bluuebunny/crossref_metadata_2025_split huggingface dataset:
Model‐Based Drug–Drug Interaction Extrapolation Strategy From Adults to Children: Risdiplam in Pediatric Patients With Spinal Muscular Atrophy
Authors: Cleary Yumi , Gertz Michael , Grimsey Paul , Günther Andreas , Heinig Katja , Ogungbenro Kayode , Aarons Leon , Galetin Aleksandra , Kletzl Heidemarie 
Published: August 2021

Risdiplam (Evrysdi) improves motor neuron function in patients with spinal muscular atrophy (SMA) and has been approved for the treatment of patients ≥2 months old. Risdiplam exhibits time‐dependent inhibition of cytochrome P450 (CYP) 3A in vitro. While many pediatric patients receive risdiplam, a drug–drug interaction (DDI) study in pediatric patients with SMA was not feasible. Therefore, a novel physiologically‐based pharmacokinetic (PBPK) model‐based strategy was proposed to extrapolate DDI risk from healthy adults to children with SMA in an iterative manner. A clinical DDI study was performed in healthy adults at relevant risdiplam exposures observed in children. Risdiplam caused an 1.11‐fold increase in the ratio of midazolam area under the curve with and without risdiplam (AUCR)), suggesting an 18‐fold lower in vivo CYP3A inactivation constant compared with the in vitro value. A pediatric PBPK model for risdiplam was validated with independent data and combined with a validated midazolam pediatric PBPK model to extrapolate DDI from adults to pediatric patients with SMA. The impact of selected intestinal and hepatic CYP3A ontogenies on the DDI susceptibility in children relative to adults was investigated. The PBPK analysis suggests that primary CYP3A inhibition by risdiplam occurs in the intestine rather than the liver. The PBPK‐predicted risdiplam CYP3A inhibition risk in pediatric patients with SMA aged 2 months–18 years was negligible (midazolam AUCR of 1.09–1.18) and included in the US prescribing information of risdiplam. Comprehensive evaluation of the sensitivity of predicted CYP3A DDI on selected intestinal and hepatic CYP3A ontogeny functions, together with PBPK model‐based strategy proposed here, aim to guide and facilitate DDI extrapolations in pediatric populations.
Multiyear drought exacerbates long‐term effects of climate on an invasive ant species
Authors: Couper Lisa I. , Sanders Nathan J. , Heller Nicole E. , Gordon Deborah M. 
Published: August 2021

AbstractInvasive species threaten biodiversity, ecosystem function, and human health, but the long‐term drivers of invasion dynamics remain poorly understood. We use data from a 28‐yr ongoing survey of a Northern California ant community invaded by the Argentine ant (Linepithema humile) to investigate the influence of abiotic and biotic factors on invasion dynamics. We found that the distribution of L. humile retracted following an extreme drought that occurred in the region from 2012 to 2015. The distribution of several native ant species also contracted, but overall native ant diversity was higher after the drought and for some native ant species, distributions expanded over the 28‐yr survey period. Using structural equation models, we found the strongest impact on the distribution of L. humile was from direct effects of climate, namely, cumulative precipitation and summer maximum temperatures, with only a negligible role for biotic resistance and indirect effects of climate mediated by native ants. The increasing drought and high temperature extremes projected for northern California because of anthropogenic‐driven climate change may limit the spread, and possibly the impact, of L. humile in invaded regions. The outcome will depend on the response of native ant communities to these climatic stressors.
A comprehensive sensitivity analysis on the performance of pseudo‐steady propane thermal cracking process
Authors: Ghasemi Hossein Mohammad , Gilani Neda , Shirmohammadi Reza , Rosen Marc A. 
Published: August 2021

AbstractThe propane thermal cracking reactor process is investigated in an industrial furnace with an alternative wall burner arrangement. Temperature and heat distribution of the furnace is obtained by three‐dimensional computational fluid dynamics (CFD) simulation technique using Ansys Fluent software. Ten calculation domains are adopted to decrease calculation costs. Different fuel rate ratios are selected as the main effective parameter on reactor performance. Different ratios of base fuel rate (0.0695 kg/s) have been considered. The obtained reactor tube wall temperature profile is used for a one‐dimensional pseudo‐steady reactor operation. By the proposed new arrangement, the created coke layer thickness is lower about 3 mm compared with the base case after 700 h. Meanwhile, Propane conversion is increased by 4%. Besides, reactor feed flow rate variations are considered one of the essential parameter on reactor operation. Despite surging in propylene yield after coke formation, ethylene yield decreases during the process. By increasing the fuel rate in each reactor flow rate, ethylene increased while propylene yield descended. The maximum allowable pressure drop is 2.7 bar. At 0.5ṁ fuel rate and 0.85 kg/s reactor flow rate, pressure drop, reactor lifetime, and ethylene yield are 1.23 bar, 1444 h, and 28%; respectively. In the reactor flow of 0.85 kg/s, by raising fuel rate 0.5–2ṁ ethylene yield is increased from 28% to 46.83%, while process operating time is reduced to 780 h. According to the results, 0.8–0.85 kg/s could be considered as an appropriate range for reactor feed flow rate.
Bioprospecting of native algal strains with unique lipids, proteins, and carbohydrates signatures: A time dependent study
Authors: Samadhiya Kanchan , Ghosh Atreyee , Kashyap Mrinal , Anand Vishal , Bala Kiran 
Published: August 2021

AbstractAim of this study is uncovering potential strains of microalgae from Indore, Madhya Pradesh situated in central India with a diverse climate for sustainable production of different bio‐products. Assessing the entire biochemical profile is crucial to select species‐ specific metabolites for sustainability of algal bio‐refinery processes. In the current study, seven algal species (C. proboscideum, Desmodesmus psuedocommunis, Asterarcys quadricellulare, Ettlia texensis, Pediludiela daitoensis, Coelastrella sp., Pectinodesmus sp.) were isolated and identified using Internal Transcribed Spacer (ITS) and 18 s rRNA sequences, and these species found to be from the Chlorophyta phylum. The highest biomass productivity (51.25 ± 1.96 μg/ml/day) with chlorophyll content (33.07 ± 0.63 μg/ml) was observed in A. quadricellulare on 21st day (P < 0.0001). Biochemical profiling of isolated species showed each species is unique in its biochemical composition (total lipids, carbohydrates, and proteins). Coelastrella sp. and Pectinodesmus sp. was found to be accumulating considerable quantities of (P < 0.0001) carbohydrates (303.3 ± 1.11 μg/mg dry cell weight) and lipids (212.67 ± 2.53 μg/mg per dry cell weight), respectively. Whereas P. daitoensis was found best (P < 0.0001) for protein production (205.78 ± 2.56 μg/mg dry cell weight), on 21st day. Highest total fatty acid content was detected in Pectinodesmus sp. (115.74 μg/mg) on 21st day, which has shown good saturated fatty acid (SFA) and mono unsaturated fatty acid (MUFA) percentage, inflicting high quality biodiesel production. Confocal microscopy further supported the data. Assessing the biochemical profile at different phases of growth for each species therefore reduce the production time of biofuels as well as make this process much more cost‐effective.
Marine Debris and Human Health: An Exposure Pathway of Persistent Organic Pollutants?
Authors: Conlon Katie 
Published: August 2021

Abstract
Although there are not any direct studies linking persistent organic pollutants (POPs) accumulated on marine debris to human health, there are numerous studies showing human health impacts from repeated and high-level POP exposure, as well as studies showing that POPs accumulate on plastic debris in the marine environment. With this knowledge, there is a need for greater awareness of the risks of POP exposure for those who handle marine debris regularly, especially in contexts of higher exposure such as those working in marine debris–concentrated areas. Among the scientific community, understanding of the exposure risk might be high, but others who handle marine debris, for instance, citizen groups in the Global South, are not necessarily aware of this exposure pathway. Moreover, global consumers who are marketed “ocean plastics” upcycled products are also not aware of potential POP exposure. Before marine plastics are accepted into the upcycled economy, these risks warrant further examination. This is a perspectives piece that aims to draw awareness to these emergent POP exposure pathways and considerations regarding marine plastic pollution. Environ Toxicol Chem 2022;41:263–265. © 2021 SETAC
Cost‐effective process for the production of Monascus pigments using potato pomace as carbon source by fed‐batch submerged fermentation
Authors: Chen Xiaoju , Chen Minmin , Wu Xuefeng , Li Xingjiang 
Published: August 2021

AbstractPotato pomace, generated from starch‐processing industry, was applied as a cost‐effective resource for producing Monascus pigments via submerged fermentation. First, the pigment‐production capacity of potato pomace and its hydrolysate was compared. The results indicated that potato pomace was superior to its hydrolysate when used for producing Monascus pigments. The red and yellow pigments produced in potato pomace medium reached 27.8 and 19.7 OD units/ml in 7 days, with the yield of total pigments at 1,187.5 OD units/g, respectively, increased by 127.9%, 19.4%, and 46.3% compared with the data obtained from hydrolysate. Meanwhile, the citrinin produced in potato pomace medium decreased by 22.6%. Afterward, potato pomace, without hydrolysis, was used as carbon source to obtain the optimal pigment production conditions. In the batch fermentation process, it was found that high amount of pomace inhibited the growth rate of mycelia and the productivity of pigments, and the fed‐batch fermentation process could enhance the yield and productivity of pigments. With the same final amount of pomace (80 g/L), the maximal levels of total pigments and productivity obtained from fed‐batch process reached 118.8 OD units/ml and 13.2 OD units/(ml·day), which presented an increase of 35.2% and 67.1% compared with the not fed‐batch group, respectively. The results demonstrated that potato pomace was a cost‐effective substrate for producing Monascus pigments in terms of pigment production capacity and productivity when fed‐batch submerged fermentation was applied.
Optimized reinforcement in longitudinal joints of segmental tunnel linings
Authors: Proksch‐Weilguni Clemens , Wolfger Hannes , Kollegger Johann 
Published: August 2021

AbstractWhen building tunnels using segmental lining, the segmental lining takes over the supporting role of the excavated soil. With the workspace in tunnel construction being very constricted the circular, segmental linings are divided into small segments called tubbings which are assembled by a tunnel boring machine. This kind of construction results in numerous longitudinal and circumferential joints. The loading situation for the longitudinal joints is typically dominated by the compressive normal forces combined with relatively small bending moments. The thickness of the tubbings usually depends on the longitudinal joints of the individual segments. The cross‐sectional area of the tubbings has to be reduced at the joints in order to avoid spalling of the concrete leading to higher compression in the joints themselves. The Institute of Structural Engineering of TU Wien developed a new reinforcement design for tubbings with strengthened longitudinal joints. With a patent application pending, the newly designed joints were manufactured and tested demonstrating that the TU Wien proposal significantly increases the load‐bearing capacity of the tubbings in comparison to conventional tubbing solutions. The very satisfying results, obtained from the large‐scale tests of the newly developed joint design, show great potential for the construction of tunnels with thinner tubbings in the near future.
Efficacy and safety of arbidol (umifenovir) in patients with COVID‐19: A systematic review and meta‐analysis
Authors: Amani Behnam , Amani Bahman , Zareei Sara , Zareei Mahsa 
Published: August 2021

AbstractObjectiveTo provide the latest evidence for the efficacy and safety of arbidol (umifenovir) in COVID‐19 treatment.MethodsA literature systematic search was carried out in PubMed, Cochrane Library, Embase, and medRxiv up to May 2021. The Cochrane risk of bias tool and Newcastle–Ottawa scale were used to assess the quality of included studies. Meta‐analysis was performed using RevMan 5.3.ResultsSixteen studies were met the inclusion criteria. No significant difference was observed between arbidol and non‐antiviral treatment groups neither for primary outcomes, including the negative rate of PCR (NR‐PCR) on Day 7 (risk ratio [RR]: 0.94; 95% confidence interval (CI): 0.78–1.14) and Day 14 (RR: 1.10; 95% CI: 0.96–1.25), and PCR negative conversion time (PCR‐NCT; mean difference [MD]: 0.74; 95% CI: −0.87 to 2.34), nor secondary outcomes (p > .05). However, arbidol was associated with higher adverse events (RR: 2.24; 95% CI: 1.06–4.73). Compared with lopinavir/ritonavir, arbidol showed better efficacy for primary outcomes (p < .05). Adding arbidol to lopinavir/ritonavir also led to better efficacy in terms of NR‐PCR on Day 7 and PCR‐NCT (p < .05). There was no significant difference between arbidol and chloroquine in primary outcomes (p > .05). No remarkable therapeutic effect was observed between arbidol and other agents (p > .05).ConclusionThe present meta‐analysis showed no significant benefit of using arbidol compared with non‐antiviral treatment or other therapeutic agents against COVID‐19 disease. High‐quality studies are needed to establish the efficacy and safety of arbidol for COVID‐19.
Alternative microexon splicing by RBFOX2 and PTBP1 is associated with metastasis in colorectal cancer
Authors: Mochizuki Yasushi , Funayama Ryo , Shirota Matsuyuki , Kikukawa Yuna , Ohira Masahiro , Karasawa Hideaki , Kobayashi Minoru , Ohnuma Shinobu , Unno Michiaki , Nakayama Keiko 
Published: August 2021

AbstractThe splicing of microexons (very small exons) is frequently dysregulated in the brain of individuals with autism spectrum disorder. However, little is known of the patterns, regulatory mechanisms and roles of microexon splicing in cancer. We here examined the transcriptome‐wide profile of microexon splicing in matched colorectal cancer (CRC) and normal tissue specimens. Out of 1492 microexons comprising 3 to 15 nucleotides, 21 (1%) manifested differential splicing between CRC and normal tissue. The 21 genes harboring the differentially spliced microexons were enriched in gene ontology terms related to cell adhesion and migration. RNA interference‐mediated knockdown experiments identified two splicing factors, RBFOX2 and PTBP1, as regulators of microexon splicing in CRC cells. RBFOX2 and PTBP1 were found to directly bind to microexon‐containing pre‐mRNAs and to control their splicing in such cells. Differential microexon splicing was shown to be due, at least in part, to altered expression of RBFOX2 and PTBP1 in CRC tissue compared to matched normal tissue. Finally, we found that changes in the pattern of microexon splicing were associated with CRC metastasis. Our data thus suggest that altered expression of RBFOX2 and PTBP1 might influence CRC metastasis through the regulation of microexon splicing.
Preclinical mouse model of optical coherence tomography for subcortical brain imaging without dissection
Authors: Lee Jae Meen , Han Inho , Nam Kyoung Hyup , Kim Dong Hwan , Song Seunghwan , Park Heejeong , Kim Hongki , Kim Minkyu , Choi Jeonghun , Lee Jae Il 
Published: August 2021

AbstractThe purpose of this study was to investigate the feasibility of using optical coherence tomography (OCT) to identify internal brain lesions, specifically intracerebral hemorrhage, without dissection. Mice with artificially injected brain hematomas were used to test the OCT system, and the recorded images were compared with microscopic images of the same mouse brains after hematoxylin and eosin staining. The intracranial structures surrounding the hematomas were clearly visualized by the OCT system without dissection. These images reflect the ability of OCT to determine the extent of a lesion in several planes. OCT is a useful technology, and these findings could be used as a starting point for future research in intraoperative imaging.
Arbutin attenuates ethanol‐induced acute hepatic injury by the modulation of oxidative stress and Nrf‐2/HO‐1 signaling pathway
Authors: Wang Rongsheng , Mu Jinji 
Published: August 2021

AbstractAlcoholic liver disease (ALD) is a pervasive ailment due to the excessive consumption of alcohol and there is no operative drug for its treatment. The current exploration was intended to examine the hepatoprotective efficacy of arbutin against ethanol‐provoked liver injury in rats via the modulation of the Nrf‐2/HO‐1 signaling cascade. Wistar rats were challenged with the 3 g/kg/day (40% v/v) of ethanol for 4 weeks to provoke the ALD and concomitantly supplemented with 40 mg/kg of arbutin. The liver function markers enzymes, inflammatory cytokines, and oxidative stress markers levels were scrutinized by using the respective assay kits. The mRNA expression of Nrf‐2/HO‐1 signaling proteins was studied by reverse‐transcription polymerase chain reaction. The histological alterations of liver tissues were examined. HepG2 cells were used for the in vitro studies. The levels of oxidative stress markers and liver marker enzymes were examined by using kits. Reactive oxygen species (ROS) and apoptotic cell death was detected by using fluorescent staining. There were no major differences in the body weight and liver weight of experimental animals. Arbutin treatment appreciably reduced the liver marker enzymes, upregulated superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and the hydroxyl scavenging ability, and diminished the tumor necrosis factor‐α and interleukin‐6 levels in the serum of ethanol provoked animals. Arbutin triggered Nrf‐2/HO‐1 signaling cascade liver tissues of ethanol‐provoked animals. Histological findings proved the preventing effects of arbutin. Arbutin did not demonstrate toxicity to the HepG2 cells. It reduced the aspartate aminotransferase and alanine aminotransferase, ROS, apoptotic cell death, lipid peroxidation and improved the antioxidants' levels in the ethanol‐challenged HepG2 cells. In conclusion, our findings unveiled the hepatoprotective efficacy of arbutin against ethanol‐provoked liver injury in rats. It could be a promising agent to treat alcoholic liver disease in the future.
Structure‐based virtual screening and computational study towards identification of novel inhibitors of hypoxanthine‐guanine phosphoribosyltransferase of Trypanosoma cruzi
Authors: Vidhya Venkataramani Malathi , Ponnuraj Karthe 
Published: August 2021

AbstractHypoxanthine‐guanine phosphoribosyltransferase (HGPRT) is the key regulatory enzyme of the purine salvage pathway present in the members of trypanosomatids. The parasite solely depends on this pathway for the synthesis of nucleotides due to the absence of the de novo pathway. This study intends to identify putative inhibitors towards Trypanosoma cruzi HGPRT (TcHGPRT). Initial virtual screening was performed with substructures of phosphoribosyl pyrophosphate (PRPP), an original substrate of HGPRT. Twenty compounds that had greater binding energy than the substrate was treated as hits and was further screened and narrowed down through induced fit docking which resulted in top five compounds which was distinguished into two groups based on the ligand occupancy within the PRPP binding site of TcHGPRT. Group‐I compounds (PubChem CID 130316561 and 134978234) are analogous to PRPP structure with greater occupancy, were preferred over Group‐II compounds which had lesser occupancy than the substrate. However, one compound (22404820) among Group II was chosen for further analysis considering its significant electrostatic interactions. Molecular docking studies revealed the requirement of an electronegative moiety like phosphate group to be present in the ligand due to the presence of metal ions in the substrate binding site. The three chosen compounds along with PRPP were subjected to molecular dynamics analysis, which indicated a strong presence of electrostatic interaction. Considering the dynamic stability of interactions as well as pharmacological properties of ligands based on absorption, distribution, metabolism, excretion prediction, Group‐I compounds were selected as lead compounds and were subjected to molecular electrostatic potential analysis to determine the charge distribution of the compound. The overall analysis thus suggests both 130316561 and 134978234 can be used as TcHGPRT inhibitors. Furthermore, these computational results emphasize the requirement of phosphorylated ligands which are essential in mediating electrostatic interactions and to compete with the binding affinity of the original substrate.
Kinetics of platelet adhesion to a fibrinogen‐coated surface in whole blood under flow conditions
Authors: Gabbasov Zufar A. , Avtaeva Yuliya N. , Melnikov Ivan S. , Okhota Sergey D. , Caprnda Martin , Mozos Ioana , Prosecky Robert , Rodrigo Luis , Kruzliak Peter , Zozulya Nadezhda I. 
Published: August 2021

AbstractAimTo test a novel method of assessment of platelet adhesion to a fibrinogen‐coated surface in whole blood under flow conditions.MethodsWe developed a fluidic device that mimics blood flow in vessels. The method of detection of platelet adhesion is based on recording of a scattered laser light signal from a fibrinogen‐covered surface. Testing was performed in platelet‐rich plasma (PRP) and whole blood of healthy volunteers. Control measurements were performed, followed by tests with inhibition of platelet GPIIa/IIIb and GPIb receptors. Then, the same testing sequence was performed in whole blood of persons with autoimmune thrombocytopenia and type 3 von Willebrand disease.ResultsThe change in intensity of scattered light was 2.7 (2.4; 4.1) times higher in whole blood (0.2 ± 0.08V, n = 7) than in PRP (0.05 ± 0.02 V, n = 7), p < 0.01. The blocking of GP IIb/IIIa receptors decreased the intensity of scattered light to 8.5 (6.5;12)%; the blocking of GPIb receptors decreased it to 34 (23;58)%, p < 0.01. In the whole blood of a person with autoimmune thrombocytopenia, the inhibition of GPIb receptors decreased platelet adhesion, but no effect was observed in type 3 von Willebrand disease. Inhibition of platelet GPIIb/IIIa receptors alone or combined inhibition of GPIb and GPIIb/IIIa receptors resulted in almost total suppression of adhesion in both cases.ConclusionOur system effectively registers platelet adhesion to a fibrinogen‐coated surface under controlled‐flow conditions and may successfully be applied to the investigation of platelet adhesion kinetics.