bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Insights into the Evolutionary Rate of Hepatitis B Virus at Different Biological Scales
Authors: Lin You-Yu , Liu Chieh , Chien Wei-Hung , Wu Li-Ling , Tao Yong , Wu Dafei , Lu Xuemei , Hsieh Chia-Hung , Chen Pei-Jer , Wang Hurng-Yi , Kao Jia-Horng , Chen Ding-Shinn 
Published: January 2015

ABSTRACT

The evolutionary rates of hepatitis B virus (HBV) estimated using contemporary sequences are 10
2
to 10
4
times higher than those derived from archaeological and genetic evidence. This discrepancy makes the origin of HBV and the time scale of its spread, both of which are critical for studying the burden of HBV pathogenicity, largely unresolved. To evaluate whether the dual demands (i.e., adaptation within hosts and colonization between hosts) of the viral life cycle affect this conundrum, the HBV quasispecies dynamics within and among hosts from a family consisting of a grandmother, her 5 children, and her 2 granddaughters, all of whom presumably acquired chronic HBV through mother-to-infant transmission, were examined by PCR cloning and next-generation sequencing methods. We found that the evolutionary rate of HBV between hosts was considerably lower than that within hosts. Moreover, the between-host substitution rates of HBV decreased as transmission numbers between individuals increased. Both observations were due primarily to changes at nonsynonymous rather than synonymous sites. There were significantly more multiple substitutions than expected for random mutation processes, and 97% of substitutions were changed from common to rare amino acid residues in the database. Continual switching between colonization and adaptation resulted in a rapid accumulation of mutations at a limited number of positions, which quickly became saturated, whereas substitutions at the remaining regions occurred at a much lower rate. Our study may help to explain the time-dependent HBV substitution rates reported in the literature and provide new insights into the origin of the virus.

IMPORTANCE
It is known that the estimated hepatitis B virus (HBV) substitution rate is time dependent, but the reason behind this observation is still elusive. We hypothesize that owing to the small genome size of HBV, transmission between hosts and adaptation within hosts must exhibit high levels of fitness trade-offs for the virus. By studying the HBV quasispecies dynamics for a chain of sequentially infected transmissions within a family, we found the HBV substitution rate between patients to be negatively correlated with the number of transmissions. Continual switching between hosts resulted in a rapid accumulation of mutations at a limited number of genomic sites, which quickly became saturated in the short term. Nevertheless, substitutions at the remaining regions occurred at a much lower rate. Therefore, the HBV substitution rate decreased as the divergence time increased.
Antigenic Relationships among Porcine Epidemic Diarrhea Virus and Transmissible Gastroenteritis Virus Strains
Authors: Lin Chun-Ming , Gao Xiang , Oka Tomoichiro , Vlasova Anastasia N , Esseili Malak A. , Wang Qiuhong , Saif Linda J. 
Published: January 2015

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV) are economically important swine enteropathogenic coronaviruses. These two viruses belong to two distinct species of the
Alphacoronavirus
genus within
Coronaviridae
and induce similar clinical signs and pathological lesions in newborn piglets, but they are presumed to be antigenically distinct. In the present study, two-way antigenic cross-reactivity examinations between the prototype PEDV CV777 strain, three distinct U.S. PEDV strains (the original highly virulent PC22A, S indel Iowa106, and S 197del PC177), and two representative U.S. TGEV strains (Miller and Purdue) were conducted by cell culture immunofluorescent (CCIF) and viral neutralization (VN) assays. None of the pig TGEV antisera neutralized PEDV and vice versa. One-way cross-reactions were observed by CCIF between TGEV Miller hyperimmune pig antisera and all PEDV strains. Enzyme-linked immunosorbent assays, immunoblotting using monoclonal antibodies and
Escherichia coli
-expressed recombinant PEDV and TGEV nucleocapsid (N) proteins, and sequence analysis suggested at least one epitope on the N-terminal region of PEDV/TGEV N protein that contributed to this cross-reactivity. Biologically, PEDV strain CV777 induced greater cell fusion in Vero cells than did U.S. PEDV strains. Consistent with the reported genetic differences, the results of CCIF and VN assays also revealed higher antigenic variation between PEDV CV777 and U.S. strains.

IMPORTANCE
Evidence of antigenic cross-reactivity between porcine enteric coronaviruses, PEDV and TGEV, in CCIF assays supports the idea that these two species are evolutionarily related, but they are distinct species defined by VN assays. Identification of PEDV- or TGEV-specific antigenic regions allows the development of more specific immunoassays for each virus. Antigenic and biologic variations between the prototype and current PEDV strains could explain, at least partially, the recurrence of PEDV epidemics. Information on the conserved antigenicity among PEDV strains is important for the development of PEDV vaccines to protect swine from current highly virulent PEDV infections.
Warfarin prescription and administration: reducing the delay, improving the safety
Authors: Dyar Rebecca , Hall Simon , McIntyre Bethannie 
Published: January 2015

AbstractWarfarin is frequently administered to hospital patients. The prescription and administration of this medication are particularly susceptible to error. Factors contributing to this include the narrow therapeutic index, patient-specific target range, and the need for regular INR monitoring. NICE guidelines state that warfarin should be given at the same time every day and the Bristol Royal Infirmary guidelines are warfarin to be given at 14:00. The 14:00 dosing ensures standardisation of administration; poor adherence to this recommendation may cause patient harm. We noticed that many warfarin doses were often given outside of maximal staffing hours and it was often left to the on call doctor to prescribe warfarin at erratic and inconsistent times.Our primary aim was to reduce the number of adverse outcomes associated with warfarin prescription and administration. We targeted two system measures: the proportion of warfarin administrations occurring within an hour of the 14:00 prescription and the proportion of INR results outside target range. We employed the model for improvement and carried out our project across seven acute medical wards. Baseline data showed that only 24% of doses were being given within an hour of the recommended time and 64% of doses were being given after 17:00 during minimal staffing hours. We successfully introduced a warfarin box within our trust which demonstrated an improvement in warfarin administration from 24% of patients receiving their warfarin within an hour of 14:00 to 49% and this was subsequently associated with a reduction in INRs above target range (23% to 9%).
Selectivity and mixed reactant fuel cells
Authors: Riess Ilan 
Published: January 2015

Mixed reactant fuel cells (MR-FCs), are aimed at using a uniform mixture of fuel and oxygen applied to both the anode and the cathode. This allows redesign of fuel cells with a significantly simpler construction, having potentially a higher power density, better fuel utilization and be less expensive. The challenge in realizing MR-FCs is finding selective electrodes that can enhance oxygen reduction at the cathode, fuel oxidation at the anode while inhibiting the chemical reaction between the fuel and oxygen in the gas mixture. This task is in particular challenging in solid oxide fuel cells (SOFCs), as they operate at elevated temperatures, where many reactions are easily activated and selectivity is difficult to achieve. As a result no true MR-FC of the SOFC type were reported while some were found for low temperature fuel cells (FCs). The so-called single-chamber-SOFC are not true MR-FCs as they do not contain two selective electrodes, as required. We shall discuss potential ways to search for and develop selective anodes and cathodes for SOFC type MR-FCs. We first consider material properties which should contribute to that goal. This refers to electronic properties of the bulk, band banding under adsorbed specie, point defects in the bulk and on the surface. We then proceed to show how cell design, in particular electrode structure, can contribute to selectivity. Finally operation conditions are considered and it is shown that they also can contribute to selectivity. The operation condition considered are gas mixture composition, gas mixture residence time in the hot zone, hence gas flow rate, current density and temperature. The topics discussed hold for all FC types but are crucial for the SOFC type because of the difficulty to achieve selectivity at elevated temperatures. It is suggested that a concerted effort taking advantage of all those options should allow development of a true SOFC type MR-FC.
Tree-Antimagicness of Disconnected Graphs
Authors: Bača Martin , Kimáková Zuzana , Semaničová-Feňovčíková Andrea , Umar Muhammad Awais 
Published: January 2015

A simple graphGadmits anH-covering if every edge inE(G)belongs to a subgraph ofGisomorphic toH. The graphGis said to be (a,d)-H-antimagic if there exists a bijection from the vertex setV(G)and the edge setE(G)onto the set of integers1, 2, …,VG+E(G)such that, for all subgraphsH′ofGisomorphic toH, the sum of labels of all vertices and edges belonging toH′constitute the arithmetic progression with the initial termaand the common differenced.Gis said to be a super (a,d)-H-antimagic if the smallest possible labels appear on the vertices. In this paper, we study super tree-antimagic total labelings of disjoint union of graphs.
Establishment and Characterization of a Cell Line from Human Circulating Colon Cancer Cells
Authors: Cayrefourcq Laure , Mazard Thibault , Joosse Simon , Solassol Jérôme , Ramos Jeanne , Assenat Eric , Schumacher Udo , Costes Valérie , Maudelonde Thierry , Pantel Klaus , Alix-Panabières Catherine 
Published: January 2015

Abstract
Circulating tumor cells (CTC) in blood are promising new biomarkers potentially useful for prognostic prediction and monitoring of therapies in patients with solid tumors including colon cancer. Moreover, CTC research opens a new avenue for understanding the biology of metastasis in patients with cancer. However, an in-depth investigation of CTCs is hampered by the very low number of these cells, especially in the blood of patients with colorectal cancer. Thus, the establishment of cell cultures and permanent cell lines from CTCs has become the most challenging task over the past year. Here, we describe, for the first time, the establishment of cell cultures and a permanent cell line from CTCs of one patient with colon cancer. The cell line designated CTC-MCC-41 has been cultured for more than one year, and the cells have been characterized at the genome, transcriptome, proteome, and secretome levels. This thorough analysis showed that CTC-MCC-41 cells resemble characteristics of the original tumor cells in the patient with colon cancer and display a stable phenotype characterized by an intermediate epithelial/mesenchymal phenotype, stem cell–like properties, and an osteomimetic signature, indicating a bone marrow origin. Functional studies showed that CTC-MCC-41 cells induced rapidly in vitro endothelial cell tube formation and in vivo tumors after xenografting in immunodeficient mice. The establishment of this first colon cancer CTC line allows now a wealth of functional studies on the biology of CTCs as well as in vitro and in vivo drug testing. Cancer Res; 75(5); 892–901. ©2015 AACR.
A Comparative Study of Molecular Characteristics of Diffuse Large B-cell Lymphoma from Patients with and without Human Immunodeficiency Virus Infection
Authors: Chao Chun , Silverberg Michael J. , Xu Lanfang , Chen Lie-Hong , Castor Brandon , Martínez-Maza Otoniel , Abrams Donald I. , Zha Hongbin D. , Haque Reina , Said Jonathan 
Published: January 2015

Abstract
Purpose: HIV-related diffuse large B-cell lymphoma (DLBCL) may be biologically different from DLBCL in the general population. We compared, by HIV status, the expression and prognostic significance of selected oncogenic markers in DLBCL diagnosed at Kaiser Permanente in California, between 1996 and 2007.
Experimental Design: Eighty HIV-infected DLBCL patients were 1:1 matched to 80 HIV-uninfected DLBCL patients by age, gender, and race. Twenty-three markers in the following categories were examined using IHC: (i) cell-cycle regulators, (ii) B-cell activators, (iii) antiapoptotic proteins, and (iv) others, such as IgM. Tumor marker expression was compared across HIV infection status by Fisher exact test. For markers differentially expressed in HIV-related DLBCL, logistic regression was used to evaluate the association between tumor marker expression and 2-year overall mortality, adjusting for International Prognostic Index, cell-of-origin phenotype, and DLBCL morphologic variants.
Results: Expression of cMYC (% positive in HIV-related and -unrelated DLBCL: 64% vs. 32%), BCL6 (45% vs. 10%), PKC-β2 (61% vs. 4%), MUM1 (59% vs. 14%), and CD44 (87% vs. 56%) was significantly elevated in HIV-related DLBCLs, whereas expression of p27 (39% vs. 75%) was significantly reduced. Of these, cMYC expression was independently associated with increased 2-year mortality in HIV-infected patients [relative risk = 3.09 (0.90–10.55)] in multivariable logistic regression.
Conclusions: These results suggest that HIV-related DLBCL pathogenesis more frequently involves cMYC and BCL6 among other factors. In particular, cMYC-mediated pathogenesis may partly explain the more aggressive clinical course of DLBCL in HIV-infected patients. Clin Cancer Res; 21(6); 1429–37. ©2015 AACR.
Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors
Authors: Cani Andi K. , Hovelson Daniel H. , McDaniel Andrew S. , Sadis Seth , Haller Michaela J. , Yadati Venkata , Amin Anmol M. , Bratley Jarred , Bandla Santhoshi , Williams Paul D. , Rhodes Kate , Liu Chia-Jen , Quist Michael J. , Rhodes Daniel R. , Grasso Catherine S. , Kleer Celina G. , Tomlins Scott A. 
Published: January 2015

Abstract
Phyllodes tumors are rare fibroepithelial tumors with variable clinical behavior accounting for a small subset of all breast neoplasms, yet little is known about the genetic alterations that drive tumor initiation and/or progression. Here, targeted next-generation sequencing (NGS) was used to identify somatic alterations in formalin-fixed paraffin-embedded (FFPE) patient specimens from malignant, borderline, and benign cases. NGS revealed mutations in mediator complex subunit 12 (MED12) affecting the G44 hotspot residue in the majority (67%) of cases spanning all three histologic grades. In addition, loss-of-function mutations in p53 (TP53) as well as deleterious mutations in the tumor suppressors retinoblastoma (RB1) and neurofibromin 1 (NF1) were identified exclusively in malignant tumors. High-level copy-number alterations (CNA) were nearly exclusively confined to malignant tumors, including potentially clinically actionable gene amplifications in IGF1R and EGFR. Taken together, this study defines the genomic landscape underlying phyllodes tumor development, suggests potential molecular correlates to histologic grade, expands the spectrum of human tumors with frequent recurrent MED12 mutations, and identifies IGF1R and EGFR as potential therapeutic targets in malignant cases.
Implications: Integrated genomic sequencing and mutational profiling provides insight into the molecular origin of phyllodes tumors and indicates potential druggable targets in malignant disease.
Visual Overview: http://mcr.aacrjournals.org/content/early/2015/04/02/1541-7786.MCR-14-0578/F1.large.jpg.
Mol Cancer Res; 13(4); 613–9. ©2015 AACR.
Factor VIII organisation on nanodiscs with different lipid composition
Authors: Grushin Kirill , Miller Jaimy , Dalm Daniela , Stoilova-McPhie Svetla 
Published: January 2015

SummaryNanodiscs (ND) are lipid bilayer membrane patches held by amphiphilic scaffolding proteins (MSP) of ~10 nm in diameter. Nanodiscs have been developed as lipid nanoplatforms for structural and functional studies of membrane and membrane associated proteins. Their size and monodispersity have rendered them unique for electron microscopy (EM) and single particle analysis studies of proteins and complexes either spanning or associated to the ND membrane. Binding of blood coagulation factors and complexes, such as the Factor VIII (FVIII) and the Factor VIIIa - Factor IXa (intrinsic tenase) complex to the negatively charged activated platelet membrane is required for normal haemostasis. In this study we present our work on optimising ND, specifically designed to bind FVIII at close to physiological conditions. The binding of FVIII to the negatively charged ND rich in phosphatidylserine (PS) was followed by electron microscopy at three different PS compositions and two different membrane scaffolding protein (MSP1D1) to lipid ratios. Our results show that the ND with highest PS content (80 %) and lowest MSP1D1 to lipid ratio (1:47) are the most suitable for structure determination of the membrane-bound FVIII by single particle EM. Our preliminary FVIII 3D reconstruction as bound to PS containing ND demonstrates the suitability of the optimised ND for structural studies by EM. Further assembly of the activated FVIII form (FVIIIa) and the whole FVIIIa-FIXa complex on ND, followed by EM and single particle reconstruction will help to identify the protein-protein and protein-membrane interfaces critical for the intrinsic tenase complex assembly and function.
Association between pneumoconiosis and pulmonary emboli
Authors: Shen Chih-Hao , Chen Hsuan-Ju , Lin Te-Yu , Huang Wen-Yen , Li Tsai-Chung , Kao Chia-Hung 
Published: January 2015

SummaryStudies on the association between pneumoconiosis and deep-vein thrombosis (DVT) and pulmonary thromboembolism (PE) are few. This study was based on data obtained from the Taiwan National Health Insurance Database from 2000 to 2006, with a follow-up period extending to the end of 2011. We identified 3719 pneumoconiosis patients and 14876 non-pneumoconiosis patients who were selected by frequency matched based on sex, age, and the index year. We analysed the risks of DVT and PE by using Cox proportional hazards regression models by including sex, age, and CCI score. The risk of developing PE was 1.90-fold in the patients with pneumoconiosis compared with the comparison cohort after adjustments for age, sex, and CCI score. By contrast, we did not observe significant effect of pneumoconiosis on DVT. However, the cumulative incidence curves for DVT were similar in the pneumoconiosis patients and non-pneumoconiosis patients. The multiplicative increased risks of PE were significant in patients with pneumoconiosis and CCI score of one and more. In conclusion, physicians should include pneumoconiosis in evaluating pulmonary embolism risk.
Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension
Authors: Ranchoux Benoît , Antigny Fabrice , Rucker-Martin Catherine , Hautefort Aurélie , Péchoux Christine , Bogaard Harm Jan , Dorfmüller Peter , Remy Séverine , Lecerf Florence , Planté Sylvie , Chat Sophie , Fadel Elie , Houssaini Amal , Anegon Ignacio , Adnot Serge , Simonneau Gerald , Humbert Marc , Cohen-Kaminsky Sylvia , Perros Frédéric 
Published: January 2015

Background—
The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly the accumulation of α-smooth muscle actin–expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those α-smooth muscle actin–expressing cells.

Methods and Results—

In situ evidence of EndoMT in human PAH was obtained by using confocal microscopy of multiple fluorescent stainings at the arterial level, and by using transmission electron microscopy and correlative light and electron microscopy at the ultrastructural level. Findings were confirmed by in vitro analyses of human PAH and control cultured pulmonary artery endothelial cells. In addition, the mRNA and protein signature of EndoMT was recognized at the arterial and lung level by quantitative real-time polymerase chain reaction and Western blot analyses. We confirmed our human observations in established animal models of pulmonary hypertension (monocrotaline and SuHx). After establishing the first genetically modified rat model linked to
BMPR2
mutations (BMPR2
Δ140Ex1/+
rats), we demonstrated that EndoMT is linked to alterations in signaling of BMPR2, a gene that is mutated in 70% of cases of familial PAH and in 10% to 40% of cases of idiopathic PAH. We identified molecular actors of this pathological transition, including twist overexpression and vimentin phosphorylation. We demonstrated that rapamycin partially reversed the protein expression patterns of EndoMT, improved experimental PAH, and decreased the migration of human pulmonary artery endothelial cells, providing the proof of concept that EndoMT is druggable.

Conclusions—
EndoMT is linked to alterations in BPMR2 signaling and is involved in the occlusive vas cular remodeling of PAH, findings that may have therapeutic implications.
Effect of Decompressive Craniectomy on Outcome Following Subarachnoid Hemorrhage in Mice
Authors: Bühler Dominik , Azghandi Sepiede , Schüller Kathrin , Plesnila Nikolaus 
Published: January 2015

Background and Purpose—
Elevated intracranial pressure (ICP) is a key feature of subarachnoid hemorrhage (SAH). Here, we examined the role of elevated ICP in the pathophysiology of SAH, and we investigated whether decreasing ICP by performing decompressive craniectomy (DC) can improve outcome.

Methods—

SAH was induced in male C57BL/6 mice via endovascular Circle of Willis perforation in the following 4 groups: sham surgery, SAH, DC after SAH, and DC before SAH. DC was performed either 15 minutes before or after SAH induction. ICP, cerebral blood flow, heart rate, oxygen saturation, and end-tidal P
CO
2
were monitored for 45 minutes. After surgery, neurological function was evaluated daily for 7 days. After killing, hippocampal neurons, corpus callosum thickness, and ventricular volume were evaluated on paraformaldehyde-fixed coronal brain sections.

Results—
Although DC reduced SAH-induced ICP, it yielded no beneficial effect with respect to posthemorrhagic hypoperfusion; moreover, DC increased the incidence of rebleeding, induced more severe neurological impairments, and caused higher mortality. Post SAH, mice that survived 7 days had no histopathologic differences, regardless of whether DC was performed.

Conclusions—
Performing DC to reduce ICP either during or acutely after SAH resulted in more severe bleeding, a higher incidence of rebleeding, and poorer outcome. Thus, elevated post-hemorrhagic ICP plays an important role in controlling bleeding after SAH and should therefore not be reduced acutely. If DC is considered for treating a patient with SAH, the timing of decompression should take these effects into consideration.