bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Structure of Integral Group Rings of Sporadic Groups
Authors: Bleher Frauke M. , Kimmerle Wolfgang
Published: October 2010

The object of this article is to examine a conjecture of Zassenhaus and certain variations of it for integral group rings of sporadic groups. We prove the ℚ-variation and the Sylow variation for all sporadic groups and their automorphism groups. The Zassenhaus conjecture is established for eighteen of the sporadic simple groups, and for all automorphism groups of sporadic simple groups G which are different from G. The proofs are given with the aid of the GAP computer algebra program by applying a computational procedure to the ordinary and modular character tables of the groups. It is also shown that the isomorphism problem of integral group rings has a positive answer for certain almost simple groups, in particular for the double covers of the symmetric groups.
Relaminarization of Axisymmetric Turbulent Flow With Combined Axial Jet and Side Injection in a Pipe
Authors: Majumder Snehamoy , Sanyal Dipankar
Published: October 2010

The effect of side mass injection on turbulent flow with axial entry to a circular duct in the form of centrally confined jet has been investigated. A standard κ-ε model modified for streamline curvature has been used for detailed analysis following a comparison with a κ-ω model for some test cases. Results show that flow stabilization and relaminarization could occur due to the side injection. The predicted recirculation zone, friction factor, total turbulent energy, turbulent shear stress, Taylor scale Reynolds number, and turbulent energy flux show gradual reduction with increase in the side injection velocity.
Experimental and Numerical Study of Laminar Round Jet Flows Along a Wall
Authors: Adane K. F. K. , Tachie M. F.
Published: October 2010

In the present study, both experimental and numerical techniques were employed to study three-dimensional laminar wall jet flows. The wall jet was created using a circular pipe of diameter 7×10−3 m and flows into an open water tank. The inlet Reynolds numbers based on the pipe diameter and jet exit velocity were 310 and 800. A particle image velocimetry (PIV) was used to conduct detailed measurements at various streamwise-transverse and streamwise-spanwise planes. The complete nonlinear incompressible Navier–Stokes equation was also solved using a collocated finite volume based in-house computational fluid dynamics (CFD) code. The computation was performed for three inlet Reynolds numbers, namely, 310, 420, and 800. From the PIV measurements and CFD results, velocity profiles and jet half-widths were extracted at selected downstream locations. It was observed that the numerical results are in reasonable agreement with the experimental data. The distributions of the velocities, jet spread rates, and vorticity were used to provide insight into the characteristics of three-dimensional laminar wall jet flows.
Electron detection performance of diamond avalanche diode
Authors: Morishita Hideo , Ohshima Takashi , Hatano Michio , Iwakaji Yoko , Maida Osamu , Ito Toshimichi
Published: October 2010

The authors evaluated the electron detection performance of a diamond avalanche diode (DAD) detector. In the electrode region, the gain was uniformly about 103 with little noise. Meanwhile, an avalanche multiplication occurred locally. In the avalanche region, a total gain of 5×104 was obtained. In some regions where the electric field is regarded to be intensified, the avalanche multiplication gain was estimated to be approximately 100–300, and the signal-to-noise ratio (S/N) was nearly equal to 1. The DAD can be applied to an electron detector for a scanning electron microscope due to its high gain and small dark current. However, it is necessary to improve the S/N and homogenize the gain to use the DAD detector as an electron detector.
Thin film transistors with a ZnO channel and gate dielectric layers of HfO2 by atomic layer deposition
Authors: Grundbacher Ronald , Chikkadi Kiran , Hierold Christofer
Published: October 2010

Thin film transistors (TFTs) have been fabricated with a zinc oxide (ZnO) channel layer and a hafnium dioxide (HfO2) gate dielectric layer. The oxide layers were deposited using an atomic layer deposition (ALD) system. The use of ALD for ZnO deposition allows subnanometer thickness control of the deposited layer, and thereby provides a means to vary TFT threshold voltage by controlling the carrier density in the ZnO channel: the carrier density is dependent on the layer thickness because band structure changes result in charge depletion in thinner layers. Enhancement-mode devices have been fabricated and have an on-off current ratio above 106. The enhancement-mode devices of the inverted (gate down) TFT structure were realized by decreasing the ZnO channel layer thickness to 15 nm and below, thereby reducing the carrier density of the as-deposited n-type ZnO layer. An important aspect of the fabrication of the inverted TFTs was the use of either an aluminum sacrificial layer or a thin HfO2 cap layer to eliminate the etching of the ZnO during the photolithography process. The results demonstrate that enhancement-mode TFTs with as-deposited n-type ZnO channels can be produced by tailoring the thickness of the ZnO channel by ALD and are the first reported TFTs in which both the ZnO channel and HfO2 gate dielectric are deposited by ALD to the authors’ knowledge.
The LCROSS Cratering Experiment
Authors: Schultz Peter H. , Hermalyn Brendan , Colaprete Anthony , Ennico Kimberly , Shirley Mark , Marshall William S.
Published: October 2010

Watering the Moon

About a year ago, a spent upper stage of an Atlas rocket was deliberately crashed into a crater at the south pole of the Moon, ejecting a plume of debris, dust, and vapor. The goal of this event, the Lunar Crater Observation and Sensing Satellite (LCROSS) experiment, was to search for water and other volatiles in the soil of one of the coldest places on the Moon: the permanently shadowed region within the Cabeus crater. Using ultraviolet, visible, and near-infrared spectroscopy data from accompanying craft,

Colaprete
et al.

(p.
463
; see the news story by

Kerr

; see the cover) found evidence for the presence of water and other volatiles within the ejecta cloud.

Schultz
et al.

(p.
468
) monitored the different stages of the impact and the resulting plume.

Gladstone
et al.

(p.
472
), using an ultraviolet spectrograph onboard the Lunar Reconnaissance Orbiter (LRO), detected H
2
, CO, Ca, Hg, and Mg in the impact plume, and

Hayne
et al.

(p.
477
) measured the thermal signature of the impact and discovered that it had heated a 30 to 200 square-meter region from ∼40 kelvin to at least 950 kelvin.

Paige
et al.

(p. 479) mapped cryogenic zones predictive of volatile entrapment, and

Mitrofanov
et al.

(p.
483
) used LRO instruments to confirm that surface temperatures in the south polar region persist even in sunlight. In all, about 155 kilograms of water vapor was emitted during the impact; meanwhile, the LRO continues to orbit the Moon, sending back a stream of data to help us understand the evolution of its complex surface structures.
Oscillatory Mass Transport in Vapor-Liquid-Solid Growth of Sapphire Nanowires
Authors: Oh Sang Ho , Chisholm Matthew F. , Kauffmann Yaron , Kaplan Wayne D. , Luo Weidong , Rühle Manfred , Scheu Christina
Published: October 2010

Growing Nanowires

In vapor-liquid-solid (VLS) growth of nanowires, the liquid phase acts as a transporter to bring material from the gas phase to the growing solid. By heating a single crystal of sapphire in a high-resolution transmission microscope,

Oh
et al.

(p.
489
) monitored the growth of sapphire (α-Al2O3) nanowires out of an aluminum droplet. The liquid aluminum brings oxygen to the growing wire surface, in alternating growth and dissolution reactions at the edge of the wire. The oscillation created an optimum face at the self-catalytic site for atomic stacking and regenerated the junction between the VLS phases, allowing growth of the nanowire.
ATM Activation by Oxidative Stress
Authors: Guo Zhi , Kozlov Sergei , Lavin Martin F. , Person Maria D. , Paull Tanya T.
Published: October 2010

Stress, DNA Damage, and ATM

The protein kinase ATM (ataxia-telangiectasia mutated) is a key component of the signaling pathway through which cells are protected from DNA damage. ATM becomes activated within a protein complex at sites of double-stranded breaks in DNA. ATM is also activated in response to increased production of reactive oxygen species (ROS). Such activation was thought to reflect DNA damage caused by ROS, but

Guo
et al.

(p.
517
) showed that ATM was in fact directly activated by ROS. A cysteine residue in ATM contributes to the formation of disulfide-linked dimers of activated ATM on exposure to ROS in vitro. Experiments using mutated forms of the enzyme suggested that two distinct mechanisms regulated ATM activity.
Species Selection Maintains Self-Incompatibility
Authors: Goldberg Emma E. , Kohn Joshua R. , Lande Russell , Robertson Kelly A. , Smith Stephen A. , Igić Boris
Published: October 2010

Incompatible Self-Compatibility

Macroevolutionary processes driving species differences in diversification rates are important in explaining the variation we see in nature, but the extent of this process and how much the traits within a single species can drive changes in the diversification rate are unknown.

Goldberg
et al.

(p.
493
; see the Perspective by

Wright and Barrett

) analyzed the phylogenetics of the plant family Solanaceae and found that rates of extinction are greater for self-pollinating species than outbreeding species. Species-level selection against the deleterious effects of inbreeding may explain why self-fertilization, despite its short-term evolutionary advantages, has not spread to become more common in the flowering plants.
Widespread Divergence Between Incipient
Anopheles gambiae
Species Revealed by Whole Genome Sequences
Authors: Lawniczak M. K. N. , Emrich S. J. , Holloway A. K. , Regier A. P. , Olson M. , White B. , Redmond S. , Fulton L. , Appelbaum E. , Godfrey J. , Farmer C. , Chinwalla A. , Yang S.-P. , Minx P. , Nelson J. , Kyung K. , Walenz B. P. , Garcia-Hernandez E. , Aguiar M. , Viswanathan L. D. , Rogers Y.-H. , Strausberg R. L. , Saski C. A. , Lawson D. , Collins F. H. , Kafatos F. C. , Christophides G. K. , Clifton S. W. , Kirkness E. F. , Besansky N. J.
Published: October 2010

Signals of Mosquito Speciation

Malaria in Africa is transmitted by the mosquito species complex
Anopheles gambiae
.

Neafsey
et al.

(p.
514
) made high-resolution single-nucleotide arrays to map genetic divergence among members of the species. Differentiation between populations was observed and evidence obtained for selective sweeps within populations. Most divergence occurred within inversion regions around the centrosome and in genes associated with development, pheromone signaling, and from the X chromosome. The analysis also revealed signals of sympatric speciation occurring within similar chromosomal regions in mosquitoes from different regions in Africa.

Lawniczak
et al.

(p.
512
) sequenced the genomes of two molecular forms (known as M and S) of
A. gambiae
, which have distinctive behavioral phenotypes and appear to be speciating. This effort resolves problems arising from the apparently chimeric nature of the reference genome and confirms the observed genome-wide divergences. This kind of analysis has the potential to contribute to control programs that can adapt to population shifts in mosquito behavior arising from the selective effects of the control measures themselves.
A Naturalizer's Vision
Never Pure
Historical Studies of Science as if It Was Produced by People with Bodies, Situated in Time, Space, Culture, and Society, and Struggling for Credibility and Authority

by Steven Shapin

Johns Hopkins University Press, Baltimore, MD, 2010. 564 pp. $70. ISBN 9780801894206. Paper, $30. ISBN 9780801894213.
Authors: Kohler Robert E.
Published: October 2010

This collection of essays samples Shapin's explorations of where, how, and by whom science has been produced.
The Long-Term Benefits of Self-Rejection
Authors: Wright Stephen I. , Barrett Spencer C. H.
Published: October 2010

A trait that prevents self-fertilization in plants appears to promote evolutionary diversification.
After Red Mud Flood, Scientists Try to Halt Wave of Fear and Rumors
Authors: Enserink Martin
Published: October 2010

Two weeks after caustic sludge—a byproduct of the aluminum industry whose pH can reach a dizzying 13—broke through a reservoir near Kolontár, Hungary, scientists say its environmental impact may be less severe than widely broadcast images suggested at first.
Iraq Banks on Peer Review to Rebuild Its Research Base
Authors: Bhattacharjee Yudhijit
Published: October 2010

As part of an effort to build a research infrastructure, an Iraqi delegation visited the United States recently to study the U.S. system. Last week,
Science
spoke to two leaders of the delegation: Samir Raouf, Iraq's senior deputy minister for science and technology, and Hamid Ahmed, who advises the prime minister on education and higher education.
Reanalysis of French Cave Could Deal Setback to Neandertal Smarts
Authors: Balter Michael
Published: October 2010

According to a study published online this week, new radiocarbon dating at a celebrated site in France indicates that jewelry and tools once attributed to Neandertals may be the work of modern humans.
An Intranasally Delivered Toll-Like Receptor 7 Agonist Elicits Robust Systemic and Mucosal Responses to Norwalk Virus-Like Particles
Authors: Velasquez Lissette S. , Hjelm Brooke E. , Arntzen Charles J. , Herbst-Kralovetz Melissa M.
Published: October 2010

Norwalk virus (NV) is an enteric pathogen from the genusNorovirusand a major cause of nonbacterial gastroenteritis in humans. NV virus-like particles (VLPs) are known to elicit systemic and mucosal immune responses when delivered nasally; however, the correlates of immune protection are unknown, and codelivery with a safe and immunogenic mucosal adjuvant may enhance protective anti-NV immune responses. Resiquimod (R848), an imidazoquinoline-based Toll-like receptor 7 and/or 8 (TLR7/8) agonist, is being evaluated as an adjuvant in FDA-approved clinical vaccine trials. As such, we evaluated the adjuvant activity of two imidazoquinoline-based TLR7 and TLR7/8 agonists when codelivered intranasally with plant-derived NV VLPs. We also compared the activity of these agonists to the gold standard mucosal adjuvant, cholera toxin (CT). Our results indicate that codelivery with the TLR7 agonist, gardiquimod (GARD), induces NV VLP-specific serum IgG and IgG isotype responses and mucosal IgA responses in the gastrointestinal, respiratory, and reproductive tracts that are superior to those induced by R848 and comparable to those induced by the mucosal adjuvant CT. This study supports the continued investigation of GARD as a mucosal adjuvant for NV VLPs and possible use for other VLP-based vaccines for which immune responses at distal mucosal sites (e.g., respiratory and reproductive tracts) are desired.
Fast Detection of Volatile Organic Compounds from Bacterial Cultures by Secondary Electrospray Ionization-Mass Spectrometry
Authors: Zhu Jiangjiang , Bean Heather D. , Kuo Yin-Ming , Hill Jane E.
Published: October 2010

We propose a novel application of secondary electrospray ionization-mass spectrometry (SESI-MS) as a real-time clinical diagnostic tool for bacterial infection. It is known that volatile organic compounds (VOCs), produced in different combinations and quantities by bacteria as metabolites, generate characteristic odors for certain bacteria. These VOCs comprise a specific metabolic profile that can be used for species or serovar identification, but rapid and sensitive analytical methods are required for broad utility. In this study, the VOC profiles of five bacterial groups from four genera,
Pseudomonas aeruginosa
,
Staphylococcus aureus
,
Escherichia coli
,
Salmonella enterica
serovar Typhimurium, and
Salmonella enterica
serovar Pullorum, were characterized by SESI-MS. Thirteen compounds were identified from these bacterial cultures, and the combination of these VOCs creates a unique pattern for each genus. In addition, principal component analysis (PCA) was applied for the purpose of species or serovar discrimination. The first three principal components exhibit a clear separation between the metabolic volatile profiles of these five bacterial groups that is independent of the growth medium. As a first step toward addressing the complexity of clinical application,
in vitro
tests for mixed cultures were conducted. The results show that individual species or serovars in a mixed culture are identifiable among a biological VOC background, and the ratios of the detected volatiles reflect the proportion of each bacterium in the mixture. Our data confirm the utility of SESI-MS in real-time identification of bacterial species or serovars
in vitro
, which, in the future, may play a promising clinical role in diagnosing infections.
The Liposome PCR Assay Is More Sensitive than the
Vibrio cholerae
Enterotoxin and
Escherichia coli
Heat-Labile Enterotoxin Reversed Passive Latex Agglutination Test at Detecting Cholera Toxin in Feces and Water
Authors: Evers David L. , He Junkun , Mason Jeffrey T. , O'Leary Timothy J.
Published: October 2010

Practical detection of cholera toxin (CT) by a liposome PCR (LPCR) immunoassay was compared to that of an established
V. cholerae
enterotoxin and
Escherichia coli
heat-labile enterotoxin reversed passive latex agglutination (VET-RPLA) assay. LPCR detected CT in the range of 10 pg/ml to 100 ng/ml in simulated feces and environmental water. Detection by VET-RPLA required at least 4 to 19 ng/ml CT.
Chikungunya Virus Induces IPS-1-Dependent Innate Immune Activation and Protein Kinase R-Independent Translational Shutoff
Authors: White Laura K. , Sali Tina , Alvarado David , Gatti Evelina , Pierre Philippe , Streblow Daniel , DeFilippis Victor R.
Published: October 2010

Chikungunya virus (CHIKV) is an arthritogenic mosquito-transmitted alphavirus that is undergoing reemergence in areas around the Indian Ocean. Despite the current and potential danger posed by this virus, we know surprisingly little about the induction and evasion of CHIKV-associated antiviral immune responses. With this in mind we investigated innate immune reactions to CHIKV in human fibroblasts, a demonstrable
in vivo
target of virus replication and spread. We show that CHIKV infection leads to activation of the transcription factor interferon regulatory factor 3 (IRF3) and subsequent transcription of IRF3-dependent antiviral genes, including beta interferon (IFN-β). IRF3 activation occurs by way of a virus-induced innate immune signaling pathway that includes the adaptor molecule interferon promoter stimulator 1 (IPS-1). Despite strong transcriptional upregulation of these genes, however, translation of the corresponding proteins is not observed. We further demonstrate that translation of cellular (but not viral) genes is blocked during infection and that although CHIKV is found to trigger inactivation of the translational molecule eukaryotic initiation factor subunit 2α by way of the double-stranded RNA sensor protein kinase R, this response is not required for the block to protein synthesis. Furthermore, overall diminution of cellular RNA synthesis is also observed in the presence of CHIKV and transcription of IRF3-dependent antiviral genes appears specifically blocked late in infection. We hypothesize that the observed absence of IFN-β and antiviral proteins during infection results from an evasion mechanism exhibited by CHIKV that is dependent on widespread shutoff of cellular protein synthesis and a targeted block to late synthesis of antiviral mRNA transcripts.
Macaque Long-Term Nonprogressors Resist Superinfection with Multiple CD8
+
T Cell Escape Variants of Simian Immunodeficiency Virus
Authors: Weinfurter Jason T. , May Gemma E. , Soma Taeko , Hessell Ann J. , León Enrique J. , MacNair Caitlin E. , Piaskowski Shari M. , Weisgrau Kim , Furlott Jessica , Maness Nicholas J. , Reed Jason , Wilson Nancy A. , Rakasz Eva G. , Burton Dennis R. , Friedrich Thomas C.
Published: October 2010

Human immunodeficiency virus (HIV)-positive individuals can be superinfected with different virus strains. Individuals who control an initial HIV infection are therefore still at risk for subsequent infection with divergent viruses, but the barriers to such superinfection remain unclear. Here we tested long-term nonprogressors' (LTNPs') susceptibility to superinfection using Indian rhesus macaques that express the major histocompatibility complex class I (MHC-I) allele
Mamu-B*17
, which is associated with control of the pathogenic AIDS virus SIVmac239. The Mamu-B*17-restricted CD8
+
T cell repertoire is focused almost entirely on 5 epitopes. We engineered a series of SIVmac239 variants bearing mutations in 3, 4, or all 5 of these epitopes and used them to serially challenge 2
Mamu-B*17-
positive LTNPs. None of the escape variants caused breakthrough replication in LTNPs, although they readily infected
Mamu-B*17-
negative naive macaques.
In vitro
competing coculture assays and examination of viral evolution in hosts lacking
Mamu-B*17
suggested that the mutant viruses had negligible defects in replicative fitness. Both LTNPs maintained robust immune responses, including simian immunodeficiency virus (SIV)-specific CD8
+
and CD4
+
T cells and neutralizing antibodies. Our results suggest that escape mutations in epitopes bound by “protective” MHC-I molecules may not be sufficient to establish superinfection in LTNPs.
Hepatitis C Virus NS2 Protein Serves as a Scaffold for Virus Assembly by Interacting with both Structural and Nonstructural Proteins
Authors: Ma Yinghong , Anantpadma Manu , Timpe Jennifer M. , Shanmugam Saravanabalaji , Singh Sher M. , Lemon Stanley M. , Yi MinKyung
Published: October 2010

Many aspects of the assembly of hepatitis C virus (HCV) remain incompletely understood. To characterize the role of NS2 in the production of infectious virus, we determined NS2 interaction partners among other HCV proteins during productive infection. Pulldown assays showed that NS2 forms complexes with both structural and nonstructural proteins, including E1, E2, p7, NS3, and NS5A. Confocal microscopy also demonstrated that NS2 colocalizes with E1, E2, and NS5A in dot-like structures near lipid droplets. However, NS5A did not coprecipitate with E2 and interacted only weakly with NS3 in pulldown assays. Also, there was no demonstrable interaction between p7 and E2 or NS3 in such assays. Therefore, NS2 is uniquely capable of interacting with both structural and nonstructural proteins. Among mutations in p7, NS2, and NS3 that prevent production of infectious virus, only p7 mutations significantly reduced NS2-mediated protein interactions. These p7 mutations altered the intracellular distribution of NS2 and E2 and appeared to modulate the membrane topology of the C-terminal domain of NS2. These results suggest that NS2 acts to coordinate virus assembly by mediating interactions between envelope proteins and NS3 and NS5A within replication complexes adjacent to lipid droplets, where virus particle assembly is thought to occur. p7 may play an accessory role by regulating NS2 membrane topology, which is important for NS2-mediated protein interactions and therefore NS2 function.
Marek's Disease Virus Type 1 MicroRNA miR-M3 Suppresses Cisplatin-Induced Apoptosis by Targeting SMAD2 of the Transforming Growth Factor Beta Signal Pathway
Authors: Xu Shun , Xue Chunyi , Li Jianping , Bi Yingzuo , Cao Yongchang
Published: October 2010

Viruses cause about 15% of the cancers that are still the leading causes of human mortality. The discovery of viral oncogenes has enhanced our understanding of viral oncogenesis. However, the underlying molecular mechanisms of virus-induced cancers are complex and require further investigation. The present study has attempted to investigate the effects of the microRNAs (miRNAs) encoded by Marek's disease virus 1 (MDV1), a chicken herpesvirus causing acute T-cell lymphomas and solid visceral tumors in chickens, on anti-cancer drug-induced apoptosis and identify the targets of the miRNAs. The results showed that of the total 14 miRNAs encoded by MDV1, MDV1-miR-M3 significantly promoted cell survival under treatment with cisplatin, a widely used chemotherapy drug. MDV1-miR-M3 suppressed cisplatin-induced apoptosis by directly downregulating expression at the protein but not the mRNA level of Smad2, a critical component in the transforming growth factor β signal pathway. Our data suggest that latent/oncogenic viruses may encode miRNAs to directly target cellular factors involved in antiviral processes including apoptosis, thus proactively creating a cellular environment beneficial to viral latency and oncogenesis. Furthermore, the knowledge of the apoptosis resistance conferred by viral miRNAs has great practical implications for improving the efficacy of chemotherapies for treating cancers, especially those induced by oncogenic viruses.
Dynamics of Two Separate but Linked HIV-1 CRF01_AE Outbreaks among Injection Drug Users in Stockholm, Sweden, and Helsinki, Finland
Authors: Skar Helena , Axelsson Maria , Berggren Ingela , Thalme Anders , Gyllensten Katarina , Liitsola Kirsi , Brummer-Korvenkontio Henrikki , Kivelä Pia , Spångberg Erika , Leitner Thomas , Albert Jan
Published: October 2010

Detailed phylogenetic analyses were performed to characterize an HIV-1 outbreak among injection drug users (IDUs) in Stockholm, Sweden, in 2006. This study investigated the source and dynamics of HIV-1 spread during the outbreak as well as associated demographic and clinical factors. Seventy Swedish IDUs diagnosed during 2004 to 2007 were studied. Demographic, clinical, and laboratory data were collected, and the V3 region of the HIV-1 envelope gene was sequenced to allow detailed phylogenetic analyses. The results showed that the Stockholm outbreak was caused by a CRF01_AE variant imported from Helsinki, Finland, around 2003, which was quiescent until the outbreak started in 2006. Local Swedish subtype B variants continued to spread at a lower rate. The number of new CRF01_AE cases over a rooted phylogenetic tree accurately reflected the transmission dynamics and showed a temporary increase, by a factor of 12, in HIV incidence during the outbreak. Virus levels were similar in CRF01_AE and subtype B infections, arguing against differences in contagiousness. Similarly, there were no major differences in other baseline characteristics. Instead, the outbreak in Stockholm (and Helsinki) was best explained by an introduction of HIV into a standing network of previously uninfected IDUs. The combination of phylogenetics and epidemiological data creates a powerful tool for investigating outbreaks of HIV and other infectious diseases that could improve surveillance and prevention.
Novel F141L Pre-S2 Mutation in Hepatitis B Virus Increases the Risk of Hepatocellular Carcinoma in Patients with Chronic Genotype C Infections
Authors: Mun Ho-Suk , Lee Seoung-Ae , Kim Hong , Hwang Eung-Soo , Kook Yoon-Hoh , Kim Bum-Joon
Published: October 2010

Several lines of evidence have suggested that some naturally occurring mutations of hepatitis B virus (HBV) play a critical role in hepatocellular carcinoma (HCC). Here, we describe a novel HCC-related pre-S2 mutation, F141L. To prove the relationship between the F141L mutation and HCC, molecular epidemiology studies using MboII PCR restriction analysis (PRA) were performed, and the molecular mechanism was investigated through construction of a stable hepatocyte cell line expressing the large surface HB protein (LHB) with the F141L mutation (F141L-LHB). Application of MboII PRA to samples from 241 Korean patients with chronic liver diseases of different clinical stages confirmed that F141L mutants were significantly related to HCC, even in comparison to liver cirrhosis (HCC, 26.3% of patients, or 26/99; liver cirrhosis, 3.8% of patients, or 2/52;
P
= 0.001). By studying stable cell lines, we found that F141L-LHBs could induce cell cycle progression by downregulating the p53 and p21 pathways and upregulating CDK4 and cyclin A. Furthermore, we found that in a colony-forming assay, the colony-forming rates in cell lines expressing F141L-LHBs were about twice as high as those of the wild type. In conclusion, our results suggest that F141L-LHBs may contribute importantly to the pathogenesis of HCC by inducing cell proliferation and transformation. So, the F141L mutation examined in this study could serve as a diagnostic marker for the prognosis of HCC.
Identification of Binary Interactions between Human Cytomegalovirus Virion Proteins
Authors: Phillips Stacia L. , Bresnahan Wade A.
Published: October 2010

Human cytomegalovirus (HCMV) virions are composed of a DNA-containing nucleocapsid surrounded by a tegument layer and host-derived lipid envelope studded with virally encoded glycoproteins. These complex virions are estimated to be composed of more than 50 viral proteins. Assembly of HCMV virions is poorly understood, especially with respect to acquisition of the tegument; however, it is thought to involve the stepwise addition of virion components through protein-protein interactions. We sought to identify interactions among HCMV virion proteins using yeast two-hybrid analysis. Using 33 known capsid and tegument proteins, we tested 1,089 pairwise combinations for binary interaction in the two-hybrid assay. We identified 24 interactions among HCMV virion proteins, including 13 novel interactions among tegument proteins and one novel interaction between capsid proteins. Several of these novel interactions were confirmed by coimmunoprecipitation of protein complexes from transfected cells. In addition, we demonstrate three of these interactions in the context of HCMV infection. This study reveals several new protein-protein interactions among HCMV tegument proteins, some of which are likely important for HCMV replication and pathogenesis.
Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission
Authors: Brimacombe Claire L. , Grove Joe , Meredith Luke W. , Hu Ke , Syder Andrew J. , Flores Maria Victoria , Timpe Jennifer M. , Krieger Sophie E. , Baumert Thomas F. , Tellinghuisen Timothy L. , Wong-Staal Flossie , Balfe Peter , McKeating Jane A.
Published: October 2010

Hepatitis C virus (HCV) can initiate infection by cell-free particle and cell-cell contact-dependent transmission. In this study we use a novel infectious coculture system to examine these alternative modes of infection. Cell-to-cell transmission is relatively resistant to anti-HCV glycoprotein monoclonal antibodies and polyclonal immunoglobulin isolated from infected individuals, providing an effective strategy for escaping host humoral immune responses. Chimeric viruses expressing the structural proteins representing the seven major HCV genotypes demonstrate neutralizing antibody-resistant cell-to-cell transmission. HCV entry is a multistep process involving numerous receptors. In this study we demonstrate that, in contrast to earlier reports, CD81 and the tight-junction components claudin-1 and occludin are all essential for both cell-free and cell-to-cell viral transmission. However, scavenger receptor BI (SR-BI) has a more prominent role in cell-to-cell transmission of the virus, with SR-BI-specific antibodies and small-molecule inhibitors showing preferential inhibition of this infection route. These observations highlight the importance of targeting host cell receptors, in particular SR-BI, to control viral infection and spread in the liver.
Multiple Innate Immune Pathways Contribute to the Immunogenicity of Recombinant Adenovirus Vaccine Vectors
Authors: Rhee Elizabeth G. , Blattman Joseph N. , Kasturi Sudhir P. , Kelley R. Phelps , Kaufman David R. , Lynch Diana M. , La Porte Annalena , Simmons Nathaniel L. , Clark Sarah L. , Pulendran Bali , Greenberg Philip D. , Barouch Dan H.
Published: October 2010

The innate immune pathways that contribute to the potent immunogenicity of recombinant adenovirus (rAd) vaccine vectors remain largely undefined. Previous studies assessing innate immunity triggered by vaccine vectors have largely focused on
in vitro
studies involving antigen-presenting cells and on early
in vivo
inflammatory responses. Here, we systematically explore the Toll-like receptor (TLR) signaling requirements for the generation of cellular immune responses by intramuscular immunization with common and alternative serotype rAd vectors in mice. Antigen-specific CD8
+
T-lymphocyte responses elicited by these rAd vectors were significantly diminished in MyD88
−/−
mice but not in TRIF
−/−
or TLR3
−/−
mice, suggesting the importance of MyD88-dependent TLR signaling. However, the absence of each individual TLR resulted in minimal to no effect on vaccine-elicited cellular immune responses. Moreover, responses were not diminished in IL-1R
−/−
or IL-18R
−/−
mice. These data suggest that rAd vectors engage multiple MyD88-dependent signaling pathways, none of which are individually critical; rather, they are integrated to contribute to the potent immunogenicity of rAd vectors. Stimulation of multiple innate immune mechanisms may prove a generalizable property of potent vaccines, and this strategy could be harnessed in the development of next-generation vaccine vectors and adjuvants.
The Alphaherpesvirus US3/ORF66 Protein Kinases Direct Phosphorylation of the Nuclear Matrix Protein Matrin 3
Authors: Erazo Angela , Yee Michael B. , Banfield Bruce W. , Kinchington Paul R.
Published: October 2010

The protein kinase found in the short region of alphaherpesviruses, termed US3 in herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) and ORF66 in varicella-zoster virus (VZV), affects several viral and host cell processes, and its specific targets remain an area of active investigation. Reports suggesting that HSV-1 US3 substrates overlap with those of cellular protein kinase A (PKA) prompted the use of an antibody specific for phosphorylated PKA substrates to identify US3/ORF66 targets. HSV-1, VZV, and PRV induced very different substrate profiles that were US3/ORF66 kinase dependent. The predominant VZV-phosphorylated 125-kDa species was identified as matrin 3, one of the major nuclear matrix proteins. Matrin 3 was also phosphorylated by HSV-1 and PRV in a US3 kinase-dependent manner and by VZV ORF66 kinase at a novel residue (KRRRT150EE). Since VZV-directed T150 phosphorylation was not blocked by PKA inhibitors and was not induced by PKA activation, and since PKA predominantly targeted matrin 3 S188, it was concluded that phosphorylation by VZV was PKA independent. However, purified VZV ORF66 kinase did not phosphorylate matrin 3
in vitro
, suggesting that additional cellular factors were required. In VZV-infected cells in the absence of the ORF66 kinase, matrin 3 displayed intranuclear changes, while matrin 3 showed a pronounced cytoplasmic distribution in late-stage cells infected with US3-negative HSV-1 or PRV. This work identifies phosphorylation of the nuclear matrix protein matrin 3 as a new conserved target of this kinase group.
PB2 Residue 158 Is a Pathogenic Determinant of Pandemic H1N1 and H5 Influenza A Viruses in Mice
Authors: Zhou Bin , Li Yan , Halpin Rebecca , Hine Erin , Spiro David J. , Wentworth David E.
Published: October 2010

Influenza A viruses are human and animal pathogens that cause morbidity and mortality, which range from mild to severe. The 2009 H1N1 pandemic was caused by the emergence of a reassortant H1N1 subtype (H1N1pdm) influenza A virus containing gene segments that originally circulated in human, avian, and swine virus reservoirs. The molecular determinants of replication and pathogenesis of H1N1pdm viruses in humans and other mammals are poorly understood. Therefore, we set out to elucidate viral determinants critical to the pathogenesis of this novel reassortant using a mouse model. We found that a glutamate-to-glycine substitution at residue 158 of the PB2 gene (PB2-E158G) increased the morbidity and mortality of the parental H1N1pdm virus. Results from mini-genome replication assays in human cells and virus titration in mouse tissues demonstrated that PB2-E158G is a pathogenic determinant, because it significantly increases viral replication rates. The virus load in PB2-E158G-infected mouse lungs was 1,300-fold higher than that of the wild-type virus. Our data also show that PB2-E158G had a much stronger influence on the RNA replication and pathogenesis of H1N1pdm viruses than PB2-E627K, which is a known pathogenic determinant. Remarkably, PB2-E158G substitutions also altered the pathotypes of two avian H5 viruses in mice, indicating that this residue impacts genetically divergent influenza A viruses and suggesting that this region of PB2 could be a new antiviral target. Collectively, the data presented in this study demonstrate that PB2-E158G is a novel pathogenic determinant of influenza A viruses in the mouse model. We speculate that PB2-E158G may be important in the adaptation of avian PB2 genes to other mammals, and BLAST sequence analysis identified a naturally occurring human H1N1pdm isolate that has this substitution. Therefore, future surveillance efforts should include scrutiny of this region of PB2 because of its potential impact on pathogenesis.
Role of RNase MRP in Viral RNA Degradation and RNA Recombination
Authors: Jaag Hannah M. , Lu Qiasheng , Schmitt Mark E. , Nagy Peter D.
Published: October 2010

RNA degradation, together with RNA synthesis, controls the steady-state level of viral RNAs in infected cells. The endoribonucleolytic cleavage of viral RNA is important not only for viral RNA degradation but for RNA recombination as well, due to the participation of some RNA degradation products in the RNA recombination process. To identify host endoribonucleases involved in degradation of
Tomato bushy stunt virus
(TBSV) in a
Saccharomyces cerevisiae
model host, we tested eight known endoribonucleases. Here we report that downregulation of
SNM1
, encoding a component of the RNase MRP, and a temperature-sensitive mutation in the
NME1
gene, coding for the RNA component of RNase MRP, lead to reduced production of the endoribonucleolytically cleaved TBSV RNA in yeast. We also show that the highly purified yeast RNase MRP cleaves the TBSV RNA
in vitro
, resulting in TBSV RNA degradation products similar in size to those observed in yeast cells. Knocking down the
NME1
homolog in
Nicotiana benthamiana
also led to decreased production of the cleaved TBSV RNA, suggesting that in plants, RNase MRP is involved in TBSV RNA degradation. Altogether, this work suggests a role for the host endoribonuclease RNase MRP in viral RNA degradation and recombination.
Human Pluripotent Stem Cells Produce Natural Killer Cells That Mediate Anti-HIV-1 Activity by Utilizing Diverse Cellular Mechanisms
Authors: Ni Zhenya , Knorr David A. , Clouser Christine L. , Hexum Melinda K. , Southern Peter , Mansky Louis M. , Park In-Hyun , Kaufman Dan S.
Published: October 2010

Cell-based therapies against HIV/AIDS have been gaining increased interest. Natural killer (NK) cells are a key component of the innate immune system with the ability to kill diverse tumor cells and virus-infected cells. While NK cells have been shown to play an important role in the control of HIV-1 replication, their functional activities are often compromised in HIV-1-infected individuals. We have previously demonstrated the derivation of NK cells from human embryonic stem cells (hESCs) with the ability to potently kill multiple types of tumor cells both
in vitro
and
in vivo
. We now demonstrate the derivation of functional NK cells from human induced pluripotent stem cells (iPSCs). More importantly, both hESC- and iPSC-derived NK cells are able to inhibit HIV-1 NL4-3 infection of CEM-GFP cells. Additional studies using HIV-1-infected human primary CD4
+
T cells illustrated that hESC- and iPSC-derived NK cells suppress HIV-1 infection by at least three distinct cellular mechanisms: killing of infected targets through direct lysis, antibody-dependent cellular cytotoxicity, and production of chemokines and cytokines. Our results establish the potential to utilize hESC- and iPSC-derived NK cells to better understand anti-HIV-1 immunity and provide a novel cellular immunotherapeutic approach to treat HIV/AIDS.
Simian Immunodeficiency Virus from the Sooty Mangabey and Rhesus Macaque Is Modified with O-Linked Carbohydrate
Authors: Stansell Elizabeth , Canis Kevin , Haslam Stuart M. , Dell Anne , Desrosiers Ronald C.
Published: October 2010

Although stretches of serine and threonine are sometimes sites for O-linked carbohydrate attachment, specific sequence and structural determinants for O-linked attachment remain ill defined. The gp120 envelope protein of SIVmac239 contains a serine-threonine-rich stretch of amino acids at positions 128 to 139. Here we show that lectin protein from jackfruit seed (jacalin), which binds to non- and monosialylated core 1 O-linked carbohydrate, potently inhibited the replication of SIVmac239. Selection of a jacalin-resistant SIVmac239 variant population resulted in virus with specific substitutions within amino acids 128 to 139. Cloned simian immunodeficiency virus (SIV) variants with substitutions in the 128-to-139 region had infectivities equivalent to, or within 1 log unit of, that of SIVmac239 and were resistant to the inhibitory effects of jacalin. Characterization of the SIVmac239 gp120 O-linked glycome showed the presence of core 1 and core 2 O-linked carbohydrate; a 128-to-139-substituted variant gp120 from jacalin-resistant SIV lacked O-linked carbohydrate. Unlike that of SIVmac239, the replication of HIV-1 strain NL4-3 was resistant to inhibition by jacalin. Purified gp120s from four SIVmac and SIVsm strains bound jacalin strongly in an enzyme-linked immunosorbent assay, while nine different HIV-1 gp120s, two SIVcpz gp120s, and 128-to-139-substituted SIVmac239 gp120 did not bind jacalin. The ability or inability to bind jacalin thus correlated with the presence of the serine-threonine-rich stretch in the SIVmac and SIVsm gp120s and the absence of such stretches in the SIVcpz and HIV-1 gp120s. Consistent with sequence predictions, two HIV-2 gp120s bound jacalin, while one did not. These data demonstrate the presence of non- and monosialylated core 1 O-linked carbohydrate on the gp120s of SIVmac and SIVsm and the lack of these modifications on HIV-1 and SIVcpz gp120s.
Varicella-Zoster Virus Glycoprotein E Is a Critical Determinant of Virulence in the SCID Mouse-Human Model of Neuropathogenesis
Authors: Zerboni Leigh , Berarducci Barbara , Rajamani Jaya , Jones Carol D. , Zehnder James L. , Arvin Ann
Published: October 2010

Varicella-zoster virus (VZV) is a neurotropic alphaherpesvirus. VZV infection of human dorsal root ganglion (DRG) xenografts in immunodeficient mice models the infection of sensory ganglia. We examined DRG infection with recombinant VZV (recombinant Oka [rOka]) and the following gE mutants: gEΔ27-90, gEΔCys, gE-AYRV, and gE-SSTT. gEΔ27-90, which lacks the gE domain that interacts with a putative receptor insulin-degrading enzyme (IDE), replicated as extensively as rOka, producing infectious virions and significant cytopathic effects within 14 days of inoculation. Since neural cells express IDE, the gE/IDE interaction was dispensable for VZV neurotropism. In contrast, gEΔCys, which lacks gE/gI heterodimer formation, was significantly impaired at early times postinfection; viral genome copy numbers increased slowly, and infectious virus production was not detected until day 28. Delayed replication was associated with impaired cell-cell spread in ganglia, similar to the phenotype of a gI deletion mutant (rOkaΔgI). However, at later time points, infection of satellite cells and other supportive nonneuronal cells resulted in extensive DRG tissue damage and cell loss such that cytopathic changes observed at day 70 were more severe than those for rOka-infected DRG. The replication of gE-AYRV, which is impaired for
trans
-Golgi network (TGN) localization, and the replication of gE-SSTT, which contains mutations in an acidic cluster, were equivalent to that of rOka, causing significant cytopathic effects and infectious virus production by day 14; genome copy numbers were equivalent to those of rOka. These experiments suggest that the gE interaction with cellular IDE, gE targeting to TGN sites of virion envelopment, and phosphorylation at SSTT are dispensable for VZV DRG infection, whereas the gE/gI interaction is critical for VZV neurovirulence.
Injury in elite county-level hurling: a prospective study
Authors: Murphy John C , Gissane Conor , Blake Catherine
Published: October 2010

Objective

To determine the incidence, prevalence and nature of sports injuries in elite male hurling players.

Design

Prospective study of county-grade hurling teams. Incidence, prevalence and descriptions of injuries were collated.

Setting

Four county teams during the 2007 season; January to September inclusive.

Participants

A total of 127 male players were followed over 34 weeks. Data were collected on a median (IQR) of 31 (30–32) players per team per week. The mean age was 23.3±2.5 years.

Results

There were 204 injuries to 104 players (82%, 95% CI (74 to 88)). Injury incidence rate during match-play (102.5 (84.4 to 123.2)) was 19 times higher than for training (5.3 (4.2 to 6.5)) (RR=19.5 (14.8 to 25.6)). The mean weekly prevalence of injury was 13.9% (12.5 to 14.8). Most injuries were new (n=170, 83.3%, (77.6 to 87.8)) and acute (n=165, 80.9% (74.9 to 85.7)). Muscle strain (n=86) accounted for 42.2% (35.6 to 49) of the total. 71% of injuries were to the lower limb (n=143, (63.5 to 76.0)) with hamstring strain (n=33, 16.5% (11.8 to 21.8)) predominating. Fractures constituted 7.4% injuries (n=15, 95% CI (4.5 to 11.8)), 12 of which were to the upper limb. There were three (1.5% (0.5 to 4.2)) eye injuries and one concussion injury (0.5% (0.1 to 2.7)).

Conclusions

These results provide data on hurling injuries using definitions that reflect international consensus statements. Injury incidence from match-play in particular is high compared with other sports. These findings have relevance for clinicians and coaches.
Array-based comparative genomic hybridisation analysis reveals recurrent chromosomal alterations in primary diffuse large B cell lymphoma of bone
Authors: Heyning F H , Jansen P M , Hogendoorn P C W , Szuhai K
Published: October 2010

Aims

Primary non-Hodgkin's lymphoma of bone (PLB) is a rare subtype of primary extranodal diffuse large B cell lymphoma. PLB has morphological homogeneity and a relatively favourable clinical behaviour. Recent studies report that array-based comparative genomic hybridisation (array-CGH) analysis can be used to classify lymphomas into clinically and biologically relevant phenotypes and possibly reveal differences in oncogenic mechanisms. Here the authors performed the first array-CGH study to detect illness related genomic alterations in nine, clinically well-staged primary lymphoma of bone cases.

Methods

Nine frozen samples from primary lymphoma of bone patients were immunophenotyped and subsequently investigated using a well-established array-CGH platform. The array-CGH results were confirmed by fluorescence in situ hybridisation. Clinical data and follow-up were obtained for all nine patients.

Results

Of the nine patients, eight reached complete remission, and one had progressive disease and died of primary lymphoma of bone. Frequent aberrations were: loss of 14q32 (n=7), trisomy 7 (n=6), gain of the long arm of chromosome 1 (n=5) and amplification of 2p16.1 (n=4). No statistically significant correlation between genetic abnormalities and clinical outcome was found.

Conclusions

The authors found several recurrent genomic aberrations, including five cases with gain of 1q and four cases with 2p16.1 amplification. These findings are associated with a germinal centre-like phenotype and favourable treatment outcome, and differ from chromosomal aberrations found in other extranodal lymphomas. These findings further substantiate the notion that primary lymphoma of bone should be considered as a distinct entity not only on clinic-pathological grounds but also on the genomic level as well.