed in order to compensate for differences in sensitivity and specificity, and the possibility of inhibitors masking an activity. All the IR202 variants tested were shown to secrete constitutively varying amount of interleukin (IL-6). In addition, most of the cells produce IL-10 and TGF-beta, except clones C4 and C2, respectively. Moreover, supernatants from clone B4, C2, C4, and D3 may contain low levels of soluble IL-1. Membrane-bound IL-1 was found on the surface of B4, C4, and D3 cells. None of the IR202 variants, however, produced IL-2, IL-4, tumor necrosis factor-alpha (TNF-alpha), or LT. These results are consistent with the concept of a new type of intratumor heterogeneity and the ability of immunocytoma tumors to generate different immunoregulatory molecules in tumor-bearing hosts.

Animals↗
PubMed2005

Combinatorial microRNA target predictions.

MicroRNAs are small noncoding RNAs that recognize and bind to partially complementary sites in the 3' untranslated regions of target genes in animals and, by unknown mechanisms, regulate protein production of the target transcript. Different combinations of microRNAs are expressed in different cell types and may coordinately regulate cell-specific target genes. Here, we present PicTar, a computational method for identifying common targets of microRNAs. Statistical tests using genome-wide alignments of eight vertebrate genomes, PicTar's ability to specifically recover published microRNA targets, and experimental validation of seven predicted targets suggest that PicTar has an excellent success rate in predicting targets for single microRNAs and for combinations of microRNAs. We find that vertebrate microRNAs target, on average, roughly 200 transcripts each. Furthermore, our results suggest widespread coordinate control executed by microRNAs. In particular, we experimentally validate common regulation of Mtpn by miR-375, miR-124 and let-7b and thus provide evidence for coordinate microRNA control in mammals.

Algorithms↗
PubMed2006

High-demand jobs: age-related diversity in work ability?

High-demand jobs include 'specific' job demands that are not preventable with state of the art ergonomics knowledge and may overburden the bodily capacities, safety or health of workers. An interesting question is whether the age of the worker is an important factor in explanations of diversity in work ability in the context of high-demand jobs. In this paper, the work ability of ageing workers is addressed according to aspects of diversity in specific job demands and the research methods that are needed to shed light upon the relevant associated questions. From the international literature, a body of evidence was elicited concerning rates of chronological ageing in distinct bodily systems and functions. Intra-age-cohort differences in capacities and work ability, however, require (not yet existing) valid estimates of functional age or biological age indices for the specific populations of workers in high-demand jobs. Many studies have drawn on the highly demanding work of fire-fighters, ambulance workers, police officers, medical specialists, pilots/astronauts and submarine officers. Specific job demands in these jobs can be physical, mental or psychosocial in origin but may cause combined task-level loadings. Therefore, the assessment of single demands probably will not reveal enough relevant information about work ability in high-demand jobs and there will be a call for more integrated measures. Existing studies have used a variety of methodologies to address parts of the issue: task analyses for quantifying physical work demands, observations of psychological and physiological parameters, measures of psychosocial work demands and health complaints. Specific details about the work ability of ageing workers in high-demand jobs are scarce. In general, specific demands are more likely to overtax the capacities of older workers than those of younger workers in high-demand jobs, implying greater repercussions for health, although these effects also vary considerably within age cohorts. Functional tests for job-specific work ability should be developed for high-demand jobs in order to monitor individual functional ageing and to facilitate well-timed intervention. It is concluded that a shift from 'no-diversity thinking' to 'diversity thinking' is needed in the context of deciding about the work ability of ageing workers in high-demand jobs.

Adult↗
PubMed2004

Herpes simplex virus-specific CD8+ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation.

HSV infects skin or mucosal epithelium as well as entering the sensory nerves and ganglia. We have used TCR-transgenic T cells specific for the immunodominant class I-restricted determinant from HSV glycoprotein B (gB) combined with a flank zosteriform model of infection to examine the ability of CD8+ T cells to deal with infection. During the course of zosteriform disease, virus rapidly spreads from the primary inoculation site in the skin to sensory dorsal root ganglia and subsequently reappears in the distal flank. Virus begins to be cleared from all sites about 5 days after infection when gB-specific CD8+ T cells first appear within infected tissues. Although activated gB-specific effectors can partially limit virus egress from the skin, they do so only at the earliest times after infection and are ineffective at halting the progression of zosteriform disease once virus has left the inoculation site. In contrast, these same T cells can completely clear ongoing lytic replication if transferred into infected immunocompromised RAG-1-/- mice. Therefore, we propose that the role of CD8+ T cells during the normal course of disease is to clear replicating virus after infection is well established rather than limit the initial spread of HSV from the primary site of inoculation.

Administration, Cutaneous↗
PubMed2003

Oriented and vectorial immobilization of linear M13 dsDNA between interdigitated electrodes--towards single molecule DNA nanostructures.

The ability to control molecules at a resolution well below that offered by photolithography has gained much interest recently. DNA is a promising candidate for this task since it offers excellent specificity in base-pairing combined with addressability at the nanometer scale. New applications in biosensing, e.g. interaction analysis at the single molecule level, or nanobiotechnology, e.g. ultradense DNA microarrays, have been devised that rely on stretched DNA bridges. The basic technology required is the ability to deposit spatially defined, stretched DNA-bridges between anchoring structures on surfaces. In this paper we present two techniques for spanning 2 microm long dsDNA bridges between neighboring interdigitated electrodes (IDEs). The extended DNA used was linearized M13 dsDNA (M13mp18 7231 bp, ca. 2.5 microm length), either unmodified, or with chemical modifications at both ends. The first approach is based on the dielectrophoretic (DEP) concentration and alignment of linearized wild-type dsDNA. IDEs with 1.7 microm spacing are driven with an AC voltage around 1 MHz leading to field strengths in the order of 1 MV m(-1). The dsDNA is polarized and linearized by the force field and accumulates in the gap between two neighboring electrodes. This process is reversible and was visualized by fluorescence staining of M13 DNA using PicoGreen, as intercalating dye. The resulting dsDNA bridges and their orientation are discernible under the fluorescence microscope using fluorescent particles of different color. The particles are tagged with sequence specific peptide nucleic acid (PNA) probes that bind to the DNA double strand at specific sites. The second approach is based on asymmetric electrochemical modification of a gold IDE with 2.0 microm spacings followed by spontaneous or stimulated deposition of a chemically modified M13-DNA. One side of the IDE was selectively coated with streptavidin by electropolymerization of a novel hydrophilic conductive polymer in the presence of the binding protein. The second side was modified with gold nanoparticles by reductive plating from aqueous gold chloride solution. An asymmetric double stranded (ds) M13 DNA carrying a 5'-thiol group at one end and a 5'-biotin at the other end was obtained by polymerase chain reaction (PCR) using two differently labeled primers. For DNA bridges to form spontaneously the modified IDE was incubated over night with a 50 nM solution of the modified M13 DNA. Potential applications of DNA-bridge formation in biosensing and biotechnology are discussed.

Adsorption↗
PubMed2001

Analysis of mammalian cytochrome P450 structure and function by site-directed mutagenesis.

Over the past decade, site-directed mutagenesis has become an essential tool in the study of mammalian cytochrome P450 structure-function relationships. Residues affecting substrate specificity, cooperativity, membrane localization, and interactions with redox partners have been identified using a combination of amino-acid sequence alignments, homology modeling, chimeragenesis, and site-directed mutagenesis. As homology modeling and substrate docking technology continue to improve, the ability to predict more precise functions for specific residues will also advance, making it possible to utilize site-directed mutagenesis to test these predictions. Future studies will employ site-directed mutagenesis to learn more about cytochrome P450 substrate access channels, to define the role of residues that do not lie within substrate recognition sites, to engineer additional soluble forms of microsomal cytochromes P450 for x-ray crystallography, and to engineer more efficient enzymes for drug activation and/or bioremediation.

Animals↗
PubMed1991

Purification and characterization of an enhancer-binding protein of the fibroin gene. I. Complete purification of fibroin factor 1.

An enhancer-binding protein of the fibroin gene, fibroin factor 1 (FF1), has been purified to homogeneity from crude nuclear extracts of posterior silk gland cells where this gene is transcribed specifically. There is a multiplicity of FF1; the FF1 activity was eluted as at least three major fractions on column chromatographies. FF1 is able to form a stable complex with the enhancer DNA sequence in the presence of another proteinous factor named FF2, which lacks ability to bind DNA molecules by itself. One of FF1 forms, FF1a, was purified with a combination of classical purification techniques without using a sequence-specific affinity column, and identified as a protein with molecular mass 125 kDa using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. To obtain homogeneous protein of FF1a, purification of more than 26,000-fold from the starting nuclear extract was necessary.

Animals↗