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C Meier

Publications and source records attributed to C Meier.

At least 19 recordsLinked to original sources
PubMed2006

SPINE workshop on automated X-ray analysis: a progress report.

The Structural Proteomics In Europe (SPINE) consortium contained a workpackage to address the automated X-ray analysis of macromolecules. The aim of this workpackage was to increase the throughput of three-dimensional structures while maintaining the high quality of conventional analyses. SPINE was able to bring together developers of software with users from the partner laboratories. Here, the results of a workshop organized by the consortium to evaluate software developed in the member laboratories against a set of bacterial targets are described. The major emphasis was on molecular-replacement suites, where automation was most advanced. Data processing and analysis, use of experimental phases and model construction were also addressed, albeit at a lower level.

Algorithms↗
PubMed2006

Application of high-throughput technologies to a structural proteomics-type analysis of Bacillus anthracis.

A collaborative project between two Structural Proteomics In Europe (SPINE) partner laboratories, York and Oxford, aimed at high-throughput (HTP) structure determination of proteins from Bacillus anthracis, the aetiological agent of anthrax and a biomedically important target, is described. Based upon a target-selection strategy combining ;low-hanging fruit' and more challenging targets, this work has contributed to the body of knowledge of B. anthracis, established and developed HTP cloning and expression technologies and tested HTP pipelines. Both centres developed ligation-independent cloning (LIC) and expression systems, employing custom LIC-PCR, Gateway and In-Fusion technologies, used in combination with parallel protein purification and robotic nanolitre crystallization screening. Overall, 42 structures have been solved by X-ray crystallography, plus two by NMR through collaboration between York and the SPINE partner in Utrecht. Three biologically important protein structures, BA4899, BA1655 and BA3998, involved in tRNA modification, sporulation control and carbohydrate metabolism, respectively, are highlighted. Target analysis by biophysical clustering based on pI and hydropathy has provided useful information for future target-selection strategies. The technological developments and lessons learned from this project are discussed. The success rate of protein expression and structure solution is at least in keeping with that achieved in structural genomics programs.

Bacillus anthracis↗
PubMed2006

Early experience with the retrievable OptEase vena cava filter in high-risk trauma patients.

OBJECTIVES: Prophylactic vena cava filters (VCF) are efficient in preventing pulmonary embolism. Filter retrieval avoids the potential long-term complications of permanent VCF. Clinical evaluation was focused on filter-related complications and feasibility of retrieval in high-risk trauma patients. METHODS: Analysis of single-institution consecutive case series of patients who received a prophylactic OptEase VCF after multiple trauma between 08/2003 and 12/2004. Data were collected prospectively. RESULTS: A total of 37 OptEase filters were inserted prophylactically after multiple trauma (median patient age 35 years, range, 17-73 years, median ISS 41, range, 17-59). All patients had contraindications for pharmacological prophylaxis for thromboembolic events. 32 filters (86%) were retrieved after 16 days (range, 7-25 days). 12 of 33 filters (36%) demonstrated trapped clots/thrombosis within the filter structure on pre-retrieval cavography. Two patients received anticoagulation before filter retrieval due to filter thrombosis (6%). Symptomatic PE was observed in 1 patient (3%) 5 days after VCF retrieval. Minor caudal filter migration was observed in 1 patient (3%). Overall mortality was 3%. CONCLUSIONS: Retrieval of the OptEase filter is safe and feasible. Temporary filter placement avoids possible long-term complications of permanent VCF. It is an efficient form of PE prophylaxis when temporary contraindications to anticoagulation are present.

Adolescent↗
PubMed2006

Application of the cycloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules.

Pronucleotides represent a promising tool to improve the biological activity of nucleoside analogs in antiviral and cancer chemotherapy. The cycloSal-approach is one of several conceptually different pronucleotide systems. This approach can be applied to various nucleoside analogs. A salicyl alcohol as a cyclic bifunctional masking unit is used, and shown to afford a chemically driven release of the particular nucleotide from the lipophilic phosphate triester precursor molecule. A conceptual extension of the cycloSal-approach results in the design of "lock-in"-cycloSal-derivatives. The cycloSal-approach is not restricted to the delivery of bioactive nucleotides but also useful for the intracellular delivery of hexose-1-phosphates.

Antiviral Agents↗
PubMed2006

Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling.

The impact of the 3-hydroxy-3methylglutaryl CoA reductase inhibitor simvastatin on human small-cell lung cancer (SCLC) cell growth and survival was investigated. Simvastatin profoundly impaired basal and growth factor-stimulated SCLC cell growth in vitro and induced apoptosis. SCLC cells treated with simvastatin were sensitized to the effects of the chemotherapeutic agent etoposide. Moreover, SCLC tumour growth in vivo was inhibited by simvastatin. These responses correlated with the inhibition of stem cell factor (SCF)-stimulated activation of extracellular signal-regulated kinase (Erk), protein kinase B (PKB) and ribosomal S6 kinase by simvastatin. Constitutive activation of the Erk pathway was sufficient to rescue SCLC cell from the effects of simvastatin. The drug did not directly affect activation of c-Kit or its localization to lipid rafts, but in addition to its ability to block Ras membrane localization, it selectively downregulated H-Ras protein levels at the post-translational level. Downregulation of either H- or K-Ras by RNA interference (RNAi) did not impair Erk activation by growth factors, whereas an RNAi specific for N-Ras inhibited activation of Erk, PKB and SCLC cell growth. Together our data demonstrate that inhibiting Ras signalling with simvastatin potently disrupts growth and survival in human SCLC cells.

Animals↗
PubMed2006

Does the additional use of heparin-coated extracorporeal circuits (ECC) optimize the effect of modified ultrafiltration (MUF) in pediatric perfusion?

BACKGROUND: Modified ultrafiltration (MUF) has been shown to exert beneficial effects on the coagulation system and the capillary leak after pediatric cardiac surgery using extracorporeal circulation (ECC). The aim of this study was to investigate whether the additional use of heparin-coated circuits is a useful option for improving biocompatibility. METHODS: We randomized 28 children, using heparin-coated ECC circuits in group A (n = 14) and an uncoated equivalent set in group B (n = 14). After congenital heart surgery, MUF was performed post ECC in a standardized fashion. Blood samples were analyzed preoperatively, 10 min, 30 min, 1 h, and 48 h after ECC by flow cytometric analysis (FACSort) using surface antigens CD62/CD41b (platelets) and CD45/CD14 (monocytes). RESULTS: No significant difference was found with respect to mean age (20.6 months vs. 21.6 months), mean body weight (9.2 kg vs. 8.4 kg), mean ultrafiltration rate (9.1 ml/kg vs. 11.4 ml/kg), chest tube drainage, blood products, ICU stay, and 30-d survival. The percentage of CD62/CD41-positive platelets in group A (vs. B) increased up to 118 % at 60 min vs. 130 % ( P < 0.05) and declined to 98 % at 48 h postop. vs. 99 % (n. s.). The percentage of CD45/CD14-positive monocytes in group A (vs. B) increased up to 158 % at 60 min vs. 155 % (n. s.) and declined to 122 % (A) at 48 h postop. vs. 61 % (B) ( P > 0.05). CONCLUSIONS: Heparin coating of ECC in addition to MUF leads to a lower platelet activation. Monocyte surface markers CD45 and CD14 indicated a marked activation during ECC in both groups but additional heparin coating showed a better postoperative regeneration of monocyte markers in the late course indicating a beneficial additive effect.

Antigens, Surface↗
PubMed2006

Study of the efficacy of a pronucleotide of 2-chloro-2'-deoxyadenosine in deoxycytidine kinase-deficient lymphoma cells.

2-Chloro-2 '-deoxyadenosine (CdA, cladribine) is a nucleoside analogue (NA) used for the treatment of lymphoproliferative disorders. Phosphorylation of the drug to CdAMP by deoxycytidine kinase (dCK) and its subsequent conversion to CdATP is essential for its efficacy. DCK deficiency is a common mechanism of resistance to NA, which could be overcome by the pronucleotide approach. The latter consists of using the nucleoside monophosphate conjugated to a lipophilic group enabling CdAMP to enter the cells by passive diffusion. In this study, we show that cycloSaligenyl-2-chloro-2 '-deoxyadenosine monophosphate (cycloSal-CdAMP) is 10-fold more potent that CdA in a dCK-deficient lymphoma cell line. These results suggest that the use of cycloSal-nucleotides could be a strategy to counteract resistance caused by dCK deficiency.

Cell Line, Tumor↗
PubMed2005

Development of a locking femur nail for mice.

We herein report on a novel locking intramedullary nail system in a murine closed femur fracture model. The nail system consists of a modified 24-gauge injection needle and a 0.1-mm-diameter tungsten guide wire. Rotation stability was accomplished by flattening the proximal and distal end of the needle. Torsional mechanical testing of the implants in osteotomized cadaveric femora revealed a superiority of the locking nail (3.9+/-1.0 degrees rotation at a torque of 0.9 Nmm, n=10) compared to the unmodified injection needle (conventional nail; 52.4+/-3.2 degrees, n=10, p<0.05). None of the implants, however, achieved the rotation stability of unfractured femora (0.3+/-0.5 degrees, n=10). In a second step, we tested the feasibility of the in vivo application of the locking nail to stabilize a closed femoral midshaft fracture in C57BL/6 mice. Of interest, none of the 10 animals showed a dislocation of the locking nail over a 5-week period, while 3 of 4 animals with conventional nail fracture stabilization showed a significant pin dislocation within the first 3 days (p<0.05). Mechanical testing after 5-weeks stabilization with the locking nail revealed an appropriate bone healing with a torque at failure of 71.6+/-3.4% and a peak rotation before failure of 68.4+/-5.3% relative to the unfractured contralateral femur. With the advantage that closed fractures can be fixed with rotation stability, the herein introduced model may represent an ideal tool to study bone healing in transgenic and knockout mice.

Animals↗
PubMed2005

Pro-A-type and N-terminal pro-B-type natriuretic peptides in different thyroid function states.

QUESTIONS UNDER STUDY: Natriuretic peptides are produced predominantly in the heart and secreted in response to volume expansion and pressure overload. A wide spectrum of cardiac changes is observed in thyroid dysfunctions. This study investigates mid regional pro A-type (proANP) and N-terminal pro-B-type natriuretic peptide (NTproBNP) levels in different thyroid states and evaluates the effect of L-thyroxine treatment on natriuretic peptides in patients with subclinical hypothyroidism. METHODS: Case-control and double-blind, placebo-controlled trial. Sera from 161 female patients (35 with overt, 63 with subclinical hypothyroidism; 10 with overt, 14 with subclinical hyperthyroidism; 40 euthyroid controls) were analysed. ProANP and NT-proBNP were measured at baseline and 48 weeks after L-thyroxine treatment in subclinical hypothyroidism. RESULTS: Circulating proANP and NT-proBNP levels were higher in hyperthyroid patients than in hypothyroid and euthyroid patients (p <0.001). Plasma proANP levels tended to be lower in overt hypothyroidism than in subclinical hypothyroidism. ProANP and NT-proBNP levels correlated weakly to thyroid stimulating hormone (TSH) (r = -0.3 and -0.2, respectively). The natriuretic peptide levels of subclinical and overt hypothyroid subjects showed no difference with those of euthyroid subjects. L-thyroxine treatment had no effect on natriuretic peptide levels in subclinical hypothyroidism. CONCLUSION: Natriuretic peptide levels are altered in different thyroid states with a more pronounced effect in hyperthyroidism than in hypothyroidism. Hyperthyroidism should be considered in patients presenting with unclear symptoms and mildly elevated natriuretic peptide levels, as overt hyperthyroidism results in increased serum A- and B-type natriurectic peptide levels, typically seen in mild heart failure.

Atrial Natriuretic Factor↗
PubMed2005

Instantaneous dynamics and quantum control fields: principle and numerical applications.

The relation between laser pulses serving the purpose of controlling elementary molecular processes and the instantaneous dynamics of the perturbed system is investigated. The application of the conditions assuring a controlled change of the expectation value of an observable directly links the internal motion to the external perturbation. Several numerical applications document that the derived control fields are efficient and can be interpreted clearly on physical grounds.

Journal Article↗
PubMed2005

Coulomb-interaction-induced incomplete shell filling in the hole system of InAs quantum dots.

We have studied the hole charging spectra of self-assembled InAs quantum dots in perpendicular magnetic fields by capacitance-voltage spectroscopy. From the magnetic-field dependence of the individual peaks we conclude that the s-like ground state is completely filled with two holes but that the fourfold degenerate p shell is only half filled with two holes before the filling of the d shell starts. The resulting six-hole ground state is highly polarized. This incomplete shell filling can be explained by the large influence of the Coulomb interaction in this system.

Journal Article↗
PubMed2005

In vitro activity of cycloSal-nucleoside monophosphates and polyhydroxycarboxylates against orthopoxviruses.

Because variola virus might be used as a pathogen in biological attacks, there is an urgent need to provide effective antiviral drugs for the treatment of orthopoxvirus infections. Thus, the aim of the present study was to test the antiviral activity of 3 pro-nucleotides of the acyclic nucleoside analogues aciclovir (ACV), 3 of penciclovir (PCV) and 38 of the cyclic nucleoside analogue brivudin (BVDU), on the basis of cycloSaligenyl-nucleoside monophosphate approach against vaccinia virus and cowpox virus in vitro. In further experiments, 13 synthetic humic acid-like polymers, so-called polyhydroxycarboxylates, were examined. Antiviral screening was performed by means of the plaque reduction assay and for quantification of the cytotoxicity of the test compounds the XTT-based tetrazolium reduction assay EZ4U was used. As result, three cycloSal-monophosphate derivatives of ACV proved to be potent inhibitors of both vaccinia virus and cowpox virus replication in vitro. Among the tested monophosphate derivatives of cycloSal-PCV and cycloSal-BVDU, selected substances showed a promising antiviral activity against vaccinia virus and cowpox virus. For the polyanionic compounds, no relevant antiviral activity was detected. In conclusion, by the delivery of nucleoside monophosphates from neutral, membrane-permeable prodrugs on the basis of the cycloSaligenyl-nucleotide concept, different ACV, PCV and BVDU derivatives can act as potent and selective inhibitors of orthopoxvirus replication. However, most of the cycloSal-monophosphate derivatives of BVDU had a higher cytotoxicity than their parent nucleosides.

Acyclovir↗
PubMed2005

"Lock-in" modified cyclosal nucleotides--the second generation of cyclosal prodrugs.

A new generation of cycloSal-pronucleotides is presented. CycloSal-d4TMPs have been modified by introduction of an esterase-cleavable site in order to trap them inside cells. Hydrolysis studies in different media (PBS, CEM/0- and liver extracts) and anti-HIV evaluation of separated diastereomers revealed unexpected differences between the isomers.

Anti-HIV Agents↗
PubMed2005

Synthesis of carbocyclic nucleotides as potential substrates for thymidylate kinase.

Enantiomerically pure carbocyclic 2'-deoxy-3'-azidothymidine monophosphate (AZTMP) and carba-2'deoxy-3'-thiocyanatothymidine monophosphate were synthesized to study their behavior toward their phosphorylation by thymidylate kinase. The nucleotides were synthesized starting from the parent nucleosides by an alkaline hydrolysis of the corresponding cycloSal-phosphate triesters.

Antineoplastic Agents↗
PubMed2004

Value of gonadotropin-releasing hormone testing in the differential diagnosis of androgen deficiency in elderly men.

Elderly men with low testosterone (T) levels are increasingly diagnosed to have partial androgen deficiency of the aging male (PADAM). Frequently, magnetic resonance imaging is performed to exclude pituitary adenoma. The value of GnRH testing to differentiate PADAM from secondary hypogonadism is unknown. Serum levels of T as well as LH and FSH at baseline and after GnRH were evaluated in the following groups: 1) 24 elderly men with low serum T (<11.7 nmol/liter), 2) 25 elderly men with normal serum T levels (>11.7 nmol/liter), 3) 10 men with primary hypogonadism, 4) 24 men with secondary hypogonadism, and 5) 13 healthy young volunteers. In elderly men, T levels were lower (P < 0.001) and gonadotropin levels higher (P = 0.03) compared with younger controls. LH and FSH response to GnRH was higher in elderly men with low T levels (PADAM) compared with elderly men with normal T levels (P = 0.02 and P < 0.001) in the presence of similar basal gonadotropin levels. To differentiate secondary hypogonadism from PADAM with a sensitivity of 100%, a T less than 10 nmol/liter had a specificity of 50%. This specificity was improved to 75% by using a cutoff of less than or equal to 15 mU/liter increase of LH upon GnRH stimulation. Overall, decreased T levels and increased LH levels in elderly men suggest a primary Leydig cell dysfunction. In the subgroup of elderly men with low T levels, an increased LH response to GnRH with normal basal LH levels suggests additional, possibly hypothalamic changes. To exclude secondary hypogonadism in PADAM, diagnostic accuracy can be improved by using GnRH testing.

Adult↗
PubMed2004

Different approaches for the calculation of electronic excited states of nonstoichiometric alkali halide clusters: the example of Na3F.

The electronic structure and excited states of the Na(3)F cluster are investigated using different approximate, but numerically efficient, computational schemes, such as a 2e hybrid quantum/classical pseudopotential model with full-configuration interaction or time-dependent density-functional theory. Various quantities such as geometries and transition energies are compared with results previously obtained by multireference configuration interaction calculations, taken as reference data. The potential energy surfaces of the lowest excited states are investigated and the finite-temperature absorption spectra are calculated. The good agreement with recent beam experiments [J.-M. L'Hermite, V. Blanchet, A. Le Padellec, B. Lamory, and P. Labastie, Eur. Phys. J. D 28, 361 (2004)] leads to the conclusion that the absorption spectrum observed experimentally corresponds to the lowest energy isomer which has a C(2v) planar rhombic geometry.

Journal Article↗