Evaluation of computational tools using serial mixtures of human plasma and vegetable juice (part - II)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Blood
PROVIDER: ST001162 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description: Not available
| ST001161 | MetabolomicsWorkbench
Project description:This study aimed to build a physiologically based pharmacokinetic (PBPK) model coupled with age-appropriate in vitro dissolution data to describe drug performance in adults and pediatric patients. Montelukast sodium was chosen as a model drug. Two case studies were investigated: case study 1 focused on the description of formulation performance from adults to children; case study 2 focused on the description of the impact of medicine co-administration with vehicles on drug exposure in infants. The PBPK model for adults and pediatric patients was developed in Simcyp® v18.2 informed by age-appropriate in vitro dissolution results obtained in a previous study. Oral administration of montelukast was simulated with the ADAM™ model. For case study 1, the developed PBPK model accurately described montelukast exposure in adults and children populations after the administration of montelukast chewable tablets. Two-stage dissolution testing in simulated fasted gastric to intestinal conditions resulted in the best description of in vivo drug performance in adults and children. For case study 2, a good description of in vivo drug performance in infants after medicine co-administration with vehicles was achieved by incorporating in vitro drug dissolution (under simulated fasted gastric to fed intestinal conditions) into a fed state PBPK model with consideration of the in vivo dosing conditions (mixing of formulation with applesauce or formula). The case studies presented demonstrate how a PBPK absorption modelling strategy can facilitate the description of drug performance in the pediatric population to support decision-making and biopharmaceutics understanding during pediatric drug development.
| S-EPMC8816611 | biostudies-literature
Project description:Stoffenmanager®v4.5 and Advanced REACH Tool (ART) v1.5, two higher tier exposure assessment tools for use under REACH, were evaluated by determining accuracy and robustness. A total of 282 exposure measurements from 51 exposure situations (ESs) were collected and categorized by exposure category. In this study, only the results of liquids with vapor pressure (VP) > 10 Pa category having a sufficient number of exposure measurements (n = 251 with 42 ESs) were utilized. In addition, the results were presented by handling/activity description and input parameters for the same exposure category. It should be noted that the performance results of Stoffenmanager and ART in this study cannot be directly compared for some ESs because ART allows a combination of up to four subtasks (and nonexposed periods) to be included, whereas the database for Stoffenmanager, separately developed under the permission of the legal owner of Stoffenmanager, permits the use of only one task to predict exposure estimates. Thus, it would be most appropriate to compare full-shift measurements against ART predictions (full shift including nonexposed periods) and task-based measurements against task-based Stoffenmanager predictions. For liquids with VP > 10 Pa category, Stoffenmanager®v4.5 appeared to be reasonably accurate and robust when predicting exposures [percentage of measurements exceeding the tool's 90th percentile estimate (%M > T) was 15%]. Areas that could potentially be improved include ESs involving the task of handling of liquids on large surfaces or large work pieces, allocation of high and medium VP inputs, and absence of local exhaust ventilation input. Although the ART's median predictions appeared to be reasonably accurate for liquids with VP > 10 Pa, the %M > T for the 90th percentile estimates was 41%, indicating that variance in exposure levels is underestimated by ART. The %M > T using the estimates of the upper value of 90% confidence interval (CI) of the 90th percentile estimate (UCI90) was considerably reduced to 18% for liquids with VP > 10 Pa. On the basis of this observation, users might be to consider using the upper limit value of 90% CI of the 90th percentile estimate for predicting reasonable worst case situations. Nevertheless, for some activities and input parameters, ART still shows areas to be improved. Hence, it is suggested that ART developers review the assumptions in relation to exposure variability within the tool, toward improving the tool performance in estimating percentile exposure levels. In addition, for both tools, only some handling/activity descriptions and input parameters were considered. Thus, further validation studies are still necessary.
| S-EPMC6939284 | biostudies-literature
Project description:Long non-coding RNAs (lncRNAs) are recently characterized players that are involved in the regulatory circuitry of self-renewal in human embryonic stem cells (hESCs). However, the specific roles of lncRNAs in this circuitry are poorly understood. Here, we determined that growth-arrest-specific transcript 5 (GAS5), which is a known tumor suppressor and growth arrest gene, is abundantly expressed in the cytoplasm of hESCs and essential for hESC self-renewal. GAS5 depletion in hESCs significantly impaired their pluripotency and self-renewal ability, whereas GAS5 overexpression in hESCs accelerated the cell cycle, enhanced their colony formation ability and increased pluripotency marker expression. By RNA sequencing and bioinformatics analysis, we determined that GAS5 activates NODAL-SMAD2/3 signaling by sustaining the expression of NODAL, which plays a key role in hESC self-renewal but not in somatic cell growth. Further studies indicated that GAS5 functions as a competing endogenous RNA (ceRNA) to protect NODAL mRNA against degradation and that GAS5 transcription is directly controlled by the core pluripotency transcriptional factors (TFs). Taken together, we suggest that the core TFs, GAS5 and NODAL-SMAD2/3 form a feed-forward loop to maintain the hESC self-renewal process. These findings are specific to ESCs and did not occur in the somatic cell lines we tested; therefore, our findings also provide evidence that the functions of lncRNAs vary in different biological contexts. We analyzed long non-coding RNAs in two hESC cell lines (X-01 and H1), and found GAS5 is highly expressed and functional in maintaining hESC self-renewal. We generate stable overexpressed or knockdown hESC cell lines using lentiviral approach. We transfected cells initialy after passage, and lentiviruses are added with daily medium change for three days (at a final concentration of 10^5 IU/ml). Puromycin is added for selection and supplied with daily medium change. Stable cell lines are established after two passages and verified under fluorescence scope. Total RNAs and miRNAs are extracted separately of all three cell lines (LV-NC, LV-GAS5 and LV-shGAS5) and put to sequencing.
2016-03-17 | E-GEOD-66993 | biostudies-arrayexpress
Project description:The Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2), is NASA's latest reanalysis for the satellite era (1980 onward) using the Goddard Earth Observing System, version 5 (GEOS-5), Earth system model. MERRA-2 provides several improvements over its predecessor (MERRA-1), including aerosol assimilation for the entire period. MERRA-2 assimilates bias-corrected aerosol optical depth (AOD) from the Moderate Resolution Imaging Spectroradiometer and the Advanced Very High Resolution Radiometer instruments. Additionally, MERRA-2 assimilates (non bias corrected) AOD from the Multiangle Imaging SpectroRadiometer over bright surfaces and AOD from Aerosol Robotic Network sunphotometer stations. This paper, the second of a pair, summarizes the efforts to assess the quality of the MERRA-2 aerosol products. First, MERRA-2 aerosols are evaluated using independent observations. It is shown that the MERRA-2 absorption aerosol optical depth (AAOD) and ultraviolet aerosol index (AI) compare well with Ozone Monitoring Instrument observations. Next, aerosol vertical structure and surface fine particulate matter (PM2.5) are evaluated using available satellite, aircraft, and ground-based observations. While MERRA-2 generally compares well to these observations, the assimilation cannot correct for all deficiencies in the model (e.g., missing emissions). Such deficiencies can explain many of the biases with observations. Finally, a focus is placed on several major aerosol events to illustrate successes and weaknesses of the AOD assimilation: the Mount Pinatubo eruption, a Saharan dust transport episode, the California Rim Fire, and an extreme pollution event over China. The article concludes with a summary that points to best practices for using the MERRA-2 aerosol reanalysis in future studies.
| S-EPMC7477811 | biostudies-literature
Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. MicroRNAs are small nucleatides that function as regulators of gene expression in almost any biological process. However, few microRNAs are reported to have a role in the pathological process of OPLL. Therefore, we performed high-throughput microRNA sequencing and transcriptome sequencing of primary OPLL and PLL cells in order to decipher the interacting network of microRNAs in OPLL. MRNA and microRNA profiles were done using primary culture cells of human ossification of the posterior longitudinal ligament (OPLL) tissue and normal posterior longitudinal ligament (PLL) tissue.
2016-04-04 | E-GEOD-69787 | biostudies-arrayexpress
Project description:We used ATLAS-seq to comprehensively map the genomic location of LINE-1 elements belonging to the youngest and potentially polymorphic subfamily (L1HS-Ta). This was performed in a panel of 12 human primary or transformed cell lines (BJ, IMR90, MRC5, H1, K562, HCT116, HeLa S3, HepG2, MCF7, HEK-293, HEK-293T, 2102Ep). In brief, ATLAS-seq relies on the random mechanical fragmentation of the genomic DNA to ensure high-coverage, ligation of adapter sequences, suppression PCR-amplification of L1HS-Ta element junctions, and Ion Torrent sequencing using single-end 400 bp read chemistry. A notable aspect of ATLAS-seq is that we can obtain both L1 downstream and upstream junctions (3'- and 5'-ATLAS-seq libraries, respectively), for full-length L1 elements. Note that a 10-nt sample-specific barcode has been removed at the 5' end of the reads in the .fastq files upon demultiplexing. This was achieved using cutadapt v1.9.2.dev0 (with the following parameters: -e 0.1 -q 10 -m 25 -g <barcode_name>=^<barcode_sequence>)
2016-05-24 | E-MTAB-4676 | biostudies-arrayexpress
Project description:Next-generation RNA-sequencing (RNA-seq) has revolutionized transcriptome profiling, gene expression analysis, and RNA-based diagnostics. Here, we developed a new RNA-seq method that exploits thermostable group II intron reverse transcriptases (TGIRTs) and used it to profile human plasma RNAs. TGIRTs have higher thermostability, processivity, and fidelity than conventional reverse transcriptases, plus a novel template-switching activity that can efficiently attach RNA-seq adapters to target RNA sequences without RNA ligation. The new TGIRT-seq method enabled construction of RNA-seq libraries from <1 ng of plasma RNA in <5 h. TGIRT-seq of RNA in 1-mL plasma samples from a healthy individual revealed RNA fragments mapping to a diverse population of protein-coding gene and long ncRNAs, which are enriched in intron and antisense sequences, as well as nearly all known classes of small ncRNAs, some of which have never before been seen in plasma. Surprisingly, many of the small ncRNA species were present as full-length transcripts, suggesting that they are protected from plasma RNases in ribonucleoprotein (RNP) complexes and/or exosomes. This TGIRT-seq method is readily adaptable for profiling of whole-cell, exosomal, and miRNAs, and for related procedures, such as HITS-CLIP and ribosome profiling.
| S-EPMC4691826 | biostudies-literature
Project description:ObjectiveTo evaluate preferences and decision-making among high-risk pregnant women offered a choice between Non-Invasive Prenatal Testing (NIPT), invasive testing or no further testing.MethodsNationwide implementation study (TRIDENT) offering NIPT as contingent screening test for women at increased risk for fetal aneuploidy based on first-trimester combined testing (>1:200) or medical history. A questionnaire was completed after counseling assessing knowledge, attitudes and participation following the Multidimensional Measure of Informed Choice.ResultsA total of 1091/1253 (87%) women completed the questionnaire. Of these, 1053 (96.5%) underwent NIPT, 37 (3.4%) invasive testing and 1 (0.1%) declined testing. 91.7% preferred NIPT because of test safety. Overall, 77.9% made an informed choice, 89.8% had sufficient knowledge and 90.5% had positive attitudes towards NIPT. Women with intermediate (odds ratio (OR) = 3.51[1.70-7.22], p < 0.001) or high educational level (OR = 4.36[2.22-8.54], p < 0.001) and women with adequate health literacy (OR = 2.60[1.36-4.95], p = 0.004) were more likely to make an informed choice. Informed choice was associated with less decisional conflict and less anxiety (p < 0.001). Intention to terminate the pregnancy for Down syndrome was higher among women undergoing invasive testing (86.5%) compared to those undergoing NIPT (58.4%) (p < 0.001).ConclusionsThe majority of women had sufficient knowledge and made an informed choice. Continuous attention for counseling is required, especially for low-educated and less health-literate women. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
| S-EPMC5213994 | biostudies-literature
Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. Recently, disorders of metabolism are thought to be the center of many diseases such as OPLL. Advanced glycation end product (AGE) are accumulated in many extracellular matrixes such as ligament fibers, and it can functions as cellular signal through its receptor (RAGE), contributing to various events such as atherosclerosis or oxidative stress. However, its role in OPLL formation is not yet known. Therefore, we performed high-through-put RNA sequencing on primary posterior longitudinal ligament cells treated with different doses of AGEs (1µM, 5µM and negative control), with or without BMP2 (1µM). mRNA profiles of Primary human posterior longitudinal ligament cells stimulated with various stimuli (Control, 1µM AGE-BSA, 5µM AGE-BSA, 1µM AGE-BSA with BMP2, 5µM AGE-BSA with BMP2) were generated by deep sequencing on Ion Proton
2016-02-16 | E-GEOD-65952 | biostudies-arrayexpress