bluuebunny/crossref_metadata_2025_split huggingface dataset:
Things as They Seem
Authors: Scruton Roger 
Published: July 2019

AbstractI respond to the five papers of criticism in this issue of Philosophy. I argue that my cognitive dualism, which may be open to the theological objections levelled by Fiona Ellis, is vindicated by its ability to explain both freedom and inter-personal relations. I defend the inter-subjectivity of aesthetic judgment against Simon Blackburn's argument from ‘the acquaintance principle’, and my vision of cultural decline against the sceptical arguments of Samuel Hughes. The crucial role played by subjectivity in my fiction, discussed by Alicja Gescinska, enables me to add to David McPherson's account of existential conservatism, with which I largely concur. I end on a note of puzzlement, as to why such innocent arguments should be the target of such implacable hatred.
Compact filtering power dividers with wide upper stopband
Authors: Dong Gaoya , Wang Weimin , Liu Yuanan 
Published: July 2019

AbstractA series of compact filtering power dividers (FPDs) with simple layouts are proposed based on coupling topology. The structure of the presented FPD1 is composed of three resonators and one isolating resistor. These FPDs can be designed based on coupling matrix filter theory. A half-wave transmission line is employed in FPD2 to introduce a transmission zero (TZ) locating at 1.27f0. The FPD3 is designed by replacing quarter-wave transmission lines in FPD2 with quarter-wave coupled lines, which will produce a TZ locating at 1.96 f0 and extend upper stopband bandwidth. For verification, three FPDs centered at 2.45 GHz are fabricated and measured. All measured results are in good agreement with the full-wave simulation results.
Stress and Coping in Pediatric Asthma: The Experiences of Low-SES Latinx Families
Authors: Rodríguez Erin M. , Gulbas Lauren E. , Horner Sharon D. , Alba-Suarez Juliana , George-Jones Julia , Davidson Savannah , Lehning Emily , Esperanza Catherine , Alvarado Cinthia 
Published: July 2019

Objective: Low-socioeconomic status (SES) Latinx youth experience disproportionate rates of poor asthma control, which can disrupt school, work, and quality of life. The current study examined low-SES Latinx families’ experiences of asthma-related stress and coping to inform intervention approaches with this population. Method: We used a sequential mixed-method design, with qualitative findings used to enrich interpretation of quantitative results. Cross-sectional quantitative data was collected from low-SES Latinx youth with asthma ages 9–17 and their parents ( N = 39), who reported on their levels of asthma-related stressors and their coping with asthma. Focus groups were conducted with additional low-SES Latinx youth with asthma and their parents ( N = 11). Qualitative data were coded using a grounded theory approach. Results: Parents reported higher levels of asthma-related stressors than children. Higher levels of stress were correlated with less secondary control coping for children, and less primary and secondary control coping for parents. SES-relevant processes (e.g., health literacy) and Latinx-relevant processes (e.g., spirituality, transnational health care) shaped families’ experiences of asthma-related stressors and coping. Conclusions: Findings highlight the challenges of controlling asthma and the consequences of poorly controlled asthma, as well as potential intervention strategies to support asthma management and psychosocial adjustment for low-SES Latinx families. Implications for Impact Statement This study examined the stress and coping experiences of low-SES Latinx families of children with asthma. Coping that involved trying to change stressors (for parents) or trying to adapt to stressors (for children and parents) was related to lower levels of asthma-related stress. It may be helpful for clinicians to leverage cultural factors such as spirituality to promote more effective coping and asthma management in low-SES Latinx families.
Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells
Authors: Pham Dan Duc , Bruelle Céline , Thi Do Hai , Pajanoja Ceren , Jin Congyu , Srinivasan Vignesh , Olkkonen Vesa M. , Eriksson Ove , Jauhiainen Matti , Lalowski Maciej , Lindholm Dan 
Published: July 2019

AbstractLipid-induced toxicity is part of several human diseases, but the mechanisms involved are not fully understood. Fatty liver is characterized by the expression of different growth and tissue factors. The neurotrophin, nerve growth factor (NGF) and its pro-form, pro-NGF, are present in fatty liver together with p75 neurotrophin receptor (p75NTR). Stimulation of human Huh7 hepatocyte cells with NGF and pro-NGF induced Sterol-regulator-element-binding protein-2 (SREBP2) activation and increased Low-Density Lipoprotein Receptor (LDLR) expression. We observed that phosphorylation of caspase-2 by p38 MAPK was essential for this regulation involving a caspase-3-mediated cleavage of SREBP2. RNA sequencing showed that several genes involved in lipid metabolism were altered in p75NTR-deficient mouse liver. The same lipogenic genes were downregulated in p75NTR gene-engineered human Huh7 cells and reciprocally upregulated by stimulation of p75NTRs. In the knock-out mice the serum cholesterol and triglyceride levels were reduced, suggesting a physiological role of p75NTRs in whole-body lipid metabolism. Taken together, this study shows that p75NTR signaling influences a network of genes involved in lipid metabolism in liver and hepatocyte cells. Modulation of p75NTR signaling may be a target to consider in various metabolic disorders accompanied by increased lipid accumulation.
Cell-free DNA analysis in healthy individuals by next-generation sequencing: a proof of concept and technical validation study
Authors: Alborelli Ilaria , Generali Daniele , Jermann Philip , Cappelletti Maria Rosa , Ferrero Giuseppina , Scaggiante Bruna , Bortul Marina , Zanconati Fabrizio , Nicolet Stefan , Haegele Jasmin , Bubendorf Lukas , Aceto Nicola , Scaltriti Maurizio , Mucci Giuseppe , Quagliata Luca , Novelli Giuseppe 
Published: July 2019

AbstractPre-symptomatic screening of genetic alterations might help identify subpopulations of individuals that could enter into early access prevention programs. Since liquid biopsy is minimally invasive it can be used for longitudinal studies in healthy volunteers to monitor events of progression from normal tissue to pre-cancerous and cancerous condition. Yet, cell-free DNA (cfDNA) analysis in healthy individuals comes with substantial challenges such as the lack of large cohort studies addressing the impact of mutations in healthy individuals or the low abundance of cfDNA in plasma. In this study, we aimed to investigate the technical feasibility of cfDNA analysis in a collection of 114 clinically healthy individuals. We first addressed the impact of pre-analytical factors such as cfDNA yield and quality on sequencing performance and compared healthy to cancer donor samples. We then confirmed the validity of our testing strategy by evaluating the mutational status concordance in matched tissue and plasma specimens collected from cancer patients. Finally, we screened our group of healthy donors for genetic alterations, comparing individuals who did not develop any tumor to patients who developed either a benign neoplasm or cancer during 1–10 years of follow-up time. To conclude, we have established a rapid and reliable liquid biopsy workflow that allowed us to study genomic alterations with a limit of detection as low as 0.08% of variant allelic frequency in healthy individuals. We detected pathogenic cancer mutations in four healthy donors that later developed a benign neoplasm or invasive breast cancer up to 10 years after blood collection. Even though larger prospective studies are needed to address the specificity and sensitivity of liquid biopsy as a clinical tool for early cancer detection, systematic screening of healthy individuals will help understanding early events of tumor formation.
Discovery of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido) phenylurea-based thymidylate synthase (TS) inhibitor as a novel multi-effects antitumor drugs with minimal toxicity
Authors: Li Xin-yang , Zhang Ting-jian , Kamara Mohamed Olounfeh , Lu Guo-qing , Xu Hai-li , Wang De-pu , Meng Fan-hao 
Published: July 2019

AbstractThymidylate synthase (TS) is a hot target for tumor chemotherapy, and its inhibitors are an essential direction for anti-tumor drug research. To our knowledge, currently, there are no reported thymidylate synthase inhibitors that could inhibit cancer cell migration. Therefore, for optimal therapeutic purposes, combines our previous reports and findings, we hope to obtain a multi-effects inhibitor. This study according to the principle of flattening we designed and synthesized 18 of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)phenyl urea derivatives as multi-effects inhibitors. The biological evaluation results showed that target compounds could significantly inhibit the hTS enzyme, BRaf kinase and EGFR kinase activity in vitro, and most of the compounds had excellent anti-cell viability for six cancer cell lines. Notably, the candidate compound L14e (IC50 = 0.67 μM) had the superior anti-cell viability and safety to A549 and H460 cells compared with pemetrexed. Further studies had shown that L14e could cause G1/S phase arrest then induce intrinsic apoptosis. Transwell, western blot, and tube formation results proved that L14e could inhibit the activation of the EGFR signaling pathway, then ultimately achieve the purpose of inhibiting cancer cell migration and angiogenesis in cancer tissues. Furthermore, in vivo pharmacology evaluations of L14e showed significant antitumor activity in A549 cells xenografts with minimal toxicity. All of these results demonstrated that the L14e has the potential for drug discovery as a multi-effects inhibitor and provides a new reference for clinical treatment of non-small cell lung cancer.
A next-generation sequencing method for gene doping detection that distinguishes low levels of plasmid DNA against a background of genomic DNA
Authors: de Boer Eddy N. , van der Wouden Petra E. , Johansson Lennart F. , van Diemen Cleo C. , Haisma Hidde J. 
Published: July 2019

AbstractGene doping confers health risks for athletes and is a threat to fair competition in sports. Therefore the anti-doping community has given attention on its detection. Previously published polymerase chain reaction-based methodologies for gene doping detection are targeting exon–exon junctions in the intron-less transgene. However, because these junctions are known, it would be relatively easy to evade detection by tampering with the copyDNA sequences. We have developed a targeted next-generation sequencing based assay for the detection of all exon–exon junctions of the potential doping genes,EPO,IGF1,IGF2,GH1,andGH2, which is resistant to tampering. Using this assay, all exon–exon junctions of copyDNA of doping genes could be detected with a sensitivity of 1296 copyDNA copies in 1000 ng of genomic DNA. In addition, promotor regions and plasmid-derived sequences are readily detectable in our sequence data. While we show the reliability of our method for a selection of genes, expanding the panel to detect other genes would be straightforward. As we were able to detect plasmid-derived sequences, we expect that genes with manipulated junctions, promotor regions, and plasmid or virus-derived sequences will also be readily detected.
NF-Y controls fidelity of transcription initiation at gene promoters through maintenance of the nucleosome-depleted region
Authors: Oldfield Andrew J. , Henriques Telmo , Kumar Dhirendra , Burkholder Adam B. , Cinghu Senthilkumar , Paulet Damien , Bennett Brian D. , Yang Pengyi , Scruggs Benjamin S. , Lavender Christopher A. , Rivals Eric , Adelman Karen , Jothi Raja 
Published: July 2019

AbstractFaithful transcription initiation is critical for accurate gene expression, yet the mechanisms underlying specific transcription start site (TSS) selection in mammals remain unclear. Here, we show that the histone-fold domain protein NF-Y, a ubiquitously expressed transcription factor, controls the fidelity of transcription initiation at gene promoters in mouse embryonic stem cells. We report that NF-Y maintains the region upstream of TSSs in a nucleosome-depleted state while simultaneously protecting this accessible region against aberrant and/or ectopic transcription initiation. We find that loss of NF-Y binding in mammalian cells disrupts the promoter chromatin landscape, leading to nucleosomal encroachment over the canonical TSS. Importantly, this chromatin rearrangement is accompanied by upstream relocation of the transcription pre-initiation complex and ectopic transcription initiation. Further, this phenomenon generates aberrant extended transcripts that undergo translation, disrupting gene expression profiles. These results suggest NF-Y is a central player in TSS selection in metazoans and highlight the deleterious consequences of inaccurate transcription initiation.
Crystal structures of Rea1-MIDAS bound to its ribosome assembly factor ligands resembling integrin–ligand-type complexes
Authors: Ahmed Yasar Luqman , Thoms Matthias , Mitterer Valentin , Sinning Irmgard , Hurt Ed 
Published: July 2019

AbstractThe Rea1 AAA+-ATPase dislodges assembly factors from pre-60S ribosomes upon ATP hydrolysis, thereby driving ribosome biogenesis. Here, we present crystal structures of Rea1-MIDAS, the conserved domain at the tip of the flexible Rea1 tail, alone and in complex with its substrate ligands, the UBL domains of Rsa4 or Ytm1. These complexes have structural similarity to integrin α-subunit domains when bound to extracellular matrix ligands, which for integrin biology is a key determinant for force-bearing cell–cell adhesion. However, the presence of additional motifs equips Rea1-MIDAS for its tasks in ribosome maturation. One loop insert cofunctions as an NLS and to activate the mechanochemical Rea1 cycle, whereas an additional β-hairpin provides an anchor to hold the ligand UBL domains in place. Our data show the versatility of the MIDAS fold for mechanical force transmission in processes as varied as integrin-mediated cell adhesion and mechanochemical removal of assembly factors from pre-ribosomes.
Strain-level metagenomic assignment and compositional estimation for long reads with MetaMaps
Authors: Dilthey Alexander T. , Jain Chirag , Koren Sergey , Phillippy Adam M. 
Published: July 2019

AbstractMetagenomic sequence classification should be fast, accurate and information-rich. Emerging long-read sequencing technologies promise to improve the balance between these factors but most existing methods were designed for short reads. MetaMaps is a new method, specifically developed for long reads, capable of mapping a long-read metagenome to a comprehensive RefSeq database with >12,000 genomes in <16 GB or RAM on a laptop computer. Integrating approximate mapping with probabilistic scoring and EM-based estimation of sample composition, MetaMaps achieves >94% accuracy for species-level read assignment and r2 > 0.97 for the estimation of sample composition on both simulated and real data when the sample genomes or close relatives are present in the classification database. To address novel species and genera, which are comparatively harder to predict, MetaMaps outputs mapping locations and qualities for all classified reads, enabling functional studies (e.g. gene presence/absence) and detection of incongruities between sample and reference genomes.
Practical access to axially chiral sulfonamides and biaryl amino phenols via organocatalytic atroposelective N-alkylation
Authors: Lu Shenci , Ng Shawn Voon Hwee , Lovato Kaitlyn , Ong Jun-Yang , Poh Si Bei , Ng Xiao Qian , Kürti László , Zhao Yu 
Published: July 2019

AbstractThe importance of axial chirality in enantioselective synthesis has been widely recognized for decades. The practical access to certain structures such as biaryl amino phenols known as NOBINs in enantiopure form, however, still remains a challenge. In drug delivery, the incorporation of axially chiral molecules in systematic screening has also received a great deal of interest in recent years, which calls for innovation and practical synthesis of structurally different axially chiral entities. Herein we present an operationally simple catalytic N-alkylation of sulfonamides using commercially available chiral amine catalysts to deliver two important classes of axially chiral compounds: structurally diverse NOBIN analogs as well as axially chiral N-aryl sulfonamides in excellent enantiopurity. Structurally related chiral sulfonamide has shown great potential in drug molecules but enantioselective synthesis of them has never been accomplished before. The practical catalytic procedures of our methods also bode well for their wide application in enantioselective synthesis.
Regulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling
Authors: Batlle Raquel , Andrés Eva , Gonzalez Lorena , Llonch Elisabet , Igea Ana , Gutierrez-Prat Núria , Berenguer-Llergo Antoni , Nebreda Angel R. 
Published: July 2019

AbstractThe formation of new blood vessels is essential for normal development, tissue repair and tumor growth. Here we show that inhibition of the kinase p38α enhances angiogenesis in human and mouse colon tumors. Mesenchymal cells can contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. We show that p38α negatively regulates an angiogenic program in mesenchymal stem/stromal cells (MSCs), multipotent progenitors found in perivascular locations. This program includes the acquisition of an endothelial phenotype by MSCs mediated by both TGF-β and JNK, and negatively regulated by p38α. Abrogation of p38α in mesenchymal cells increases tumorigenesis, which correlates with enhanced angiogenesis. Using genetic models, we show that p38α regulates the acquisition of an endothelial-like phenotype by mesenchymal cells in colon tumors and damage tissue. Taken together, our results indicate that p38α in mesenchymal cells restrains a TGF-β-induced angiogenesis program including their ability to transdifferentiate into endothelial cells.
Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation
Authors: Holliday Michael J. , Witt Axel , Rodríguez Gama Alejandro , Walters Benjamin T. , Arthur Christopher P. , Halfmann Randal , Rohou Alexis , Dueber Erin C. , Fairbrother Wayne J. 
Published: July 2019

AbstractCARD9 and CARD11 drive immune cell activation by nucleating Bcl10 polymerization, but are held in an autoinhibited state prior to stimulation. Here, we elucidate the structural basis for this autoinhibition by determining the structure of a region of CARD9 that includes an extensive interface between its caspase recruitment domain (CARD) and coiled-coil domain. We demonstrate, for both CARD9 and CARD11, that disruption of this interface leads to hyperactivation in cells and to the formation of Bcl10-templating filaments in vitro, illuminating the mechanism of action of numerous oncogenic mutations of CARD11. These structural insights enable us to characterize two similar, yet distinct, mechanisms by which autoinhibition is relieved in the course of canonical CARD9 or CARD11 activation. We also dissect the molecular determinants of helical template assembly by solving the structure of the CARD9 filament. Taken together, these findings delineate the structural mechanisms of inhibition and activation within this protein family.
Interface-based tuning of Rashba spin-orbit interaction in asymmetric oxide heterostructures with 3d electrons
Authors: Lin Weinan , Li Lei , Doğan Fatih , Li Changjian , Rotella Hélène , Yu Xiaojiang , Zhang Bangmin , Li Yangyang , Lew Wen Siang , Wang Shijie , Prellier Wilfrid , Pennycook Stephen J. , Chen Jingsheng , Zhong Zhicheng , Manchon Aurelien , Wu Tom 
Published: July 2019

AbstractThe Rashba effect plays important roles in emerging quantum materials physics and potential spintronic applications, entailing both the spin orbit interaction (SOI) and broken inversion symmetry. In this work, we devise asymmetric oxide heterostructures of LaAlO3//SrTiO3/LaAlO3 (LAO//STO/LAO) to study the Rashba effect in STO with an initial centrosymmetric structure, and broken inversion symmetry is created by the inequivalent bottom and top interfaces due to their opposite polar discontinuities. Furthermore, we report the observation of a transition from the cubic Rashba effect to the coexistence of linear and cubic Rashba effects in the oxide heterostructures, which is controlled by the filling of Ti orbitals. Such asymmetric oxide heterostructures with initially centrosymmetric materials provide a general strategy for tuning the Rashba SOI in artificial quantum materials.
Bio-inspired creation of heterogeneous reaction vessels via polymerization of supramolecular ion pair
Authors: Dong Ke , Sun Qi , Tang Yongquan , Shan Chuan , Aguila Briana , Wang Sai , Meng Xiangju , Ma Shengqian , Xiao Feng-Shou 
Published: July 2019

AbstractPrecise control of the outer-sphere environment around the active sites of heterogeneous catalysts to modulate the catalytic outcomes has long been a challenge. Here, we demonstrate how this can be fulfilled by encapsulating catalytic components into supramolecular capsules, used as building blocks for materials synthesis, whereby the microenvironment of each active site is tuned by the assembled wall. Specifically, using a cationic template equipped with a polymerizable functionality, anionic ligands can be encapsulated by ion pair-directed supramolecular assembly, followed by construction into porous frameworks. The hydrophilic ionic wall enables reactions to be achieved in water that usually requires organic solvents and also facilitates the enrichment of the substrate into the hydrophobic pocket, leading to superior catalytic performances as demonstrated by the industrially relevant hydroformylation. Remarkably, the formation of the supramolecular assembly and catalyst encapsulation further engenders reaction selectivity, which reaches an even greater extent after construction of the porous framework.
High-throughput computational discovery of In2Mn2O7 as a high Curie temperature ferromagnetic semiconductor for spintronics
Authors: Chen Wei , George Janine , Varley Joel B. , Rignanese Gian-Marco , Hautier Geoffroy 
Published: July 2019

AbstractMaterials combining strong ferromagnetism and good semiconducting properties are highly desirable for spintronic applications (e.g., in spin-filtering devices). In this work, we conduct a search for concentrated ferromagnetic semiconductors through high-throughput computational screening. Our screening reveals the limited availability of semiconductors combining ferromagnetism and a low effective mass. We identify the manganese pyrochlore oxide In2Mn2O7 as especially promising for spin transport as it combines low electron effective mass (0.29 m0), a large exchange splitting of the conduction band (1.1 eV), stability in air, and a Curie temperature (about 130 K) among the highest of concentrated ferromagnetic semiconductors. We rationalise the high performance of In2Mn2O7 by the unique combination of a pyrochlore lattice favouring ferromagnetism with an adequate alignment of O–2p, Mn–3d, and In–5s forming a dispersive conduction band while enhancing the Curie temperature.