bluuebunny/crossref_metadata_2025_split huggingface dataset:
Competitive Fitness of Oseltamivir-Sensitive and -Resistant Highly Pathogenic H5N1 Influenza Viruses in a Ferret Model
Authors: Govorkova Elena A. , Ilyushina Natalia A. , Marathe Bindumadhav M. , McClaren Jennifer L. , Webster Robert G. 
Published: June 2010

ABSTRACTThe fitness of oseltamivir-resistant highly pathogenic H5N1 influenza viruses has important clinical implications. We generated recombinant human A/Vietnam/1203/04 (VN; clade 1) and A/Turkey/15/06 (TK; clade 2.2) influenza viruses containing the H274Y neuraminidase (NA) mutation, which confers resistance to NA inhibitors, and compared the fitness levels of the wild-type (WT) and resistant virus pairs in ferrets. The VN-H274Y and VN-WT viruses replicated to similar titers in the upper respiratory tract (URT) and caused comparable disease signs, and none of the animals survived. On days 1 to 3 postinoculation, disease signs caused by oseltamivir-resistant TK-H274Y virus were milder than those caused by TK-WT virus, and all animals survived. We then studied fitness by using a novel approach. We coinoculated ferrets with different ratios of oseltamivir-resistant and -sensitive H5N1 viruses and measured the proportion of clones in day-6 nasal washes that contained the H274Y NA mutation. Although the proportion of VN-H274Y clones increased consistently, that of TK-H274Y virus decreased. Mutations within NA catalytic (R292K) and framework (E119A/K, I222L, H274L, and N294S) sites or near the NA enzyme active site (V116I, I117T/V, Q136H, K150N, and A250T) emerged spontaneously (without drug pressure) in both pairs of viruses. The NA substitutions I254V and E276A could exert a compensatory effect on the fitness of VN-H274Y and TK-H274Y viruses. NA enzymatic function was reduced in both drug-resistant H5N1 viruses. These results show that the H274Y NA mutation affects the fitness of two H5N1 influenza viruses differently. Our novel method of assessing viral fitness accounts for both virus-host interactions and virus-virus interactions within the host.
Influence of pr-M Cleavage on the Heterogeneity of Extracellular Dengue Virus Particles
Authors: Junjhon Jiraphan , Edwards Thomas J. , Utaipat Utaiwan , Bowman Valorie D. , Holdaway Heather A. , Zhang Wei , Keelapang Poonsook , Puttikhunt Chunya , Perera Rushika , Chipman Paul R. , Kasinrerk Watchara , Malasit Prida , Kuhn Richard J. , Sittisombut Nopporn 
Published: June 2010

ABSTRACT
During dengue virus replication, an incomplete cleavage of the envelope glycoprotein prM, generates a mixture of mature (prM-less) and prM-containing, immature extracellular particles. In this study, sequential immunoprecipitation and cryoelectron microscopy revealed a third type of extracellular particles, the partially mature particles, as the major prM-containing particles in a dengue serotype 2 virus. Changes in the proportion of viral particles in the pr-M junction mutants exhibiting altered levels of prM cleavage suggest that the partially mature particles may represent an intermediate subpopulation in the virus maturation pathway. These findings are consistent with a model suggesting the progressive mode of prM cleavage.
A Polymorphism in the Hemagglutinin of the Human Isolate of a Highly Pathogenic H5N1 Influenza Virus Determines Organ Tropism in Mice
Authors: Mänz Benjamin , Matrosovich Mikhail , Bovin Nicolai , Schwemmle Martin 
Published: June 2010

ABSTRACT

We characterized a human H5N1 virus isolate (KAN-1) encoding a hemagglutinin (HA) with a K-to-E substitution at amino acid position 222 that was previously described to be selected in the lung of the infected patient. In mice, the growth of the HA
222E
-encoding virus was mainly confined to the lung, but reversion to 222K allowed virus to spread to the brain. The HA
222E
variant showed an overall reduced binding affinity compared to that of HA
222K
for synthetic Neu5Ac2-3Gal-terminated receptor analogues, except for one analogue [Neu5Acα2-3Galβ1-4(Fucα1-3)(6-HSO
3
)GlcNAcβ, Su-SLe
x
]. Our results suggest that human-derived mutations in HA of H5N1 viruses can affect viral replication efficiency and organ tropism.
The 3C Protein of Enterovirus 71 Inhibits Retinoid Acid-Inducible Gene I-Mediated Interferon Regulatory Factor 3 Activation and Type I Interferon Responses
Authors: Lei Xiaobo , Liu Xinlei , Ma Yijie , Sun Zhenmin , Yang Yaowu , Jin Qi , He Bin , Wang Jianwei 
Published: June 2010

ABSTRACT
Enterovirus 71 (EV71) is a human pathogen that induces hand, foot, and mouth disease and fatal neurological diseases. Immature or impaired immunity is thought to associate with increased morbidity and mortality. In a murine model, EV71 does not facilitate the production of type I interferon (IFN) that plays a critical role in the first-line defense against viral infection. Administration of a neutralizing antibody to IFN-α/β exacerbates the virus-induced disease. However, the molecular events governing this process remain elusive. Here, we report that EV71 suppresses the induction of antiviral immunity by targeting the cytosolic receptor retinoid acid-inducible gene I (RIG-I). In infected cells, EV71 inhibits the expression of IFN-β, IFN-stimulated gene 54 (ISG54), ISG56, and tumor necrosis factor alpha. Among structural and nonstructural proteins encoded by EV71, the 3C protein is capable of inhibiting IFN-β activation by virus and RIG-I. Nevertheless, EV71 3C exhibits no inhibitory activity on MDA5. Remarkably, when expressed in mammalian cells, EV71 3C associates with RIG-I via the caspase recruitment domain. This precludes the recruitment of an adaptor IPS-1 by RIG-I and subsequent nuclear translocation of interferon regulatory factor 3. An R84Q or V154S substitution in the RNA binding motifs has no effect. An H40D substitution is detrimental, but the protease activity associated with 3C is dispensable. Together, these results suggest that inhibition of RIG-I-mediated type I IFN responses by the 3C protein may contribute to the pathogenesis of EV71 infection.
An Antibody against a Novel and Conserved Epitope in the Hemagglutinin 1 Subunit Neutralizes Numerous H5N1 Influenza Viruses
Authors: Oh Hsueh-Ling Janice , Åkerström Sara , Shen Shuo , Bereczky Sándor , Karlberg Helen , Klingström Jonas , Lal Sunil K. , Mirazimi Ali , Tan Yee-Joo 
Published: June 2010

ABSTRACT
The spread of the recently emerged, highly pathogenic H5N1 avian influenza virus has raised concern. Preclinical studies suggest that passive immunotherapy could be a new form of treatment for H5N1 virus infection. Here, a neutralizing monoclonal antibody (MAb) against the hemagglutinin (HA) of the influenza A/chicken/Hatay/2004 H5N1 virus, MAb 9F4, was generated and characterized. MAb 9F4 binds both the denatured and native forms of HA. It was shown to recognize the HA proteins of three heterologous strains of H5N1 viruses belonging to clades 1, 2.1, and 2.2, respectively. By use of lentiviral pseudotyped particles carrying HA on the surface, MAb 9F4 was shown to effectively neutralize the homologous strain, Hatay04, and another clade 1 strain, VN04, at a neutralization titer of 8 ng/ml. Furthermore, MAb 9F4 also neutralized two clade 2 viruses at a neutralizing titer of 40 ng/ml. The broad cross-neutralizing activity of MAb 9F4 was confirmed by its ability to neutralize live H5N1 viruses of clade 2.2.2. Epitope-mapping analysis revealed that MAb 9F4 binds a previously uncharacterized epitope below the globular head of the HA1 subunit. Consistently, this epitope is well conserved among the different clades of H5N1 viruses. MAb 9F4 does not block the interaction between HA and its receptor but prevents the pH-mediated conformational change of HA. MAb 9F4 was also found to be protective, both prophylactically and therapeutically, against a lethal viral challenge of mice. Taken together, our results showed that MAb 9F4 is a neutralizing MAb that binds a novel and well-conserved epitope in the HA1 subunit of H5N1 viruses.
Chikungunya Virus Arthritis in Adult Wild-Type Mice
Authors: Gardner Joy , Anraku Itaru , Le Thuy T. , Larcher Thibaut , Major Lee , Roques Pierre , Schroder Wayne A. , Higgs Stephen , Suhrbier Andreas 
Published: June 2010

ABSTRACTChikungunya virus is a mosquito-borne arthrogenic alphavirus that has recently reemerged to produce the largest epidemic ever documented for this virus. Here we describe a new adult wild-type mouse model of chikungunya virus arthritis, which recapitulates the self-limiting arthritis, tenosynovitis, and myositis seen in humans. Rheumatic disease was associated with a prolific infiltrate of monocytes, macrophages, and NK cells and the production of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ). Infection with a virus isolate from the recent Reunion Island epidemic induced significantly more mononuclear infiltrates, proinflammatory mediators, and foot swelling than did an Asian isolate from the 1960s. Primary mouse macrophages were shown to be productively infected with chikungunya virus; however, the depletion of macrophages ameliorated rheumatic disease and prolonged the viremia. Only 1 μg of an unadjuvanted, inactivated, whole-virus vaccine derived from the Asian isolate completely protected against viremia and arthritis induced by the Reunion Island isolate, illustrating that protection is not strain specific and that low levels of immunity are sufficient to mediate protection. IFN-α treatment was able to prevent arthritis only if given before infection, suggesting that IFN-α is not a viable therapy. Prior infection with Ross River virus, a related arthrogenic alphavirus, and anti-Ross River virus antibodies protected mice against chikungunya virus disease, suggesting that individuals previously exposed to Ross River virus should be protected from chikungunya virus disease. This new mouse model of chikungunya virus disease thus provides insights into pathogenesis and a simple and convenient system to test potential new interventions.
Mutations in the M112/M113-Coding Region Facilitate Murine Cytomegalovirus Replication in Human Cells
Authors: Schumacher Uwe , Handke Wiebke , Jurak Igor , Brune Wolfram 
Published: June 2010

ABSTRACT

Cytomegaloviruses, representatives of the
Betaherpesvirinae
, cause opportunistic infections in immunocompromised hosts. They infect various cells and tissues in their natural host but are highly species specific. For instance, human cytomegalovirus (HCMV) does not replicate in mouse cells, and human cells are not permissive for murine cytomegalovirus (MCMV) infection. However, the underlying molecular mechanisms are so far poorly understood. In the present study we isolated and characterized a spontaneously occurring MCMV mutant that has gained the capacity to replicate rapidly and to high titers in human cells. Compared to the parental wild-type (wt) virus, this mutant formed larger nuclear replication compartments and replicated viral DNA more efficiently. It also disrupted promyelocytic leukemia (PML) protein nuclear domains with greater efficiency but caused less apoptosis than did wt MCMV. Sequence analysis of the mutant virus genome revealed mutations in the M112/M113-coding region. This region is homologous to the HCMV UL112-113 region and encodes the viral early 1 (E1) proteins, which are known to play an important role in viral DNA replication. By introducing the M112/M113 mutations into wt MCMV, we demonstrated that they are sufficient to facilitate MCMV replication in human cells and are, at least in part, responsible for the efficient replication capability of the spontaneously adapted virus. However, additional mutations probably contribute as well. These results reveal a previously unrecognized role of the viral E1 proteins in regulating viral replication in different cells and provide new insights into the mechanisms of the species specificity of cytomegaloviruses.
Coal workers' pneumoconiosis and progressive massive fibrosis are increasingly more prevalent among workers in small underground coal mines in the United States
Authors: Laney A Scott , Attfield Michael D 
Published: June 2010

ObjectiveTo determine whether the prevalence of coal workers' pneumoconiosis (CWP) or progressive massive fibrosis (PMF) among United States underground miners is associated with mine size.MethodsWe examined chest radiographs from 1970 to 2009 of working miners who participated in the National Coal Workers Health Surveillance Program for the presence of small and large opacities consistent with pneumoconiosis, based upon the International Labour Organization classification system.ResultsA total of 145 512 miners contributed 240 067 radiographs for analysis. From the 1990s to the 2000s, the prevalence of radiographic CWP increased among miners in mines of all sizes, while miners working in mines with fewer than 50 employees had a significantly higher prevalence of CWP compared to miners who worked in mines with 50 or more employees (p<0.0001). When adjusted for age and within-miner correlation, the difference in prevalence of CWP by mine size was significant for all decades. Since 1999, miners from small mines were five times more likely to have radiographic evidence of PMF (1.0% of miners) compared to miners from larger mines (0.2% of miners) with a prevalence ratio of 5.0 and 95% CI 3.3 to 7.5.ConclusionThe prevalence of CWP among United States coal miners is increasing in mines of all sizes, while CWP and PMF are much more prevalent among workers from underground mines with fewer than 50 workers.
INTERMEDIATE MODEL FOR SPATIAL EVOLUTION IN NONLINEAR OPTICS
Authors: LESCARRET VINCENT 
Published: June 2010

This paper follows the work of Colin–Gallice–Laurioux6 in which a new model generalizing the Schrödinger (NLS) model of the diffractive optics is derived for the laser propagation in nonlinear media. In particular, it provides good approximate solutions of the Maxwell–Lorentz system for highly oscillating initial data with broad spectrum. In real situations one is given boundary data. We propose to derive a similar evolution model but in the variable associated to the direction of propagation. However, since the space directions for the Maxwell equations are not hyperbolic, the boundary problem is ill-posed and one needs to apply a cutoff defined in the Fourier space, selecting those frequencies for which the operator is hyperbolic. The model we obtain is nearly L2 conservative on its domain of validity. We then give a justification of the derivation. For this purpose we introduce a related well-posed initial boundary value problem. Finally, we perform numerical computations on the example of Maxwell with Kerr nonlinearity in some cases of short or spectrally chirped data where our model outperforms the Schrödinger one.
A Novel Nanoparticulate Formulation of Arsenic Trioxide with Enhanced Therapeutic Efficacy in a Murine Model of Breast Cancer
Authors: Ahn Richard W. , Chen Feng , Chen Haimei , Stern Stephan T. , Clogston Jeffrey D. , Patri Anil K. , Raja Meera R. , Swindell Elden P. , Parimi Vamsi , Cryns Vincent L. , O'Halloran Thomas V. 
Published: June 2010

Abstract
Purpose: The clinical success of arsenic trioxide (As2O3) in hematologic malignancies has not been replicated in solid tumors due to poor pharmacokinetics and dose-limiting toxicity. We have developed a novel nanoparticulate formulation of As2O3 encapsulated in liposomal vesicles or “nanobins” [(NB(Ni,As)] to overcome these hurdles. We postulated that nanobin encapsulation of As2O3 would improve its therapeutic index against clinically aggressive solid tumors, such as triple-negative breast carcinomas.
Experimental Design: The cytotoxicity of NB(Ni,As), the empty nanobin, and free As2O3 was evaluated against a panel of human breast cancer cell lines. The plasma pharmacokinetics of NB(Ni,As) and free As2O3 were compared in rats to measure drug exposure. In addition, the antitumor activity of these agents was evaluated in an orthotopic model of human triple-negative breast cancer.
Results: The NB(Ni,As) agent was much less cytotoxic in vitro than free As2O3 against a panel of human breast cancer cell lines. In contrast, NB(Ni,As) dramatically potentiated the therapeutic efficacy of As2O3 in vivo in an orthotopic model of triple-negative breast cancer. Reduced plasma clearance, enhanced tumor uptake, and induction of tumor cell apoptosis were observed for NB(Ni,As).
Conclusions: Nanobin encapsulation of As2O3 improves the pharmacokinetics and antitumor efficacy of this cytotoxic agent in vivo. Our findings demonstrate the therapeutic potential of this nanoscale agent and provide a foundation for future clinical studies in breast cancer and other solid tumors. Clin Cancer Res; 16(14); 3607–17. ©2010 AACR.
Two Good Choices to Prevent Breast Cancer: Great Taste, Less Filling
Authors: Hortobagyi Gabriel N. , Brown Powel H. 
Published: June 2010

Abstract
An important report in this issue of the journal by Vogel et al. (beginning on p. 696) discloses long-term follow-up data of the Study of Tamoxifen and Raloxifene (STAR) showing persisting strong effects of both drugs in preventing invasive and noninvasive breast cancer after drugs were stopped in 2006. In addition, safety improved with longer follow-up (median of 81 months versus 47 months for the initial report). For 12 years, the public has avoided Food and Drug Administration–approved tamoxifen or raloxifene for breast cancer risk reduction; it is time to reemphasize the great preventive benefit of these agents to the public. Cancer Prev Res; 3(6); 681–5. ©2010 AACR.
Chromogranin B in Heart Failure
Authors: Røsjø Helge , Husberg Cathrine , Dahl Mai Britt , Stridsberg Mats , Sjaastad Ivar , Finsen Alexandra Vanessa , Carlson Cathrine Rein , Øie Erik , Omland Torbjørn , Christensen Geir 
Published: June 2010

Background—
Chromogranin B (CgB) is a member of the granin protein family. Because CgB is often colocalized with chromogranin A (CgA), a recently discovered cardiac biomarker, we hypothesized that CgB is regulated during heart failure (HF) development.

Methods and Results—

CgB regulation was investigated in patients with chronic HF and in a post–myocardial infarction HF mouse model. Animals were phenotypically characterized by echocardiography and euthanized 1 week after myocardial infarction. CgB mRNA levels were 5.2-fold increased in the noninfarcted part of the left ventricle of HF animals compared with sham-operated animals (
P
<0.001). CgB mRNA level in HF animals correlated closely with animal lung weight (
r
=0.74,
P
=0.04) but not with CgA mRNA levels (
r
=0.20,
P
=0.61). CgB protein levels were markedly increased in both the noninfarcted (110%) and the infarcted part of the left ventricle (70%) but unaltered in other tissues investigated. Myocardial CgB immunoreactivity was confined to cardiomyocytes. Norepinephrine, angiotensin II, and transforming growth factor-β increased CgB gene expression in cardiomyocytes. Circulating CgB levels were increased in HF animals (median levels in HF animals versus sham, 1.23 [interquartile range, 1.03 to 1.93] versus 0.98 [0.90 to 1.04] nmol/L;
P
=0.003) and in HF patients (HF patients versus control, 1.66 [1.48 to 1.85] versus 1.47 [1.39 to 1.58] nmol/L;
P
=0.007), with levels increasing in proportion to New York Heart Association functional class (
P
=0.03 for trend). Circulating CgB levels were only modestly correlated with CgA (
r
=0.31,
P
=0.009) and B-type natriuretic peptide levels (
r
=0.27,
P
=0.014).

Conclusions—
CgB production is increased and regulated in proportion to disease severity in the left ventricle and circulation during HF development.
Action Perception in Individuals with Congenital Blindness or Deafness: How Does the Loss of a Sensory Modality from Birth Affect Perception-induced Motor Facilitation?
Authors: Alaerts Kaat , Swinnen Stephan P. , Wenderoth Nicole 
Published: June 2010

AbstractSeeing or hearing manual actions activates the mirror neuron system, that is, specialized neurons within motor areas which fire when an action is performed but also when it is passively perceived. Using TMS, it was shown that motor cortex of typically developed subjects becomes facilitated not only from seeing others' actions, but also from merely hearing action-related sounds. In the present study, TMS was used for the first time to explore the “auditory” and “visual” responsiveness of motor cortex in individuals with congenital blindness or deafness. TMS was applied over left primary motor cortex (M1) to measure cortico-motor facilitation while subjects passively perceived manual actions (either visually or aurally). Although largely unexpected, congenitally blind or deaf subjects displayed substantially lower resonant motor facilitation upon action perception compared to seeing/hearing control subjects. Moreover, muscle-specific changes in cortico-motor excitability within M1 appeared to be absent in individuals with profound blindness or deafness. Overall, these findings strongly argue against the hypothesis that an increased reliance on the remaining sensory modality in blind or deaf subjects is accompanied by an increased responsiveness of the “auditory” or “visual” perceptual–motor “mirror” system, respectively. Moreover, the apparent lack of resonant motor facilitation for the blind and deaf subjects may challenge the hypothesis of a unitary mirror system underlying human action recognition and may suggest that action perception in blind and deaf subjects engages a mode of action processing that is different from the human action recognition system recruited in typically developed subjects.
An fMRI Investigation of Attributing Negative Social Treatment to Racial Discrimination
Authors: Masten Carrie L. , Telzer Eva H. , Eisenberger Naomi I. 
Published: June 2010

Abstract
We used fMRI to examine the neural responses that occur during experiences of perceived racial discrimination. Previous neuroimaging studies have focused exclusively on the processes underlying racial bias from the perpetrator's perspective and have yet to examine the processes that occur when individuals are being discriminated against. To extend this work, we examined the neural correlates associated with attributing negative social treatment to racial discrimination to explore the cognitive and affective processes that occur as discrimination is being experienced. To do this, we scanned Black participants while they were ostensibly excluded by Whites and then measured distress levels and race-based attributions for exclusion. In response to being socially excluded by Whites, Black participants who appeared to be more distressed showed greater social pain-related neural activity and reduced emotion regulatory neural activity. In addition, those who attributed exclusion to racial discrimination displayed less social pain-related and more emotion regulatory neural activity. The potential negative impact that frequent negative social treatment and discrimination-related distress regulation might have on individuals' long-term mental and physical health is discussed.