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At least 469 records · Page 26Linked to original sources
PubMed2003

Interference with T cell receptor-HLA-DR interactions by Epstein-Barr virus gp42 results in reduced T helper cell recognition.

Epstein-Barr virus (EBV) persists lifelong in infected hosts despite the presence of antiviral immunity. Many viral antigens are expressed during lytic infection. Thus, for EBV to spread, it must have evolved effective ways to evade immune recognition. Here, we report that HLA class II-restricted antigen presentation to T helper cells is hampered in the presence of the lytic-phase protein gp42. This interference with T cell activation involves association of gp42 with class II peptide complexes. Using HLA-DR tetramers, we identify a block in T cell receptor (TCR)-class II interactions imposed by gp42 as the underlying mechanism. EBV gp42 sterically clashes with TCR Valpha-domains as visualized by superimposing the crystal structures for gp42-HLA-DR1 and TCR-MHC class II complexes. Blocking TCR recognition provides a previously undescribed strategy for viral immune evasion.

Flow Cytometry↗
PubMed2002

From information management to protein annotation: preparing protein structures for drug discovery.

In contrast to academic pursuits of structural genomics, Structural GenomiX (SGX) solves protein structures at high throughput for the main purpose of enhancing drug-discovery projects, either internally or in partnership with pharmaceutical/biotechnology companies. This involves a radical redesign of the pipeline of methods that turn a gene sequence into a three-dimensional protein structure. The various processes all report electronically to a Laboratory Information Management System (LIMS) to make sure all the parameters of the experiment are recorded in an accessible and 'mineable' form, helping guarantee reproducibility of results. Quality control at several key points keeps the process from branching out on a wrong hypothesis. Protein annotation, in a broad sense, takes care of the interpretation of a protein crystal structure or the crystal structure of one or several protein-ligand complexes. This interpretation both gathers all necessary biological information (protein function, mechanism, specific features within a protein family etc.) and hands over this information in a form accessible to medicinal chemistry teams designing specific small-molecule agonists or antagonists.

Crystallization↗
PubMedDate not supplied

Polycyclic aromatic hydrocarbon release from a soil matrix in the in vitro gastrointestinal tract.

Soil ingestion is an important exposure route by which immobile soil contaminants enter the human body. We assessed polycyclic aromatic hydrocarbon (PAH) release from a contaminated soil, containing 49 mg PAH kg(-1), using a SHIME (Simulator of the Human Intestinal Microbial Ecosystem) reactor comprising the stomach, duodenal, and colon compartments. Polycyclic aromatic hydrocarbon release was defined as that fraction remaining in the digest supernatant after centrifugation for 5 min at 1500 x g. The PAH release in the stomach digest was only 0.44% of the total PAH present in soil, resulting in PAH concentrations of 23 micrograms PAH L(-1) chyme. The lower PAH releases in duodenum (0.13%) and colon (0.30%) digests, compared with the stomach digest, were thought to be attributed to combined complexation and precipitation with bile salts, dissolved organic matter, or colon microbiota. We studied these complexation processes in an intestinal suspension more in depth by preparing mixtures of 9-anthracenepropionic acid, a Bacillus subtilis culture, and cholin as model compounds for PAHs, organic matter, and bile salts, respectively. Bile salts or organic matter in the aqueous phase initially enhance PAH desorption from soil. However, desorbed PAHs may form large aggregates with bile and organic matter, lowering the freely dissolved PAH fraction in the supernatant. Using the model compounds, mathematical equations were developed and validated to predict PAH complexation processes in the gastrointestinal tract. Contaminant release and subsequent complexation in the gut is an important prerequisite to intestinal absorption and thus bioavailability of that contaminant. The data from this research may help in understanding the processes to which PAHs are subjected in the gastrointestinal tract, before intestinal absorption.

Absorption↗
PubMed2004

Complexity made simple. Interview by David Ollier Weber.

In a preview of his keynote address at July's Health Forum and AHA Summit, Petzinger describes how--as in nature--everything in an organization is interconnected and why recognizing that fact can lead to real solutions to all sorts of problems.

Decision Making, Organizational↗
PubMed2005

The cyclin-dependent kinase inhibitor KRP2 controls the onset of the endoreduplication cycle during Arabidopsis leaf development through inhibition of mitotic CDKA;1 kinase complexes.

Exit from the mitotic cell cycle and initiation of cell differentiation frequently coincides with the onset of endoreduplication, a modified cell cycle during which DNA continues to be duplicated in the absence of mitosis. Although the mitotic cell cycle and the endoreduplication cycle share much of the same machinery, the regulatory mechanisms controlling the transition between both cycles remain poorly understood. We show that the A-type cyclin-dependent kinase CDKA;1 and its specific inhibitor, the Kip-related protein, KRP2 regulate the mitosis-to-endocycle transition during Arabidopsis thaliana leaf development. Constitutive overexpression of KRP2 slightly above its endogenous level only inhibited the mitotic cell cycle-specific CDKA;1 kinase complexes, whereas the endoreduplication cycle-specific CDKA;1 complexes were unaffected, resulting in an increase in the DNA ploidy level. An identical effect on the endoreduplication cycle could be observed by overexpressing KRP2 exclusively in mitotically dividing cells. In agreement with a role for KRP2 as activator of the mitosis-to-endocycle transition, KRP2 protein levels were more abundant in endoreduplicating than in mitotically dividing tissues. We illustrate that KRP2 protein abundance is regulated posttranscriptionally through CDK phosphorylation and proteasomal degradation. KRP2 phosphorylation by the mitotic cell cycle-specific CDKB1;1 kinase suggests a mechanism in which CDKB1;1 controls the level of CDKA;1 activity through regulating KRP2 protein abundance. In accordance with this model, KRP2 protein levels increased in plants with reduced CDKB1;1 activity. Moreover, the proposed model allowed a dynamical simulation of the in vivo observations, validating the sufficiency of the regulatory interactions between CDKA;1, KRP2, and CDKB1;1 in fine-tuning the mitosis-to-endocycle transition.

Arabidopsis↗
PubMed2003

An extensible and systematic force field, ESFF, for molecular modeling of organic, inorganic, and organometallic systems.

ESFF is a rule-based force field designed for modeling organic, inorganic, and organometallic systems. To cover this broad range of molecular systems, ESFF was developed in an extensible and systematic manner. Several unique features were introduced including pseudoangle and a dot product function representing torsion energy terms. The partial atomic charges that are topology-dependent are determined from ab initio (DFT) calculated electronegativity and hardness for valence orbitals. The van der Waals parameters are charge-dependent, and correlated with the ionization potential for atoms in various valence states. To obtain a set of well-defined and physically meaningful parameters, ESFF employs semiempirical rules to translate atomic-based parameters to parameters typically associated with a covalent valence force field. The atomic parameters depend not only on atom type, but also on internal type, thus resulting in a more accurate force field. This article presents the theory and the method used to develop the force field. The force field has been applied to molecular simulations of a wide variety of systems including nucleic acids, peptides, hydrocarbons, porphyrins, transition metal complexes, zeolites, and organometallic compounds. Agreement with the experimental results indicates that ESFF is a valuable tool in molecular simulations for understanding and predicting both crystal and gas phase molecular structures.

Algorithms↗
PubMed2002

A conserved proline residue is present in the transmembrane-spanning domain of Tom7 and other tail-anchored protein subunits of the TOM translocase.

The TOM translocase consists of several integral membrane proteins organised around the channel forming protein Tom40. Here we show that one of these protein subunits, Tom7, is a tail-anchored protein. The carboxy-terminal 33 amino acids of Tom7 contain the information for targeting the protein to the mitochondrial outer membrane, and a conserved proline residue within the transmembrane segment is required for efficient targeting of Tom7 to the outer membrane. An equivalent proline residue is important in targeting each of the other three tail-anchored proteins that associate with Tom40 to form the core of the TOM translocase.

Carrier Proteins↗
PubMed2003

Economic evaluation of specialist cancer and palliative nursing: a literature review.

Little progress has been made in economic evaluation of specialist cancer and palliative care nursing. A literature review of economic studies of clinical nurse specialists (CNSs) was undertaken to assess how the measurement of economic outcomes has been tackled in the literature to date. The initial search found 400 studies. Abstracts from all the studies were reviewed but only 17 studies met the basic criteria for inclusion, reporting primary cost and outcomes data, and clearly specifying the role of a CNS. All of the studies but one focused on direct patient care rather than other CNS roles and were undertaken alongside effectiveness studies. The economic evaluations considered only a narrow range of costs, but a wide range of outcomes. Specific nursing outcomes were only reported in a minority of studies. None of the studies reported cost-effectiveness ratios. However, CNS interventions were reported to be both less costly and more effective than alternative forms of care, negating the need for further cost-effectiveness analysis. Overall, the papers were not of good quality, reducing the validity of the findings. Robust economic evaluations of the CNS role need to be undertaken. These should involve nursing researchers and practitioners so that evaluations reflect the complex and multidimensional nature of CNS care and meet the required standard of evidence to influence practice.

Cost-Benefit Analysis↗
PubMed2004

Pancreatic transplantation at the University of Pittsburgh.

Campath-1H preconditioning with tacrolimus monotherapy is an effective immunosuppressive regimen for pancreas transplantation, with acceptable patient and graft survival rates early after transplantation. Rejection rates are low under this protocol if the tacrolimus level is kept consistently >10 ng/ml. This immunosuppressive protocol, combined with recent technical refinements, has resulted in lower rates of thrombosis and overall complications. Pancreatic transplantation en-bloc with visceral grafts has the following unique features: Diabetes is a rare indication, and HLA matching is not required. The gland is immunologically protected by the simultaneously transplanted visceral organs. Disease gravity, surgical complexity and gut alloimmunity influence the overall pancreatic allograft survival. The current UNOS listing criteria and data registry should be modified for obvious logistic and scientific reasons.

Adolescent↗
PubMed2004

Condensed mitotic chromatin is accessible to transcription factors and chromatin structural proteins.

During mitosis, chromosomes are highly condensed and transcription is silenced globally. One explanation for transcriptional repression is the reduced accessibility of transcription factors. To directly test this hypothesis and to investigate the dynamics of mitotic chromatin, we evaluate the exchange kinetics of several RNA polymerase I transcription factors and nucleosome components on mitotic chromatin in living cells. We demonstrate that these factors rapidly exchange on and off ribosomal DNA clusters and that the kinetics of exchange varies at different phases of mitosis. In addition, the nucleosome component H1c-GFP also shows phase-specific exchange rates with mitotic chromatin. Furthermore, core histone components exchange at detectable levels that are elevated during anaphase and telophase, temporally correlating with H3-K9 acetylation and recruitment of RNA polymerase II before the onset of bulk RNA synthesis at mitotic exit. Our findings indicate that mitotic chromosomes in general and ribosomal genes in particular, although highly condensed, are accessible to transcription factors and chromatin proteins. The phase-specific exchanges of nucleosome components during late mitotic phases are consistent with an emerging model of replication independent core histone replacement.

Acetylation↗
PubMed2003

Histone H2A/H2B dimer exchange by ATP-dependent chromatin remodeling activities.

ATP-dependent chromatin remodeling activities function to manipulate chromatin structure during gene regulation. One of the ways in which they do this is by altering the positions of nucleosomes along DNA. Here we provide support for the ability of these complexes to move nucleosomes into positions in which DNA is unraveled from one edge. This is expected to result in the loss of histone-DNA contacts that are important for retention of one H2A/H2B dimer within the nucleosome. Consistent with this we find that several chromatin remodeling complexes are capable of catalyzing the exchange of H2A/H2B dimers between chromatin fragments in an ATP-dependent reaction. This provides eukaryotes with additional means by which they may manipulate chromatin structure.

Adenosine Triphosphatases↗
PubMed2002

Novel ATPase of SNF2-like protein family interacts with androgen receptor and modulates androgen-dependent transcription.

Nuclear receptors, including the androgen receptor (AR), regulate target cell transcription through interaction with auxiliary proteins to modify chromatin structure. We describe herein a novel AR-interacting protein, termed ARIP4, that has structural features typical of the SNF2-like protein family. With regard to the Snf2 domain, the closest homolog of ARIP4 is the ATRX protein. ARIP4 is a nuclear protein and comprises 1466 amino acids. It interacts with AR in vitro and in cultured yeast and mammalian cells. ARIP4 can be labeled with 8-azido-[gamma-32P]ATP and exhibits DNA-dependent ATPase activity. Like several ATP-dependent chromatin remodeling proteins, ARIP4 generates superhelical torsion within linear DNA fragments in an ATP-dependent manner. With a stably integrated target promoter, ARIP4 elicits a modest enhancement of AR-dependent transactivation. In transient cotransfection assays, ARIP4 modulates AR function in a promoter-dependent manner; it enhances receptor activity on minimal promoters, but does not activate more complex promoters. ARIP4 mutants devoid of ATPase activity fail to alter DNA topology and behave as trans-dominant negative regulators of AR function in transient assays.

Adenosine Triphosphatases↗
PubMed2003

High- versus low-fat diets in human diseases.

PURPOSE OF REVIEW: To evaluate the evidence with regard to high-versus low-fat diets in the context of the prevention and management of obesity, type 2 diabetes and coronary heart disease. RECENT FINDINGS: Despite the increasing prevalence of obesity, there is no evidence to support the view that this is caused by an increased intake of fat. Fat sensors play an important role in regulating energy balance and lipid metabolism, and hypoenergetic diets containing 30-35% energy from fat promote weight loss. High intakes of carbohydrates with a high glycaemic index can result in insulin resistance, but this effect can be modulated by increased physical activity. SUMMARY: Although arguments to decrease the intake of trans and saturated fatty acids are cogent, the scientific basis for a reduction in the proportion of energy from fat below 30% energy is not supported by experimental evidence. A modest reduction in fat intake to 30-35% energy, with the bulk of carbohydrates being derived from complex carbohydrates from unrefined sources, would appear to be the best option for the prevention of obesity and cardiovascular disease. Increased physical activity appears to be particularly important in modulating the adverse effects associated with high-carbohydrate low-fat diets.

Coronary Disease↗
PubMed2006

A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling.

Protein degradation, chromatin remodeling, and membrane trafficking are critically regulated by ubiquitylation. The presence of several coexisting ubiquitin-dependent processes, each of crucial importance to the cell, is remarkable. This brings up questions on how the usage of this versatile regulator is negotiated between the different cellular processes. During proteotoxic stress, the accumulation of ubiquitylated substrates coincides with the depletion of ubiquitylated histone H2A and chromatin remodeling. We show that this redistribution of ubiquitin during proteotoxic stress is a direct consequence of competition for the limited pool of free ubiquitin. Thus, the ubiquitin cycle couples various ubiquitin-dependent processes because of a rate-limiting pool of free ubiquitin. We propose that this ubiquitin equilibrium may allow cells to sense proteotoxic stress in a genome-wide fashion.

Active Transport, Cell Nucleus↗
PubMed2004

Disruption of intestinal motility by a calcium channel-stimulating autoantibody in type 1 diabetes.

BACKGROUND & AIMS: Autonomic neuropathy, including gastrointestinal dysfunction, is a common complication of type 1 diabetes; however, its cause is uncertain. This study aimed to test whether functional autoantibodies cause the gastrointestinal dysfunction. METHODS: We used isolated mouse colon undergoing colonic migrating motor complex (MMC) activity to test for autoantibodies that disrupt colonic motility. Purified immunoglobulin G (IgG) from patients with type 1 diabetes or from controls was tested either in vitro or after passive transfer. Pharmacological studies of the interaction between the IgG and L-type calcium channel activator (Bay K8644) and inhibitors (nicardipine and verapamil) were performed. The effect of IgG on nerve-evoked contraction of the vas deferens longitudinal smooth muscle was also assessed. RESULTS: MMC activity was disrupted by IgG (0.2 mg/mL) from 8 of 16 patients with type 1 diabetes but not by control IgG. Passive transfer of diabetic IgG to mice also disrupted MMCs, showing access to the antigen in vivo. The acute effect of the autoantibody was mimicked by the dihydropyridine agonist, Bay K8644 (2-10 nmol/L), and both Bay K8644 and the autoantibody competitively inhibited the effect on MMC contraction of the dihydropyridine antagonist, nicardipine. Diabetic IgG, but not control IgG, altered the nerve-evoked contractile activity of vas deferens smooth muscle effects mimicked by Bay K8644. CONCLUSIONS: A novel functional autoantibody that activates smooth muscle L-type calcium channels at the dihydropyridine binding site is produced specifically by patients with type 1 diabetes and may mediate gastrointestinal and autonomic dysfunction in these patients.

Adult↗
PubMed2004

In vivo kinetics of Cajal body components.

Cajal bodies (CBs) are subnuclear domains implicated in small nuclear ribonucleoprotein (snRNP) biogenesis. In most cell types, CBs coincide with nuclear gems, which contain the survival of motor neurons (SMN) complex, an essential snRNP assembly factor. Here, we analyze the exchange kinetics of multiple components of CBs and gems in living cells using photobleaching microscopy. We demonstrate differences in dissociation kinetics of CB constituents and relate them to their functions. Coilin and SMN complex members exhibit relatively long CB residence times, whereas components of snRNPs, small nucleolar RNPs, and factors shared with the nucleolus have significantly shorter residence times. Comparison of the dissociation kinetics of these shared proteins from either the nucleolus or the CB suggests the existence of compartment-specific retention mechanisms. The dynamic properties of several CB components do not depend on their interaction with coilin because their dissociation kinetics are unaltered in residual nuclear bodies of coilin knockout cells. Photobleaching and fluorescence resonance energy transfer experiments demonstrate that coilin and SMN can interact within CBs, but their interaction is not the major determinant of their residence times. These results suggest that CBs and gems are kinetically independent structures.

Animals↗
PubMed2005

Applicability of the SQM force field method to the vibrational spectra of sodium acetate.

The applicability of the scaled quantum mechanical force field (SQM FF) method to the prediction of the vibrational spectra of a charged molecule has been studied by the example of the acetate ion (CH3CO2-) in sodium acetate for which an efficient empirical valence force field (SVFF) based on observed IR spectra of six isotopomers of sodium acetate is available in the literature. Standard SQM FF calculations done on a free acetate ion at the B3LYP/6-31G level failed to give an acceptable estimation of even the most characteristic features of the observed spectra, which can be exemplified by the gross overestimation of the frequency separation of the nu(a)CO2- and nu(s)CO2- vibrations. In search for a better description, SQM calculations were done for three simple structural models of sodium acetate, testing different QM methods. The results indicate that in addition to taking into account the dielectric field effect of the surrounding medium, incorporation of a Na+ counterion is necessary to achieve a realistic simulation of the IR and Raman spectra. Satisfactory results were obtained with a bidentate Na-acetate complex by the SQM method coupled with a continuum model at the B3LYP/6-31+G level, whereas the use of the Onsager-type spherical cavity model and the polarizable continuum model (PCM) were found preferable over SCI-PCM.

Journal Article↗
PubMed2004

Protein engineering of cytochrome b562 for quinone binding and light-induced electron transfer.

The central photochemical reaction in photosystem II of green algae and plants and the reaction center of some photosynthetic bacteria involves a one-electron transfer from a light-activated chlorin complex to a bound quinone molecule. Through protein engineering, we have been able to modify a protein to mimic this reaction. A unique quinone-binding site was engineered into the Escherichia coli cytochrome b(562) by introducing a cysteine within the hydrophobic interior of the protein. Various quinones, such as p-benzoquinone and 2,3-dimethoxy-5-methyl-1,4-benzoquinone, were then covalently attached to the protein through a cysteine sulfur addition reaction to the quinone ring. The cysteine placement was designed to bind the quinone approximately 10 A from the edge of the bound porphyrin. Fluorescence measurements confirmed that the bound hydroquinone is incorporated toward the protein's hydrophobic interior and is partially solvent-shielded. The bound quinones remain redox-active and can be oxidized and rereduced in a two-electron process at neutral pH. The semiquinone can be generated at high pH by a one-electron reduction, and the midpoint potential of this can be adjusted by approximately 500 mV by binding different quinones to the protein. The heme-binding site of the modified cytochrome was then reconstituted with the chlorophyll analogue zinc chlorin e(6). By using EPR and fast optical techniques, we show that, in the various chlorin-protein-quinone complexes, light-induced electron transfer can occur from the chlorin to the bound oxidized quinone but not the hydroquinone, with electron transfer rates in the order of 10(8) s(-1).

Binding Sites↗