bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Hypervariable Region 1 for the Interplay of Hepatitis C Virus with Entry Factors and Lipoproteins
Authors: Bankwitz Dorothea , Vieyres Gabrielle , Hueging Kathrin , Bitzegeio Julia , Doepke Mandy , Chhatwal Patrick , Haid Sibylle , Catanese Maria Teresa , Zeisel Mirjam B. , Nicosia Alfredo , Baumert Thomas F. , Kaderali Lars , Pietschmann Thomas 
Published: August 2014

ABSTRACT
Hepatitis C virus (HCV) particles associate with lipoproteins and infect cells by using at least four cell entry factors. These factors include scavenger receptor class B type I (SR-BI), CD81, claudin 1 (CLDN1), and occludin (OCLN). Little is known about specific functions of individual host factors during HCV cell entry and viral domains that mediate interactions with these factors. Hypervariable region 1 (HVR1) within viral envelope protein 2 (E2) is involved in the usage of SR-BI and conceals the viral CD81 binding site. Moreover, deletion of this domain alters the density of virions. We compared lipoprotein interaction, surface attachment, receptor usage, and cell entry between wild-type HCV and a viral mutant lacking this domain. Deletion of HVR1 did not affect CD81, CLDN1, and OCLN usage. However, unlike wild-type HCV, HVR1-deleted viruses were not neutralized by antibodies and small molecules targeting SR-BI. Nevertheless, modulation of SR-BI cell surface expression altered the infection efficiencies of both viruses to similar levels. Analysis of affinity-purified virions revealed comparable levels of apolipoprotein E (ApoE) incorporation into viruses with or without HVR1. However, ApoE incorporated into these viruses was differentially recognized by ApoE-specific antibodies. Thus, SR-BI has at least two functions during cell entry. One of them can be neutralized by SR-BI-targeting molecules, and it is critical only for wild-type HCV. The other one is important for both viruses but apparently is not inactivated by the SR-BI binding antibodies and small molecules evaluated here. In addition, HVR1 modulates the conformation and/or epitope exposure of virus particle-associated ApoE.

IMPORTANCE
HCV cell entry is SR-BI dependent irrespective of the presence or absence of HVR1. Moreover, this domain modulates the properties of ApoE on the surface of virus particles. These findings have implications for the development of SR-BI-targeting antivirals. Furthermore, these findings highlight separable functions of SR-BI during HCV cell entry and reveal a novel role of HVR1 for the properties of virus-associated lipoproteins.
Epstein-Barr Virus Glycoprotein gB and gHgL Can Mediate Fusion and Entry in
trans
, and Heat Can Act as a Partial Surrogate for gHgL and Trigger a Conformational Change in gB
Authors: Chesnokova Liudmila S. , Ahuja Munish K. , Hutt-Fletcher Lindsey M. 
Published: August 2014

ABSTRACT

Epstein-Barr virus (EBV) fusion with an epithelial cell requires virus glycoproteins gHgL and gB and is triggered by an interaction between gHgL and integrin αvβ5, αvβ6, or αvβ8. Fusion with a B cell requires gHgL, gp42, and gB and is triggered by an interaction between gp42 and human leukocyte antigen class II. We report here that, like alpha- and betaherpesviruses, EBV, a gammaherpesvirus, can mediate cell fusion if gB and gHgL are expressed in
trans
. Entry of a gH-null virus into an epithelial cell is possible if the epithelial cell expresses gHgL, and entry of the same virus, which phenotypically lacks gHgL and gp42, into a B cell expressing gHgL is possible in the presence of a soluble integrin. Heat is capable of inducing the fusion of cells expressing only gB, and the proteolytic digestion pattern of gB in virions changes in the same way following the exposure of virus to heat or to soluble integrins. It is suggested that the Gibbs free energy released as a result of the high-affinity interaction of gHgL with an integrin contributes to the activation energy required to cause the refolding of gB from a prefusion to a postfusion conformation.

IMPORTANCE
The core fusion machinery of herpesviruses consists of glycoproteins gB and gHgL. We demonstrate that as in alpha- and betaherpesvirus, gB and gHgL of the gammaherpesvirus EBV can mediate fusion and entry when expressed in
trans
in opposing membranes, implicating interactions between the ectodomains of the proteins in the activation of fusion. We further show that heat and exposure to a soluble integrin, both of which activate fusion, result in the same changes in the proteolytic digestion pattern of gB, possibly representing the refolding of gB from its prefusion to its postfusion conformation.
Residue 82 of the Chikungunya Virus E2 Attachment Protein Modulates Viral Dissemination and Arthritis in Mice
Authors: Ashbrook Alison W. , Burrack Kristina S. , Silva Laurie A. , Montgomery Stephanie A. , Heise Mark T. , Morrison Thomas E. , Dermody Terence S. 
Published: August 2014

ABSTRACT

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-Saharan Africa, Southeast Asia, and the Caribbean. Like other arthritogenic alphaviruses, mechanisms of CHIKV pathogenesis are not well defined. Using the attenuated CHIKV strain 181/25 and virulent strain AF15561, we identified a residue in the E2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pathogenesis
in vivo
. Viruses containing an arginine at E2 residue 82 displayed enhanced infectivity in mammalian cells but reduced infectivity in mosquito cells and diminished virulence in a mouse model of CHIKV disease. Mice inoculated with virus containing an arginine at this position exhibited reduced swelling at the site of inoculation with a concomitant decrease in the severity of necrosis in joint-associated tissues. Viruses containing a glycine at E2 residue 82 produced higher titers in the spleen and serum at early times postinfection. Using wild-type and glycosaminoglycan (GAG)-deficient Chinese hamster ovary (CHO) cell lines and soluble GAGs, we found that an arginine at residue 82 conferred greater dependence on GAGs for infection of mammalian cells. These data suggest that CHIKV E2 interactions with GAGs diminish dissemination to lymphoid tissue, establishment of viremia, and activation of inflammatory responses early in infection. Collectively, these results suggest a function for GAG utilization in regulating CHIKV tropism and host responses that contribute to arthritis.

IMPORTANCE
CHIKV is a reemerging alphavirus of global significance with high potential to spread into new, immunologically naive populations. The severity of CHIKV disease, particularly its propensity for chronic musculoskeletal manifestations, emphasizes the need for identification of genetic determinants that dictate CHIKV virulence in the host. To better understand mechanisms of CHIKV pathogenesis, we probed the function of an amino acid polymorphism in the E2 viral attachment protein using a mouse model of CHIKV musculoskeletal disease. In addition to influencing glycosaminoglycan utilization, we identified roles for this polymorphism in differential infection of mammalian and mosquito cells and targeting of CHIKV to specific tissues within infected mice. These studies demonstrate a correlation between CHIKV tissue tropism and virus-induced pathology modulated by a single polymorphism in E2, which in turn illuminates potential targets for vaccine and antiviral drug development.
Intrabronchial Infection of Rhesus Macaques with Simian Varicella Virus Results in a Robust Immune Response in the Lungs
Authors: Haberthur Kristen , Meyer Christine , Arnold Nicole , Engelmann Flora , Jeske Daniel R. , Messaoudi Ilhem 
Published: August 2014

ABSTRACTVaricella-zoster virus (VZV) is the etiological agent of varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection is believed to occur via the inhalation of virus either in respiratory droplets or from shedding varicella lesions or by direct contact with infectious vesicular fluid. However, the ensuing immune response in the lungs remains incompletely understood. We have shown that intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, recapitulates the hallmarks of acute and latent VZV infection in humans. In this study, we performed an in-depth analysis of the host immune response to acute SVV infection in the lungs and peripheral blood. We report that acute SVV infection results in a robust innate immune response in the lungs, characterized by the production of inflammatory cytokines, chemokines, and growth factors as well as an increased frequency of plasmacytoid dendritic cells (DCs) that corresponded with alpha interferon (IFN-α) production and a rapid decrease in viral loads in the lungs. This is followed by T and B cell proliferation, antibody production, T cell differentiation, and cytokine production, which correlate with the complete cessation of viral replication. Although terminally differentiated CD8 T cells became the predominant T cell population in bronchoalveolar lavage cells, a higher percentage of CD4 T cells were SVV specific, which suggests a critical role for these cells in the resolution of primary SVV infection in the lungs. Given the homology between SVV and VZV, our data provide insight into the immune response to VZV within the lung.IMPORTANCEAlthough primary VZV infection occurs primarily via the respiratory route, the host response in the lungs and its contribution to the cessation of viral replication and establishment of latency remain poorly understood. The difficulty in accessing lung tissue and washes from individuals infected with VZV has hampered efforts to address this knowledge gap. SVV infection of rhesus macaques is an important model of VZV infection of humans; therefore, we utilized this animal model to gain a comprehensive view of the kinetics of the immune response to SVV in the lung and its relationship to the resolution of acute infection in respiratory tissues. These data not only advance our understanding of host immunity to VZV, a critical step in developing new vaccines, but also provide additional insight into immunity to respiratory pathogens.
Acupuncture for patients with Alzheimer's disease: a systematic review protocol
Authors: Zhou Jing , Peng Weina , Li Wang , Liu Zhishun 
Published: August 2014

IntroductionThe aim of this protocol is to provide the methods used to assess the effectiveness and safety of acupuncture for the treatment of patients with Alzheimer's disease.Methods and analysisWe will search the following electronic databases: The Cochrane Library, PubMed, Medline, Embase, PsycINFO, Chinese Biomedical Literature Database, Chinese Medical Current Contents and China National Knowledge Infrastructure without restriction of language and publication status. Other sources such as Chinese acupuncture journals and the reference list of selected studies will also be searched. After screening the studies, a meta-analysis of randomised controlled trials will be conducted, if possible. Results expressed as risk ratios for dichotomous data and standardised or weighted mean differences for continuous data, will be used for data synthesis.DisseminationThe protocol of this systematic review will be disseminated in a peer-reviewed journal and presented at a relevant conference.Trial registration numberPROSPERO CRD42014009619
Association of nucleated red blood cells with mortality in critically ill dogs
Authors: Müller M. , Dörfelt R. , Hamacher L. , Wess G. 
Published: August 2014

The occurrence of nucleated red blood cells (NRBC) in the peripheral blood of critically ill human patients is associated with increased mortality. In dogs, the presence of NRBCs in peripheral blood has been used as a sensitive and specific marker of complications and outcome associated with heatstroke. However, no study has investigated their prevalence in critically ill dogs. Thus, the aim of this study was to determine the prevalence of NRBCs in the peripheral blood, and to evaluate their occurrence as a prognostic factor in critically ill dogs. One hundred and one dogs were prospectively included; the presence of NRBCs was studied on a daily basis from the time of admission until day 3 in the intensive care unit (or less if discharged or death occurred earlier). Dogs fulfilled at least two systemic inflammatory response syndrome (SIRS) criteria and suffered from various diseases. Survival was defined as being alive 28 days postdischarge from hospital. In 42 dogs, NRBCs were detected at least once; 59 patients were NRBC negative. Mortality was significantly higher in NRBC‐positive than NRBC‐negative patients (54.8 v 30.5 per cent) (P=0.014). However, this association was not present when anaemic dogs were excluded from the analysis. Detection of NRBCs in the peripheral blood may be an indicator for regenerative anaemia and may have potential for use as a prognostic tool or in addition to established scoring systems in critically ill dogs.
Longitudinal Time-Dependent Effects of Irradiation on Multidrug Resistance in a Non–Small Lung Cancer Cell Line
Authors: Kono Yumiko , Utsunomiya Keita , Kanno Shohei , Tanigawa Noboru 
Published: August 2014

Abstract
Multidrug resistance (MDR) in cancer is known to decrease the therapeutic efficacy of chemotherapy. The effects of irradiation on MDR in cancer cells remain unclear. Tc-99m methoxyisobutylisonitrile (MIBI) exhibits the same ATP-binding cassette (ABC) transporter kinetics as the chemotherapeutic compound doxorubicin. In this study, we investigated the synergistic effects of chemotherapeutics and irradiation [0 Gy: C (control) group; 3, 6, 9, 12 Gy: I (irradiation) group] in the human non–small lung cancer cell line H1299 exhibiting MDR, on MIBI and doxorubicin ABC transporter kinetics, in vitro and in vivo, respectively. In vitro, inhibition of H1299 cell proliferation by irradiation was found to be irradiation dose dependent. The degree and duration of MDR inhibition in vitro in H1299 were also dose dependent. In the cells of both the C group and 3-Gy I group, no significant difference of MIBI accumulation was observed. In the 6-Gy I group, a higher MIBI accumulation was observed at only 7 days after irradiation relative to the C group. A higher MIBI accumulation in the 9- and 12-Gy I groups with a significant difference from the C group was observed at 4 to 14 days after irradiation. A significant negative correlation between intracellular MIBI accumulation and cell replication was found. In vivo, high accumulation and retention of doxorubicin were observed in irradiated tumors in the H1299 xenograft mice group at 4 to 14 days after 9-Gy irradiation compared with the control mice group. These results provide evidence for a synergistic effect of concurrent chemotherapy and radiotherapy. Mol Cancer Ther; 13(11); 2706–12. ©2014 AACR.
Constitutively Active ErbB2 Regulates Cisplatin-Induced Cell Death in Breast Cancer Cells via Pro- and Antiapoptotic Mechanisms
Authors: Sigurðsson Haraldur H. , Olesen Christina W. , Dybboe Rie , Lauritzen Gitte , Pedersen Stine F. 
Published: August 2014

AbstractDespite the frequent expression of N-terminally truncated ErbB2 (ΔNErbB2/p95HER2) in breast cancer and its association with Herceptin resistance and poor prognosis, it remains poorly understood how ΔNErbB2 affects chemotherapy-induced cell death. Previously it was shown that ΔNErbB2 upregulates acid extrusion from MCF-7 breast cancer cells and that inhibition of the Na+/H+ exchanger (SLC9A1/NHE1) strongly sensitizes ΔNErbB2-expressing MCF-7 cells to cisplatin chemotherapy. The aim of this study was to identify the mechanism through which ΔNErbB2 regulates cisplatin-induced breast cancer cell death, and determine how NHE1 regulates this process. Cisplatin treatment elicited apoptosis, ATM phosphorylation, upregulation of p53, Noxa (PMAIP1), and PUMA (BBC3), and cleavage of caspase-9, -7, fodrin, and PARP-1 in MCF-7 cells. Inducible ΔNErbB2 expression strongly reduced cisplatin-induced ATM- and p53-phosphorylation, augmented Noxa upregulation and caspase-9 and -7 cleavage, doubled p21WAF1/Cip1 (CDKN1A) expression, and nearly abolished Bcl-2 expression. LC3-GFP analysis demonstrated that autophagic flux was reduced by cisplatin in a manner augmented by ΔNErbB2, yet did not contribute to cisplatin-induced death. Using knockdown approaches, it was shown that cisplatin-induced caspase-7 cleavage in ΔNErbB2-MCF-7 cells was Noxa- and caspase-9 dependent. This pathway was augmented by NHE1 inhibition, while the Na+/HCO3− cotransporter (SLC4A7/NBCn1) was internalized following cisplatin exposure.Implications: This work reveals that ΔNErbB2 strongly affects several major pro- and antiapoptotic pathways and provides mechanistic insight into the role of NHE1 in chemotherapy resistance. These findings have relevance for defining therapy regimens in breast cancers with ΔNErbB2 and/or NHE1 overexpression. Mol Cancer Res; 13(1); 63–77. ©2014 AACR.
SIRT1 Inactivation Evokes Antitumor Activities in NSCLC through the Tumor Suppressor p27
Authors: Zhu Lijia , Chiao Christine Y. , Enzer Katelyn G. , Stankiewicz Alexander J. , Faller Douglas V. , Dai Yan 
Published: August 2014

Abstract
P27Kip1 (CDKN1B) regulates cellular proliferation and senescence, and p27Kip1 deficiency in cancer is strongly correlated with poor prognosis of multiple cancer types. Understanding the mechanism of p27Kip1 loss in cancer and the consequences of restoring p27Kip1 levels is therefore critical for effective management during therapy. Here, SIRT1, a class III histone deacetylase (HDAC), is identified as an important regulator of p27Kip1 expression. Mechanistically, SIRT1 reduces p27Kip1 expression by decreasing p27Kip1 protein stability through the ubiquitin–proteasome pathway. In addition, SIRT1 silencing suppresses non–small cell lung cancer (NSCLC) proliferation and induces senescence in a p27Kip1-dependent manner. Furthermore, SIRT1 silencing dramatically suppresses tumor formation and proliferation in two distinct NSCLC xenograft mouse models. Collectively, these data demonstrate that not only SIRT1 is an important regulator of p27Kip1 but also SIRT inhibition induces senescence and antigrowth potential in lung cancer in vivo.
Implications: SIRT1 is a key regulator of p27 protein levels and SIRT1 inhibition is a viable strategy for NSCLC therapy by means of p27 reactivation. Mol Cancer Res; 13(1); 41–49. ©2014 AACR.
BIRO1, a Cell-Permeable BH3 Peptide, Promotes Mitochondrial Fragmentation and Death of Retinoblastoma Cells
Authors: Allaman-Pillet Nathalie , Oberson Anne , Schorderet Daniel F. 
Published: August 2014

AbstractRetinoblastoma is the most common pediatric intraocular neoplasm. While retinoblastoma development requires the inactivation of both alleles of the retinoblastoma tumor suppressor gene (RB1) in the developing retina, additional genomic changes are involved in tumor progression, which progressively lead to resistance of tumor cells to death. Therapeutics acting at very downstream levels of death signaling pathways should therefore be interesting in killing retinoblastoma cells. The BH3-only proteins promote apoptosis by modulating the interaction between the pro- and antiapoptotic members of the BCL2 protein family, and this effect can be recapitulated by the BH3 domains. This report analyzes the effect of various BH3 peptides, corresponding to different BH3-only proteins, on two retinoblastoma cell lines, Y79 and WERI-Rb, as well as on the photoreceptor cell line 661W. The BH3 peptide BIRO1, derived from the BCL2L11 death domain, was very effective in promoting Y79 and WERI-Rb cell death without affecting the 661W photoreceptor cells. This cell death was efficient even in absence of BAX and was shown to be caspase independent. While ROS production or AIF release was not detected from mitochondria of treated cells, BIRO1 initiated mitochondria fragmentation in a short period of time following treatment.Implications: The BIRO1 peptide is highly effective at killing retinoblastoma cells and has potential as a peptidomimetic. Mol Cancer Res; 13(1); 86–97. ©2014 AACR.
Visualization of Epicardial Cryoablation Lesions Using Endogenous Tissue Fluorescence
Authors: Swift Luther , Gil Daniel A.B. , Jaimes Rafael , Kay Matthew , Mercader Marco , Sarvazyan Narine 
Published: August 2014

Background—
Percutaneous cryoballoon ablation is a commonly used procedure to treat atrial fibrillation. One of the major limitations of the procedure is the inability to directly visualize tissue damage and functional gaps between the lesions. We seek to develop an approach that will enable real-time visualization of tissue necrosis during cryo- or radiofrequency ablation procedures.

Methods and Results—

Cryoablation of either blood-perfused or saline-perfused hearts was associated with a marked decrease in nicotinamide adenine dinucleotide (NADH) fluorescence, leading to a 60% to 70% loss of signal intensity at the lesion site. The total lesion area observed on the NADH channel exhibited a strong correlation with the area identified by triphenyl tetrazolium staining (
r
=0.89,
P
<0.001). At physiological temperatures, loss of NADH became visually apparent within 26±8 s after detachment of the cryoprobe from the epicardial surface and plateaued within minutes after which the boundaries of the lesions remained stable for several hours. The loss of electrical activity within the cryoablation site exhibited a close spatial correlation with the loss of NADH (
r
=0.84±0.06,
P
<0.001). Cryoablation led to a decrease in diffuse reflectance across the entire visible spectrum, which was in stark contrast to radiofrequency ablation that markedly increased the intensity of reflected light at the lesion sites.

Conclusions—
We confirmed the feasibility of using endogenous NADH fluorescence for the real-time visualization of cryoablation lesions in blood-perfused cardiac muscle preparations and revealed similarities and differences between imaging cryo- and radiofrequency ablation lesions when using ultraviolet and visible light illumination.
D. H. Lawrence’s Theology of the Body: Intersections with John Paul II’s Man and Woman He Created Them
Authors: Boone N. S. 
Published: August 2014

This article examines the philosophical foundations of both D. H. Lawrence’s sexual ethics and the “theology of the body” developed by Pope John Paul II. Although Lawrence is often viewed, rightly in most cases, as a critic of Christianity, and even though his work has been scorned or outright banned by Christian groups over the years, Lawrence’s overarching view of life in his later years was remarkably amenable to Catholic Christianity. Linking Lawrence with Christian and even Catholic thought is not unique, as two books from the 1950s make claims very similar to mine. But these critical works are almost six decades past, and this article primarily contributes to this earlier criticism by aligning Lawrence with the theology of sexuality developed by Pope John Paul II. Though the Pope and Lawrence do differ on some points, they do not differ substantially in their philosophical stances regarding the mind/body relationship or the absolute necessity of full reciprocity in sexual intercourse. This essay does not claim that Lawrence was a Catholic, or even a Christian, or that if he had lived longer he would have converted to Catholicism. In his own mind, he had made a clean break with Christianity. But as some of his late essays extol the virtues of the Catholic Church’s development of the sacrament of marriage, Lawrence may not have been surprised to see how thoroughly his thoughts on sex and marriage align with those of the late Pope.