bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of physiologically based pharmacokinetic modeling for sertraline dosing recommendations in pregnancy
Authors: George Blessy , Lumen Annie , Nguyen Christine , Wesley Barbara , Wang Jian , Beitz Julie , Crentsil Victor 
Published: November 2020

AbstractPregnancy is a period of significant change that impacts physiological and metabolic status leading to alterations in the disposition of drugs. Uncertainty in drug dosing in pregnancy can lead to suboptimal therapy, which can contribute to disease exacerbation. A few studies show there are increased dosing requirements for antidepressants in late pregnancy; however, the quantitative data to guide dose adjustments are sparse. We aimed to develop a physiologically based pharmacokinetic (PBPK) model that allows gestational-age dependent prediction of sertraline dosing in pregnancy. A minimal physiological model with defined gut, liver, plasma, and lumped placental-fetal compartments was constructed using the ordinary differential equation solver package, ‘mrgsolve’, in R. We extracted data from the literature to parameterize the model, including sertraline physicochemical properties, in vitro metabolism studies, disposition in nonpregnant women, and physiological changes during pregnancy. The model predicted the pharmacokinetic parameters from a clinical study with eight subjects for the second trimester and six subjects for the third trimester. Based on the model, gestational-dependent changes in physiology and metabolism account for increased clearance of sertraline (up to 143% at 40 weeks gestational age), potentially leading to under-dosing of pregnant women when nonpregnancy doses are used. The PBPK model was converted to a prototype web-based interactive dosing tool to demonstrate how the output of a PBPK model may translate into optimal sertraline dosing in pregnancy. Quantitative prediction of drug exposure using PBPK modeling in pregnancy will support clinically appropriate dosing and increase the therapeutic benefit for pregnant women.
A comprehensive diagnostic approach combining phylogenetic disease bracketing and CT imaging reveals osteomyelitis in a Tyrannosaurus rex
Authors: Hamm C. A. , Hampe O. , Schwarz D. , Witzmann F. , Makovicky P. J. , Brochu C. A. , Reiter R. , Asbach P. 
Published: November 2020

AbstractTraditional palaeontological techniques of disease characterisation are limited to the analysis of osseous fossils, requiring several lines of evidence to support diagnoses. This study presents a novel stepwise concept for comprehensive diagnosis of pathologies in fossils by computed tomography imaging for morphological assessment combined with likelihood estimation based on systematic phylogenetic disease bracketing. This approach was applied to characterise pathologies of the left fibula and fused caudal vertebrae of the non-avian dinosaur Tyrannosaurus rex. Initial morphological assessment narrowed the differential diagnosis to neoplasia or infection. Subsequent data review from phylogenetically closely related species at the clade level revealed neoplasia rates as low as 3.1% and 1.8%, while infectious-disease rates were 32.0% and 53.9% in extant dinosaurs (birds) and non-avian reptiles, respectively. Furthermore, the survey of literature revealed that within the phylogenetic disease bracket the oldest case of bone infection (osteomyelitis) was identified in the mandible of a 275-million-year-old captorhinid eureptile Labidosaurus. These findings demonstrate low probability of a neoplastic aetiology of the examined pathologies in the Tyrannosaurus rex and in turn, suggest that they correspond to multiple foci of osteomyelitis.
A cell-based bioluminescence assay reveals dose-dependent and contextual repression of AP-1-driven gene expression by BACH2
Authors: Vardaka Panagiota , Lozano Teresa , Bot Christopher , Ellery Jonathan , Whiteside Sarah K. , Imianowski Charlotte J. , Farrow Stuart , Walker Simon , Okkenhaug Hanneke , Yang Jie , Okkenhaug Klaus , Kuo Paula , Roychoudhuri Rahul 
Published: November 2020

AbstractWhereas effector CD4+ and CD8+ T cells promote immune activation and can drive clearance of infections and cancer, CD4+ regulatory T (Treg) cells suppress their function, contributing to both immune homeostasis and cancer immunosuppression. The transcription factor BACH2 functions as a pervasive regulator of T cell differentiation, promoting development of CD4+ Treg cells and suppressing the effector functions of multiple effector T cell (Teff) lineages. Here, we report the development of a stable cell-based bioluminescence assay of the transcription factor activity of BACH2. Tetracycline-inducible BACH2 expression resulted in suppression of phorbol 12-myristate 13-acetate (PMA)/ionomycin-driven activation of a luciferase reporter containing BACH2/AP-1 target sequences from the mouse Ifng + 18k enhancer. BACH2 expression repressed the luciferase signal in a dose-dependent manner but this activity was abolished at high levels of AP-1 signalling, suggesting contextual regulation of AP-1 driven gene expression by BACH2. Finally, using the reporter assay developed, we find that the histone deacetylase 3 (HDAC3)-selective inhibitor, RGFP966, inhibits BACH2-mediated repression of signal-driven luciferase expression. In addition to enabling mechanistic studies, this cell-based reporter may enable identification of small molecule agonists or antagonists of BACH2 function for drug development.
Intestinal miRNAs regulated in response to dietary lipids
Authors: Gil-Zamorano Judit , Tomé-Carneiro João , Lopez de las Hazas María-Carmen , del Pozo-Acebo Lorena , Crespo M. Carmen , Gómez-Coronado Diego , Chapado Luis A. , Herrera Emilio , Latasa María-Jesús , Ruiz-Roso María Belén , Castro-Camarero Mónica , Briand Olivier , Dávalos Alberto 
Published: November 2020

AbstractThe role of miRNAs in intestinal lipid metabolism is poorly described. The small intestine is constantly exposed to high amounts of dietary lipids, and it is under conditions of stress that the functions of miRNAs become especially pronounced. Approaches consisting in either a chronic exposure to cholesterol and triglyceride rich diets (for several days or weeks) or an acute lipid challenge were employed in the search for intestinal miRNAs with a potential role in lipid metabolism regulation. According to our results, changes in miRNA expression in response to fat ingestion are dependent on factors such as time upon exposure, gender and small intestine section. Classic and recent intestinal in vitro models (i.e. differentiated Caco-2 cells and murine organoids) partially mirror miRNA modulation in response to lipid challenges in vivo. Moreover, intestinal miRNAs might play a role in triglyceride absorption and produce changes in lipid accumulation in intestinal tissues as seen in a generated intestinal Dicer1-deletion murine model. Overall, despite some variability between the different experimental cohorts and in vitro models, results show that some miRNAs analysed here are modulated in response to dietary lipids, hence likely to participate in the regulation of lipid metabolism, and call for further research.
Demystifying the catalytic pathway of Mycobacterium tuberculosis isocitrate lyase
Authors: Ibeji Collins U. , Salleh Nor Amirah Mohd , Sum Jia Siang , Ch’ng Angela Chiew Wen , Lim Theam Soon , Choong Yee Siew 
Published: November 2020

AbstractPulmonary tuberculosis, caused by Mycobacterium tuberculosis, is one of the most persistent diseases leading to death in humans. As one of the key targets during the latent/dormant stage of M. tuberculosis, isocitrate lyase (ICL) has been a subject of interest for new tuberculosis therapeutics. In this work, the cleavage of the isocitrate by M. tuberculosis ICL was studied using quantum mechanics/molecular mechanics method at M06-2X/6-31+G(d,p): AMBER level of theory. The electronic embedding approach was applied to provide a better depiction of electrostatic interactions between MM and QM regions. Two possible pathways (pathway I that involves Asp108 and pathway II that involves Glu182) that could lead to the metabolism of isocitrate was studied in this study. The results suggested that the core residues involved in isocitrate catalytic cleavage mechanism are Asp108, Cys191 and Arg228. A water molecule bonded to Mg2+ acts as the catalytic base for the deprotonation of isocitrate C(2)–OH group, while Cys191 acts as the catalytic acid. Our observation suggests that the shuttle proton from isocitrate hydroxyl group C(2) atom is favourably transferred to Asp108 instead of Glu182 with a lower activation energy of 6.2 kcal/mol. Natural bond analysis also demonstrated that pathway I involving the transfer of proton to Asp108 has a higher intermolecular interaction and charge transfer that were associated with higher stabilization energy. The QM/MM transition state stepwise catalytic mechanism of ICL agrees with the in vitro enzymatic assay whereby Asp108Ala and Cys191Ser ICL mutants lost their isocitrate cleavage activities.
Polypharmacy, hospitalization, and mortality risk: a nationwide cohort study
Authors: Chang Tae Ik , Park Haeyong , Kim Dong Wook , Jeon Eun Kyung , Rhee Connie M. , Kalantar-Zadeh Kamyar , Kang Ea Wha , Kang Shin-Wook , Han Seung Hyeok 
Published: November 2020

AbstractPolypharmacy is a growing and major public health issue, particularly in the geriatric population. This study aimed to examine the association between polypharmacy and the risk of hospitalization and mortality. We included 3,007,620 elderly individuals aged ≥ 65 years who had at least one routinely-prescribed medication but had no prior hospitalization within a year. The primary exposures of interest were number of daily prescribed medications (1–2, 3–4, 5–6, 7–8, 9–10, and ≥ 11) and presence of polypharmacy (≥ 5 prescription drugs per day). The corresponding comparators were the lowest number of medications (1–2) and absence of polypharmacy. The study outcomes were hospitalization and all-cause death. The median age of participants was 72 years and 39.5% were men. Approximately, 46.6% of participants experienced polypharmacy. Over a median follow-up of 5.0 years, 2,028,062 (67.4%) hospitalizations and 459,076 (15.3%) all-cause deaths were observed. An incrementally higher number of daily prescribed medications was found to be associated with increasingly higher risk for hospitalization and mortality. These associations were consistent across subgroups of age, sex, residential area, and comorbidities. Furthermore, polypharmacy was associated with greater risk of hospitalization and death: adjusted HRs (95% CIs) were 1.18 (1.18–1.19) and 1.25 (1.24–1.25) in the overall and 1.16 (1.16–1.17) and 1.25 (1.24–1.25) in the matched cohorts, respectively. Hence, polypharmacy was associated with a higher risk of hospitalization and all-cause death among elderly individuals.
Thermodynamic analysis of cooperative ligand binding by the ATP-binding DNA aptamer indicates a population-shift binding mechanism
Authors: Slavkovic Sladjana , Zhu Yanrui , Churcher Zachary R. , Shoara Aron A. , Johnson Anne E. , Johnson Philip E. 
Published: November 2020

AbstractThe ATP-binding DNA aptamer is often used as a model system for developing new aptamer-based biosensor methods. This aptamer follows a structure-switching binding mechanism and is unusual in that it binds two copies of its ligand. We have used isothermal titration calorimetry methods to study the binding of ATP, ADP, AMP and adenosine to the ATP-binding aptamer. Using both individual and global fitting methods, we show that this aptamer follows a positive cooperative binding mechanism. We have determined the binding affinity and thermodynamics for both ligand-binding sites. By separating the ligand-binding sites by an additional four base pairs, we engineered a variant of this aptamer that binds two adenosine ligands in an independent manner. Together with NMR and thermal stability experiments, these data indicate that the ATP-binding DNA aptamer follows a population-shift binding mechanism that is the source of the positive binding cooperativity by the aptamer.
Contaminating DNA in human saliva alters the detection of variants from whole genome sequencing
Authors: Samson C. A. , Whitford W. , Snell R. G. , Jacobsen J. C. , Lehnert K. 
Published: November 2020

AbstractCells obtained from human saliva are commonly used as an alternative DNA source when blood is difficult or less convenient to collect. Although DNA extracted from saliva is considered to be of comparable quality to that derived from blood, recent studies have shown that non-human contaminating DNA derived from saliva can confound whole genome sequencing results. The most concerning complication is that non-human reads align to the human reference genome using standard methodology, which can critically affect the resulting variant genotypes identified in a genome. We identified clusters of anomalous variants in saliva DNA derived reads which aligned in an atypical manner. These reads had only short regions of identity to the human reference sequence, flanked by soft clipped sequence. Sequence comparisons of atypically aligning reads from eight human saliva-derived samples to RefSeq genomes revealed the majority to be of bacterial origin (63.46%). To partition the non-human reads during the alignment step, a decoy of the most prevalent bacterial genome sequences was designed and utilised. This reduced the number of atypically aligning reads when trialled on the eight saliva-derived samples by 44% and most importantly prevented the associated anomalous genotype calls. Saliva derived DNA is often contaminated by DNA from other species. This can lead to non-human reads aligning to the human reference genome using current alignment best-practices, impacting variant identification. This problem can be diminished by using a bacterial decoy in the alignment process.
Subtilase cytotoxin induces a novel form of Lipocalin 2, which promotes Shiga-toxigenic Escherichia coli survival
Authors: Yahiro Kinnosuke , Ogura Kohei , Goto Yoshiyuki , Iyoda Sunao , Kobayashi Tatsuya , Takeuchi Hiroki , Ohnishi Makoto , Moss Joel 
Published: November 2020

AbstractShiga-toxigenic Escherichia coli (STEC) infection causes severe bloody diarrhea, renal failure, and hemolytic uremic syndrome. Recent studies showed global increases in Locus for Enterocyte Effacement (LEE)-negative STEC infection. Some LEE-negative STEC produce Subtilase cytotoxin (SubAB), which cleaves endoplasmic reticulum (ER) chaperone protein BiP, inducing ER stress and apoptotic cell death. In this study, we report that SubAB induces expression of a novel form of Lipocalin-2 (LCN2), and describe its biological activity and effects on apoptotic cell death. SubAB induced expression of a novel LCN2, which was regulated by PRKR-like endoplasmic reticulum kinase via the C/EBP homologous protein pathway. SubAB-induced novel-sized LCN2 was not secreted into the culture supernatant. Increased intracellular iron level by addition of holo-transferrin or FeCl3 suppressed SubAB-induced PARP cleavage. Normal-sized FLAG-tagged LCN2 suppressed STEC growth, but this effect was not seen in the presence of SubAB- or tunicamycin-induced unglycosylated FLAG-tagged LCN2. Our study demonstrates that SubAB-induced novel-sized LCN2 does not have anti-STEC activity, suggesting that SubAB plays a crucial role in the survival of LEE-negative STEC as well as inducing apoptosis of the host cells.
Measurement of bunch length and temporal distribution using accelerating radio frequency cavity in low-emittance injector
Authors: Hwang Ji-Gwang , Miyajima Tsukasa , Honda Yosuke , Kim Eun-San 
Published: November 2020

AbstractWe demonstrate an experimental methodology for measuring the temporal distribution of pico-second level electron bunch with low energy using radial electric and azimuthal magnetic fields of an accelerating ($$\hbox {TM}_{01}$$TM01mode) radio frequency (RF) cavity that is used for accelerating electron beams in a linear accelerator. In this new technique, an accelerating RF cavity provides a phase-dependent transverse kick to the electrons, resulting in the linear coupling of the trajectory angle with the longitudinal position inside the bunch. This method does not require additional devices on the beamline since it uses an existing accelerating cavity for the projection of the temporal distribution to the transverse direction. We present the theoretical basis of the proposed method and validate it experimentally in the compact-energy recovery linac accelerator at KEK. Measurements were demonstrated using a 2-cell superconducting booster cavity with a peak on-axis accelerating field ($$E_0$$E0) of 7.21 MV/m.
Effect of the similarity of gut microbiota composition between donor and recipient on graft function after living donor kidney transplantation
Authors: Kim Ji Eun , Kim Hyo-Eun , Cho Hyunjeong , Park Ji In , Kwak Min-Jung , Kim Byung-Yong , Yang Seung Hee , Lee Jung Pyo , Kim Dong Ki , Joo Kwon Wook , Kim Yon Su , Kim Bong-Soo , Lee Hajeong 
Published: November 2020

AbstractGraft outcomes of unrelated donor kidney transplant are comparable with those of related donor kidney transplant despite their genetic distance. This study aimed to identify whether the similarity of donor–recipient gut microbiota composition affects early transplant outcomes. Stool samples from 67 pairs of kidney transplant recipients and donors were collected. Gut microbiota differences between donors and recipients were determined using weighted UniFrac distance. Among the donor–recipient pairs, 30 (44.8%) pairs were related, while 37 (55.2%) were unrelated. The unrelated pairs, especially spousal pairs, had similar microbial composition, and they more frequently shared their meals than related pairs did. The weighted UniFrac distance showed an inverse correlation with the 6-month allograft function (p = 0.034); the correlation was significant in the unrelated pairs (p = 0.003). In the unrelated pairs, the microbial distance showed an excellent accuracy in predicting the estimated glomerular filtration rate of < 60 mL/min/1.73 m2 at 6-months post-transplantation and was better than human leukocyte antigen incompatibility and rejection. The incidence of infection within 6 months post-transplantation increased in the recipients having dissimilar microbiota with donors compared to the other recipients. Thus, pre-transplantation microbial similarity in unrelated donors and recipients may be associated with 6-month allograft function.
The role of FOXD2-AS1 in cancer: a comprehensive study based on data mining and published articles
Authors: Zhang Yongping , Liang Chaojie , Zhang Yu , Wang Zhinmin , Li Ruihuan , Wei Zhigang , Guo Jiansheng 
Published: November 2020

Abstract
Background and aims: Long non-coding RNA (lncRNA) FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) is aberrantly expressed in various cancers and associated with cancer progression. A comprehensive meta-analysis was performed based on published literature and data in the Gene Expression Omnibus database, and then the Cancer Genome Atlas (TCGA) dataset was used to assess the clinicopathological and prognostic value of FOXD2-AS1 in cancer patients.
Methods: Gene Expression Omnibus databases of microarray data and published articles were used for meta-analysis, and TCGA dataset was also explored using the GEPIA analysis program. Hazard ratios (HRs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the role of FOXD2-AS1 in cancers.
Results: This meta-analysis included 21 studies with 2391 patients and 25 GEO datasets with 3311 patients. The pooled HRs suggested that highly expressed FOXD2-AS1 expression was correlated with poor overall survival (OS) and disease-free survival (DFS). Similar results were obtained by analysis of TCGA data for 9502 patients. The pooled results also indicated that FOXD2-AS1 expression was associated with bigger tumor size and advanced TNM stage, but was not related to age, gender, differentiation and lymph node metastasis.
Conclusion: The present study demonstrated that FOXD2-AS1 is closely related to tumor size and TNM stage. Additionally, increased FOXD2-AS1 was a risk factor of OS and DFS in cancer patients, suggesting FOXD2-AS1 may be a potential biomarker in human cancers.
Parent and Professional Perceptions and Feedback on the Content of an eHealth Hearing Aid Learning Series for Parents of Children Who Are Deaf or Hard-of-Hearing
Authors: Whicker John J. , Smith Brenda K. , Muñoz Karen 
Published: November 2020

Purpose

To qualitatively explore parent and professional perspectives regarding the content of select
Hear to Learn
tutorials to identify usefulness and meaningfulness of the tutorials, and to inform regarding key components to enhance usefulness of eHealth platforms.

Method
This study used a qualitative design with two stakeholder focus groups. Stakeholder groups included four parents of children who are deaf or hard-of-hearing, and six professionals serving children who are deaf or hard-of-hearing.

Results
Findings indicate that both stakeholders valued the tutorials generally as helpful; however, areas for improvement were suggested.

Conclusion
Use of visuals, step-by-step instructions, and depth of content were identified as key elements that may be considered to optimize benefits of eHealth material for parents.
SOLAR-v: A new solar spectral irradiance dataset based on SOLAR/SOLSPEC observations during solar cycle 24
Authors: Meftah M. , Snow M. , Damé L. , Bolseé D. , Pereira N. , Cessateur G. , Bekki S. , Keckhut P. , Sarkissian A. , Hauchecorne A. 
Published: November 2020

Context. Solar spectral irradiance (SSI) is the wavelength-dependent energy input to the top of the Earth’s atmosphere. Solar ultraviolet (UV) irradiance represents the primary forcing mechanism for the photochemistry, heating, and dynamics of the Earth’s atmosphere. Hence, both temporal and spectral variations in solar UV irradiance represent crucial inputs to the modeling and understanding of the behavior of the Earth’s atmosphere. Therefore, measuring the long-term solar UV irradiance variations over the 11-year solar activity cycle (and over longer timescales) is fundamental. Thus, each new solar spectral irradiance dataset based on long-term observations represents a major interest and can be used for further investigations of the long-term trend of solar activity and the construction of a homogeneous solar spectral irradiance record.
Aims. The main objective of this article is to present a new solar spectral irradiance database (SOLAR-v) with the associated uncertainties. This dataset is based on solar UV irradiance observations (165−300 nm) of the SOLAR/SOLSPEC space-based instrument, which provides measurements of the full-disk SSI during solar cycle 24.
Methods. SOLAR/SOLSPEC made solar acquisitions between April 5, 2008 and February 10, 2017. During this period, the instrument was affected by the harsh space environment that introduces instrumental trends (degradation) in the SSI measurements. A new method based on an adaptation of the Multiple Same-Irradiance-Level (MuSIL) technique was used to separate solar variability and any uncorrected instrumental trends in the SOLAR/SOLSPEC UV irradiance measurements.
Results. A new method for correcting degradation has been applied to the SOLAR/SOLSPEC UV irradiance records to provide new solar cycle variability results during solar cycle 24. Irradiances are reported at a mean solar distance of 1 astronomical unit (AU). In the 165−242 nm spectral region, the SOLAR/SOLSPEC data agrees with the observations (SORCE/SOLSTICE) and models (SATIRE-S, NRLSSI 2) to within the 1-sigma error envelope. Between 242 and 300 nm, SOLAR/SOLSPEC agrees only with the models.