bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flexibility in Surface-Exposed Loops in a Virus Capsid Mediates Escape from Antibody Neutralization
Authors: Kolawole Abimbola O. , Li Ming , Xia Chunsheng , Fischer Audrey E. , Giacobbi Nicholas S. , Rippinger Christine M. , Proescher Jody B. G. , Wu Susan K. , Bessling Seneca L. , Gamez Monica , Yu Chenchen , Zhang Rebecca , Mehoke Thomas S. , Pipas James M. , Wolfe Joshua T. , Lin Jeffrey S. , Feldman Andrew B. , Smith Thomas J. , Wobus Christiane E. 
Published: February 2014

ABSTRACT
New human norovirus strains emerge every 2 to 3 years, partly due to mutations in the viral capsid that allow escape from antibody neutralization and herd immunity. To understand how noroviruses evolve antibody resistance, we investigated the structural basis for the escape of murine norovirus (MNV) from antibody neutralization. To identify specific residues in the MNV-1 protruding (P) domain of the capsid that play a role in escape from the neutralizing monoclonal antibody (MAb) A6.2, 22 recombinant MNVs were generated with amino acid substitutions in the A′B′ and E′F′ loops. Six mutations in the E′F′ loop (V378F, A382K, A382P, A382R, D385G, and L386F) mediated escape from MAb A6.2 neutralization. To elucidate underlying structural mechanisms for these results, the atomic structure of the A6.2 Fab was determined and fitted into the previously generated pseudoatomic model of the A6.2 Fab/MNV-1 virion complex. Previously, two distinct conformations, A and B, of the atomic structures of the MNV-1 P domain were identified due to flexibility in the two P domain loops. A superior stereochemical fit of the A6.2 Fab to the A conformation of the MNV P domain was observed. Structural analysis of our observed escape mutants indicates changes toward the less-preferred B conformation of the P domain. The shift in the structural equilibrium of the P domain toward the conformation with poor structural complementarity to the antibody strongly supports a unique mechanism for antibody escape that occurs via antigen flexibility instead of direct antibody-antigen binding.

IMPORTANCE
Human noroviruses cause the majority of all nonbacterial gastroenteritis worldwide. New epidemic strains arise in part by mutations in the viral capsid leading to escape from antibody neutralization. Herein, we identify a series of point mutations in a norovirus capsid that mediate escape from antibody neutralization and determine the structure of a neutralizing antibody. Fitting of the antibody structure into the virion/antibody complex identifies two conformations of the antibody binding domain of the viral capsid: one with a superior fit and the other with an inferior fit to the antibody. These data suggest a unique mode of antibody neutralization. In contrast to other viruses that largely escape antibody neutralization through direct disruption of the antibody-virus interface, we identify mutations that acted indirectly by limiting the conformation of the antibody binding loop in the viral capsid and drive the antibody binding domain into the conformation unable to be bound by the antibody.
Recognition of the Murine Coronavirus Genomic RNA Packaging Signal Depends on the Second RNA-Binding Domain of the Nucleocapsid Protein
Authors: Kuo Lili , Koetzner Cheri A. , Hurst Kelley R. , Masters Paul S. 
Published: February 2014

ABSTRACT
The coronavirus nucleocapsid (N) protein forms a helical ribonucleoprotein with the viral positive-strand RNA genome and binds to the principal constituent of the virion envelope, the membrane (M) protein, to facilitate assembly and budding. Besides these structural roles, N protein associates with a component of the replicase-transcriptase complex, nonstructural protein 3, at a critical early stage of infection. N protein has also been proposed to participate in the replication and selective packaging of genomic RNA and the transcription and translation of subgenomic mRNA. Coronavirus N proteins contain two structurally distinct RNA-binding domains, an unusual characteristic among RNA viruses. To probe the functions of these domains in the N protein of the model coronavirus mouse hepatitis virus (MHV), we constructed mutants in which each RNA-binding domain was replaced by its counterpart from the N protein of severe acute respiratory syndrome coronavirus (SARS-CoV). Mapping of revertants of the resulting chimeric viruses provided evidence for extensive intramolecular interactions between the two RNA-binding domains. Through analysis of viral RNA that was packaged into virions we identified the second of the two RNA-binding domains as a principal determinant of MHV packaging signal recognition. As expected, the interaction of N protein with M protein was not affected in either of the chimeric viruses. Moreover, the SARS-CoV N substitutions did not alter the fidelity of leader-body junction formation during subgenomic mRNA synthesis. These results more clearly delineate the functions of N protein and establish a basis for further exploration of the mechanism of genomic RNA packaging.

IMPORTANCE
This work describes the interactions of the two RNA-binding domains of the nucleocapsid protein of a model coronavirus, mouse hepatitis virus. The main finding is that the second of the two domains plays an essential role in recognizing the RNA structure that allows the selective packaging of genomic RNA into assembled virions.
Family planning and pregnancy issues for women with systemic inflammatory diseases: patient and physician perspectives
Authors: Chakravarty Eliza , Clowse Megan E B , Pushparajah Daphnee S , Mertens Sarah , Gordon Caroline 
Published: February 2014

ObjectivesTo identify family planning and pregnancy (FPP) issues for female patients of childbearing age living with a chronic inflammatory disease and to assess whether current clinical practice routinely provides adequate support to alleviate these concerns.SettingMultinational survey and an analysis of online patient activity.ParticipantsPremenopausal women (aged 20–45 years; N=969) were surveyed in the USA, the UK, Germany, France, Italy and Spain. Rheumatologists were surveyed in Germany (N=50), France (N=50), Italy (N=50) and the USA (N=100), and gastroenterologists were also surveyed in the USA (N=100).Primary and secondary outcome measuresTwo online surveys were undertaken to identify FPP issues for physicians and patients. The surveys examined the frequency of dialogue on these topics between physicians and patients, alongside assessment of patient satisfaction regarding these conversations. Online analysis identified key themes for patient discussion outside their doctors’ office/clinic/surgery.Results32–56% of physicians spontaneously reported having talked about FPP with their female patients of childbearing age. When prompted, the majority of rheumatologists (74–92%) and gastroenterologists (74%) reported having discussed conception/pregnancy with female patients; however, less than half reported consulting their patient's treating general practitioner/gynaecologist about these topics. The majority of patients reported their FPP-related concerns are not adequately addressed/settled during their medical appointments. Furthermore, only 30–40% of patients considered advice/information to be consistent across multiple healthcare professionals. Key online FPP-related patient discussions included disease state, adverse effects, treatment, switch behaviour and wash-out requirements.ConclusionsFemale patients who live with chronic inflammatory disease have important FPP concerns. The majority of patients, however, do not feel that their FPP concerns are adequately addressed in current clinical practice and report that they receive inconsistent advice from the various healthcare professionals who manage different aspects of their care. There is a clear need for provision of up-to-date and consistent information/support to female patients.
Midwives’ experiences and views of giving postpartum contraceptive advice and providing long-acting reversible contraception: a qualitative study
Authors: McCance Kirsty , Cameron Sharon 
Published: February 2014

BackgroundNational sexual health frameworks in the UK advise that women in maternity units who are at risk of unintended pregnancy should receive contraceptive advice and supplies of the most effective long-acting reversible methods of contraception (LARC). In the UK, midwives currently deliver contraceptive advice to women following childbirth. There is a lack of information on how midwives currently view their role as provider of contraceptive advice and how they would feel about expanding this to include provision of LARC.ObjectiveTo explore midwives’ experiences and views of giving postpartum contraceptive advice and of possible expansion of role to include provision of LARC.MethodsSemi-structured, audio-recorded interviews were carried out with 12 midwives involved in the postpartum care of women in Edinburgh, Scotland, UK. Interviews were transcribed verbatim and analysed using thematic analysis.ResultsMidwives confirmed that they all routinely give contraceptive advice but that this was mostly cursory. They viewed this part of their job as of lesser importance and one that they felt inadequately trained for. Many barriers to discussing contraception were identified including lack of time and privacy, or mothers being preoccupied with concerns about their baby. Midwives expressed concern about taking on a greater role in giving contraceptive advice or providing LARC, given their current heavy workload.ConclusionsMidwives require ongoing training and support to be effective in their current role as provider of contraceptive advice. Better links between midwifery and specialist sexual and reproductive health services should therefore be encouraged, particularly if a midwife's role is expanded to include provision of contraception such as LARC.
Note on the Invariance Properties of Operator Products Involving Generalized Inverses
Authors: Liu Xiaoji , Zhang Miao , Yu Yaoming 
Published: February 2014

We investigate further the invariance properties of the bounded linear operator productAC1 B1 Dand its range with respect to the choice of the generalized inversesXandYof bounded linear operators. Also, we discuss the range inclusion invariance properties of the operator product involving generalized inverses.
Getting More Out of Survival Data by Using the Hazard Function
Authors: Hess Kenneth R. , Levin Victor A. 
Published: February 2014

Abstract
Information about the survival experience for a group of patients is almost exclusively conveyed using plots of the survival function. However, the hazard function provides information about the survival experience that is not readily evident from inspection of the survival function. The hazard function tracks the instantaneous failure rate over time among the surviving patients and can be readily estimated with available software. We illustrate how these estimates can be used in conjunction with estimates of the survival function to glean clinically relevant information from survival data. Clin Cancer Res; 20(6); 1404–9. ©2014 AACR.
Contribution of Tumor Heterogeneity in a New Animal Model of CNS Tumors
Authors: Chen Fuyi , Becker Albert J. , LoTurco Joseph J. 
Published: February 2014

AbstractThe etiology of central nervous system (CNS) tumor heterogeneity is unclear. To clarify this issue, a novel animal model was developed of glioma and atypical teratoid/rhabdoid-like tumor (ATRT) produced in rats by nonviral cellular transgenesis initiated in utero. This model system affords the opportunity for directed oncogene expression, clonal labeling, and addition of tumor-modifying transgenes. By directing HRasV12 and AKT transgene expression in different cell populations with promoters that are active ubiquitously (CAG promoter), astrocyte-selective (glial fibrillary acidic protein promoter), or oligodendrocyte-selective (myelin basic protein promoter) we generated glioblastoma multiforme and anaplastic oligoastrocytoma, respectively. Importantly, the glioblastoma multiforme and anaplastic oligoastrocytoma tumors were distinguishable at both the cellular and molecular level. Furthermore, proneural basic helix-loop-helix (bHLH) transcription factors, Ngn2 (NEUROG2) or NeuroD1, were expressed along with HRasV12 and AKT in neocortical radial glia, leading to the formation of highly lethal ATRT like tumors. This study establishes a unique model in which determinants of CNS tumor diversity can be parsed out and reveals that both mutation and expression of neurogenic bHLH transcription factors contribute to CNS tumor diversity.Implications: A novel CNS tumor model reveals that oncogenic events occurring in disparate cell types and/or molecular contexts lead to different tumor types; these findings shed light on the sources of brain tumor heterogeneity. Mol Cancer Res; 12(5); 742–53. ©2014 AACR.
Curcumin Implants, Not Curcumin Diet, Inhibit Estrogen-Induced Mammary Carcinogenesis in ACI Rats
Authors: Bansal Shyam S. , Kausar Hina , Vadhanam Manicka V. , Ravoori Srivani , Pan Jianmin , Rai Shesh N. , Gupta Ramesh C. 
Published: February 2014

Abstract
Curcumin is widely known for its antioxidant, anti-inflammatory, and antiproliferative activities in cell-culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvent oral bioavailability issues, and tested their potential against 17β-estradiol (E2)–mediated mammary tumorigenesis. Female Augustus Copenhagen Irish (ACI) rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2 cm; 200 mg each; 20% drug load) 4 days before grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Curcumin implants were changed after 4.5 months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months, and after the tumor incidence reached &gt;80% (∼6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2 ± 1 vs. 5 ± 3; P = 0.001) and tumor volume (184 ± 198 mm3 vs. 280 ± 141 mm3; P = 0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity, whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in the presence of E2. Because CYP1A and CYP3A4 metabolize most of the E2 to its noncarcinogenic 2-OH metabolite, and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by high-performance liquid chromatography showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered. Cancer Prev Res; 7(4); 456–65. ©2014 AACR.
Safety and Chemopreventive Effect of Polyphenon E in Preventing Early and Metastatic Progression of Prostate Cancer in TRAMP Mice
Authors: Kim Seung Joon , Amankwah Ernest , Connors Shahnjayla , Park Hyun Y. , Rincon Maria , Cornnell Heather , Chornokur Ganna , Hashim Arig Ibrahim , Choi Junsung , Tsai Ya-Yu , Engelman Robert W. , Kumar Nagi , Park Jong Y. 
Published: February 2014

Abstract
Prostate cancer treatment is often accompanied by untoward side effects. Therefore, chemoprevention to reduce the risk and inhibit the progression of prostate cancer may be an effective approach to reducing disease burden. We investigated the safety and efficacy of Polyphenon E, a green tea extract, in reducing the progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. A total of 119 male TRAMP and 119 C57BL/6J mice were treated orally with one of 3 doses of Polyphenon E (200, 500, and 1,000 mg/kg/day) in drinking water ad libitum replicating human achievable doses. Baseline assessments were performed before treatments. Safety and efficacy assessments during treatments were performed when mice were 12, 22, and 32 weeks old. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. In untreated 32 weeks old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period. Furthermore, Polyphenon E treatment significantly inhibited metastasis in TRAMP mice in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with Polyphenon E was safe and well tolerated with no evidence of toxicity in C57BL/6J mice. Polyphenon E is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in TRAMP mice. Polyphenon E showed no toxicity in these mouse models. Our findings provide additional evidence for the safety and chemopreventive effect of Polyphenon E in preventing metastatic progression of prostate cancer. Cancer Prev Res; 7(4); 435–44. ©2014 AACR.
Long-term Complete Remission Following Radiosurgery and Immunotherapy in a Melanoma Patient with Brain Metastasis: Immunologic Correlates
Authors: Karbach Julia , Gnjatic Sacha , Biskamp Melina , Atmaca Akin , Weidmann Eckhart , Brandt Kathrin , Wahle Claudia , Bernhard Helga , Knuth Alexander , Jäger Elke 
Published: February 2014

AbstractA melanoma patient with brain metastases was treated by gamma-knife radiosurgery and immunotherapy with autologous tumor-lysate–loaded dendritic cells (DC). Ten years after the combined treatment, the patient remains in complete remission. Remarkable immunologic correlates to the clinical development were the transient induction of NY-ESO-1 antibody and the durable expansion of MAGE-A1p161–169 EADPTGHSY–specific CD8+ T cells. Although the induction of NY-ESO-1 antibody most likely resulted from gamma-knife–mediated “auto-vaccination,” the persistence of circulating MAGE-A1–specific T cells, which are still detectable ex vivo in the absence of any tumor manifestation, coincides with DC-based vaccination administered monthly until today. Cancer Immunol Res; 2(5); 404–9. ©2014 AACR.
Proteome of human plasma very low-density lipoprotein and low-density lipoprotein exhibits a link with coagulation and lipid metabolism
Authors: Dashty Monireh , Motazacker Mohammad M. , Levels Johannes , Vries Marcel de , Mahmoudi Morteza , Peppelenbosch Maikel P. , Rezaee Farhad 
Published: February 2014

SummaryApart from transporting lipids through the body, the human plasma lipoproteins very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) are also thought to serve as a modality for intra-organismal protein transfer, shipping proteins with important roles in inflammation and thrombosis from the site of synthesis to effector locations. To better understand the role of VLDL and LDL in the transport of proteins, we applied a combination of LTQ ORBITRAP-XL (nLC-MS/MS) with both in-SDS-PAGE gel and in-solution tryptic digestion of pure and defined VLDL and LDL fractions. We identified the presence of 95 VLDL-and 51 LDL-associated proteins including all known apolipoproteins and lipid transport proteins, and intriguingly a set of coagulation proteins, complement system and anti-microbial proteins. Prothrombin, protein S, fibrinogen γ, PLTP, CETP, CD14 and LBP were present on VLDL but not on LDL. Prenylcysteine oxidase 1, dermcidin, cathelicidin antimicrobial peptide, TFPI-1 and fibrinogen α chain were associated with both VLDL and LDL. Apo A-V is only present on VLDL and not on LDL. Collectively, this study provides a wealth of knowledge on the protein constituents of the human plasma lipoprotein system and strongly supports the notion that protein shuttling through this system is involved in the regulation of biological processes. Human diseases related to proteins carried by VLDL and LDL can be divided in three major categories: 1 – dyslipidaemia, 2 – atherosclerosis and vascular disease, and 3 – coagulation disorders.
Treatment with Angiotensin-(1–7) reduces inflammation in carotid atherosclerotic plaques
Authors: Savergnini Silvia Q. , Montecucco Fabrizio , Nencioni Alessio , Caffa Irene , Soncini Debora , Costa-Fraga Fabiana P. , De Sousa Frederico B. , Sinisterra Ruben D. , Capettini Luciano A. S. , Lenglet Sébastien , Galan Katia , Pelli Graziano , Bertolotto Maria , Pende Aldo , Spinella Giovanni , Pane Bianca , Dallegri Franco , Palombo Domenico , Mach François , Stergiopulos Nikolaos , Santos Robson A. S. , da Silva Rafaela F. , Fraga-Silva Rodrigo A. 
Published: February 2014

SummaryAngiotensin (Ang)-(1–7), acting through the receptor Mas, has atheroprotective effects; however, its role on plaque vulnerability has been poorly studied. Here, we investigated the expression of the renin-angiotensin system (RAS) components in stable and unstable human carotid plaques. In addition, we evaluated the effects of the chronic treatment with an oral formulation of Ang-(1–7) in a mouse model of shear stress-determined carotid atherosclerotic plaque. Upstream and downstream regions of internal carotid plaques were obtained from a recently published cohort of patients asymptomatic or symptomatic for ischaemic stroke. Angiotensinogen and renin genes were strongly expressed in the entire cohort, indicating an intense intraplaque modulation of the RAS. Intraplaque expression of the Mas receptor mRNA was increased in the downstream portion of asymptomatic patients as compared to corresponding region in symptomatic patients. Conversely, AT1 receptor gene expression was not modified between asymptomatic and symptomatic patients. Treatment with Ang-(1–7) in ApoE-/- mice was associated with increased intraplaque collagen content in the aortic root and low shear stress-induced carotid plaques, and a decreased MMP-9 content and neutrophil and macrophage infiltration. These beneficial effects were not observed in the oscillatory shear stress-induced plaque. In vitro incubation with Ang-(1–7) did not affect ICAM-1 expression and apoptosis on cultured endothelial cells. In conclusion, Mas receptor is up regulated in the downstream portions of human stable carotid plaques as compared to unstable lesions. Treatment with the oral formulation of Ang-(1–7) enhances a more stable phenotype in atherosclerotic plaques, depending on the local pattern of shear stress forces.