A pathway-driven predictive model of tramadol pharmacogenetics

Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.Peer reviewe

Effect of site of lactate infusion on regional lactate exchange in pigs

Background The rate of extra-hepatic lactate production and the route of influx of lactate to the liver may influence both hepatic and extra-hepatic lactate exchange. We assessed the dose-response of hepatic and extra-hepatic lactate exchange during portal and central venous lactate infusion. Methods Eighteen pigs randomly received either portal (n=5) or central venous (n=7) lactate infusion or saline (n=6). Sodium lactate was infused at 33, 66, 99, and 133 µmol kg−1 min−1 for 20 min each. Systemic and regional abdominal blood flows and plasma lactate were measured at 20 min intervals until 1 h post-infusion, and regional lactate exchange was calculated (area under lactate uptake-time curve). Results Total hepatic lactate uptake [median (95% confidence interval)] during the experimental protocol (140 min) was higher during portal [8198 (5487-12 798) µmol kg−1] than during central venous lactate infusion [4530 (3903-5514) µmol kg−1, P<0.05]. At a similar hepatic lactate delivery (∼400 µmol kg−1 min−1), hepatic lactate uptake [mean and standard deviation (sd)] was higher during portal [118 (sd 55) µmol kg−1 min−1] than during central venous lactate infusion [44 (12) µmol kg−1 min−1, P<0.05]. Time courses of arterial lactate concentrations and lactate uptake at other measured regions were similar in both groups. Conclusions Higher hepatic lactate uptake during portal compared with central venous lactate infusion at a similar total hepatic lactate influx underlines the role of portal vein lactate concentration in total hepatic lactate uptake capacity. Arterial lactate concentration does not depend on the site of lactate infusion. At higher arterial lactate concentrations, all regions participated in lactate uptak

The influence of learner characteristics on degree and type of participation in a CSCL environment

Computer-Supported Collaborative Learning (CSCL) is often presented as a promising learning method. However, it is also facing some new challenges. Apart from answering the question of whether or not working with CSCL generates satisfying learning outcomes, it is important to determine whether or not all participants profit from collaboration, with the computer as a means of communication. This paper describes the implementation and effects of an experimental program in 5 classes with a total of 120 students in elementary education who, in groups of four, engaged in Knowledge Forum discussion tasks on the subject of healthy eating. The study explores whether or not differences occur in the participation of students who differ in gender, sociocultural background and ability, and whether or not computer skills, computer attitudes, comprehensive reading scores and popularity with classmates are related to student participation. Students’ participation in this CSCL environment appears to be dependent on a number of learner characteristics. Girls contribute more words to the discussions than boys do and are more dependent on their computer skills in this production. Students who are good at comprehensive reading also contribute more words. Popularity among classmates appears to influence the degree of participation further. We also found indications that students with immigrant parents write fewer contributions than those whose parents are not immigrants

Recombinant family 3 carbohydrate-binding module as a new additive for enhanced enzymatic saccharification of whole slurry from autohydrolyzed eucalyptus globulus wood

By-products resulting from lignocellulosics pretreatment affect the digestibility of resulting whole slurries, but this can be minimized by additives supplementation. In this work, a family 3 carbohydrate-binding module (CBM3), recombinantly produced from Escherichia coli, was used as additive in the enzymatic hydrolysis of the whole slurry from autohydrolyzed Eucalyptus globulus wood (EGW). At the higher dosage used (30 mg/gsolids), CBM3 led to an increase in glucose yield from 75 to 89%. A similar result was obtained for bovine serum albumin (BSA) (11% increase), which has a well-documented additive effect. CBM3 had no effect on the non-productive binding of enzymes, since it could not bind to EGW lignin, while it rapidly bound to cellulose, as shown by fluorescence microscopy. CBM3 is a valid additive for enhanced lignocellulosic saccharification and a valuable alternative to costly additives (e.g. polyethylene glycol) as it can be affordably produced from heterologous bacterium, thus contributing to more cost-efficient biomass valorization bioprocesses.This work was developed under the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01-0145-FEDER-006684) and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020—Programa Operacional Regional do Norte. The research leading to the reported results has received funding from Fundação para a Ciência e a Tecnologia (FCT) through the project MultiBiorefinery (POCI-01–0145-FEDER-016403) and through grants to C. Oliveira (SFRH/BPD/110640/2015) and D. Gomes (SFRH/BD/88623/2012).info:eu-repo/semantics/publishedVersio

Genome sequencing and population genomic analyses provide insights into the adaptive landscape of silver birch

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Assessing the potential for sea-based macroalgae cultivation and its application for nutrient removal in the Baltic Sea

Marine eutrophication is a pervasive and growing threat to global sustainability. Macroalgal cultivation is a promising circular economy solution to achieve nutrient reduction and food security. However, the location of production hotspots is not well known. In this paper the production potential of macroalgae of high commercial value was predicted across the Baltic Sea region. In addition, the nutrient limitation within and adjacent to macroalgal farms was investigated to suggest optimal site-specific configuration of farms. The production potential of Saccharina latissima was largely driven by salinity and the highest production yields are expected in the westernmost Baltic Sea areas where salinity is >23. The direct and interactive effects of light availability, temperature, salinity and nutrient concentrations regulated the predicted changes in the production of Ulva intestinalis and Fucus vesiculosus. The western and southern Baltic Sea exhibited the highest farming potential for these species, with promising areas also in the eastern Baltic Sea. Macroalgal farming did not induce significant nutrient limitation. The expected spatial propagation of nutrient limitation caused by macroalgal farming was less than 100–250 m. Higher propagation distances were found in areas of low nutrient and low water exchange (e.g. offshore areas in the Baltic Proper) and smaller distances in areas of high nutrient and high water exchange (e.g. western Baltic Sea and Gulf of Riga). The generated maps provide the most sought-after input to support blue growth initiatives that foster the sustainable development of macroalgal cultivation and reduction of in situ nutrient loads in the Baltic Sea.</p

A haemagglutination test for rapid detection of antibodies to SARS-CoV-2

Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world