bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneous networks integration for disease–gene prioritization with node kernels
Authors: Tran Van Dinh , Sperduti Alessandro , Backofen Rolf , Costa Fabrizio 
Published: January 2020

Abstract

Motivation
The identification of disease–gene associations is a task of fundamental importance in human health research. A typical approach consists in first encoding large gene/protein relational datasets as networks due to the natural and intuitive property of graphs for representing objects’ relationships and then utilizing graph-based techniques to prioritize genes for successive low-throughput validation assays. Since different types of interactions between genes yield distinct gene networks, there is the need to integrate different heterogeneous sources to improve the reliability of prioritization systems.

Results
We propose an approach based on three phases: first, we merge all sources in a single network, then we partition the integrated network according to edge density introducing a notion of edge type to distinguish the parts and finally, we employ a novel node kernel suitable for graphs with typed edges. We show how the node kernel can generate a large number of discriminative features that can be efficiently processed by linear regularized machine learning classifiers. We report state-of-the-art results on 12 disease–gene associations and on a time-stamped benchmark containing 42 newly discovered associations.

Availability and implementation
Source code: https://github.com/dinhinfotech/DiGI.git.

Supplementary information
Supplementary data are available at Bioinformatics online.
LAMPA, LArge Multidomain Protein Annotator, and its application to RNA virus polyproteins
Authors: Gulyaeva Anastasia A , Sigorskih Andrey I , Ocheredko Elena S , Samborskiy Dmitry V , Gorbalenya Alexander E 
Published: January 2020

Abstract

Motivation
To facilitate accurate estimation of statistical significance of sequence similarity in profile–profile searches, queries should ideally correspond to protein domains. For multidomain proteins, using domains as queries depends on delineation of domain borders, which may be unknown. Thus, proteins are commonly used as queries that complicate establishing homology for similarities close to cutoff levels of statistical significance.

Results
In this article, we describe an iterative approach, called LAMPA, LArge Multidomain Protein Annotator, that resolves the above conundrum by gradual expansion of hit coverage of multidomain proteins through re-evaluating statistical significance of hit similarity using ever smaller queries defined at each iteration. LAMPA employs TMHMM and HHsearch for recognition of transmembrane regions and homology, respectively. We used Pfam database for annotating 2985 multidomain proteins (polyproteins) composed of &gt;1000 amino acid residues, which dominate proteomes of RNA viruses. Under strict cutoffs, LAMPA outperformed HHsearch-mediated runs using intact polyproteins as queries by three measures: number of and coverage by identified homologous regions, and number of hit Pfam profiles. Compared to HHsearch, LAMPA identified 507 extra homologous regions in 14.4% of polyproteins. This Pfam-based annotation of RNA virus polyproteins by LAMPA was also superior to RefSeq expert annotation by two measures, region number and annotated length, for 69.3% of RNA virus polyprotein entries. We rationalized the obtained results based on dependencies of HHsearch hit statistical significance for local alignment similarity score from lengths and diversities of query-target pairs in computational experiments.

Availability and implementation
LAMPA 1.0.0 R package is placed at github (https://github.com/Gorbalenya-Lab/LAMPA).

Supplementary information
Supplementary data are available at Bioinformatics online.
Lowering cutoffs for initial and confirmation testing for cocaine and marijuana: large-scale study of effects on the rates of drug-positive results
Authors: Wingert William E 
Published: January 2020

Abstract
A large-scale study was conducted to determine whether lowering the initial testing and confirmation testing cutoffs in urine would significantly affect the positive rates for cocaine (COC) and marijuana (THC). Customary cutoffs for COC are 300 μg/L and 150 μg/L for initial testing (screening) and gas chromatography–mass spectrometry (GC-MS; confirmation), respectively; for THC, the usual respective cutoffs are 50 μg/L and 10 μg/L. By applying a screening cutoff of 100 μg/L for COC and lowering the GC-MS cutoff to 50 μg/L, the COC-positive rate increased from 1.2% to 2.1%. For THC, lowering the screening cutoff to 20 μg/L while leaving the GC-MS cutoff at 10 μg/L increased the THC-positive rate from 2.8% to 4.1%. These increases appear noteworthy.
A case of sulfhemoglobinemia and emergency measurement of sulfhemoglobin with an OSM3 CO-oximeter
Authors: Wu Caicai , Kenny Margaret A 
Published: January 2020

Abstract
We describe a case of sulfhemoglobinemia associated with toxic paint ingestion. Blood gases, oxygen content, and fractional hemoglobin derivatives were assayed with Radiometer 520 and OSM3 instruments. Although the CO-oximeters indicated the presence of sulfhemoglobin (SulfHb), the results were not quantitative. An OSM3 service software program was activated to obtain the actual concentrations of the hemoglobin fractions. Subsequently, we evaluated the performance of the OSM3 service program for the analysis of SulfHb by performing precision studies and comparing OSM3 results with those of an AVL 912 CO-oximeter. Retrospectively, we determined that the patient’s specimens contained 6% SulfHb. There was an obvious deviation between standard OSM3 oxyhemoglobin fraction measurements and those obtained by using its service program—the effect of a high SulfHb content.
Counterpoint The inseparable triad: analytical sensitivity, measurement uncertainty, and quantitative resolution
Authors: Pardue Harry L 
Published: January 2020

AbstractThe formal definition of sensitivity associates the term with the change in the response of a system for a small change of the stimulus causing the response, i.e., the ratio of the response of a system to the stimulus causing it. One interpretation of sensitivity associates the rate of change of the response for a small change of the stimulus as the slope of a calibration plot of response vs stimulus. An alternative interpretation associates sensitivity with the smallest value of the stimulus that can be resolved with a given degree of confidence, i.e., the detection limit. Applications of the first usage to analytical chemistry date at least to the beginning of this century; applications of the second interpretation are of more recent origin. The accompanying paper argues in favor of the second interpretation on the basis that, among other things, the “slope” interpretation conflicts with the formal definition of sensitivity and is meaningless as a descriptor of the performance of a measuring system. In this paper I offer arguments to support my belief that the slope definition of sensitivity is consistent with both formal definitions and accepted usage in analytical chemistry and, more importantly, that it is an invaluable descriptor of one of the most important characteristics of any analytical method. I include information to support my belief that proper use of the slope definition yields much more information than is available in the “detection limit” interpretation.
Molecular diagnostics of infectious diseases
Authors: Tang Yi-Wei , Procop Gary W , Persing David H 
Published: January 2020

AbstractOver the past several years, the development and application of molecular diagnostic techniques has initiated a revolution in the diagnosis and monitoring of infectious diseases. Microbial phenotypic characteristics, such as protein, bacteriophage, and chromatographic profiles, as well as biotyping and susceptibility testing, are used in most routine laboratories for identification and differentiation. Nucleic acid techniques, such as plasmid profiling, various methods for generating restriction fragment length polymorphisms, and the polymerase chain reaction (PCR), are making increasing inroads into clinical laboratories. PCR-based systems to detect the etiologic agents of disease directly from clinical samples, without the need for culture, have been useful in rapid detection of unculturable or fastidious microorganisms. Additionally, sequence analysis of amplified microbial DNA allows for identification and better characterization of the pathogen. Subspecies variation, identified by various techniques, has been shown to be important in the prognosis of certain diseases. Other important advances include the determination of viral load and the direct detection of genes or gene mutations responsible for drug resistance. Increased use of automation and user-friendly software makes these technologies more widely available. In all, the detection of infectious agents at the nucleic acid level represents a true synthesis of clinical chemistry and clinical microbiology techniques.
Evaluation of a near-patient test for C-reactive protein used in daily routine in primary healthcare by use of difference plots
Authors: Dahler-Eriksen Bjarne Steen , Lassen Jens Flensted , Petersen Per Hyltoft , Lund Erik Dalsgaard , Lauritzen Torsten , Brandslund Ivan 
Published: January 2020

Abstract
We have assessed the technical performance and robustness of NycoCard® CRP Whole Blood, a near-patient test for C-reactive protein (CRP), when used in realistic daily routine situations in general practice clinics (GPC). Thirteen GPCs participated, five of them with technician staff. From 898 patients, split-sample measurements for CRP were made. Results from GPCs were compared with results from a turbidimetric laboratory method, traceable to international reference preparations (IFCC CRM 470). Results were evaluated in difference plots where the expected distribution, due to an estimated analytical variation, was compared with measured differences. Of all difference points, 91.5% (n = 819) were within a 95% prediction interval based on the imprecision of both methods. Mean bias (95% confidence interval) was −0.3 mg/L (−0.9 to 0.3). No differences in analytic quality were found between GPCs with technician staffs and GPCs without, and between test results obtained within the first and second week, compared with the rest of the study period. We find the test as good when used in GPCs as could be expected from laboratory testing, and consequently robust, which is a necessity for use in routine situations in general practice. General application of difference plots in test evaluations are discussed in detail.
Differentiation between naproxen, naproxen–protein conjugates, and naproxen–lysine in plasma via micellar electrokinetic capillary chromatography—a new approach in the bioanalysis of drug targeting preparations
Authors: Albrecht Christiane , Reichen Jürg , Visser Jan , Meijer Dirk K F , Thormann Wolfgang 
Published: January 2020

Abstract
Pharmacotherapy through the targeting of drugs is a promising new approach that requires adequate analytical methods capable of differentiating between the free drug, the drug carrier, and metabolites. Using micellar electrokinetic capillary chromatography (MECC), we report the separation of naproxen (NAP) from NAP covalently coupled to human serum albumin or to mannosylated serum albumin and the metabolite naproxen–lysine. An assay for selective analysis of the different forms of NAP by direct plasma injection was developed with salicylate as internal standard and solute detection by laser-induced fluorescence. Compared with previously applied techniques, including HPLC and total plasma fluorescence, MECC offers the advantage that free and covalently bound NAP can be differentiated in one run and can be accurately monitored in microliter quantities of plasma. Summation of all NAP equivalents determined by MECC revealed data that compare well with those produced by total plasma fluorescence and HPLC.
Quantification of c-erbB-2 gene expression in breast cancer by competitive RT-PCR
Authors: Révillion Françoise , Hornez Louis , Peyrat Jean-Philippe 
Published: January 2020

Abstract
We adapted competitive reverse transcription-polymerase chain reaction (RT-PCR) for quantitative evaluation of c-erbB-2 expression in breast cancer. A fixed amount of cDNA target was coamplified with dilutions of a nonhomologous DNA sequence used as an internal standard (IS). The IS and the target shared the same primer sequences but yielded PCR products of different sizes (348 and 340 bp, respectively). A fluorescent sense primer was used so that the PCR products separated on denaturing polyacrylamide gels could be quantified with an automated DNA sequencer. In human breast cancer cell lines, c-erbB-2 expression was found to range from 0.151 to 652 zmol/μg total RNA (i.e., 91 to 391 200 molecules/μg total RNA; 1 zmol = 10−3 amol), with the two highest values corresponding to the c-erbB-2 overexpressing cell lines MDA-MB-453 and SK-BR-3. In a series of 39 breast cancer biopsies, the concentrations ranged from 0.117 zmol/μg to 1.15 amol/μg total RNA (i.e., 70 to 690 000 molecules/μg total RNA). The c-erbB-2 oncoprotein (p185) was determined in 30 samples by an enzyme immunoassay. A close correlation was found between c-erbB-2 gene and oncoprotein expression (P = 0.0067). Thus, this competitive RT-PCR method appears to be a reliable way to evaluate the expression of c-erbB-2 in small tumor samples.
Fiber-optic immunosensor for measurement of myoglobin
Authors: Hanbury C Michael , Miller W Greg , Harris Robert B 
Published: January 2020

Abstract
A self-contained fiber-optic immunosensor was developed to measure the 16 500-Da protein myoglobin. The sensing element was constructed by entrapment of Cascade Blue-labeled antibody within polyacrylamide gel at the distal face of an optical fiber 300 μm in core diameter. The polyacrylamide gel composition was optimized to allow diffusion of myoglobin but to exclude hemoglobin and higher-molecular-mass proteins from the sensing area. The analytical signal was derived from fluorescence energy transfer between Cascade Blue and the heme group of myoglobin. Fluorescence quenching occurred when myoglobin bound to labeled antibody. The total amount of fluorescence quench was dependent on the antibody labeling conditions and the amount of antibody incorporated in the sensor gel matrix. Myoglobin concentrations &gt;5 nmol/L (83 μg/L) were measurable with response times of 15 to 130 min limited by diffusion into the sensing element. This report demonstrates the technical feasibility for a self-contained immunosensor to measure a protein analyte.
Thyroxine, thyrotropin, and age in a euthyroid hospital patient population
Authors: Davey Richard 
Published: January 2020

Abstract
The diagnosis of thyroid disease now often can be achieved reliably by measuring thyrotropin (TSH) alone. Thyroxine (T4), triiodothyronine, and other analytes are only needed if TSH and the accompanying clinical condition are discordant. We describe here work that confirms the age independence of TSH in both inpatient and outpatient euthyroid hospital populations between ages 20 and at least 80 years, and demonstrates that although free T4 does vary with age, the range of variation remains within the T4reference interval. On this basis, TSH-based thyroid diagnostic algorithms can be used reliably in adults without reference to age-related reference intervals.
Effects of uremic toxins and fatty acids on serum protein binding of furosemide: possible mechanism of the binding defect in uremia
Authors: Takamura Norito , Maruyama Toru , Otagiri Masaki 
Published: January 2020

Abstract
To elucidate the mechanism of impaired serum binding of furosemide observed in patients with renal dysfunction, we examined in vitro the serum protein binding of furosemide in the absence and presence of uremic toxins that are endogenously retained solutes in uremic serum and act as inhibitors of drug binding. Analysis of the binding data of furosemide at its therapeutic concentration (6.6 mg/L) indicated that, among the four uremic toxins studied, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) showed the greatest inhibitory potency for the binding of furosemide to serum; moreover, the inhibition was competitive. CMPF thus most likely represents the primary determinant for the serum binding defect of furosemide in uremia. However, CMPF and oleate appear to exert a synergistic effect on the inhibition of furosemide serum binding—perhaps through a cascade effect on furosemide-binding inhibition in the oleate–CMPF–furosemide system, in which the binding of oleate to its low-affinity sites indirectly displaces furosemide from albumin and thus increases the transiently liberated CMPF molecules. Similar cascade effects on furosemide binding in the presence of CMPF were also originated by other long-chain (C18) fatty acids, linoleate and stearate, although to a lesser extent. Because CMPF is not effectively removed by ordinary hemodialysis treatment, the combined direct and cascade effects of CMPF and fatty acids appear to contribute to the increase in the free fraction of furosemide during hemodialysis.
Protein tyrosine phosphatase-like protein IA2-antibodies plus glutamic acid decarboxylase 65 antibodies (GADA) indicates autoimmunity as frequently as islet cell antibodies assay in children with recently diagnosed diabetes mellitus
Authors: Borg Henrik , Fernlund Per , Sundkvist Göran 
Published: January 2020

AbstractIslet cell antibodies (ICA), the classical autoimmunity marker for insulin-dependent diabetes mellitus (IDDM), are detected in ∼85% of children with recently diagnosed diabetes. Because the ICA assay is semiquantitative and difficult to standardize, alternative assays are needed. When glutamic acid decarboxylase 65 (GAD 65) was discovered as a major islet antigen, the measurement of antibodies to GAD 65 (GADA) was considered a good alternative to ICA. Recently, however, we showed that 1 in 3 ICA-positive diabetic patients do not have GADA. Now, antibodies against the protein tyrosine phosphatase-like protein IA2 (IA2-ab) have been detected in IDDM. To find out whether measurements of IA2-ab combined with those of GADA could detect autoimmunity to the same extent as ICA, we have measured all three kinds of antibodies (using radioligand binding assays for IA2-ab and GADA) in 100 recently diagnosed diabetic and 100 control children: ICA were found in 87, IA2-ab in 69, and GADA in 66 of the 100 diabetic patients, whereas in the 100 control children ICA were found in 2, IA2-ab in 1, and GADA in 3. Among the 87 ICA-positive patients, 45 (52%) had both IA2-ab and GADA, 21 (24%) had only IA2-ab, and 16 (18%) had only GADA, whereas 5 (6%) lacked both IA2-ab and GADA. Among the 13 ICA-negative patients, 1 (8%) had both IA2-ab and GADA, 2 (15%) had only IA2-ab, and 4 (31%) had only GADA. Thus, 6 of the 100 patients had neither ICA, IA2-ab, nor GADA. Combining the IA2-ab and GADA assays gave positive results for autoimmunity in 89 of the 100 patients, compared with 87 by the ICA assay. The combination of the IA2-ab and GADA assays appears to be an effective alternative to the ICA assay.
Kinetics and proposed mechanism of the reaction of an immunoinhibition, particle-enhanced immunoassay
Authors: Thompson John C , Craig Alan R , Davey Carol L , Newman David J , Lonsdale Michele L , Bucher William J , Nagle Patrick D , Price Christopher P 
Published: January 2020

AbstractWe report kinetic studies on the reaction of a latex agglutination immunoassay used to quantify phenytoin in serum. In this assay, polystyrene particles with a covalently attached analog of phenytoin react with an antiphenytoin monoclonal antibody to form light-scattering aggregates, with the rate of this reaction being decreased by addition of phenytoin from sample. In the absence of free (sample) phenytoin, this reaction did not exhibit a maximum rate of agglutination in the presence of excess antibody, i.e., an equivalence point. Furthermore, agglutination was inhibitable by free phenytoin even when the latter was added after agglutination of particles with antibody had begun. Most significantly, the immunoagglutination proceeded in an identical fashion with monovalent F(ab) fragment. These data are consistent with low-affinity immunospecific particle–antibody complexation, which then induces colloidal aggregation, without requiring immunospecific bridging by antibody molecules. The described mechanism is not generalizable to all latex agglutination immunoassays, although disturbance of colloidal stability may be a component in most assays.
The relation between chemically measured total iron-binding capacity concentrations and immunologically measured transferrin concentrations in human serum
Authors: Gambino Raymond , Desvarieux Edouard , Orth Michael , Matan Holly , Ackattupathil Tomy , Lijoi Elenore , Wimmer Cathy , Bower John , Gunter Elaine 
Published: January 2020

AbstractWe sought to determine if serum total iron-binding capacity (TIBC) is equivalent to serum transferrin (TRF) so that a low-cost colorimetric chemical assay for unsaturated iron-binding capacity (UIBC) could be substituted for a high-cost immunologic assay for TRF. Our study design included independent and blinded measurements of UIBC, serum iron, and TRF concentrations in human serum samples. Data from five independent correlation studies carried out at three different Quest Diagnostics laboratories were combined into one data set containing 570 paired results for TIBC and TRF. r2 was 0.941 when three outliers were eliminated from the 570-sample data set. Scatter about the regression line was fully accounted for by the CVs for the TIBC and TRF assays. When each test is measured precisely and without bias, the ratio of TIBC (μmol/L) to TRF (g/L) in SI units is close to the theoretically expected value of 25.0.
Screening children exposed to lead: an assessment of the capillary blood lead fingerstick test
Authors: Parsons Patrick J , Reilly Andrew A , Esernio-Jenssen Debra 
Published: January 2020

AbstractWe describe results of a 3-year study in which 499 paired venous and capillary blood specimens, collected by fingerstick on the same day, were analyzed for lead (BPb) and erythrocyte protoporphyrin (EP). False-positive rates (FPRs) and the proportion of false positives were calculated at four BPb thresholds. At the 100 μg/L threshold, the FPR for all data was 13%, but the proportion of false positives was only 5%. The log ratios of capillary-to-venous BPb data indicate that, with the exception of eight outliers, two subpopulations exist that follow a log-normal distribution. These two subpopulations, the “core” (n = 303) and “shifted” (n = 188) groups, on average generated a positive bias at 100 μg/L BPb of 8.6% and 30.3%, respectively. The log ratios of capillary-to-venous EP data followed a normal distribution, indicating that capillary EP is not statistically different from venous EP.