bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing Host-Virus Codivergence for Close Relatives of Merkel Cell Polyomavirus Infecting African Great Apes
Authors: Madinda Nadège F. , Ehlers Bernhard , Wertheim Joel O. , Akoua-Koffi Chantal , Bergl Richard A. , Boesch Christophe , Akonkwa Dieudonné Boji Mungu , Eckardt Winnie , Fruth Barbara , Gillespie Thomas R. , Gray Maryke , Hohmann Gottfried , Karhemere Stomy , Kujirakwinja Deo , Langergraber Kevin , Muyembe Jean-Jacques , Nishuli Radar , Pauly Maude , Petrzelkova Klara J. , Robbins Martha M. , Todd Angelique , Schubert Grit , Stoinski Tara S. , Wittig Roman M. , Zuberbühler Klaus , Peeters Martine , Leendertz Fabian H. , Calvignac-Spencer Sébastien 
Published: July 2016

ABSTRACT

It has long been hypothesized that polyomaviruses (PyV; family
Polyomaviridae
) codiverged with their animal hosts. In contrast, recent analyses suggested that codivergence may only marginally influence the evolution of PyV. We reassess this question by focusing on a single lineage of PyV infecting hominine hosts, the Merkel cell polyomavirus (MCPyV) lineage. By characterizing the genetic diversity of these viruses in seven African great ape taxa, we show that they exhibit very strong host specificity. Reconciliation analyses identify more codivergence than noncodivergence events. In addition, we find that a number of host and PyV divergence events are synchronous. Collectively, our results support codivergence as the dominant process at play during the evolution of the MCPyV lineage. More generally, our results add to the growing body of evidence suggesting an ancient and stable association of PyV and their animal hosts.

IMPORTANCE
The processes involved in viral evolution and the interaction of viruses with their hosts are of great scientific interest and public health relevance. It has long been thought that the genetic diversity of double-stranded DNA viruses was generated over long periods of time, similar to typical host evolutionary timescales. This was also hypothesized for polyomaviruses (family
Polyomaviridae
), a group comprising several human pathogens, but this remains a point of controversy. Here, we investigate this question by focusing on a single lineage of polyomaviruses that infect both humans and their closest relatives, the African great apes. We show that these viruses exhibit considerable host specificity and that their evolution largely mirrors that of their hosts, suggesting that codivergence with their hosts played a major role in their diversification. Our results provide statistical evidence in favor of an association of polyomaviruses and their hosts over millions of years.
Response of Three Different Viruses to Interferon Priming and Dithiothreitol Treatment of Avian Cells
Authors: Lostalé-Seijo Irene , Martínez-Costas José , Benavente Javier 
Published: July 2016

ABSTRACT
We have previously shown that the replication of avian reovirus (ARV) in chicken cells is much more resistant to interferon (IFN) than the replication of vesicular stomatitis virus (VSV) or vaccinia virus (VV). In this study, we have investigated the role that the double-stranded RNA (dsRNA)-activated protein kinase (PKR) plays in the sensitivity of these three viruses toward the antiviral action of chicken interferon. Our data suggest that while interferon priming of avian cells blocks vaccinia virus replication by promoting PKR activation, the replication of vesicular stomatitis virus appears to be blocked at a pretranslational step. Our data further suggest that the replication of avian reovirus in chicken cells is quite resistant to interferon priming because this virus uses strategies to downregulate PKR activation and also because translation of avian reovirus mRNAs is more resistant to phosphorylation of the alpha subunit of initiation factor eIF2 than translation of their cellular counterparts. Our results further reveal that the avian reovirus protein sigmaA is able to prevent PKR activation and that this function is dependent on its double-stranded RNA-binding activity. Finally, this study demonstrates that vaccinia virus and avian reovirus, but not vesicular stomatitis virus, express/induce factors that counteract the ability of dithiothreitol to promote eIF2 phosphorylation. Our data demonstrate that each of the three different viruses used in this study elicits distinct responses to interferon and to dithiothreitol-induced eIF2 phosphorylation when infecting avian cells.

IMPORTANCE
Type I interferons constitute the first barrier of defense against viral infections, and one of the best characterized antiviral strategies is mediated by the double-stranded RNA-activated protein kinase R (PKR). The results of this study revealed that IFN priming of avian cells has little effect on avian reovirus (ARV) replication but drastically diminishes the replication of vaccinia virus (VV) and vesicular stomatitis virus (VSV) by PKR-dependent and -independent mechanisms, respectively. Our data also demonstrate that the dsRNA-binding ability of ARV protein sigmaA plays a key role in the resistance of ARV toward IFN by preventing PKR activation. Our findings will contribute to improve the current understanding of the interaction of viruses with the host's innate immune system. Finally, it would be of interest to uncover the mechanisms that allow avian reovirus transcripts to be efficiently translated under conditions (moderate eIF2 phosphorylation) that block the synthesis of cellular proteins.
The Interaction between Herpes Simplex Virus 1 Tegument Proteins UL51 and UL14 and Its Role in Virion Morphogenesis
Authors: Oda Shinya , Arii Jun , Koyanagi Naoto , Kato Akihisa , Kawaguchi Yasushi 
Published: July 2016

ABSTRACT
To investigate the molecular mechanism(s) by which herpes simplex virus 1 (HSV-1) tegument protein UL51 promotes viral replication, we screened for viral proteins that interact with UL51 in infected cells. Affinity purification of tagged UL51 in HSV-1-infected Vero cells was coupled with immunoblotting of the purified UL51 complexes with various antibodies to HSV-1 virion proteins. Subsequent analyses revealed that UL51 interacted with another tegument protein, UL14, in infected cells. Mutational analyses of UL51 showed that UL51 amino acid residues Leu-111, Ile-119, and Tyr-123 were required for interaction with UL14 in HSV-1-infected cells. Alanine substitutions of these UL51 amino acid residues reduced viral replication and produced an accumulation of unenveloped and partially enveloped nucleocapsids in the cytoplasm at levels comparable to those of UL51-null, UL14-null, and UL51/UL14 double-null mutations. In addition, although UL51 and UL14 colocalized at juxtanuclear domains in HSV-1-infected cells, the amino acid substitutions in UL51 produced aberrant localization of UL51 and UL14. The effects of these substitutions on localization of UL51 and UL14 were similar to those of the UL51-null and UL14-null mutations on localization of UL14 and UL51, respectively. These results suggested that the interaction between UL51 and UL14 was required for proper localization of these viral proteins in infected cells and that the UL51-UL14 complex regulated final viral envelopment for efficient viral replication.

IMPORTANCE
Herpesviruses contain a unique virion structure designated the tegument, which is a protein layer between the nucleocapsid and the envelope. HSV-1 has dozens of viral proteins in the tegument, which are thought to facilitate viral envelopment by interacting with other virion components. However, although numerous interactions among virion proteins have been reported, data on how these interactions facilitate viral envelopment is limited. In this study, we have presented data showing that the interaction of HSV-1 tegument proteins UL51 and UL14 promoted viral final envelopment for efficient viral replication. In particular, prevention of this interaction induced aberrant accumulation of partially enveloped capsids in the cytoplasm, suggesting that the UL51-UL14 complex acted in the envelopment process but not in an upstream event, such as transport of capsids to the site for envelopment. This is the first report showing that an interaction between HSV-1 tegument proteins directly regulated final virion envelopment.
A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice
Authors: Caine Elizabeth A. , Moncla Louise H. , Ronderos Monica D. , Friedrich Thomas C. , Osorio Jorge E. 
Published: July 2016

ABSTRACT

Hand, foot, and mouth disease (HFMD) has spread throughout the Asia-Pacific region, affecting millions of young children, who develop symptoms ranging from painful blisters around their mouths and hands to neurological complications. Many members of the genus
Enterovirus
(family
Picornaviridae
) cause HFMD. Enterovirus 71 (EV71) is one of the primary causative agents and has been linked to severe disease. Vaccine efficacy and pathogenesis studies for EV71 have been limited because there is a lack of suitable animal models. Previously, we generated a mouse-adapted EV71 (mEV71) capable of infecting 12-week-old interferon receptor-deficient AG129 mice and used the model to evaluate the efficacy of candidate HFMD vaccines. Here, we present data investigating the genetic correlates of EV71 adaptation and characterize the virus's tissue tropism in mice. Using reverse genetics, a VP1 mutation (K244E) was shown to be necessary for mEV71 virulence in adult mice. Another VP1 mutation (H37R) was required for mEV71 recovery on rhabdomyosarcoma (RD) cells. Viral loads determined by real-time reverse transcription (RT)-PCR confirmed the presence of mEV71 in the sera and multiple organs of mice. Histological analysis revealed signs of meningitis and encephalitis, characteristic of severe human disease. The further description of this model has provided insight into EV71 pathogenesis and demonstrates the importance of the VP1 region in facilitating mEV71 adaptation.

IMPORTANCE
EV71 is a reemerging pathogen, and little is known about the genetic determinants involved in its pathogenesis. The absence of animal models has contributed to this lack of knowledge. The data presented here improve upon the existing animal models by characterizing a mouse-adapted strain of EV71. We determined that a VP1 mutation (K244E) was needed for EV71 virulence in adult AG129 mice. While this mutation was found previously for EV71 adaptation in 5-day-old BALB/c mice, neurotropic disease did not develop. Using interferon-deficient mice, we raised the age of susceptibility beyond 6 weeks and provided clear evidence that our model mimics severe human infections. The model can be exploited to identify determinants of EV71 virulence and to reveal molecular mechanisms that control the virus-host interaction, especially those associated with neurotropic disease. Furthermore, these data provide useful information regarding the importance of VP1, specifically position 244, in host adaptation and tissue dissemination.
Physical activity in hypertrophic cardiomyopathy: prevalence of inactivity and perceived barriers
Authors: Sweeting Joanna , Ingles Jodie , Timperio Anna , Patterson Jillian , Ball Kylie , Semsarian Christopher 
Published: July 2016

ObjectivesThis study aimed to determine the prevalence of physical inactivity and perceived barriers to physical activity among individuals with hypertrophic cardiomyopathy (HCM), and to determine potential demographic, clinical and health-related factors influencing likelihood of meeting physical activity guidelines.MethodsThis was a cross-sectional study of consecutive patients (n=198) with HCM attending a specialist HCM centre from July 2014 to November 2015. The primary outcome measure was physical activity (minutes per day), as measured by self-report (International Physical Activity Questionnaire (IPAQ)) and objective means (ActiGraph accelerometer). For both, participants were classified as meeting guidelines if they did at least 150 min per week of physical activity. Quality of life (Short Form-36 V.2, SF-36v2), barriers to exercise and clinical–demographic data were also collected.ResultsIn total, 54.8% of participants did not meet physical activity recommendations based on IPAQ, and 12.7% did not meet guidelines based on accelerometer data. The most commonly identified barriers to exercise were ‘pain interferes with my exercise’ (33%) and ‘I have an injury/disability that stops me’ (29%). Independent factors associated with meeting guidelines included older age (OR 0.66, 95% CI 0.51 to 0.85, p=0.002), higher education level (OR 2.31, 95% CI 1.08 to 4.93, p=0.03), better physical quality of life (OR 1.05, 95% CI 1.0 to 1.09, p=0.05) and more reported barriers (OR 0.71, 95% CI 0.56 to 0.91, p=0.01).ConclusionsMore than half of the patients with HCM did not meet minimum physical activity recommendations. Several barriers to exercise among individuals with HCM exist, and provide the basis for targeted interventions to promote physical activity and improve overall health in patients with HCM.
Immunoglobulins in dogs: correspondence and maturation in 15 litters of German shepherd dogs and their dams
Authors: Vilson Åsa , Hedhammar Åke , Reynolds Arleigh , Spears Julie , Satyaraj Ebenezer , Pelker Robyn , Rottman Cari , Björkstén Bengt , Hansson‐Hamlin Helene 
Published: July 2016

Some dog breeds, including the German shepherd dog (GSD), are predisposed to immune‐related disorders. The authors prospectively described development of serum and faecal IgA and serum IgE in GSD from puppies until adulthood and the relationship between mothers and their offspring. Further, the authors tested whether dogs with lower serum IgA also have low faecal IgA and/or serum IgE. To reveal whether any of the parameters could be proven to influence the immune response, the authors also measured serum IgG against canine distemper virus (CDV). To test their hypothesis, the authors used linear mixed models to investigate the relationship of serum IgA, serum IgE and faecal IgA levels in litters and their mothers. Fifteen GSD bitches beginning at 42 days of pregnancy and subsequently all of their offspring (n=83 puppies), reared under well‐controlled conditions, were included. All dogs came from the kennel of the Swedish Armed Forces.Serum IgE, serum IgA and faecal IgA levels were lower in seven‐week‐old puppies than at one year of age. There was no relationship in Ig concentrations between bitches and their puppies at seven weeks of age. Dogs with higher faecal IgA had higher IgG titres against CDV, indicating a favourable systemic immune status.
Effects of vacuum annealing treatment on microstructures and residual stress of AlSi10Mg parts produced by selective laser melting process
Authors: Chen Tian , Wang Linzhi , Tan Sheng 
Published: July 2016

Selective laser melting (SLM)-fabricated AlSi10Mg parts were heat-treated under vacuum to eliminate the residual stress. Microstructure evolutions and tensile properties of the SLM-fabricated parts before and after vacuum annealing treatment were studied. The results show that the crystalline structure of SLM-fabricated AlSi10Mg part was not modified after the vacuum annealing treatment. Additionally, the grain refinement had occurred after the vacuum annealing treatment. Moreover, with increasing of the vacuum annealing time, the second phase increased and transformed to spheroidization and coarsening. The SLM-produced parts after vacuum annealing at 300[Formula: see text]C for 2 h had the maximum ultimate tensile strength (UTS), yield strength (YS) and elongation, while the elastic modulus decreased significantly. In addition, the tensile residual stress was found in the as-fabricated AlSi10Mg samples by the microindentation method.
The Cancer Epidemiology Descriptive Cohort Database: A Tool to Support Population-Based Interdisciplinary Research
Authors: Kennedy Amy E. , Khoury Muin J. , Ioannidis John P.A. , Brotzman Michelle , Miller Amy , Lane Crystal , Lai Gabriel Y. , Rogers Scott D. , Harvey Chinonye , Elena Joanne W. , Seminara Daniela 
Published: July 2016

Abstract
Background: We report on the establishment of a web-based Cancer Epidemiology Descriptive Cohort Database (CEDCD). The CEDCD's goals are to enhance awareness of resources, facilitate interdisciplinary research collaborations, and support existing cohorts for the study of cancer-related outcomes.
Methods: Comprehensive descriptive data were collected from large cohorts established to study cancer as primary outcome using a newly developed questionnaire. These included an inventory of baseline and follow-up data, biospecimens, genomics, policies, and protocols. Additional descriptive data extracted from publicly available sources were also collected. This information was entered in a searchable and publicly accessible database. We summarized the descriptive data across cohorts and reported the characteristics of this resource.
Results: As of December 2015, the CEDCD includes data from 46 cohorts representing more than 6.5 million individuals (29% ethnic/racial minorities). Overall, 78% of the cohorts have collected blood at least once, 57% at multiple time points, and 46% collected tissue samples. Genotyping has been performed by 67% of the cohorts, while 46% have performed whole-genome or exome sequencing in subsets of enrolled individuals. Information on medical conditions other than cancer has been collected in more than 50% of the cohorts. More than 600,000 incident cancer cases and more than 40,000 prevalent cases are reported, with 24 cancer sites represented.
Conclusions: The CEDCD assembles detailed descriptive information on a large number of cancer cohorts in a searchable database.
Impact: Information from the CEDCD may assist the interdisciplinary research community by facilitating identification of well-established population resources and large-scale collaborative and integrative research. Cancer Epidemiol Biomarkers Prev; 25(10); 1392–401. ©2016 AACR.
The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care
Authors: Paíno Teresa , Garcia-Gomez Antonio , González-Méndez Lorena , San-Segundo Laura , Hernández-García Susana , López-Iglesias Ana-Alicia , Algarín Esperanza M. , Martín-Sánchez Montserrat , Corbacho David , Ortiz-de-Solorzano Carlos , Corchete Luis A. , Gutiérrez Norma C. , Maetos María-Victoria , Garayoa Mercedes , Ocio Enrique M. 
Published: July 2016

Abstract
Purpose: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models.
Experimental Design: In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR, and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies.
Results: PIM447 is cytotoxic for myeloma cells due to cell-cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI = 0.002), lenalidomide + dexamethasone (CI = 0.065), and pomalidomide + dexamethasone (CI = 0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma.
Conclusions: Our results demonstrate dual antitumoral and bone-protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma. Clin Cancer Res; 23(1); 225–38. ©2016 AACR.
Genomic Copy Number Profiling Using Circulating Free Tumor DNA Highlights Heterogeneity in Neuroblastoma
Authors: Chicard Mathieu , Boyault Sandrine , Colmet Daage Leo , Richer Wilfrid , Gentien David , Pierron Gaelle , Lapouble Eve , Bellini Angela , Clement Nathalie , Iacono Isabelle , Bréjon Stéphanie , Carrere Marjorie , Reyes Cécile , Hocking Toby , Bernard Virginie , Peuchmaur Michel , Corradini Nadège , Faure-Conter Cécile , Coze Carole , Plantaz Dominique , Defachelles Anne Sophie , Thebaud Estelle , Gambart Marion , Millot Frédéric , Valteau-Couanet Dominique , Michon Jean , Puisieux Alain , Delattre Olivier , Combaret Valérie , Schleiermacher Gudrun 
Published: July 2016

Abstract
Purpose: The tumor genomic copy number profile is of prognostic significance in neuroblastoma patients. We have studied the genomic copy number profile of cell-free DNA (cfDNA) and compared this with primary tumor arrayCGH (aCGH) at diagnosis.
Experimental Design: In 70 patients, cfDNA genomic copy number profiling was performed using the OncoScan platform. The profiles were classified according to the overall pattern, including numerical chromosome alterations (NCA), segmental chromosome alterations (SCA), and MYCN amplification (MNA).
Results: Interpretable and dynamic cfDNA profiles were obtained in 66 of 70 and 52 of 70 cases, respectively. An overall identical genomic profile between tumor aCGH and cfDNA was observed in 47 cases (3 NCAs, 22 SCAs, 22 MNAs). In one case, cfDNA showed an additional SCA not detected by tumor aCGH. In 4 of 8 cases with a silent tumor aCGH profile, cfDNA analysis revealed a dynamic profile (3 SCAs, 1 NCA). In 14 cases, cfDNA analysis did not reveal any copy number changes. A total of 378 breakpoints common to the primary tumor and cfDNA of any given patient were identified, 27 breakpoints were seen by tumor aCGH, and 54 breakpoints were seen in cfDNA only, including two cases with interstitial IGFR1 gains and two alterations targeting TERT.
Conclusions: These results demonstrate the feasibility of cfDNA copy number profiling in neuroblastoma patients, with a concordance of the overall genomic profile in aCGH and cfDNA dynamic cases of 97% and a sensitivity of 77%, respectively. Furthermore, neuroblastoma heterogeneity is highlighted, suggesting that cfDNA might reflect genetic alterations of more aggressive cell clones. Clin Cancer Res; 22(22); 5564–73. ©2016 AACR.
See related commentary by Janku and Kurzrock, p. 5400