bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein
Authors: Leemans A. , De Schryver M. , Van der Gucht W. , Heykers A. , Pintelon I. , Hotard A. L. , Moore M. L. , Melero J. A. , McLellan J. S. , Graham B. S. , Broadbent L. , Power U. F. , Caljon G. , Cos P. , Maes L. , Delputte P. 
Published: May 2017

ABSTRACT

Respiratory syncytial virus (RSV) infections remain a major cause of respiratory disease and hospitalizations among infants. Infection recurs frequently and establishes a weak and short-lived immunity. To date, RSV immunoprophylaxis and vaccine research is mainly focused on the RSV fusion (F) protein, but a vaccine remains elusive. The RSV F protein is a highly conserved surface glycoprotein and is the main target of neutralizing antibodies induced by natural infection. Here, we analyzed an internalization process of antigen-antibody complexes after binding of RSV-specific antibodies to RSV antigens expressed on the surface of infected cells. The RSV F protein and attachment (G) protein were found to be internalized in both infected and transfected cells after the addition of either RSV-specific polyclonal antibodies (PAbs) or RSV glycoprotein-specific monoclonal antibodies (MAbs), as determined by indirect immunofluorescence staining and flow-cytometric analysis. Internalization experiments with different cell lines, well-differentiated primary bronchial epithelial cells (WD-PBECs), and RSV isolates suggest that antibody internalization can be considered a general feature of RSV. More specifically for RSV F, the mechanism of internalization was shown to be clathrin dependent. All RSV F-targeted MAbs tested, regardless of their epitopes, induced internalization of RSV F. No differences could be observed between the different MAbs, indicating that RSV F internalization was epitope independent. Since this process can be either antiviral, by affecting virus assembly and production, or beneficial for the virus, by limiting the efficacy of antibodies and effector mechanism, further research is required to determine the extent to which this occurs
in vivo
and how this might impact RSV replication.

IMPORTANCE
Current research into the development of new immunoprophylaxis and vaccines is mainly focused on the RSV F protein since, among others, RSV F-specific antibodies are able to protect infants from severe disease, if administered prophylactically. However, antibody responses established after natural RSV infections are poorly protective against reinfection, and high levels of antibodies do not always correlate with protection. Therefore, RSV might be capable of interfering, at least partially, with antibody-induced neutralization. In this study, a process through which surface-expressed RSV F proteins are internalized after interaction with RSV-specific antibodies is described. One the one hand, this antigen-antibody complex internalization could result in an antiviral effect, since it may interfere with virus particle formation and virus production. On the other hand, this mechanism may also reduce the efficacy of antibody-mediated effector mechanisms toward infected cells.
Antibody Preparations from Human Transchromosomic Cows Exhibit Prophylactic and Therapeutic Efficacy against Venezuelan Equine Encephalitis Virus
Authors: Gardner Christina L. , Sun Chengqun , Luke Thomas , Raviprakash Kanakatte , Wu Hua , Jiao Jin-an , Sullivan Eddie , Reed Douglas S. , Ryman Kate D. , Klimstra William B. 
Published: May 2017

ABSTRACT
Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne RNA virus that causes low mortality but high morbidity rates in humans. In addition to natural outbreaks, there is the potential for exposure to VEEV via aerosolized virus particles. There are currently no FDA-licensed vaccines or antiviral therapies for VEEV. Passive immunotherapy is an approved method used to protect individuals against several pathogens and toxins. Human polyclonal antibodies (PAbs) are ideal, but this is dependent upon serum from convalescent human donors, which is in limited supply. Non-human-derived PAbs can have serious immunoreactivity complications, and when “humanized,” these antibodies may exhibit reduced neutralization efficiency. To address these issues, transchromosomic (Tc) bovines have been created, which can produce potent neutralizing human antibodies in response to hyperimmunization. In these studies, we have immunized these bovines with different VEEV immunogens and evaluated the protective efficacy of purified preparations of the resultant human polyclonal antisera against low- and high-dose VEEV challenges. These studies demonstrate that prophylactic or therapeutic administration of the polyclonal antibody preparations (TcPAbs) can protect mice against lethal subcutaneous or aerosol challenge with VEEV. Furthermore, significant protection against unrelated coinfecting viral pathogens can be conferred by combining individual virus-specific TcPAb preparations.

IMPORTANCE
With the globalization and spread or potential aerosol release of emerging infectious diseases, it will be critical to develop platforms that are able to produce therapeutics in a short time frame. By using a transchromosomic (Tc) bovine platform, it is theoretically possible to produce antigen-specific highly neutralizing therapeutic polyclonal human antibody (TcPAb) preparations in 6 months or less. In this study, we demonstrate that Tc bovine-derived Venezuelan equine encephalitis virus (VEEV)-specific TcPAbs are highly effective against VEEV infection that mimics not only the natural route of infection but also infection via aerosol exposure. Additionally, we show that combinatorial TcPAb preparations can be used to treat coinfections with divergent pathogens, demonstrating that the Tc bovine platform could be beneficial in areas where multiple infectious diseases occur contemporaneously or in the case of multipathogen release.
Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection
Authors: Cui Liang , Hou Jue , Fang Jinling , Lee Yie Hou , Costa Vivian Vasconcelos , Wong Lan Hiong , Chen Qingfeng , Ooi Eng Eong , Tannenbaum Steven R. , Chen Jianzhu , Ong Choon Nam 
Published: May 2017

ABSTRACT
Dengue is an acute febrile illness caused by dengue virus (DENV) and a major cause of morbidity and mortality in tropical and subtropical regions of the world. The lack of an appropriate small-animal model of dengue infection has greatly hindered the study of dengue pathogenesis and the development of therapeutics. In this study, we conducted mass spectrometry-based serum metabolic profiling from a model using humanized mice (humice) with DENV serotype 2 infection at 0, 3, 7, 14, and 28 days postinfection (dpi). Forty-eight differential metabolites were identified, including fatty acids, purines and pyrimidines, acylcarnitines, acylglycines, phospholipids, sphingolipids, amino acids and derivatives, free fatty acids, and bile acid. These metabolites showed a reversible-change trend—most were significantly perturbed at 3 or 7 dpi and returned to control levels at 14 or 28 dpi, indicating that the metabolites might serve as prognostic markers of the disease in humice. The major perturbed metabolic pathways included purine and pyrimidine metabolism, fatty acid β-oxidation, phospholipid catabolism, arachidonic acid and linoleic acid metabolism, sphingolipid metabolism, tryptophan metabolism, phenylalanine metabolism, lysine biosynthesis and degradation, and bile acid biosynthesis. Most of these disturbed pathways are similar to our previous metabolomics findings in a longitudinal cohort of adult human dengue patients across different infection stages. Our analyses revealed the commonalities of host responses to DENV infection between humice and humans and suggested that humice could be a useful small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics.

IMPORTANCE
Dengue virus is the most widespread arbovirus, causing an estimated 390 million dengue infections worldwide every year. There is currently no effective treatment for the disease, and the lack of an appropriate small-animal model of dengue infection has greatly increased the challenges in the study of dengue pathogenesis and the development of therapeutics. Metabolomics provides global views of small-molecule metabolites and is a useful tool for finding metabolic pathways related to disease processes. Here, we conducted a serum metabolomics study on a model using humanized mice with dengue infection that had significant levels of human platelets, monocytes/macrophages, and hepatocytes. Forty-eight differential metabolites were identified, and the underlying perturbed metabolic pathways are quite similar to the pathways found to be altered in dengue patients in previous metabolomics studies, indicating that humanized mice could be a highly relevant small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics.
Neoproterozoic basement history of Wrangel Island and Arctic Chukotka: integrated insights from zircon U–Pb, O and Hf isotopic studies
Authors: Gottlieb Eric S. , Pease Victoria , Miller Elizabeth L. , Akinin Vyacheslav V. 
Published: May 2017

Abstract
The pre-Cenozoic kinematic and tectonic history of the Arctic Alaska Chukotka (AAC) terrane is not well known. The difficulties in assessing the history of the AAC terrane are predominantly due to a lack of comprehensive knowledge about the composition and age of its basement. During the Mesozoic, the AAC terrane was involved in crustal shortening, followed by magmatism and extension with localized high-grade metamorphism and partial melting, all of which obscured its pre-orogenic geological relationships. New zircon geochronology and isotope geochemistry results from Wrangel Island and western Chukotka basement rocks establish and strengthen intra- and inter-terrane lithological and tectonic correlations of the AAC terrane. Zircon U–Pb ages of five granitic and one volcanic sample from greenschist facies rocks on Wrangel Island range between 620±6 and 711±4 Ma, whereas two samples from the migmatitic basement of the Velitkenay massif near the Arctic coast of Chukotka yield 612±7 and 661±11 Ma ages. The age spectrum (0.95–2.0 Ga with a peak at 1.1 Ga and minor 2.5–2.7 Ga) and trace element geochemistry of inherited detrital zircons in a 703±5 Ma granodiorite on Wrangel Island suggests a Grenville–Sveconorwegian provenance for metasedimentary strata in the Wrangel Complex basement and correlates with the detrital zircon spectra of strata from Arctic Alaska and Pearya. Temporal patterns of zircon inheritance and O–Hf isotopes are consistent with Cryogenian–Ediacaran AAC magmatism in a peripheral/external orogenic setting (i.e. a fringing arc on rifted continental margin crust).
CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma
Authors: Wadkin James C. R. , Patten Daniel A. , Kamarajah Sivesh K. , Shepherd Emma L. , Novitskaya Vera , Berditchevski Fedor , Adams David H. , Weston Chris J. , Shetty Shishir 
Published: May 2017

CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention. NEW & NOTEWORTHY Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated in chronic liver disease and hepatocellular carcinoma (HCC) and is regulated on endothelium by tissue remodeling and procarcinogenic factors. These regulatory and functional studies identify CD151 as a potential therapeutic target to treat liver fibrosis and HCC.
Modeling of Patient-Derived Xenografts in Colorectal Cancer
Authors: Katsiampoura Anastasia , Raghav Kanwal , Jiang Zhi-Qin , Menter David G. , Varkaris Andreas , Morelli Maria P. , Manuel Shanequa , Wu Ji , Sorokin Alexey V. , Rizi Bahar Salimian , Bristow Christopher , Tian Feng , Airhart Susan , Cheng Mingshan , Broom Bradley M. , Morris Jeffrey , Overman Michael J. , Powis Garth , Kopetz Scott 
Published: May 2017

Abstract
Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient-derived xenografts (PDX) in colorectal cancer are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target, and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 colorectal cancer patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2–82.6) vs. biopsy 35% (95% CI: 22.1%–50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modeling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of colorectal cancer patients. Mol Cancer Ther; 16(7); 1435–42. ©2017 AACR.
The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells
Authors: Murone Maximilien , Radpour Ramin , Attinger Antoine , Chessex Anne Vaslin , Huguenin Anne-Laure , Schürch Christian M. , Banz Yara , Sengupta Saumitra , Aguet Michel , Rigotti Stefania , Bachhav Yogeshwar , Massière Frédéric , Ramachandra Murali , McAllister Andres , Riether Carsten 
Published: May 2017

Abstract
Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34+ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. Mol Cancer Ther; 16(8); 1497–510. ©2017 AACR.
Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice
Authors: Islam Bianca N. , Sharman Sarah K. , Hou Yali , Bridges Allison E. , Singh Nagendra , Kim Sangmi , Kolhe Ravindra , Trillo-Tinoco Jimena , Rodriguez Paulo C. , Berger Franklin G. , Sridhar Subbaramiah , Browning Darren D. 
Published: May 2017

Abstract
Intestinal cyclic guanosine monophosphate (cGMP) signaling regulates epithelial homeostasis and has been implicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5 (PDE5) inhibitor sildenafil to prevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS) inflammation-driven colorectal cancer model. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrier dysfunction. In mice treated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cell infiltration and reduced expression of iNOS, IFNγ, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration of sildenafil suppresses polyp formation and inflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans. Cancer Prev Res; 10(7); 377–88. ©2017 AACR.
See related editorial by Piazza, p. 373.
Text Independent Amharic Language Speaker Identification in Noisy Environments using Speech Processing Techniques
Authors: Mengistu Abrham Debasu , Melesew Alemayehu Dagnachew 
Published: May 2017

<p>In Ethiopia, the largest ethnic and linguistic groups are the Oromos, Amharas and Tigrayans. This paper presents the performance analysis of text-independent speaker identification system for the Amharic language in noisy environments. VQ (Vector Quantization), GMM (Gaussian Mixture Models), BPNN (Back propagation neural network), MFCC (Mel-frequency cepstrum coefficients), GFCC (Gammatone Frequency Cepstral Coefficients), and a hybrid approach had been use as techniques for identifying speakers of Amharic language in noisy environments. For the identification process, speech signals are collected from different speakers including both sexes; for our data set, a total of 90 speakers’ speech samples were collected, and each speech have 10 seconds duration from each individual. From these speakers, 59.2%, 70.9% and 84.7% accuracy are achieved when VQ, GMM and BPNN are used on the combined feature vector of MFCC and GFCC. </p>
Review of Dynamic Voltage Restorer Application for Compensation of Voltage Harmonics in Power Systems
Authors: Zadehbagheri Mahmoud , Ildarabadi Rahim , Baghaei Nejad Majid , Sutikno Tole 
Published: May 2017

<p>Power distribution networks are considered the main link between power industry and consumers and they are exposed to public judgment and evaluation more than any other section. Thus, it is essential to study power quality in distribution section. On the other hand, power distribution networks have always been exposed to traditional factors such as voltage sag, voltage swell, harmonics and capacitor switching which destruct sinusoidal waveforms and decrease power quality as well as network reliability. One of the methods by which power quality problems might be addressed is to apply power electronic devices in the form of custom power devices. One of such devices is Dynamic Voltage Restorer (DVR) which is connected in series to distribution networks. At the same time, through injection of voltage to the network it is able to control voltage amplitude and phase. It is adopted lend to compensate for voltage sags through injecting series and synchronous three phase voltage. This paper reviews on the application of DVR for Voltage Compensation in recent years and gives sets of information for each control of the DVR in distribution networks.</p>
OFDM System Performance Evaluation under Different Fading Channels and Channel Coding using Matlab Simulink
Authors: Manhas Pratima , Soni M.K 
Published: May 2017

<p>Orthogonal Frequency Division Multiplexing (OFDM) is a form of Multicarrier Modulation (MCM) technique in which larger bandwidth is divided into parallel narrow bands each of which is modulated by different subcarriers. All the subcarriers are orthogonal to each other and hence it reduces the interference among various subcarriers. OFDM technique is an efficient modulation technique used in certain wired and wireless application. During transmission, the transmitted signal can travel from transmitter to receiver over multiple reflective paths in case of wireless communication system which results to multipath fading and produces variation in amplitude, phase and angle of the received signal. The signal which is transmitted from BTS (base transceiver station) may undergo multiple reflections from the buildings nearby, before reaching the mobile station. This paper discusses the performance of OFDM system using various fading channels and channel coding. The parameter which is known as Bit error rate (BER) is calculated for different fading channels (AWGN, Rayleigh and Rician) for different digital modulation (BPSK, QPSK and QAM) and Channel coding(linear/ Cyclic coding).The tool which is used to evaluate the BER parameter is Matlab Simulink.</p>