bluuebunny/crossref_metadata_2025_split huggingface dataset:
Qualitative and Quantitative Analysis of the Binding of GII.4 Norovirus Variants onto Human Blood Group Antigens
Authors: de Rougemont A. , Ruvoen-Clouet N. , Simon B. , Estienney M. , Elie-Caille C. , Aho S. , Pothier P. , Le Pendu J. , Boireau W. , Belliot G. 
Published: February 2011

ABSTRACT
Noroviruses (NoVs) are one of the leading causes of gastroenteritis in children and adults. For the last 2 decades, genogroup II genotype 4 (GII.4) NoVs have been circulating worldwide. GII.4 NoVs can be divided into variants, and since 2002 they have circulated in the population before being replaced every 2 or 3 years, which raises questions about the role of their histo-blood group antigen (HBGA) ligands in their evolution. To shed light on these questions, we performed an analysis of the interaction between representative GII.4 variants and HBGAs, and we determined the role of selected amino acids in the binding profiles. By mutagenesis, we showed that there was a strict structural requirement for the amino acids, directly implicated in interactions with HBGAs. However, the ablation of the threonine residue at position 395 (ΔT395), an epidemiological feature of the post-2002 variants, was not deleterious to the binding of the virus-like particle (VLP) to the H antigen, while binding to A and B antigens was severely hampered. Nevertheless, the ΔT395 VLPs gained the capacity to bind to the Lewis x and sialyl-Lewis x antigens in comparison with the wild-type VLP, demonstrating that amino acid residues outside the HBGA binding site can modify the binding properties of NoVs. We also analyzed the attachment of baculovirus-expressed VLPs from six variants (Bristol, US95/96, Hunter, Yerseke, Den Haag, and Osaka) that were isolated from 1987 to 2007 to phenotyped saliva samples and synthetic HBGAs. We showed that the six variants could all attach to saliva of secretors irrespective of the ABO phenotype and to oligosaccharides characteristic of the secretor phenotype. Interestingly, Den Haag and Osaka variants additionally bound to carbohydrates present in the saliva of Lewis-positive nonsecretors. The carbohydrate binding profile and the genetic and mutagenesis analysis suggested that GII.4 binding to Lewis x and sialyl-Lewis x antigens might be a by-product of the genetic variation of the amino acids located in the vicinity of the binding site. Analysis of the binding properties for the six variants by surface plasmon resonance showed that only post-2002 variants (i.e., Hunter, Yerseke, Den Haag, and Osaka) presented strong binding to A and B antigens, suggesting that the GII.4 evolution could be related to an increased affinity for HBGAs for the post-2002 variants. The combination of increased affinity for ABH antigens and of a newly acquired ability to recognize glycans from Lewis-positive nonsecretors could have contributed to the epidemiological importance of strains such as the Den Haag GII.4 subtype.
Detection and Genetic Characterization of Enteroviruses Circulating among Wild Populations of Chimpanzees in Cameroon: Relationship with Human and Simian Enteroviruses
Authors: Harvala Heli , Sharp Colin P. , Ngole Eitel Mpoudi , Delaporte Eric , Peeters Martine , Simmonds Peter 
Published: February 2011

ABSTRACT

Enteroviruses (EVs), members of the family
Picornaviridae
, are a genetically and antigenically diverse range of viruses causing acute infections in humans and several Old World monkey (OWM) species. Despite their known wide distribution in primates, nothing is currently known about the occurrence, frequency, and genetic diversity of enteroviruses infecting apes. To investigate this, 27 chimpanzee and 27 gorilla fecal samples collected from undisturbed jungle areas with minimal human contact in Cameroon were screened for EVs. Four chimpanzee samples were positive, but none of the gorilla samples were positive. Genetic characterization of the VP1, VP4, and partial VP2 genes, the 5′ untranslated region, and partial 3Dpol sequences enabled chimpanzee-derived EVs to be identified as (i) the species A type, EV76, (ii) a new species D type assigned as EV111, along with a human isolate from the Democratic Republic of Congo previously described by the International Committee on the Taxonomy of Viruses, and (iii) a new species B type (assigned as EV110) most closely related to, although a distinct type from, the SA5 isolate recovered from a vervet monkey. The identification of EVs infecting chimpanzees related to those circulating in human and OWM populations provides evidence for cross-species transmission of EVs between primates. However, the direction of transfer and the existence of primate sources of zoonotic enterovirus infections in humans require further investigation of population exposure and more extensive characterization of EVs circulating in wild ape populations.
Effects of Receptor Binding Specificity of Avian Influenza Virus on the Human Innate Immune Response
Authors: Ramos Irene , Bernal-Rubio Dabeiba , Durham Natasha , Belicha-Villanueva Alan , Lowen Anice C. , Steel John , Fernandez-Sesma Ana 
Published: February 2011

ABSTRACT
Humans infected by the highly pathogenic H5N1 avian influenza viruses (HPAIV) present unusually high concentrations in serum of proinflammatory cytokines and chemokines, which are believed to contribute to the high pathogenicity of these viruses. The hemagglutinins (HAs) of avian influenza viruses preferentially bind to sialic acids attached through α2,3 linkages (SAα2,3) to the terminal galactose of carbohydrates on the host cell surface, while the HAs from human strains bind to α2,6-linked SA (SAα2,6). To evaluate the role of the viral receptor specificity in promoting innate immune responses in humans, we generated recombinant influenza viruses, one bearing the HA and neuraminidase (NA) genes from the A/Vietnam/1203/2004 H5N1 HPAIV in an influenza A/Puerto Rico/8/1934 (A/PR/8/34) backbone with specificity for SAα2,3 and the other a mutant virus (with Q226L and G228S in the HA) with preferential receptor specificity for SAα2,6. Viruses with preferential affinity for SAα2,3 induced higher levels of proinflammatory cytokines and interferon (IFN)-inducible genes in primary human dendritic cells (DCs) than viruses with SAα2,6 binding specificity, and these differences were independent of viral replication, as shown by infections with UV-inactivated viruses. Moreover, human primary macrophages and respiratory epithelial cells showed higher expression of proinflammatory genes after infection with the virus with SAα2,3 affinity than after infection with the virus with SAα2,6 affinity. These data indicate that binding to SAα2,3 by H5N1 HPAIV may be sensed by human cells differently than binding to SAα2,6, inducing an exacerbated innate proinflammatory response in infected individuals.
Analysis of Poliovirus Protein 3A Interactions with Viral and Cellular Proteins in Infected Cells
Authors: Teterina Natalya L. , Pinto Yuval , Weaver Joseph D. , Jensen Kenneth S. , Ehrenfeld Ellie 
Published: February 2011

ABSTRACT
Poliovirus proteins 3A and 3AB are small, membrane-binding proteins that play multiple roles in viral RNA replication complex formation and function. In the infected cell, these proteins associate with other viral and cellular proteins as part of a supramolecular complex whose structure and composition are unknown. We isolated viable viruses with three different epitope tags (FLAG, hemagglutinin [HA], and c-myc) inserted into the N-terminal region of protein 3A. These viruses exhibited growth properties and characteristics very similar to those of the wild-type, untagged virus. Extracts prepared from the infected cells were subjected to immunoaffinity purification of the tagged proteins by adsorption to commercial antibody-linked beads and examined after elution for cellular and other viral proteins that remained bound to 3A sequences during purification. Viral proteins 2C, 2BC, 3D, and 3CD were detected in all three immunopurified 3A samples. Among the cellular proteins previously reported to interact with 3A either directly or indirectly, neither LIS1 nor phosphoinositol-4 kinase (PI4K) were detected in any of the purified tagged 3A samples. However, the guanine nucleotide exchange factor GBF1, which is a key regulator of membrane trafficking in the cellular protein secretory pathway and which has been shown previously to bind enteroviral protein 3A and to be required for viral RNA replication, was readily recovered along with immunoaffinity-purified 3A-FLAG. Surprisingly, we failed to cocapture GBF1 with 3A-HA or 3A-myc proteins. A model for variable binding of these 3A mutant proteins to GBF1 based on amino acid sequence motifs and the resulting practical and functional consequences thereof are discussed.
Transcriptional Repression of C4 Complement by Hepatitis C Virus Proteins
Authors: Banerjee Arup , Mazumdar Budhaditya , Meyer Keith , Di Bisceglie Adrian M. , Ray Ratna B. , Ray Ranjit 
Published: February 2011

ABSTRACTThe fourth component of human complement (C4) plays an important role in innate immune function. C4 activity has been observed to be significantly lower in patients with chronic hepatitis C virus (HCV) infections, although the mechanism remains unknown. In this study, we have examined the mechanisms of C4 regulation by HCV. Liver biopsy specimens from patients with chronic HCV infections displayed significantly lower C4 mRNA levels than liver tissue samples from patients with unrelated liver disease. Further, C4 mRNA levels of the two isoforms (C4A and C4B) were significantly reduced in hepatocytes transfected with RNA from HCV genotype 1a or 2a. Subsequently, a significant C4 regulatory role of HCV core or NS5A upon C4 promoter activity was observed. HCV core or NS5A transgenic mice displayed a reduction in C4 mRNA. Gamma interferon (IFN-γ)-induced C4 promoter activation was also impaired in the presence of HCV proteins. We further demonstrated that HCV core reduced the expression of upstream stimulating factor 1 (USF-1), a transcription factor important for basal C4 expression. On the other hand, the expression of interferon regulatory factor 1 (IRF-1), which is important for IFN-γ-induced C4 expression, was inhibited by hepatocytes expressing HCV NS5A. These results underscore the roles of HCV proteins in innate immune regulation in establishing a chronic infection.
Mutagenesis of Varicella-Zoster Virus Glycoprotein I (gI) Identifies a Cysteine Residue Critical for gE/gI Heterodimer Formation, gI Structure, and Virulence in Skin Cells
Authors: Oliver Stefan L. , Sommer Marvin H. , Reichelt Mike , Rajamani Jaya , Vlaycheva-Beisheim Leonssia , Stamatis Shaye , Cheng Jason , Jones Carol , Zehnder James , Arvin Ann M. 
Published: February 2011

ABSTRACT

Varicella-zoster virus (VZV) is the alphaherpesvirus that causes chicken pox (varicella) and shingles (zoster). The two VZV glycoproteins gE and gI form a heterodimer that mediates efficient cell-to-cell spread. Deletion of gI yields a small-plaque-phenotype virus, ΔgI virus, which is avirulent in human skin using the xenograft model of VZV pathogenesis. In the present study, 10 mutant viruses were generated to determine which residues were required for the typical function of gI. Three phosphorylation sites in the cytoplasmic domain of gI were not required for VZV virulence
in vivo
. Two deletion mutants mapped a gE binding region in gI to residues 105 to 125. A glycosylation site, N116, in this region did not affect virulence. Substitution of four cysteine residues highly conserved in the
Alphaherpesvirinae
established that C95 is required for gE/gI heterodimer formation. The C95A and Δ105–125 (with residues 105 to 125 deleted) viruses had small-plaque phenotypes with reduced replication kinetics
in vitro
similar to those of the ΔgI virus. The Δ105–125 virus was avirulent for human skin
in vivo
. In contrast, the C95A mutant replicated
in vivo
but with significantly reduced kinetics compared to those of the wild-type virus. In addition to abolished gE/gI heterodimer formation, gI from the C95A or the Δ105–125 mutant was not recognized by monoclonal antibodies that detect the canonical conformation of gI, demonstrating structural disruption of gI in these viruses. This alteration prevented gI incorporation into virus particles. Thus, residues C95 and 105 to 125 are critical for gI structure required for gE/gI heterodimer formation, virion incorporation, and ultimately, effective viral spread in human skin.
Timing of uplift of the Troodos Massif (Cyprus) constrained by sedimentary and magnetic polarity evidence
Authors: Kinnaird Tim C. , Robertson Alastair H.F. , Morris Antony 
Published: February 2011

Abstract:

Plio-Pleistocene sediments exposed around the ophiolitic Troodos Massif document spectacular uplift from below sea level to a maximum height of
c
. 2000 m. Sedimentation reflects a dominant control of focused tectonic uplift, modified by the effects of glacio-eustatic sea-level change and climatic change. Understanding the uplift and controls on deposition has been hindered by an inadequate age model. Here, we present a preliminary investigation of the polarity of remanent magnetizations recorded within the upper part of the Pliocene succession in the Pissouri and Mesaoria basins and from the Pleistocene marine terrace deposits that border the Troodos Massif. When integrated with available lithostatigraphic and biostratigraphic data, the main results are as follows. Focused uplift of the Troodos Massif began during the Late Pliocene, either between 2.14 and 1.95 Ma or immediately prior to 1.77 Ma. Shallow-marine, ophiolite-derived clastic and bioclastic sediments accumulated in both the Mesaoria and Pissouri basins, implying that the Troodos Massif was uplifted as a single tectonic entity. Non-marine, deltaic and fluvial facies prograded into both of the basins during the Pleistocene (1.77 Ma–recent). Marine terraces in SW and south Cyprus were cut and covered by littoral sediments from <0.78 Ma, suggesting that high rates of uplift of the Troodos Massif persisted into mid- and late Pleistocene time.
Radiation and extinction patterns in Permian floras from North China as indicators for environmental and climate change
Authors: Stevens Liadan G. , Hilton Jason , Bond David P.G. , Glasspool Ian J. , Jardine Phillip E. 
Published: February 2011

Abstract:
Permian continental sequences from North China contain previously unrecognized episodes of plant radiation and elevated extinction. The earliest extinction, in the Lower Shihhotse Formation (Roadian, Guadalupian), records a 45% floral species loss and is tentatively correlated with global extinctions amongst dinocephalian reptiles. Two younger extinctions are dated by correlating the Illawara Reversal and palaeomagnetic polarity sequences from Shanxi Province against global palaeomagnetic history. Missing data from the Shanxi sequence are evaluated using a novel approach estimating likely maximum and minimum sequence changes that provide age estimates for post-Illawara events in North China. The second extinction in the middle Upper Shihhotse Formation is more significant and is dated to the mid-Capitanian, with a loss of 56% of plant species coinciding with two phases of volcanism of the Emeishan Large Igneous Province in South China, previously linked to the mid-Capitanian marine mass extinction. The youngest extinction in the upper Upper Shihhotse Formation (late Capitanian to mid-Wuchapingian) is catastrophic and represents the end of range in the sequence. Changes in sedimentary facies suggest it to be related to global climatic warming and drying. Other viable causal mechanisms for the extinction episodes include plate motion and collision, global climate change, volcanism and biological competition.
Enhanced Safety Profiles of the Telomerase-Specific Replication-Competent Adenovirus by Incorporation of Normal Cell-Specific microRNA-Targeted Sequences
Authors: Sugio Kumiko , Sakurai Fuminori , Katayama Kazufumi , Tashiro Katsuhisa , Matsui Hayato , Kawabata Kenji , Kawase Atsushi , Iwaki Masahiro , Hayakawa Takao , Fujiwara Toshiyoshi , Mizuguchi Hiroyuki 
Published: February 2011

AbstractPurpose: Oncolytic adenoviruses (Ad) have been actively pursued as potential agents for cancer treatment. Among the various types of oncolytic Ads, the telomerase-specific replication-competent Ad (TRAD), which possesses an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, has shown promising results in human clinical trials; however, the E1 gene is also slightly expressed in normal cells, leading to replication of TRAD and cellular toxicity in normal cells.Experimental Design: To overcome this problem, we utilized a microRNA (miRNA)-regulated gene expression system. Four copies of complementary sequences for miR-143, -145, -199a, or let-7a, which have been reported to be exclusively downregulated in tumor cells, were incorporated into the 3′-untranslated region of the E1 gene expression cassette.Results: Among the TRAD variants (herein called TRADs) constructed, TRADs containing the sequences complementary to miR-143, -145, or -199a showed efficient oncolytic activity comparable to the parental TRAD in the tumor cells. On the other hand, replication of the TRADs containing the miRNA complementary sequences was at most 1,000-fold suppressed in the normal cells, including primary normal cells. In addition, to suppress the replication of the TRADs in hepatocytes as well as other normal cells, we constructed a TRAD containing 2 distinct complementary sequences for miR-199a and liver-specific miR-122a (TRAD-122a/199aT). TRAD-122a/199aT exhibited more than 10-fold reduction in viral replication in all the normal cells examined, including primary hepatocytes.Conclusions: This study showed that oncolytic Ads containing the sequences complementary to normal cell-specific miRNAs showed significantly improved safety profiles without altering tumor cell lysis activity. Clin Cancer Res; 17(9); 2807–18. ©2011 AACR.
Phase I Pharmacokinetic and Pharmacodynamic Study of SJG-136, a Novel DNA Sequence Selective Minor Groove Cross-linking Agent, in Advanced Solid Tumors
Authors: Puzanov Igor , Lee Wooin , Chen Alice P. , Calcutt M. Wade , Hachey David L. , Vermeulen Wendy L. , Spanswick Victoria J. , Liao Chih-Yi , Hartley John A. , Berlin Jordan D. , Rothenberg Mace L. 
Published: February 2011

Abstract
Purpose: This phase I study assessed the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SJG-136, a sequence-specific DNA cross-linking agent, in patients with advanced cancer.
Experimental Design: In schedule A, seven patients received escalating doses of SJG-136 (6, 12, 24, and 48 μg/m2) daily for 5 of 21 days. Blood samples were collected for PK analysis on days 1 and 5 of cycle 1. In schedule B, SJG-136 was given daily for 3 of 21 days (N = 17; doses 20, 25, 30, and 35 μg/m2). Blood samples were collected on days 1 and 3 of cycles 1 and 2 for PK and PD analysis. Patients in schedule B received dexamethasone and early diuretic care.
Results: Schedule A—dose-limiting toxicities included grade 3 edema, dyspnea, fatigue, and delayed liver toxicity (grade 3–4). PK analysis revealed dose-dependent increases in AUC and Cmax. Substantial changes in volume of distribution at steady-state occurred after repeated dosing in some patients prior to the onset of edema. Schedule B—the same toxicities were manageable with steroid premedication and diuretic support. No significant myelosuppression occurred on either schedule. DNA interstrand cross-links correlated with systemic exposure of SJG-136 following the second dose in cycle 1 and were still detectable immediately before cycle 2.
Conclusions: The MTD of SJG-136 in this study was 30 μg/m2 administered on a daily 3× basis with no myelosuppression effects. Coupled with supportive management, SJG-136 is now advancing to a phase II trial in ovarian cancer. Clin Cancer Res; 17(11); 3794–802. ©2011 AACR.
Yes-Associated Protein 1 Exhibits Oncogenic Property in Gastric Cancer and Its Nuclear Accumulation Associates with Poor Prognosis
Authors: Kang Wei , Tong Joanna H.M. , Chan Anthony W.H. , Lee Tin-Lap , Lung Raymond W.M. , Leung Patrick P.S. , So Ken K.Y. , Wu Kaichun , Fan Daiming , Yu Jun , Sung Joseph J.Y. , To Ka-Fai 
Published: February 2011

Abstract
Purpose: Yes-associated protein 1 (YAP1) is a multifunctional protein that can interact with different transcription factors to activate gene expression. The role of YAP1 in tumorigenesis is unclear. We aimed to investigate the functional role of YAP1 in tumorigenesis of gastric cancer.
Experimental Design: YAP1 expresson in gastric adenocarcinoma was evaluated. The biological function was determined by proliferation assay, colony formation, cell invasion, and flow cytometric analysis through knocking down or ectopic expressing YAP1 in gastric cancer cell lines coupled with in vivo study. The possible downstream effectors of YAP1 were investigated by expression microarray.
Results: YAP1 protein expression was upregulated in gastric cancer. Nuclear accumulation of YAP1 was associated with poor disease-specific survival (P = 0.021), especially in patients with early-stage diseases (P &lt; 0.001). Knockdown YAP1 resulted in a significant reduction in proliferation, anchorage-dependent colony formation, cell invasion, and cell motility. Ectopic YAP1 expression promoted anchorage-independent colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK (mitogen-activated protein kinase) pathway by YAP1. We confirmed a constitutive activation of RAF/MEK/ERK (extracellular signal-regulated kinase) in YAP1-expressing MKN45 cells and further showed that YAP1 enhanced serum/epidermal growth factor–induced c-Fos expression in gastric cancer cells.
Conclusions: Our findings supported that YAP1 exhibits oncogenic property in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early-response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer. Clin Cancer Res; 17(8); 2130–9. ©2011 AACR.
A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency
Authors: Salojin Konstantin V. , Cabrera Robert M. , Sun Weimei , Chang Wei Chun , Lin Colin , Duncan Lindsay , Platt Ken A. , Read Robert , Vogel Peter , Liu Qingyun , Finnell Richard H. , Oravecz Tamas 
Published: February 2011

AbstractThe human proton coupled folate transporter (PCFT) is involved in low pH-dependent intestinal folate transport. In this report, we describe a new murine model of the hereditary folate malabsorption syndrome that we developed through targeted disruption of the first 3 coding exons of the murine homolog of the PCFT gene. By 4 weeks of age, PCFT-deficient (PCFT−/−) mice developed severe macrocytic normochromic anemia and pancytopenia. Immature erythroblasts accumulated in the bone marrow and spleen of PCFT−/− mice and failed to differentiate further, showing an increased rate of apoptosis in intermediate erythroblasts and reduced release of reticulocytes. In response to the inefficient hematologic development, the serum of the PCFT−/− animals contained elevated concentrations of erythropoietin, soluble transferrin receptor (sCD71), and thrombopoietin. In vivo folate uptake experiments demonstrated a systemic folate deficiency caused by disruption of PCFT-mediated intestinal folate uptake, thus confirming in vivo a critical and nonredundant role of the PCFT protein in intestinal folate transport and erythropoiesis. The PCFT-deficient mouse serves as a model for the hereditary folate malabsorption syndrome and is the most accurate animal model of folate deficiency anemia described to date that closely captures the spectrum of pathology typical of this disease.