bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arnica Montana L. Supercritical Extraction Optimization for Antibiotic and Anticancer Activity
Authors: Žitek Taja , Postružnik Vesna , Knez Željko , Golle Andrej , Dariš Barbara , Knez Marevci Maša 
Published: May 2022

Arnica montana L. flower heads are known for their antioxidant, antimicrobial, and anticancer activity. The aim of this work was to optimize the process of supercritical CO2 extraction, to achieve high extraction yield and high content of biologically active components, and to confirm the antimicrobial and anticancer activity of the extract. The influence of pressure and temperature on the total phenolic content, antioxidant activity, and proanthocyanidin content was evaluated. The pressure and temperature were found to be interdependent. A temperature of 60°C and a pressure of 30 MPa resulted in a high extraction yield, antioxidant activity and phenolic content. The content of proanthocyanidins was highest at a pressure between 18 and 24 MPa. The extracts inhibited three different microorganisms successfully; Staphylococcus aureus, Escherichia coli and Candida albicans, at concentrations ranging from 0.1 to 5.16 mg/ml and showed anticancer activity decrease up to 85% at a concentration of 0.5 mg/ml.
DFP-Induced Status Epilepticus Severity in Mixed-Sex Cohorts of Adult Rats Housed in the Same Room: Behavioral and EEG Comparisons
Authors: Rao Nikhil S. , Meyer Christina , Vasanthi Suraj S. , Massey Nyzil , Samidurai Manikandan , Gage Meghan , Putra Marson , Almanza Aida N. , Wachter Logan , Thippeswamy Thimmasettappa 
Published: May 2022

Sex is a biological variable in experimental models. In our previous diisopropylfluorophosphate (DFP) studies, female rats required a higher dose of DFP to achieve a somewhat similar severity of status epilepticus (SE) as males. In those studies, male and female rats were bought separately from the same vendor, housed in different rooms, and the DFP used was from different batches. We had also shown that surgery for epidural electrodes implantation reduces the threshold for SE. Our recent study in the soman (GD) model using a mixed-sex cohort of rats housed individually but in the same room showed that females achieved significantly higher SE severity than males for the same dose of GD. In this study, we demonstrate that housing the mixed-sex cohorts in the same room and treating them with DFP (4 mg/kg, s.c.) from the same pool, though from different batches, yielded reproducible SE severity in both sexes and both telemetry (surgery) and non-telemetry (non-surgery) groups. We conducted experiments in four mixed-sex cohorts of adult Sprague-Dawley rats. In females, the surgery for implanting the telemetry devices reduced the latency to convulsive seizure (CS) and increased SE severity compared to non-telemetry females. However, there were no sex differences in latency or SE severity within telemetry or non-telemetry groups. Once animals reached CS stage ≥3, they remained in CS stage in both sexes until midazolam was administered. Midazolam (3 mg/kg, i.m.) treatment 1-one-hour post-DFP significantly reduced epileptiform spikes in both sexes. The mortality was only 2% in 24 h. Irrespective of sex or stage of estrous cycle or surgery, the animals had continuous convulsive SE for ∼40 min. In telemetry rats, electrographic changes correlated with behavioral seizures. However, there was a significant difference in SE severity and the latency between directly-observed behavioral CS and EEG-based CS quantification in both sexes. Overall, these results suggest that housing both sexes in the same room and treating with DFP in a mixed-sex cohort from the same pool of reagents will minimize variability in SE severity. Such rigorous experiments will yield better outcomes while testing disease-modifying agents in epilepsy models.
A Pyridazinone Compound for Effectively Treating Non-alcoholic Steatohepatitis by Targeting THRβ
Authors: Cheng Hao , Wang Xiao-Bo , Zhi Ying , Liu Bo , Liu Na , Li Meng-Jun , Mu Yan-Ling 
Published: May 2022

Developing effective therapies and medicines to conquer nonalcoholic steatohepatitis (NASH) is of great significance for public health and is faced with a major challenge. The activation of the thyroid hormone receptor agonist THRβ could be regulated by target drugs that has brought huge potential to the treatment of NASH. In this work, pyridazinone compound YWS01125 was synthesized for the first time. In this study, an ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method for YWS01125 determination was established, and the pharmacokinetics of YWS01125 was evaluated. The half-life values (t1/2)of three different doses of YWS01125 was 189.12 ± 95.27, 152.64 ± 37.98, and 181.95 ± 64.25 min, respectively, and the tissue distribution studies demonstrated that YWS01125 was quickly distributed to various tissues. With successful application in the pharmacokinetics study of YWS01125, the UPLC-MS/MS method has shown characteristics of high sensitivity, rapidity, and good selectivity.
Atrioventricular Block Necessitating Chronic Ventricular Pacing After Tricuspid Valve Surgery in Patients With a Systemic Right Ventricle: Long-Term Follow-Up
Authors: Nederend Marieke , Jongbloed Monique R. M. , Kiès Philippine , Vliegen Hubert W. , Bouma Berto J. , Regeer Madelien V. , Koolbergen Dave R. , Hazekamp Mark G. , Schalij Martin J. , Egorova Anastasia D. 
Published: May 2022

BackgroundPatients with transposition of the great arteries (TGA) after an atrial switch or congenitally corrected TGA (ccTGA) are prone to systemic right ventricular (sRV) failure. Tricuspid valve (TV) regurgitation aggravates sRV dysfunction. Timely TV surgery stabilizes sRV function, yet the development of atrioventricular (AV)-conduction disturbances in the course of sRV failure can contribute to sRV dysfunction through pacing-induced dyssynchrony. This study aims to explore the incidence, timing, and functional consequences of AV-block requiring ventricular pacing after TV surgery in patients with sRV.MethodsConsecutive adolescent and adult patients with an sRV who underwent TV surgery between 1989 and 2020 and followed-up at our center were included in this observational cohort study.ResultsThe data of 28 patients (53% female, 57% ccTGA, and a mean age at surgery 38 ± 13 years) were analyzed. The mean follow-up was 9.7 ± 6.8 years. Of the remaining 22 patients at the risk of developing high degree AV-block after TV surgery, 9 (41%) developed an indication for chronic ventricular pacing during follow-up, of which 5 (56%) within 24 months postoperatively (3 prior to hospital discharge). The QRS duration, a surrogate marker for dyssynchrony, was significantly higher in patients with chronic left ventricular pacing than in patients with native AV-conduction (217 ± 24 vs. 116 ± 23 ms, p = 0.000), as was the heart failure biomarker NT-pro-BNP [2,746 (1,242–6,879) vs. 495 (355–690) ng/L, p = 0.004] and the percentage of patients with ≥1 echocardiographic class of deterioration of systolic sRV function (27 vs. 83%, p = 0.001). Of the patients receiving chronic subpulmonary ventricular pacing (n = 12), 9 (75%) reached the composite endpoint of progressive heart failure [death, ventricular assist device implantation, or upgrade to cardiac resynchronization therapy (CRT)]. Only 4 (31%) patients with native AV-conduction (n = 13) reached this composite endpoint (p = 0.027).ConclusionPatients with a failing sRV who undergo TV surgery are prone to develop AV-conduction abnormalities, with 41% developing an indication for chronic ventricular pacing during 10 years of follow-up. Patients with chronic subpulmonary ventricular pacing have a significantly longer QRS complex duration, have higher levels of the heart failure biomarker NT-pro-BNP, and are at a higher risk of deterioration of systolic sRV function and progressive heart failure.
N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization
Authors: Wu Yihao , Jiang Deying , Zhang Hao , Yin Fanxing , Guo Panpan , Zhang Xiaoxu , Bian Ce , Chen Chen , Li Shuixin , Yin Yuhan , Böckler Dittmar , Zhang Jian , Han Yanshuo 
Published: May 2022

ObjectivesThis study aimed to identify key AAA-related m1A RNA methylation regulators and their association with immune infiltration in AAA. Furthermore, we aimed to explore the mechanism that m1A regulators modulate the functions of certain immune cells as well as the downstream target genes, participating in the progression of AAA.MethodsBased on the gene expression profiles of the GSE47472 and GSE98278 datasets, differential expression analysis focusing on m1A regulators was performed on the combined dataset to identify differentially expressed m1A regulatory genes (DEMRGs). Additionally, CIBERSORT tool was utilized in the analysis of the immune infiltration landscape and its correlation with DEMRGs. Moreover, we validated the expression levels of DEMRGs in human AAA tissues by real-time quantitative PCR (RT-qPCR). Immunofluorescence (IF) staining was also applied in the validation of cellular localization of YTHDF3 in AAA tissues. Furthermore, we established LPS/IFN-γ induced M1 macrophages and ythdf3 knockdown macrophages in vitro, to explore the relationship between YTHDF3 and macrophage polarization. At last, RNA immunoprecipitation-sequencing (RIP-Seq) combined with PPI network analysis was used to predict the target genes of YTHDF3 in AAA progression.ResultsEight DEMRGs were identified in our study, including YTHDC1, YTHDF1-3, RRP8, TRMT61A as up-regulated genes and FTO, ALKBH1 as down-regulated genes. The immune infiltration analysis showed these DEMRGs were positively correlated with activated mast cells, plasma cells and M1 macrophages in AAA. RT-qPCR analysis also verified the up-regulated expression levels of YTHDC1, YTHDF1, and YTHDF3 in human AAA tissues. Besides, IF staining result in AAA adventitia indicated the localization of YTHDF3 in macrophages. Moreover, our in-vitro experiments found that the knockdown of ythdf3 in M0 macrophages inhibits macrophage M1 polarization but promotes macrophage M2 polarization. Eventually, 30 key AAA-related target genes of YTHDF3 were predicted, including CD44, mTOR, ITGB1, STAT3, etc.ConclusionOur study reveals that m1A regulation is significantly associated with the pathogenesis of human AAA. The m1A “reader,” YTHDF3, may participate in the modulating of macrophage polarization that promotes aortic inflammation, and influence AAA progression by regulating the expression of its target genes.
Formation of an Intracontinental Orogen Above the Permo-Triassic Mantle Convection Cell in the Paleo-Tethys Tectonic Realm due to Far-Field Stress Derived From Continental Margins
Authors: Zhao Lei , Zhai Mingguo , Zhou Xiwen 
Published: May 2022

The identification of intraplate orogens seemingly poses challenges to the plate tectonic theory. Delineating the formation processes of intraplate orogens can provide clues for the better understandings of the above issue. Although still controversial, the Indosinian (Permo-Triassic) orogeny in the South China Block (SCB) is potentially a good example of intracontinental orogen. In this paper, we carry out studies on the Indosinian high-grade rocks in the northeastern Cathaysia Block of the SCB, hoping to cast light on the features and formation processes of intraplate orogenic belts. These rocks exhibit HP/HT granulite facies mineral assemblages and reaction textures imply that they witnessed eclogite-facies metamorphism. Their clockwise P-T trajectories with isothermal decompression stages suggest significant crustal thickening followed by quick orogenic collapse. Immobile whole-rock trace elements indicate basaltic protoliths features, resembling E-MORB and OIB, respectively. SIMS zircon U-Pb age dating confirms Indosinian metamorphic ages of ∼248 Ma and a protolith age of ∼953 Ma. The mantle-like O isotopic compositions of the Neoproterozoic magmatic zircon cores further attest that they were primarily mantle derived rocks. The whole-rock Sm-Nd isotopic compositions show more enriched features because of metamorphic alteration, while zircon Lu-Hf isotopic results show primitive characteristics with Neoproterozoic model ages. These features suggest that the high-grade mafic rocks, as well as the metamorphosed early Precambrian metasedimentary rocks hosting them, are all continental crust components and juvenile oceanic crust components featuring plate margins are absent during the SCB Indosinian orogeny. Characteristics of these high-grade rocks and their spatial occurrences are both consistent with the proposal of an intracontinental orogen. After summarizations and comparisons of the Indosinian plate margin activities around the SCB, we suggest that this northeast-southwest trending orogenic belt is geometrically consistent with two mantle convection cells, with one conveying the SCB northward to collide with the North China Craton, and the other conveying the Paleo-Pacific plate northwestwards to form an active continental margin along the southeast SCB. The driving mechanism of the formation of the SCB Indosinian intracontinental orogenic belt could have broad implications for other intraplate orogens around the world.
Ground Surface Deformation in the Hanging Wall of the Jinshandian Underground Iron Mine in China
Authors: Wang Tianlong , Chen Congxin , Xia Kaizong , Zhang Chuqiang , Wang Yue , Liu Xuanting 
Published: May 2022

When sublevel caving is used in metal mines, the stress state in the rock mass that initially existed around the mined-out area will be destroyed. This will lead to the rock strata deforming and moving and also, potentially, to large-scale collapse and cracking of the ground surface. Such ground surface deformation can cause significant damage to buildings and other structures. Therefore, it is very important to study the mechanism responsible for this ground surface deformation so that methods can be devised to protect the mine’s production facilities as well as the property and safety of nearby residents. In this study, the mechanism responsible for the surface deformation of the hanging wall in the eastern part of the Jinshandian iron mine was investigated by analyzing monitoring data collected in situ on the surface (from 2008 to 2020) and other related information (occurrence of surface cracking and collapse and geological conditions). The results show that the ground surface deformation can be divided into four stages (initial, creep, slow, and accelerating deformation stages). A flexural toppling failure model is proposed to account for the surface deformation. The model suggests that large-scale deformation of the ground surface at the hanging wall occurs due to the combined effect of in situ ground stress, occurrence of steep dip discontinuities and faults, the dips and strikes of the two parallel orebodies, and underground mining activity. Furthermore, the surface deformation can be divided into six regions corresponding to caved, rapidly-accelerating deformation, slowly-accelerating deformation, acceptable deformation, slight deformation, and no deformation zones. In the rapidly-accelerating deformation zone, the ratio of the horizontal to vertical displacement is greater than 1 and some major cracks can be found. Large-scale cracks begin to form when the horizontal velocity of the ground surface is greater than 1 mm/day.
Design and Optimization of a Modular Wireless Charging Scheme for Electric Buses With High Misalignment Tolerance
Authors: He Rui , Gao Jian , Yang Aixi , Zhou Jing 
Published: May 2022

Modular design helps to improve the reliability and power density of power electronic systems, so cascading of power electronics modules is an effective method to improve the overall stability of the system. The application of the wireless power transfer (WPT) system to electric buses faces the challenge of higher power requirement; modularization provides a solution to the design of the wireless charging system for electric buses. A modular wireless charging system for electric buses is proposed in this study; the system consists of five identical 6.6 kW wireless charging modules distributed relatively disperse on the chassis. Through the design of coil layout, different modules on the receiver side can be decoupled from each other, which facilitate independent control. Each module utilizes the bipolar-solenoid coupling structure, which proves to have a high misalignment tolerance. In order to reduce the electromagnetic radiation for passengers on the electric bus, shielding is added on the receiver side. Five independent modules work collaboratively to compose a 30 kW wireless charging system for electric buses. The DC-DC efficiency is 87.44% in an aligned position at 200 mm transmission distance. With closed-loop control, the proposed system has high misalignment tolerance in the horizontal X-Y plane. Compared with the open loop control scheme, the average efficiency of the proposed system increases by 22.1% within 300 mm misalignment.
Tolerance of a Vascularized Composite Allograft Achieved in MHC Class-I-mismatch Swine via Mixed Chimerism
Authors: Lellouch Alexandre G. , Andrews Alec R. , Saviane Gaelle , Ng Zhi Yang , Schol Ilse M. , Goutard Marion , Gama Amon-Ra , Rosales Ivy A. , Colvin Robert B. , Lantieri Laurent A. , Randolph Mark A. , Benichou Gilles , Cetrulo Curtis L. 
Published: May 2022

BackgroundVascularized composite allografts (VCAs) allow reconstruction of devastating injuries and amputations, yet require lifelong immunosuppression that is associated with significant morbidity. Induction of immune tolerance of VCAs would permit widespread use of these procedures. VCAs are acquired from deceased donors most likely to be fully-MHC-mismatched (in contrast to living-related renal transplant donor-recipient pairs matched at one MHC haplotype). After achieving VCA tolerance in a swine model equivalent to clinical living-related renal transplants (single-haplotype MHC mismatches: e.g., “mother-daughter”/haploidentical), we tested our protocol in MHC class I, class II, and fully-MHC-mismatched pairs. Although class II mismatched swine demonstrated similar results as the haploidentical scenario (stable mixed chimerism and tolerance), our protocol failed to prevent rejection of class I and full mismatch VCAs. Here, we describe a new adapted conditioning protocol that successfully achieved tolerance across MHC class-I-mismatch barriers in swine.MethodsSwine were treated with non-myeloablative total body and thymic irradiation two days prior to infusion of bone marrow cells from an MHC class I-mismatched donor. They also received a short-term treatment with CTLA4-Ig (Belatacept®) and anti-IL6R mAb (Tociluzimab®) and were transplanted with an osteomyocutaneous VCA from the same donor.ResultsStable mixed chimerism and tolerance of MHC class-I-mismatched VCAs was achieved in 3 recipients. Allograft tolerance was associated with a sustained lack of anti-donor T cell response and a concomitant expansion of double negative CD4-CD8- T cells producing IL-10.ConclusionsThis study demonstrates the first successful mixed chimerism-induced VCA tolerance in a large animal model across a MHC class-I-mismatch. Future studies aimed at fully-mismatched donor-recipient pairs are under investigation with this protocol.
A Decentralized Kidney Transplant Biopsy Classifier for Transplant Rejection Developed Using Genes of the Banff-Human Organ Transplant Panel
Authors: van Baardwijk Myrthe , Cristoferi Iacopo , Ju Jie , Varol Hilal , Minnee Robert C. , Reinders Marlies E. J. , Li Yunlei , Stubbs Andrew P. , Clahsen-van Groningen Marian C. 
Published: May 2022

IntroductionA decentralized and multi-platform-compatible molecular diagnostic tool for kidney transplant biopsies could improve the dissemination and exploitation of this technology, increasing its clinical impact. As a first step towards this molecular diagnostic tool, we developed and validated a classifier using the genes of the Banff-Human Organ Transplant (B-HOT) panel extracted from a historical Molecular Microscope® Diagnostic system microarray dataset. Furthermore, we evaluated the discriminative power of the B-HOT panel in a clinical scenario.Materials and MethodsGene expression data from 1,181 kidney transplant biopsies were used as training data for three random forest models to predict kidney transplant biopsy Banff categories, including non-rejection (NR), antibody-mediated rejection (ABMR), and T-cell-mediated rejection (TCMR). Performance was evaluated using nested cross-validation. The three models used different sets of input features: the first model (B-HOT Model) was trained on only the genes included in the B-HOT panel, the second model (Feature Selection Model) was based on sequential forward feature selection from all available genes, and the third model (B-HOT+ Model) was based on the combination of the two models, i.e. B-HOT panel genes plus highly predictive genes from the sequential forward feature selection. After performance assessment on cross-validation, the best-performing model was validated on an external independent dataset based on a different microarray version.ResultsThe best performances were achieved by the B-HOT+ Model, a multilabel random forest model trained on B-HOT panel genes with the addition of the 6 most predictive genes of the Feature Selection Model (ST7, KLRC4-KLRK1, TRBC1, TRBV6-5, TRBV19, and ZFX), with a mean accuracy of 92.1% during cross-validation. On the validation set, the same model achieved Area Under the ROC Curve (AUC) of 0.965 and 0.982 for NR and ABMR respectively.DiscussionThis kidney transplant biopsy classifier is one step closer to the development of a decentralized kidney transplant biopsy classifier that is effective on data derived from different gene expression platforms. The B-HOT panel proved to be a reliable highly-predictive panel for kidney transplant rejection classification. Furthermore, we propose to include the aforementioned 6 genes in the B-HOT panel for further optimization of this commercially available panel.