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PubMed2025

Columba: fast approximate pattern matching with optimized search schemes.

MOTIVATION: Aligning sequencing reads to reference genomes is a fundamental task in bioinformatics. Aligners can be classified as lossy or lossless: lossy aligners prioritize speed by reporting only one or a few high-scoring alignments, whereas lossless aligners output all optimal alignments, ensuring completeness and sensitivity. RESULTS: This paper introduces Columba, a high-performance lossless aligner tailored for Illumina sequencing data. Columba processes single or paired-end reads in FASTQ format and outputs alignments in SAM format. By utilizing advanced search schemes and bit-parallel alignment techniques, Columba achieves exceptional speed. Columba is available in two variants. The first, based on the bidirectional FM-index, prioritizes speed. The second, Columba RLC, uses run-length compression using a bidirectional move structure, significantly reducing memory usage for large, repetitive datasets like pan-genomes. Benchmarks on the human genome, as well as bacterial and human pan-genome datasets, demonstrate that Columba is much faster than existing lossless aligners and even competitive with lossy tools. We integrated Columba into the OptiType HLA genotyping pipeline, where it substantially reduced computational time while maintaining accuracy. These results position Columba as a versatile, state-of-the-art tool for high-sensitivity genomic analyses. AVAILABILITY AND IMPLEMENTATION: The source code of Columba is available at https://github.com/biointec/columba under AGPL license. Scripts to reproduce the benchmarks and analyses are available at https://doi.org/10.5281/zenodo.15849246.

Software↗

PubMedDate not supplied

Simultaneous determination of DOPAC, MHPG, 5-HIAA and HVA in CSF by direct injection on a liquid chromatograph with coulometric detection.

We describe a direct analysis for simultaneous determination of 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and 4-hydroxy-3-methoxyphenylacetic acid (HVA). After ultrafiltration the samples are applied directly to a high-performance liquid chromatograph with coulometric detection. The appropriate choice of the potentials of the three-coulometric-electrode system eliminates many possible interfering substances. One chromatographic run requires less than 15 min. By this analytical system the lowest amount of DOPAC, MHPG, 5-HIAA and HVA detectable was 0.16, 0.18, 0.90, and 1.48 ng/ml respectively. Coefficient of variation was less than 5% for "within-run" precision and less than 10% for "between-run" precision.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Subtraction method for the high-performance liquid chromatographic measurement of plasma adenosine.

The measurement of plasma adenosine with traditional high-performance liquid chromatographic techniques is difficult because of its nanomolar concentration, its short half-life in blood, and because of the difficulty in isolating adenosine from interfering peaks in the chromatogram. To prevent loss of adenosine in the blood sample, a "stop solution" is used to prevent enzymatic degradation and cellular uptake. Peak-shifting techniques on fractionated samples to measure adenosine derivatives have been used in the past to avoid interfering peaks in the chromatogram. A new method has been developed by which nanomolar levels of plasma adenosine can be accurately measured despite co-eluting peaks in the chromatogram. In this method, plasma samples are collected with a stop solution, processed, and divided. Adenosine deaminase is added to part of the sample to form a blank. A computer program subtracts the blank chromatogram from the paired unknown, and the result is compared to adenosine standards prepared from the blank and subtracted in a similar fashion. With this subtraction method, the overall recovery of physiological concentrations of adenosine was 89% from dog blood, and the average coefficient of variation was 12%. In summary, the subtraction method of plasma adenosine measurement offers good recovery, reproducibility, and the ability to quantify low levels of adenosine despite interfering peaks in the chromatogram.

Adenosine↗

PubMed1975

A mathematical model of the ventilatory control system to carbon dioxide with special reference to athletes and nonathletes.

The ventilatory response curve (VRC) as a function of alveolar and arterial pCO2 was recorded in 6 high-performance athletes and 6 nonathletes. The best fit to the data points could be found for an equation of the form (see article) showing that the results are strongly related to a Gaussian probability density function (PDF). After normalizing the equation to a form (see article) (M = mean value of PDF), sigma, A and M could be determined for both groups. Sigma and A are smaller in the athletic group, whereas M did not show any systematic difference. Regarding the respiratory center consisting of functional "elements" responding indirectly to variable pCO2 it can be concluded that the frequency distribution of the different active elements is greater and spread over a wider pCO2 range in the nonathletes with the same mean value in both groups. Using Loeschcke's model (1960), the open loop gain factor for different V CO2 as a function of p(A)CO2 was computed; the gain factor showed a maximum in the physiological range of pCO2.

Adult↗

PubMed1991

Characterization of free radicals in gamma-irradiated polycrystalline uridine 5'-monophosphate: a study combining ESR, spin-trapping and HPLC.

Free radicals generated in gamma-irradiated polycrystalline uridine 5'-monophosphate (5'-UMP) were studied by ESR, spin-trapping and high-performance liquid chromatography (HPLC). After gamma-irradiation at 0 degree C (70kGy), poly-crystalline 5'-UMP was dissolved in an anaerobic aqueous solution of 2-methyl-2-nitrosopropane as a spin trap at room temperature. Since an ESR spectrum consisting of several components was observed immediately after irradiation, these components were separated with reverse-phase HPLC in the ion-suppression mode and again analysed by ESR spectrometry. Although HPLC ultimately gave four spin-adducts, one component that was originally present disappeared during HPLC. Spin adducts due to two types of C6 radicals were identified. One of these was thought to be formed by electron addition and subsequent protonation at the C6 position, and the other was presumed to be produced by electron addition and subsequent protonation at the O4 position. The spin adducts derived from the C5 and C5' radicals were also identified. The spin adduct that disappeared during HPLC was thought to correspond to the C4'-centred radical. Computer simulation of ESR spectra was carried out to estimate the hyperfine splitting constants.

Chromatography, High Pressure Liquid↗

PubMed1977

Development and use of analytical systems based on mass spectrometry.

Contemporary analytical systems based on mass spectrometry include as components a gas chromatograph, a mass spectrometer, and a computer. The form of operation is usually in electron impact ionization mode for identification and structural studies, and in chemical ionization mode for quantitative analyses. Important stages in the development of these systems included the design of "molecule separators" for the concentration of solutes in the gas phase, the use of mass spectrometers as specific ion detectors, the introduction of chemical ionization techniques, and the development of computer-based operation, data acquisition, and data analysis capabilities. A current line of investigation is concerned with the design and use of systems based on atmospheric pressure ionization. Samples are ionized in a small reaction chamber external to the low-pressure region of a quadrupole mass analyzer. The primary source of electrons is a 63Ni foil or a corona discharge. The ionization process leading to positive ions involves a sequence of ion molecule reactions, usually electrons leads to carrier gas ions leads to reagent ions leads to sample component ions. Negative ions may be formed by direct electron attachment, or by ion molecule reactions that include new types of elimination reactions. The source will accept a variety of gases and solvents. The sample may be introduced in the gas phase without solvents, by probe injection, or in the effluent stream from a gas chromatograph. Samples may be introduced in the liquid phase in solvents by injection after the fashion of gas chromatography or in the effluent stream from a high-performance liquid chromatograph. The novel aspects of atmospheric pressure ionization mass spectrometry lie in its versatility and high sensitivity of detection. Few clinical chemistry laboratories now use these systems. Significant future uses are likely to be in analytical work involving therapeutic drug monitoring and studies of drug metabolism, and in analyses for environmental biohazards including pesticides, herbicides, polyhalobiphenyls, dibenzodioxins, and other toxic compounds.

Anions↗

PubMed1991

The adenine nucleotide-binding site on yeast 3-phosphoglycerate kinase. Affinity labeling of Lys-131 by pyridoxal 5'-diphospho-5'-adenosine.

The adenine nucleotide analog [3H]pyridoxal 5'-diphospho-5'-adenosine (PLP-AMP) is a potent and highly specific inactivator of yeast 3-phosphoglycerate kinase. Supportive evidence includes the finding that 1) during a 10-min incubation, half-maximal inactivation is given by 10 microM PLP-AMP, 2) covalent incorporation of 1.2 mol of PLP-AMP/mol of enzyme is sufficient to give complete inactivation, and 3) MgATP gives near complete protection against modification and inactivation by PLP-AMP. Following reaction with PLP-AMP and reduction with NaBH4 to form a stable adduct, the enzyme was digested with endoproteinase Lys-C and peptides were separated by reversed-phase high-performance liquid chromatography. The single major labeled peptide was purified and sequenced, and the modified residue was identified as Lys-131. The crystal structure of enzyme in the open conformation shows Lys-131 to reside within a loop of flexible random coil positioned at the outer edge of the central binding cleft, approximately 2 nm from the surface of the cleft that comprises part of the MgATP-binding site (Watson, H. C., Walker, N. P. C., Shaw, P. J., Bryant, T. N., Wendell, P. L., Fothergill, L. A., Perkins, R. E., Conroy, S. C., Dobson, M. J., Tuite, M. F., Kingsman, A. J., and Kingsman, S. M. (1982) EMBO J. 1, 1635-1640). We conclude that the structural element containing Lys-131 undergoes substantial movement during the ligand-induced conformational change known to occur during formation of the ternary complex, resulting in the positioning of a basic residue near a negatively charged substrate. Since similar affinity-labeling results have been presented for hexokinase (Tamura, J. K., LaDine, J. R., and Cross, R. L. (1988) J. Biol. Chem. 263, 7907-7912), we further suggest that movement of positive charge into the central cleft may be a common step in the tight binding of nucleotides by bilobal kinases.

Adenosine Diphosphate↗

PubMed1992

On-line measurement in biotechnology: exploitation, objectives and benefits.

Sound data biologically relevant are prerequisites when developing high-performance bioprocesses. Understanding of physiological regulation as well as sophisticated control strategies are highly dependent on the observability of the culture, i.e. the generation and exploitation of suited signals even under complex environmental measurement conditions. Against this background, the increasing number of analytical systems is very supportive and, accordingly, an appropriate handling of sensors and measured data is of decisive importance. This article reports on practical experience with routines for maintenance, service and calibration of hardware sensors which improve the quality of measurements significantly. Verification and validation of signals is outlined in order to make the value of data exploitation tools obvious. A method for the characterization of information is introduced by practical examples of Saccharomyces cerevisiae cultures when explaining the specific properties of extracting biological information from raw data. Finally, examples for advantageous exploitation of on-line data are given.

Biosensing Techniques↗

PubMed1991

Automated high-performance liquid chromatographic assay of enzymatic activities.

High-performance liquid chromatography (HPLC) is a powerful technique which enables a reliable and quantitative determination of enzyme activities. The purpose of the work reported here was to develop an automatic assay of enzymatic activity. Using an automatic sample processor and injector, a program was developed which allows the complete automation of each step of analysis (calibration, enzymatic reaction, HPLC determination). This program can be adapted to different experimental requirements as each step can be performed independently and each input (time, volume, number of standards) is made by answering questions asked by instrument. Using this approach both kinetic and single-point determinations can be carried out, and in the latter case different samples can be analysed sequentially. This paper reports the automated analysis of trypsin.

Autoanalysis↗

PubMed1991

Rapid analysis for metabolites of 11C-labelled drugs: fate of [11C]-S-4-(tert.-butylamino-2-hydroxypropoxy)-benzimidazol-2-one in the dog.

Positron emission tomography (PET) requires the use of compounds labelled with short-lived, positron-emitting isotopes (e.g., t1/2 of 11C approximately 120 min). As the concentration of unbound, non-metabolised drug is required as the input function for modeling, this presents particular problems for the study of the kinetics and metabolism of such compounds. We have now developed a rapid extraction procedure, followed by high-performance liquid chromatography using a short analytical column coupled to an on-line gamma-detector to determine the metabolism and kinetics of a non-selective beta-adrenergic antagonist of high affinity, S-4-(tert.-butylamino-2-hydroxypropoxy)benzimidazol-2-one. This antagonist is potentially well suited to the non-invasive localisation of beta-receptors in vivo. The ligand was rapidly taken up into the beta-receptor pool or excreted in urine, with less than 5% of the drug converted to metabolites. Plasma protein binding was only 16%. No significant metabolism of the ligand was observed in the anaesthetised dog, and, therefore, no correction for blood metabolite concentration is required for kinetic analysis of the 11C-labelled ligand during PET studies in this species. The analytical method reported here should be widely applicable: quantification of metabolites enables accurate estimation of the input function and is critical to the interpretation of PET data.

Adrenergic beta-Antagonists↗

PubMed1978

Quantitative thin-layer and high-performance liquid chromatographic determination of the diuretic agent 2-chloro-5-[44-hydroxy-3-methyl-2-(methylimino)-4-thiazolidinyl]benzenesulphonamide hydrochloride in serum and urine.

Sensitive and specific thin-layer (TLC) and high-performance liquid chromatographic (HPLC) methods were developed for the determination of the diuretic agent 2-chloro-5-[4-hydroxy-3-methyl-2-(methylimino)-4-thiazolidinyl]benzenesulphonamide hydrochloride (HOE 740). HOE 740 can be determined in serum by HPLC. The detection is performed at a very short wavelength (202 nm), resulting in a detection limit of 10 ng/ml. By TLC only urine levels that are normally high can be determined directly (the detection limit is 70 ng/ml). For the determination of the lower serum levels it is necessary to convert the drug into its dehydration product, which has a higher absorbance and gives sufficient sensitivity (the detection limit is 10 ng/ml). Serum levels determined by the two methods correlate well. Some pharmacokinetic and excretion-kinetic data were computed using two-compartment open models.

Chromatography, High Pressure Liquid↗

PubMed1991

Analysis of barbiturates in human serum and urine by high-performance capillary electrophoresis-micellar electrokinetic capillary chromatography with on-column multi-wavelength detection.

The analysis of barbiturates in human serum (or plasma) and urine by high-performance capillary electrophoresis-electrokinetic capillary chromatography with on-column fast-scanning multi-wavelength detection is discussed. The use of a buffer of ca. pH 8 and containing sodium dodecyl sulphate provides a medium suitable for fast and high-resolution separations of barbiturates. Seven barbiturates are characterized by their retention and absorption spectra between 195 and 320 nm. Comparison of these computer-stored data with those of unknown samples is shown to allow the identification of barbiturates in samples of patients undergoing pharmacotherapy and in toxicological urine and serum specimens. Three-dimensional electropherograms provide reliable information on the requirement and suitability of sample pretreatment procedures. With urine, extraction of barbiturates prior to analysis is necessary. With human serum several barbiturates, including phenobarbital, are shown to elute in an interference-free window in front of uric acid and the proteins, allowing these substances to be determined by direct sample injection. The need for multi-wavelength detection over a relatively wide wavelength range as a means of peak confirmation in electrokinetic capillary analyses is demonstrated and limitations of this technique for compounds with similar retention behaviour and absorption spectra are discussed.

Barbiturates↗

PubMed1991

Chiral high-performance liquid chromatography of aromatic cyclic dipeptides using cyclodextrin stationary phases.

A series of enantiomers of cyclic and linear dipeptides containing aromatic amino acids was prepared and chromatographed on beta- and gamma-cyclodextrin (CD) columns. The retention times, separation factor alpha and resolution values were calculated. The relevance of the distance of the chiral center from the phenyl ring for chiral resolution was studied. A model was developed using X-ray crystallographic data for an inclusion complex of beta-CD and the enantiomers of cyclic (Phe-Gly).

Chromatography, High Pressure Liquid↗

PubMed2025

Vcfexpress: flexible, rapid user-expressions to filter and format VCFs.

MOTIVATION: Variant call format (VCF) files are the standard output format for various software tools that identify genetic variation from DNA sequencing experiments. Downstream analyses require the ability to query, filter, and modify them simply and efficiently. Several tools are available to perform these operations from the command line, including BCFTools, vembrane, slivar, and others. RESULTS: Here, we introduce vcfexpress, a new, high-performance toolset for the analysis of VCF files, written in the Rust programming language. It is nearly as fast as BCFTools, but adds functionality to execute user expressions in the lua programming language for precise filtering and reporting of variants from a VCF or BCF file. We demonstrate performance and flexibility by comparing vcfexpress to other tools using the vembrane benchmark. AVAILABILITY AND IMPLEMENTATION: vcfexpress is available under the MIT license at https://github.com/brentp/vcfexpress with code used for the manuscript deposited in https://doi.org/10.5281/zenodo.14756838.

Software↗

PubMed1992

Pharmacokinetics and metabolism of 4'-iodo-4'-deoxy-doxorubicin in humans.

PURPOSE: 4'-iodo-4'-deoxydoxorubicin is a new anthracycline that currently is under clinical evaluation. To improve the management of future trials, we have determined its pharmacokinetics and metabolism during a phase I/II study and have tried to relate the parameters obtained to the hematologic toxicity of the drug in terms of the survival of blood cells. PATIENTS AND METHODS: The pharmacologic study included 19 patients who were entered at dose levels that ranged between 6 and 90 mg/m2; nine patients were treated at 80 mg/m2, which is close to the maximum recommended dose level. Blood sampling was performed from the end of the bolus infusion to 48 hours after treatment. Drug and metabolites were extracted and analyzed by high-performance liquid chromatography (HPLC), and the data were processed by nonlinear fitting to multicompartment models. RESULTS: Plasma concentrations were best fitted to a three-compartment model with half-lives of 5.2 minutes, 0.79 hours, and 10.3 hours. The total body clearance and volume of distribution at steady state were high (350 L/h/m2 and 2,065 L/m2). The drug was metabolized extensively to a 13-dihydroderivative, 4'-iodo-4'-deoxy-doxorubicinol; the mean area under the curve (AUC) ratio metabolite/parent drug was the highest observed ever for an anthracycline (12.1 +/- 7.4); the metabolite was cleared from the plasma with an elimination half-life of 15.3 hours. The AUCs of the parent compound and its metabolite were related linearly to the dose administered, and showed no saturation phenomenon. Urinary excretion was studied in nine patients and showed a cumulative elimination of less than 6% of the dose administered, two thirds of which were eliminated in the first 12 hours after injection. Ninety-three percent to 100% of the elimination of fluorescent compounds occurred in the form of the metabolite. Drug concentration in five tumor samples showed a rapid uptake of the drug from plasma and a preferential uptake of the parent drug compared with the metabolite. Blood cell counts after 4'-iodo-4'-deoxydoxorubicin treatment showed significant correlations among the surviving fractions of both granulocytes and platelets and the AUCs of the parent drug and its metabolite; the most significant correlations were obtained for the granulocytes and the metabolite. Significant correlations between AUCs and blood-cell survivals were maintained, even if only the nine patients treated at the dose of 80 mg/m2 were taken into account for the computation. CONCLUSIONS: Our results especially show that myelosuppression that is induced by 4'-iodo-4'-deoxydoxorubicin can be well predicted by the measure of the AUC of the drug and its metabolite. This could be used for the further development of the drug toward high-dosage schedules.

Blood Platelets↗

PubMed1992

Metabolic design of combination therapy: use of enhanced fluorodeoxyglucose uptake caused by chemotherapy.

In order to quantify effects of an experimental chemotherapy, MCF7 cells were studied with 14C-fluorodeoxyglucose (FDG) and high-performance liquid chromatography (HPLC). Uptake measurements were performed 1 and 4 hr after the end of a therapy with hexadecylphosphocholine (HPC). A dose- and time-dependent increase of the FDG uptake after therapy was observed, with a maximum at 1 hr after therapy. These data were used to develop a new metabolic design of combination treatment. Several time-dose combinations of HPC and deoxyglucose (DOG) were analyzed for their effects on growth inhibition. The combinations using DOG in the period of pronounced enhancement of FDG uptake (1 hr after HPC treatment) were found to be the most effective with an improvement of up to 520% in growth inhibition. This metabolic design of combination treatment may also be applied in vivo, and PET can be used to optimize the time and dose schedule of the modified treatment protocol.

Antineoplastic Agents↗

PubMed1992

[Combined use of real-time digital subtraction radioscopy and computerized tomography: potential advantages in diagnostic and interventional radiology].

The idea of combining fluoroscopy and CT arose from the daily practice in diagnostic and interventional radiology. A Diasonics OEC high-performance image intensifier complete with a digital subtraction system was connected to a Siemens Somatom-DRH CT scanner to work in tandem. CT is used for a localization in-depth and fluoroscopy for the subsequent maneuvers within an organ or body compartment. With this combination, complex procedures such as transarterial portography, percutaneous embolizations, pain treatment and manipulation for catheterization of the bile ducts and urinary tract could be performed in one place and in one session. CTF is especially useful when patients should not be moved about from room to room or undergo an examination in several sessions, as it happens with children or critically ill or contagious patients.

Adult↗

PubMed1992

Expert system design in hematology diagnosis.

A two-part study was designed to test the hypothesis that sufficient information is available from a modern hematology analyzer (the Coulter STKS) to reach a reliable intermediate conclusion which can be used as input to the next decision-making level in the design of a high-performance expert system for hematology diagnosis. In phase one, we analyzed the performance of three probabilistic systems (using Bayes' rule) which interpret STKS data: a control system which took the traditional approach of classifying cases into specific diagnoses, and two test systems which were designed to reach only an intermediate conclusion but not a final diagnosis. One of the test systems classified cases into "textbook categories" of disease and the other utilized defined diagnostic patterns. The systems were tested with 150 cases. The pattern approach ranked the correct choice first in 141 of 150 cases (94%). In phase two, we abandoned Bayes' rule, reformulated the pattern approach into a heuristic classification system, and tested its reliability on 820 cases. The algorithm of the reformulated system was able to classify all 820 cases into the same predominant pattern as a panel of three experienced laboratory hematologists.

Algorithms↗