bluuebunny/crossref_metadata_2025_split huggingface dataset:
TNFα sensitizes hepatocytes to FasL-induced apoptosis by NFκB-mediated Fas upregulation
Authors: Faletti Laura , Peintner Lukas , Neumann Simon , Sandler Sandra , Grabinger Thomas , Mac Nelly Sabine , Merfort Irmgard , Huang Chun-Hao , Tschaharganeh Darjus , Kang Tae-Won , Heinzmann Florian , D’Artista Luana , Maurer Ulrich , Brunner Thomas , Lowe Scott , Zender Lars , Borner Christoph 
Published: September 2018

AbstractAlthough it is well established that TNFα contributes to hepatitis, liver failure and associated hepatocarcinogenesis via the regulation of inflammation, its pro-apoptotic role in the liver has remained enigmatic. On its own, TNFα is unable to trigger apoptosis. However, when combined with the transcriptional inhibitor GaLN, it can cause hepatocyte apoptosis and liver failure in mice. Moreover, along with others, we have shown that TNFα is capable of sensitizing cells to FasL- or drug-induced cell death via c-Jun N-terminal kinase (JNK) activation and phosphorylation/activation of the BH3-only protein Bim. In this context, TNFα could exacerbate hepatocyte cell death during simultaneous inflammatory and T-cell-mediated immune responses in the liver. Here we show that TNFα sensitizes primary hepatocytes, established hepatocyte cell lines and mouse embryo fibroblasts to FasL-induced apoptosis by the transcriptional induction and higher surface expression of Fas via the NFκB pathway. Genetic deletion, diminished expression or dominant-negative inhibition of the NFκB subunit p65 resulted in lower Fas expression and inhibited TNFα-induced Fas upregulation and sensitization to FasL-induced cell death. By hydrodynamic injection of p65 shRNA into the tail vein of mice, we confirm that Fas upregulation by TNFα is also NFκB-mediated in the liver. In conclusion, TNFα sensitization of FasL-induced apoptosis in the liver proceeds via two parallel signaling pathways, activation of JNK and Bim phosphorylation and NFκB-mediated Fas upregulation.
Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations
Authors: Chang Jiang , Tian Jianbo , Zhu Ying , Zhong Rong , Zhai Kan , Li Jiaoyuan , Ke Juntao , Han QiangQiang , Lou Jiao , Chen Wei , Zhu Beibei , Shen Na , Zhang Yi , Gong Yajie , Yang Yang , Zou Danyi , Peng Xiating , Zhang Zhi , Zhang Xuemei , Huang Kun , Yang Ming , Wang Li , Wu Chen , Lin Dongxin , Miao Xiaoping 
Published: September 2018

AbstractGermline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48–2.12, P = 5.35 × 10−10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50–2.27, P = 4.34 × 10−9), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72–3.16, P = 4.21 × 10−8). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.
User considerations in assessing pharmacogenomic tests and their clinical support tools
Authors: Mukerjee Gouri , Huston Andrea , Kabakchiev Boyko , Piquette-Miller Micheline , van Schaik Ron , Dorfman Ruslan 
Published: September 2018

AbstractPharmacogenomic (PGx) testing is gaining recognition from physicians, pharmacists and patients as a tool for evidence-based medication management. However, seemingly similar PGx testing panels (and PGx-based decision support tools) can diverge in their technological specifications, as well as the genetic factors that determine test specificity and sensitivity, and hence offer different values for users. Reluctance to embrace PGx testing is often the result of unfamiliarity with PGx technology, a lack of knowledge about the availability of curated guidelines/evidence for drug dosing recommendations, and an absence of wide-spread institutional implementation efforts and educational support. Demystifying an often confusing and variable PGx marketplace can lead to greater acceptance of PGx as a standard-of-care practice that improves drug outcomes and provides a lifetime value for patients. Here, we highlight the key underlying factors of a PGx test that should be considered, and discuss the current progress of PGx implementation.
Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
Authors: Cao Honghui , Wang Cong , Chen Xiang , Hou Jiwei , Xiang Zou , Shen Yi , Han Xiaodong 
Published: September 2018

AbstractAn emerging paradigm proposes a crucial role for lung resident mesenchymal stem cells (LR-MSCs) via a fibroblastic transdifferentiation event in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Aberrant activation of Wnt/β-catenin signaling occurs in virtually all fibrotic lung diseases and is relevant to the differentiation of mesenchymal stem cells (MSCs). In vitro, by measuring the protein levels of several key components involved in Wnt/β-catenin signaling, we confirmed that this signaling pathway was activated in the myofibroblast differentiation of LR-MSCs. Targeted inhibition of Wnt/β-catenin signaling by a small molecule, ICG-001, dose-dependently impeded the proliferation and transforming growth factor-β1 (TGF-β1)-mediated fibrogenic actions of LR-MSCs. In vivo, ICG-001 exerted its lung protective effects after bleomycin treatment through blocking mesenchymal-myofibroblast transition, repressing matrix gene expression, and reducing cell apoptosis. Moreover, delayed administration of ICG-001 attenuated bleomycin-induced lung fibrosis, which may present a promising therapeutic strategy for intervention of IPF. Interestingly, these antifibrotic actions of ICG-001 are operated by a mechanism independent of any disruption of Smad activation. In conclusion, our study demonstrated that Wnt/β-catenin signaling may be an essential mechanism underlying the regulation of myofibroblast differentiation of LR-MSCs and their further participation in the development of pulmonary fibrosis.
One-way Acoustic Beam Splitter
Authors: Tang Yifan , Zhu Yifan , Liang Bin , Yang Jing , Yang Jun , Cheng Jianchun 
Published: September 2018

AbstractAs a key component of various acoustic systems, acoustic beam splitter (BS) finds important application in many scenarios, yet are conventionally based on the assumption that the acoustic waves propagate as easily when incident from either input or output side. It would therefore be intriguing, from the viewpoints of both science and technology, to break through this limit by realizing acoustic BSs supporting asymmetric transmission. Here we propose the concept of one-way acoustic BS capable of splitting acoustic beam incident from the input port into multiple beams while effectively reducing the backward transmission from any of the output ports. Furthermore, our design enables flexibly adjusting the number and angle of output beams by blocking the unused line defects. The numerical results verify the theoretical predictions and demonstrate the phenomenon of one-way acoustic BS at the predesigned frequency. Our design with functionality and flexibility bridges the gap between acoustic diodes and BSs and may enable novel multi-functional devices with great application prospects in diverse fields such as acoustic integrated circuits and acoustic communication.
Population level mitogenomics of long-lived bats reveals dynamic heteroplasmy and challenges the Free Radical Theory of Ageing
Authors: Jebb David , Foley Nicole M. , Whelan Conor V. , Touzalin Frédéric , Puechmaille Sebastien J. , Teeling Emma C. 
Published: September 2018

AbstractBats are the only mammals capable of true, powered flight, which drives an extremely high metabolic rate. The “Free Radical Theory of Ageing” (FTRA) posits that a high metabolic rate causes mitochondrial heteroplasmy and the progressive ageing phenotype. Contrary to this, bats are the longest-lived order of mammals given their small size and high metabolic rate. To investigate if bats exhibit increased mitochondrial heteroplasmy with age, we performed targeted, deep sequencing of mitogenomes and measured point heteroplasmy in wild, long lived Myotis myotis. Blood was sampled from 195 individuals, aged between <1 and at 6+ years old, and whole mitochondria deep-sequenced, with a subset sampled over multiple years. The majority of heteroplasmies were at a low frequency and were transitions. Oxidative mutations were present in only a small number of individuals, suggesting local oxidative stress events. Cohort data showed no significant increase in heteroplasmy with age, while longitudinal data from recaptured individuals showed heteroplasmy is dynamic, and does not increase uniformly over time. We show that bats do not suffer from the predicted, inevitable increase in heteroplasmy as posited by the FRTA, instead heteroplasmy was found to be dynamic, questioning its presumed role as a primary driver of ageing.
GmGRP-like gene confers Al tolerance in Arabidopsis
Authors: Chen Li , Cai Yupeng , Liu Xiujie , Guo Chen , Yao Weiwei , Sun Shi , Wu Cunxiang , Jiang Bingjun , Han Tianfu , Hou Wensheng 
Published: September 2018

AbstractAluminium (Al) toxicity restrains water and nutrient uptake and is toxic to plant roots, ultimately inhibiting crop production. Here, we isolated and characterized a soybean glycine-rich protein-likegene (GmGRPL) that is mainly expressed in the root and that is regulated by Al treatment. Overexpression ofGmGRPLcan alleviate Al-induced root growth inhibition inArabidopsis. The levels of IAA and ethylene inGmGRPL-overexpressing hairy roots were lower than those in control and RNA interference-exposedGmGRPLhairy roots with or without Al stress, which were mainly regulated byTAA1andACO, respectively. In transgenic soybean hairy roots, the MDA, H2O2and O2–·content inGmGRPL-overexpressing hairy roots were less than that in control and RNA interference-exposedGmGRPLhairy roots under Al stress. In addition, IAA and ACC can enhance the expression level of theGmGRPLpromoter with or without Al stress. These results indicated thatGmGRPLcan alleviate Al-induced root growth inhibition by regulating the level of IAA and ethylene and improving antioxidant activity.
Variability in eukaryotic initiation factor iso4E in Brassica rapa influences interactions with the viral protein linked to the genome of Turnip mosaic virus
Authors: Li Guoliang , Qian Wei , Zhang Shujiang , Zhang Shifan , Li Fei , Zhang Hui , Fang Zhiyuan , Wu Jian , Wang Xiaowu , Sun Rifei 
Published: September 2018

AbstractPlant potyviruses require eukaryotic translation initiation factors (eIFs) such as eIF4E and eIF(iso)4E to replicate and spread. When Turnip mosaic virus (TuMV) infects a host plant, its viral protein linked to the genome (VPg) needs to interact with eIF4E or eIF(iso)4E to initiate translation. TuMV utilizes BraA.eIF4E.a, BraA.eIF4E.c, BraA.eIF(iso)4E.a, and BraA.eIF(iso)4E.c of Brassica rapa to initiate translation in Arabidopsis thaliana. In this study, the BraA.eIF4E.a, BraA.eIF4E.c, BraA.eIF(iso)4E.a, and BraA.eIF(iso)4E.c genes were cloned and sequenced from eight B. rapa lines, namely, two BraA.eIF4E.a alleles, four BraA.eIF4E.c alleles, four BraA.eIF(iso)4E.a alleles, and two BraA.eIF(iso)4E.c alleles. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) analyses indicated that TuMV VPg could not interact with eIF4E, but only with eIF(iso)4E of B. rapa. In addition, the VPgs of the different TuMV isolates interacted with various eIF(iso)4E copies in B. rapa. In particular, TuMV-UK1/CDN1 VPg only interacted with BraA.eIF(iso)4E.c, not with BraA.eIF(iso)4E.a. Some single nucleotide polymorphisms (SNPs) were identified that may have affected the interaction between eIF(iso)4E and VPg such as the SNP T106C in BraA.eIF(iso)4E.c and the SNP A154C in VPg. Furthermore, a three-dimensional structural model of the BraA.eIF(iso)4E.c-1 protein was constructed to identify the specific conformation of the variable amino acids from BraA.eIF(iso)4E.c. The 36th amino acid in BraA.eIF(iso)4E.c is highly conserved and may play an important role in establishing protein structural stability. The findings of the present study may lay the foundation for future investigations on the co-evolution of TuMV and eIF(iso)4E.
Exploratory analysis of the human breast DNA methylation profile upon soymilk exposure
Authors: Coussement Louis , Bolca Selin , Van Criekinge Wim , Trooskens Geert , Mensaert Klaas , Poels Katrien , Roche Nathalie , Blondeel Phillip , Godderis Lode , Depypere Herman , De Meyer Tim 
Published: September 2018

AbstractUpon soy consumption, isoflavone metabolites attain bioactive concentrations in breast tissue possibly affecting health. Though in vitro epigenetic activity of soy metabolites has been described, the in vivo impact on the epigenome is largely unknown. Therefore, in this case-control study, the breast glandular tissue DNA methylome was explored in women undergoing an aesthetic breast reduction. After a run-in phase, 10 generally healthy Belgian or Dutch women received soymilk for 5 days. MethylCap-seq methylation profiles were compared with those of 10 matched controls. Isoflavones and their microbial metabolites were quantified in urine, serum, and glandular breast tissue (liquid chromatography-mass spectrometry) and 17β-estradiol in glandular breast tissue (immunoassay). Global DNA methylation levels were obtained for 6 cases and 5 controls using liquid chromatography-mass spectrometry. Although lower MethylCap-seq coverages were observed, mass spectrometry results and computational LINE-1 methylation analysis did not provide evidence supporting global methylation alterations upon treatment. At a false discovery rate of 0.05, no differentially methylated loci were identified. Moreover, a set of previously identified loci was specifically tested, but earlier reported results could not be validated. In conclusion, after a 5-day soymilk treatment, no major general epigenetic reprogramming in breast tissue could be found in this exploratory study.
On the Stability of MHD Boundary Layer Flow over a Stretching/Shrinking Wedge
Authors: Awaludin Izyan Syazana , Ishak Anuar , Pop Ioan 
Published: September 2018

AbstractThe steady two dimensional magnetohydrodynamic (MHD) boundary layer flow and heat transfer over a stretching/shrinking permeable wedge is numerically investigated. The partial differential equations governing the flow and heat transfer are transformed into a system of ordinary differential equations using a similarity transformation. These equations are then solved numerically using the boundary value problem solver, bvp4c in Matlab software. It is found that dual solutions exist for a certain range of the shrinking strength. A stability analysis is performed to identify which solution is stable and physically reliable.
Ghrelin expression is associated with a favorable outcome in male breast cancer
Authors: Grönberg Malin , Nilsson Cecilia , Markholm Ida , Hedenfalk Ingrid , Blomqvist Carl , Holmberg Lars , Tiensuu Janson Eva , Fjällskog Marie-Louise 
Published: September 2018

AbstractGhrelin and obestatin are two gastrointestinal peptides, derived from a common precursor. Expression of both peptides have been found in breast cancer tissue and ghrelin has been associated with breast cancer development. Ghrelin expression is associated with longer survival in women diagnosed with invasive and node negative breast cancer. The clinical implications of the peptide expression in male breast cancer are unclear. The aim of this study was to investigate the role and potential clinical value of ghrelin and obestatin in male breast cancer. A tissue microarray of invasive male breast cancer specimens from 197 patients was immunostained with antibodies versus the two peptides. The expression of the peptides was correlated to previously known prognostic factors in breast cancer and to the outcome. No strong correlations were found between ghrelin or obestatin expression and other known prognostic factors. Only ghrelin expression was statistically significantly correlated to breast cancer-specific survival (HR 0.39, 95% CI 0.18–0.83) in univariate analyses and in multivariate models, adjusted for tumor size and node status (HR 0.38, 95% CI 0.17–0.87). HR for obestatin was 0.38 (95% CI 0.11–1.24). Ghrelin is a potential prognostic factor for breast cancer death in male breast cancer. Patients with tumors expressing ghrelin have a 2.5-fold lower risk for breast cancer death than those lacking ghrelin expression. Drugs targeting ghrelin are currently being investigated in clinical studies treating metabolic or nutritional disorders. Ghrelin should be further evaluated in forthcoming studies as a prognostic marker with the aim to be included in decision algorithms.
Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells
Authors: Florio Rosalba , De Lellis Laura , Veschi Serena , Verginelli Fabio , di Giacomo Viviana , Gallorini Marialucia , Perconti Silvia , Sanna Mario , Mariani-Costantini Renato , Natale Angelica , Arduini Arduino , Amoroso Rosa , Cataldi Amelia , Cama Alessandro 
Published: September 2018

AbstractParagangliomas (PGLs) are infiltrating autonomic nervous system tumors that cause important morbidity. At present, surgery is the only effective therapeutic option for this rare tumor. Thus, new agents for PGL treatment should be identified. Using unique PGL cell models established in our laboratory, we evaluated the effect of dichloroacetate (DCA) as single agent or in a novel combination with other metabolic drugs, including GW6471 and metformin. DCA and metformin had not been tested before in PGL. DCA reduced PGL cell viability and growth through mechanisms involving reactivation of PDH complex leading to promotion of oxidative metabolism, with lowering of lactate and enhanced ROS production. This resulted in cell cycle inhibition and induction of apoptosis in PGL cells, as shown by flow cytometry and immunoblot analyses. Moreover, DCA drastically impaired clonogenic activity and migration of PGL cells. Also metformin reduced PGL cell viability as single agent and the combinations of DCA, GW6471 and metformin had strong effects on cell viability. Furthermore, combined treatments had drastic and synergistic effects on clonogenic ability. In conclusion, DCA, GW6471 and metformin as single agents and in combination appear to have promising antitumor effects in unique cell models of PGL.
A carbon nanotube integrated microfluidic device for blood plasma extraction
Authors: Yeh Yin-Ting , Lin Zhong , Zheng Si-Yang , Terrones Mauricio 
Published: September 2018

AbstractBlood is a complex fluid consisting of cells and plasma. Plasma contains key biomarkers essential for disease diagnosis and therapeutic monitoring. Thus, by separating plasma from the blood, it is possible to analyze these biomarkers. Conventional methods for plasma extraction involve bulky equipment, and miniaturization constitutes a key step to develop portable devices for plasma extraction. Here, we integrated nanomaterial synthesis with microfabrication, and built a microfluidic device. In particular, we designed a double-spiral channel able to perform cross-flow filtration. This channel was constructed by growing aligned carbon nanotubes (CNTs) with average inter-tubular distances of ~80 nm, which resulted in porosity values of ~93%. During blood extraction, these aligned CNTs allow smaller molecules (e.g., proteins) to pass through the channel wall, while larger molecules (e.g., cells) get blocked. Our results show that our device effectively separates plasma from blood, by trapping blood cells. We successfully recovered albumin -the most abundant protein inside plasma- with an efficiency of ~80%. This work constitutes the first report on integrating biocompatible nitrogen-doped CNT (CNxCNT) arrays to extract plasma from human blood, thus widening the bio-applications of CNTs.
Strength and Performance Enhancement of Multilayers by Spatial Tailoring of Adherend Compliance and Morphology via Multimaterial Jetting Additive Manufacturing
Authors: Ubaid Jabir , Wardle Brian L. , Kumar S. 
Published: September 2018

AbstractMaterial tailoring of bondlayer compliance is a known effective route to enhance performance of multilayers, and here spatial material-tailoring of compliance and morphology of the adherends is examined. Multimaterial jetting additive manufacturing (AM) allows us to realize for the first time compliance- and morphology-tailored adherends, and evaluate directly the mechanical performance, including failure, of the tensile-loaded multilayers. Adherend compliance-tailoring, unlike bondlayer tailoring, requires additional consideration due to adherend bending stiffness and moment influences on bondlayer stresses. We introduce anisotropic as well as layered/sandwich adherend tailoring to address this dependence. Numerical models show that for both sub-critical and critical bondlengths (at which shear-dominated load transfer occurs through the bondlayer), adherend tailoring reduces peak stresses significantly, particularly peel stress (reductions of 47–80%) that typically controls failure in such systems. At sub-critical bondlengths, the AM-enabled layered/sandwich adherend tailoring shows significantly increased experimental performance over the baseline multilayer: strength is increased by 20%, toughness by 48%, and strain-to-break by 18%, while retaining multilayer stiffness. The adherend tailoring demonstrated here adds to the techniques available to increase the performance of bonded multilayers, suggesting that adherend tailoring is particularly well-suited to additively manufactured multilayers, but can also have application in other areas such as layered electronics and advanced structural composite laminates.