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At least 379 records · Page 21Linked to original sources
PubMed2004

The EBNA-3 gene family proteins disrupt the G2/M checkpoint.

The Epstein-Barr nuclear antigens (EBNA), EBNA-3, -4 and -6, have previously been shown to act as transcriptional regulators, however, this study identifies another function for these proteins, disruption of the G2/M checkpoint. Lymphoblastoid cell lines (LCLs) treated with a G2/M initiating drug azelaic bishydroxamine (ABHA) did not show a G2/M checkpoint response, but rather they display an increase in cell death, a characteristic of sensitivity to the cytotoxic effects of the drug. Cell cycle analysis demonstrated that the individual expression of EBNA-3, -4 or -6 are capable of disrupting the G2/M checkpoint response induced by ABHA resulting in increased toxicity, whereas EBNA-2, and -5 were not. EBNA-3 gene family protein expression also disrupted the G2/M checkpoint initiated in response to the genotoxin etoposide and the S phase inhibitor hydroxyurea. The G2 arrest in response to these drugs were sensitive to caffeine, suggesting that ATM/ATR signalling in these checkpoint responses may be blocked by the EBNA-3 family proteins. The function of EBNA-3, -4 and -6 proteins appears to be more complex than anticipated and these data suggest a role for these proteins in disrupting the host cell cycle machinery.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2003

A potent adjuvant effect of CD40 antibody attached to antigen.

There is great potential for novel vaccines based on recombinant proteins and synthetic peptides. Unfortunately these antigens often lack the immunogenicity of whole, killed pathogens used in traditional vaccines. Thus there is strong interest in the identification of immunological adjuvants with low reactogenicity, but high potency, to enhance immune responses and realize the potential of these new vaccine strategies. CD40 antibodies have been shown to have adjuvant effects when administered at very high doses. These large doses are impractical and induce a cascade of cytokine release giving rise to septic shock-like symptoms, as well as splenomegaly and polyclonal antibody production. We show here that a very small amount of CD40 antibody can exhibit potent adjuvant effects when attached to soluble antigen. The lack of detectable systemic effects indicates that this method may be a powerful and practical means of enhancing the efficacy of recombinant vaccines.

Adjuvants, Immunologic↗
PubMed2004

Statistical analysis of domains in interacting protein pairs.

MOTIVATION: Several methods have recently been developed to analyse large-scale sets of physical interactions between proteins in terms of physical contacts between the constituent domains, often with a view to predicting new pairwise interactions. Our aim is to combine genomic interaction data, in which domain-domain contacts are not explicitly reported, with the domain-level structure of individual proteins, in order to learn about the structure of interacting protein pairs. Our approach is driven by the need to assess the evidence for physical contacts between domains in a statistically rigorous way. RESULTS: We develop a statistical approach that assigns p-values to pairs of domain superfamilies, measuring the strength of evidence within a set of protein interactions that domains from these superfamilies form contacts. A set of p-values is calculated for SCOP superfamily pairs, based on a pooled data set of interactions from yeast. These p-values can be used to predict which domains come into contact in an interacting protein pair. This predictive scheme is tested against protein complexes in the Protein Quaternary Structure (PQS) database, and is used to predict domain-domain contacts within 705 interacting protein pairs taken from our pooled data set.

Algorithms↗
PubMed2006

Mcm-2 and Ki-67 have limited potential in preoperative diagnosis of thyroid malignancy.

OBJECTIVES: Minichromosome maintenance protein 2 (Mcm-2) is essential for DNA replication and serves as a useful biomarker of cell-cycle state in human tissue samples. Ki-67 is an established proliferation marker. Because Mcm-2 expression has not previously been assessed in thyroid tissue, the aim of this study was to assess the expression of both proteins in a range of thyroid lesions to determine their potential value as preoperative markers of thyroid malignancy. METHODS: Mcm-2 and Ki-67 protein expression were assessed by immunohistochemistry in formalin-fixed, paraffin-embedded thyroid tissues from 128 patients with histologic diagnoses of papillary carcinoma (n = 38), follicular carcinoma (n = 22), follicular adenoma (n = 33), and dominant nodules of multinodular goitre (n = 35). RESULTS: Mcm-2 and Ki-67-labeling indices (LIs) were both higher in follicular and papillary carcinomas than in follicular adenomas or dominant nodules. The Ki-67 LI discriminated better between follicular carcinomas and follicular adenomas (P < .0001) than Mcm-2 (P = .0273). However, the Mcm-2 and Ki-67 LIs overlapped widely between the four histologic groups, and the expression of these proteins was also noted to be heterogenous within these lesions. CONCLUSION: Neither Mcm-2 or Ki-67 can currently be reliably applied as preoperative markers to distinguish benign from malignant thyroid lesions.

Adenoma↗
PubMed2006

Identifying interaction motifs in CK2beta--a ubiquitous kinase regulatory subunit.

Casein kinase 2 (CK2) is probably the most ubiquitous serine/threonine kinase found in eukaryotes: it phosphorylates >300 cellular proteins, ranging from transcription factors to proteins involved in chromatin structure and cell division. CK2 is a heterotetrameric enzyme that induces neoplastic growth when overexpressed. The beta subunit of CK2 (CK2beta) functions as the regulator of the catalytic CK2alpha and CK2alpha' subunits, enhancing their stability, activity and specificity. However, CK2beta also functions as a multisubstrate docking platform for several other binding partners. Here, we discuss the organization and roles of interaction motifs of CK2beta, postulate new protein-interaction sites and map these to the known interaction motifs, and show how the resulting complexity of interactions mediated by CK2 gives rise to the versatile functions of this pleiotropic protein kinase.

Amino Acid Motifs↗
PubMed2007

Error analysis of ultrasonic tissue doppler velocity estimation techniques for quantification of velocity and strain.

Recent work in the field of Doppler tissue imaging has focused mainly on the quantification of results involving the use of techniques of strain and strain-rate imaging. These results are based on measuring a velocity gradient between two points, a known distance apart, in the region-of-interest. Although many recent publications have demonstrated the potential of this technique in clinical terms, the method still suffers from low repeatability. The work presented here demonstrates, through the use of a rotating phantom arrangement and a custom developed single element ultrasound system, that this is a consequence of the fundamental accuracy of the technique used to estimate the original velocities. Results are presented comparing the performance of the conventional Kasai autocorrelation velocity estimator with those obtained using time domain cross-correlation and the complex cross-correlation model based estimator. The results demonstrate that the complex cross-correlation model based technique is able to offer lower standard deviations of the velocity gradient estimations compared with the Kasai algorithm.

Algorithms↗
PubMed2005

Calculation of excitation energies of open-shell molecules with spatially degenerate ground states. I. Transformed reference via an intermediate configuration Kohn-Sham density-functional theory and applications to d1 and d2 systems with octahedral and tetrahedral symmetries.

A method for calculating the UV-vis spectra of molecules with spatially degenerate ground states using time-dependent density-functional theory (TDDFT) is proposed. The new transformed reference via an intermediate configuration Kohn-Sham TDDFT (TRICKS-TDDFT) method avoids the difficulties caused by the multireference nature of spatially degenerate states by rather than utilizing the ground state instead taking a nondegenerate excited state with desirable properties as the reference for the TDDFT calculation. The scope and practical application of the method are discussed. Like all open-shell TDDFT calculations this method at times suffers from the inability to produce transitions to states that are eigenfunctions of the total spin operator. A technique for alleviating this difficulty to some extent is proposed. The applicability and accuracy of the TRICKS-TDDFT method is demonstrated through example calculations of several d(1) and d(2) transition metal complexes with tetrahedral and octahedral symmetries. For the most part, the results of these calculations are similar in quality to to those obtained from standard TDDFT calculations.

Journal Article↗
PubMed2002

Diminished interferon-gamma production and responsiveness after endotoxin administration to healthy humans.

To obtain insight in the capacity of the lipopolysaccharide (LPS)-tolerant host to produce interferon (IFN)-gamma and to respond to this cytokine, whole blood was obtained from healthy humans before and 4 h after intravenous injection of LPS (4 ng/kg) and stimulated ex vivo. LPS exposure in vivo resulted in a diminished capacity to produce IFN-gamma after restimulation with LPS, together with a reduced ability to release the IFN-gamma-inducing cytokines interleukin (IL)-12 and IL-18 and with reduced responsiveness toward these cytokines. In addition, IFN-gamma responsiveness was strongly diminished after in vivo LPS exposure, as shown by the fact that blood obtained after LPS injection could not be primed by IFN-gamma for LPS-induced tumor necrosis factor-alpha release and that peripheral blood monocytes could not be stimulated by IFN-gamma to up-regulate major histocompatibility complex type II expression. Experimentally induced immunoparalysis is associated with strongly reduced IFN-gamma production and responsiveness.

Adult↗
PubMed2004

Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease.

The performance of the Modification of Diet in Renal Disease (MDRD) and the Cockcroft-Gault (CG) equations as compared with measured (125)I-iothalamate GFR (iGFR) was analyzed in patients with chronic kidney disease (CKD) and in potential kidney donors. All outpatients (n = 1285) who underwent an iGFR between 1996 and 2003 were considered for analysis. Of these, 828 patients had CKD and 457 were potential kidney donors. Special emphasis was put on the calibration of the serum creatinine measurements. In CKD patients with GFR <60 ml/min per 1.73 m(2), the MDRD equation performed better than the CG formula with respect to bias (-0.5 versus 3.5 ml/min per 1.73 m(2), respectively) and accuracy within 30% (71 versus 60%, respectively) and 50% (89 versus 77%, respectively). Similar results are reported for 249 CKD patients with diabetes. In the kidney donor group, the MDRD equation significantly underestimated the measured GFR when compared with the CG formula, with a bias of -9.0 versus 1.9 ml/min per 1.73 m(2), respectively (P < 0.01), and both the MDRD and CG equations overestimated the strength of the association of GFR with measured serum creatinine. The present data add further validation of the MDRD equation in outpatients with moderate to advanced kidney disease as well as in those with diabetic nephropathy but suggest that its use is problematic in healthy individuals. This study also emphasizes the complexity of laboratory calibration of serum creatinine measurements, a determining factor when estimating GFR in both healthy individuals and CKD patients with preserved GFR.

Adult↗
PubMed2002

Metabolic flux analysis of Candida tropicalis growing on xylose in an oxygen-limited chemostat.

We have studied the metabolism of xylose by Candida tropicalis in oxygen-limited chemostat. In vitro enzyme assays indicated that glycolytic and gluconeogenetic enzymes are expressed simultaneously facilitating substrate cycling. Enhancing the redox imbalance by cofeeding of formate increased xylose and oxygen consumption rates and ethanol, xylitol, glycerol and CO2 production rates at steady state. Metabolic flux analysis (MFA) indicated that fructose 6-phosphate is replenished from the pentose phosphate pathway in sufficient amounts without contribution of the gluconeogenetic pathway. Substrate cycling between pyruvate kinase, pyruvate carboxylase and phospho-enol-pyruvate kinase increased ATP turnover. Cofeeding of formate increased the ATP yield. The ATP yields of xylose and xylose-formate cultivation were 6.9 and 8.7 mol ATP/C-mol CDW, respectively, as calculated from the MFA.

Bioreactors↗
PubMed1991

Proto-oncogene transcription factors and epilepsy.

Chemically and electrically induced seizures elicit the rapid transcriptional activation in neurons of a class of genes referred to as cellular immediate-early genes. Since the products of these genes include transcription factors and cytokines, they are proposed to be involved in coupling neuronal excitation to a complex, and poorly understood, programme of cellular responses that involves the regulation of gene expression. Products of two cellular immediate-early genes, c-fos and c-jun, are components of the transcription factor AP-1. In this review, Jim Morgan and Tom Curran discuss how these gene products have begun to reveal some of the molecular details of stimulus-transcription coupling in the nervous system following seizures. In addition, these genes have provided novel reagents and concepts for investigating the biochemical and cellular sequelae of seizure in the CNS, and point towards new avenues of research and potential therapeutic targets in epilepsy.

Animals↗
PubMed2002

The hydroxyphenylpyruvate dioxygenase from Synechocystis sp. PCC 6803 is not required for plastoquinone biosynthesis.

The disruption of the Synechocystis open reading frame Deltaslr0090 encoding a gene with high homology to plant genes encoding 4-hydroxyphenylpyruvate dioxygenase results in an impairment of tocopherol biosynthesis without affecting levels of plastoquinone, carotenoids and chlorophyll as well as cell growth and photosynthesis. Our results indicate that in Synechocystis in contrast to the situation in higher plants the 4-hydroxyphenylpyruvate dioxygenase is not required for the synthesis of plastoquinone.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2002

Amino acid deletions in the cytosolic domains of the chlorophyll a-binding protein CP47 slow Q(A)- oxidation and/or prevent the assembly of photosystem II.

The Photosystem II (PSII) core antenna chlorophyll a-binding protein, CP47, contains six membrane-spanning alpha-helices separated by five hydrophilic loops: A-E. To identify important hydrophilic cytosolic regions, oligonucleotide-directed mutagenesis was employed to introduce short segment deletions into loops B and D, and the C-terminal domain. Four strains carrying deletions of between three and five residues were created in loop B. Two strains, with deletions adjacent to helices II and III, did not assemble PSII; however, the mutants delta(F123-D125) and delta(R127-S131) remained photoautotrophic with near wild-type levels of assembled reaction centers. In contrast, all deletions introduced into loop D, connecting helices IV and V, failed to assemble significant levels of PSII and were obligate photoheterotrophic mutants. However, deletions in the C-terminal domain did not prevent the assembly of PSII reaction centers although the mutant delta(S471 -T473), with a deletion adjacent to helix V1, exhibited retarded Q(A)- oxidation kinetics and the PSII-specific herbicide, atrazine, bound less tightly in the delta(S471-T473) and delta(F475-D477) strains. Deletions in the C-terminal domain also created mutants with large protein aggregates that were recognized by an antibody raised against the PSII reaction center D1 protein. Low-temperature fluorescence emission spectra of photoautotrophic strains carrying deletions in either the C-terminal domain or loop B did not provide evidence for impaired energy transfer from the phycobilisomes to the PSII reaction center. The data therefore suggest an important structural role for loop D in the assembly of PSII and a potential interaction between the C-terminal domain of CP47 and the PSII reaction center that, when perturbed, results in photoinduced protein aggregates involving the D1 protein.

Amino Acid Sequence↗
PubMed2005

Inactivation of photosynthetic electron flow during desiccation of desert biological sand crusts and Microcoleus sp.-enriched isolates.

Filamentous cyanobacteria, the main primary producers in biological sand crusts, survive harsh environmental conditions including diurnal desiccation/rehydration cycles. Here we describe the inactivation of photosystem II during dehydration of native crusts (NC) and Microcoleus sp. isolates grown on nitrocellulose filters (NCF). The morphology of NCF cells, visualized by scanning-transmission and atomic-force microscopy, disclosed long bacterial filaments encapsulated in extracellular polysaccharides (EPS) tubes consisting of parallel fibrils (100-400 nm wide and 50-100 nm high) oriented mostly perpendicular to the tube length. Presence of empty EPS tubes indicated a gliding capability of the cells. Desiccation of NC resulted in a rapid decline of F(o) and complete loss of F(v). These changes were accompanied by a decrease of 77 K PSII fluorescence emission relative to that of PSI, when excited at 430 nm, and a significant decrease of energy transfer from phycobilisomes to PSII. Lowering the turgor pressure through the addition of 1.5 M trehalose to natural crusts, reduced F(v)/F(m) by over 50% and was accompanied by a decrease of 77 K PSI fluorescence induced by chlorophyll excitation. Excitation of phycobilisomes resulted in a downshift of the PSI emission wavelength by 8 nm, indicative of reduced energy transfer from LHCI to the core PSI. Decline of F(v)/F(m) in trehalose-incubated NCF cells did not induce significant changes in 77 K fluorescence emission. These results suggest that alterations in energy transfer from antennae to reaction centers may be part of the survival strategy of Microcoleus.

Cyanobacteria↗
PubMed2005

Defining operational taxonomic units using DNA barcode data.

The scale of diversity of life on this planet is a significant challenge for any scientific programme hoping to produce a complete catalogue, whatever means is used. For DNA barcoding studies, this difficulty is compounded by the realization that any chosen barcode sequence is not the gene 'for' speciation and that taxa have evolutionary histories. How are we to disentangle the confounding effects of reticulate population genetic processes? Using the DNA barcode data from meiofaunal surveys, here we discuss the benefits of treating the taxa defined by barcodes without reference to their correspondence to 'species', and suggest that using this non-idealist approach facilitates access to taxon groups that are not accessible to other methods of enumeration and classification. Major issues remain, in particular the methodologies for taxon discrimination in DNA barcode data.

Animals↗
PubMed2004

Mastrus ridibundus parasitoids eavesdrop on cocoon-spinning codling moth, Cydia pomonella, larvae.

Cocoon-spinning larvae of the codling moth, Cydia pomonella L. (Lepidoptera: Olethreutidae) employ a pheromone that attracts or arrests conspecifics seeking pupation sites. Such intraspecific communication signals are important cues for illicit receivers such as parasitoids to exploit. We tested the hypothesis that the prepupal C. pomonella parasitoid Mastrus ridibundus Gravenhorst (Hymenoptera: Ichneumonidae) exploits the larval aggregation pheromone to locate host prepupae. In laboratory olfactometer experiments, female M. ridibundus were attracted to 3-day-old cocoons containing C. pomonella larvae or prepupae. Older cocoons containing C. pomonella pupae, or larvae and prepupae excised from cocoons, were not attractive. In gas chromatographic-electroantennographic detection (GC-EAD) analyses of bioactive Porapak Q extract of cocoon-derived airborne semiochemicals, ten compounds elicited responses from female M. ridibundus antennae. Comparative GC-mass spectrometry of authentic standards and cocoon-volatiles determined that these compounds were 3-carene, myrcene, heptanal, octanal, nonanal, decanal, (E)-2-octenal, (E)-2-nonenal, sulcatone, and geranylacetone. A synthetic 11-component blend consisting of these ten EAD-active compounds plus EAD-inactive (+)-limonene (the most abundant cocoon-derived volatile) was as effective as Porapak Q cocoon extract in attracting both female M. ridibundus and C. pomonella larvae seeking pupation sites. Only three components could be deleted from the 11-component blend without diminishing its attractiveness to M. ridibundus, which underlines the complexity of information received and processed during foraging for hosts. Mastrus ridibundus obviously "eavesdrop" on the pheromonal communication signals of C. pomonella larvae that reliably indicate host presence.

Animals↗
PubMed2006

Structure and function of Hsp78, the mitochondrial ClpB homolog.

The cellular role of Hsp100/Clp chaperones in maintaining protein stability is based on two functional aspects. Under normal growth conditions they represent components of cellular protein quality control machineries that selectively remove damaged or misfolded polypeptides in cooperation with specific proteases. After thermal stress, proteins of the ClpB subfamily have the unique ability to directly resolubilize aggregated polypeptides in concert with Hsp70-type chaperones, leading to the recovery of enzymatic activity. Hsp78, the homolog of the bacterial chaperone ClpB in mitochondria of eukaryotic organisms, participates in both protective activities. Hsp78 is involved in conferring thermotolerance to the mitochondrial compartment but also participates in protein degradation by the matrix protease Pim1. Despite the high sequence conservation between Hsp78 and ClpB, an analysis of the structural properties revealed significant differences. The identified mitochondrial Hsp78s do not contain N-terminal substrate-binding domains. In addition, formation of the oligomeric chaperone complex was more variable as anticipated from the studies with bacterial ClpB. Hsp78 predominantly formed a trimeric complex under in vivo conditions. Hence, mitochondrial Hsp78s form a distinct subgroup of the ClpB chaperone family, exhibiting specific structural and functional properties.

Amino Acid Sequence↗
PubMed2002

Differential affinity and cooperativity functions of the amino-terminal 70 residues of lambda integrase.

The site-specific recombinase (Int) of bacteriophage lambda is a heterobivalent DNA-binding protein that binds two different classes of DNA-binding sites within its recombination target sites. The several functions of Int are apportioned between a large carboxy-terminal domain that cleaves and ligates DNA at each of its four "core-type" DNA-binding sites and a small amino-terminal domain, whose primary function is binding to each of its five "arm-type" DNA sites, which are distant from the core region. Int bridges between the two classes of binding sites are facilitated by accessory DNA-bending proteins that along with Int comprise higher-order recombinogenic complexes. We show here that although the 64 amino-terminal residues of Int bind efficiently to a single arm site, this protein cannot form doubly bound complexes on adjacent arm sites. However, 1-70 Int does show the same cooperative binding to adjacent arm sites as the full length protein. We also found that 1-70 Int specifies cooperative interactions with the accessory protein Xis when the two are bound to their adjacent cognate sites P2 and X1, respectively. To complement the finding that these two amino-terminal domain functions (along with arm DNA binding) are all specified by residues 1-70, we determined that Thr75 is the first residue of the minimal carboxy-terminal domain, thereby identifying a specific interdomain linker region. We have measured the affinity constants for Int binding to each of the five arm sites and the cooperativity factors for Int binding to the two pairs of adjacent arm sites, and we have identified several DNA structural features that contribute to the observed patterns of Int binding to arm sites. Taken together, the results highlight several interesting features of arm DNA binding that invite speculation about additional levels of complexity in the regulation of lambda site-specific recombination.

Amino Acid Sequence↗