bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycorrhizal‐mediated nitrogen acquisition in switchgrass under elevated temperatures and N enrichment
Authors: Schroeder‐Moreno Michelle S. , Greaver Tara L. , Wang Shuxin , Hu Shujin , Rufty Thomas W.
Published: October 2011

Arbuscular mycorrhizal fungi (AMF) can perform key roles in ecosystem functioning through improving host nutrient acquisition. Nitrogen (N) is an essential nutrient for plant growth, however, anthropogenic N loading (e.g. crop fertilization and deposition from combustion sources) is increasing so that N now threatens ecosystem sustainability around the world by causing terrestrial and aquatic eutrophication and acidification. It is important to better understand the capacity of AMF to directly uptake N from soils and transfer it to host plants because this process may increase N recycling and retention within ecosystems. In addition to understanding the role of AMF in the N cycle in the present day it is important to understand how AMF function may change as global change proceeds. Currently the net effects of N enrichment and elevated temperature predicted with global change on AMF are unknown. In this study, we examined the effects of N enrichment by simulated N‐deposition loading, elevated temperatures expected by future global changes and their interactions on growth and AMF‐mediated N acquisition of switchgrass (Panicum virgatum var. Alamo), an important species for biofuel production. Switchgrass plants were grown in microcosm units that divided mycorrhizal roots from AMF hyphae and organic residues enriched with 15N by compartments separated by an air gap to reduce N diffusion. While AMF did not enhance switchgrass biomass, mycorrhizas significantly increased 15N in shoots and total shoot N. Neither N enrichment nor elevated temperatures influenced this mycorrhizal‐mediated N uptake and transfer. Results from this study can aid in developing sustainable bioethanol and switchgrass production practices that are less reliant on synthetic fertilizers and more dependent on internal N recycling from AMF.
Benefits Visitors Derive from Sustained Engagement with a Single Museum
Authors: Everett Michele C. , Barrett Margaret S.
Published: October 2011

Abstract  Museums are currently faced with new challenges and issues of sustainability. Consequently, they are under increasing pressure to provide funding bodies with evidence of their value and worth. This paper reports findings from a narrative study that explored the nature of returning visitors’ engagement with a single museum over time. The study’s findings document a broad range of benefits visitors derive from a sustained relationship with a museum and reveal the significant contributions that sustained engagement with a museum make towards enriching visitors’ lives.
Experimental and Numerical Investigation Into the Heat Transfer Study of Nanofluids in Microchannel
Authors: Singh Pawan K. , Harikrishna P. V. , Sundararajan T. , Das Sarit K.
Published: October 2011

There are very few detailed experimental investigations about the heat transfer behavior of nanofluids in microchannel. The heat transfer behavior of nanofluids in microchannel is investigated. Two microchannels with hydraulic diameters 218 and 303 μm are fabricated by wet etching process on silicon wafer. An experimental set-up having provision of flow in the channel and temperature measurement along with bottom wall temperature is built-up. Alumina nanofluids with concentrations of 0.25 vol. %, 0.5 vol. %, and 1 vol. % with 45 nm are prepared, stabilized, and characterized by standard methods. The thermal conductivity and viscosity used in the study were measured and analyzed. The base fluids used are water and ethylene glycol. The effect of volume fraction, channel size, particle size, and base fluids are presented and analyzed. An important phenomenon of dispersion is observed. In addition, numerical modeling is carried out by using discrete phase approach. Shear induced particle migration is identified to be the reason of difference for dispersion of particles. The Brownian and thermophoretic forces are responsible for major changes in particle concentration and their movement. Also, it was found that better heat transfer characteristics can be obtained by higher concentration of nanofluids and by low viscous base fluids.
Determination of the Number of Tube Rows to Obtain Closure for Volume Averaging Theory Based Model of Fin-and-Tube Heat Exchangers
Authors: Zhou Feng , Hansen Nicholas E. , Geb David J. , Catton Ivan
Published: October 2011

Modeling of fin-and-tube heat exchangers based on the volume averaging theory (VAT) requires proper closure of the VAT based governing equations. Closure can be obtained from reasonable lower scale solutions of a computational fluid dynamics (CFD) code, which means the tube row number chosen should be large enough, so that the closure can be evaluated for a representative elementary volume (REV) that is, not affected by the entrance or recirculation at the outlet of the fin gap. To determine the number of tube rows, three-dimensional numerical simulations for plate fin-and-tube heat exchangers were performed, with the Reynolds number varying from 500 to 6000 and the number of tube rows varying from 1 to 9. A clear perspective of the variations of both overall and local fiction factor and the Nusselt number as the tube row number increases are presented. These variation trends are explained from the view point of the field synergy principle (FSP). Our investigation shows that 4 + 1 + 1 tube rows is the minimum number to get reasonable lower scale solutions. A computational domain including 5 + 2 + 2 tube rows is recommended, so that the closure formulas for drag resistance coefficient and heat transfer coefficient could be evaluated for the sixth and seventh elementary volumes to close the VAT based model.
Thermal Behavior Analysis of Wire Mini Heat Pipe
Authors: Vieira de Paiva Kleber , Barbosa Henriques Mantelli Marcia , Kessler Slongo Leonardo
Published: October 2011

This work presents a theoretical and experimental analysis of a copper mini heat pipe (MHP), fabricated from a sandwich formed between cylindrical wires and flat plates, which are welded by means of diffusion process. The edges formed between the wires and the plates provide the working fluid capillary pressure necessary to overcome all the pressure losses. Two different experimental set ups were developed: one for test in gravity (laboratory) and other for microgravity conditions (International Space Station—ISS). The main difference between them lies in the condenser section. In the laboratory, cooling water was used to remove heat from the mini heat pipe, while at the ISS, fins and air fan were employed. In gravity, three different working fluids were tested: water, acetone, and methanol, while, for the experiments at the ISS, just water was used. A model was developed to predict the maximum heat transfer capacity of the device. In comparison to the literature models, the main difference of the present model is the variation of contact angle to adjust the mathematical model. Therefore, the main contributions of the present work are development of wire plate mini heat pipe fabrication methodology using diffusion welding, improvement of the analytical model used to predict the maximum heat transfer capacity of the device, determination of the present technology optimum design parameters, and test data obtained under microgravity conditions.
Hard vs soft constraints in the full field reconstruction of incompressible flow kinematics from noisy scattered velocimetry data
Authors: Sadati Monirosadat , Luap Clarisse , Kröger Martin , Öttinger Hans Christian
Published: October 2011

High quality flow kinematics reconstruction from noisy and spatially scattered data requires the use of regularization techniques but remains a challenge. We set out to test the effect and practical relevance of additional incompressibility constraints. To this end, we present two methods for reconstructing smooth velocity and velocity gradient fields from such data in an incompressible two-dimensional complex flow. One is based on a generalized Tikhonov regularization combined with a finite element approximation and uses a stream function formulation, which enforces incompressibility (hard constraint). This approach is compared to that in which incompressibility is asymptotically achieved by adding a divergence penalty term in the regularization expression (soft constraint). The methods are compared on synthetic velocity data, obtained for an incompressible Oldroyd–B fluid in a cross-slot channel with added noise. For such data sets, both methods are seen to lead to essentially identical results. However, for a given grid size, the stream function formulation uses a single regularization parameter and less degrees of freedom to provide the required continuity of the gradient fields. The fidelity of the reconstruction is investigated in terms of the quality of the streamlines and velocity gradient history. Incompressibility constraints turn into significant and valuable improvement for applications as we demonstrate by analyzing the stress and optical signal fields obtained by applying a constitutive equation to the reconstructed flow fields.
Shear-induced phase separation (SIPS) with shear banding in solutions of cationic surfactant and salt
Authors: Thareja Prachi , Hoffmann Ingo H. , Liberatore Matthew W. , Helgeson Matthew E. , Hu Y. Thomas , Gradzielski Michael , Wagner Norman J.
Published: October 2011

The rheological behavior and microstructure of branched, cationic wormlike micellar (WLM) solutions of 40 mM erucyl bis(hydroxyethyl)methylammonium chloride (EHAC) are studied as a function of added salt (sodium salicylate) concentration, temperature, and shear rate via Rheosmall-angle light scattering (Rheo-SALS). These WLM solutions exhibit shear-enhanced concentration fluctuations leading to shear-induced phase separation (SIPS), manifested as visual turbidity under shear and the appearance of a characteristic “butterfly” scattering pattern in Rheo-SALS experiments. Flow kinematics measurements in a Couette geometry are used to determine the relationship between SIPS and shear banding, i.e., the splitting of the flow into shear bands with different local shear rates. Modeling using the Giesekus constitutive equation aids in discrimination between banding and nonbanding solutions. The combination of Rheo-SALS, dynamic rheology, velocimetry, and constitutive equation modeling allows detailed exploration of the relationship between SIPS, shear banding, fluid microstructure, and the equilibrium phase behavior.
Paleolithic Art in Peril: Policy and Science Collide at Altamira Cave
Authors: Saiz-Jimenez Cesareo , Cuezva Soledad , Jurado Valme , Fernandez-Cortes Angel , Porca Estefania , Benavente David , Cañaveras Juan C. , Sanchez-Moral Sergio
Published: October 2011

Despite evidence of damaging human impacts, cave paintings may again be threatened if visitors are allowed access.
Picture Perfect Future Past
Out of This World
Science Fiction: But Not As You Know It

by Mike Ashley

The British Library, London, 2011. 144 pp. Paper, $29.95, £16.95. ISBN 9780712358354.
Authors: Riddihough Guy
Published: October 2011

Taking a broad view of science fiction, Ashley delivers a sumptuously illustrated survey of themes and ideas that have repeatedly appeared in imaginings of tomorrows.
Human Cells Cloned—Almost
Authors: Vogel Gretchen
Published: October 2011

Researchers have found a way to use human oocytes to reprogram adult cells, allowing them to form early embryos that can give rise to embryonic stem cells.
An Epoch Debate
Authors: Vince Gaia
Published: October 2011

There's no dispute that humans are leaving their mark on the planet, but geologists and other scientists are debating whether this imprint is distinctive and enduring enough to designate a new epoch: the Anthropocene.
A Sign of Our Times
Authors: Vince Gaia
Published: October 2011

When did the Anthropocene begin? Many human-driven planetary changes have their roots in the industrial revolution, but some think the marker should be set at 1945, when radioactive nuclei were first introduced into the environment.
Phase I Study Evaluating the Safety and Pharmacokinetics of MDX-1303, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers
Authors: Riddle Valerie , Leese Phillip , Blanset Diann , Adamcio Melany , Meldorf Matthew , Lowy Israel
Published: October 2011

MDX-1303 (Valortim) is a fully human monoclonal antibody (hMAb) with a high affinity for
Bacillus anthracis
protective antigen (PA). MDX-1303 binds to PA and interferes with the activity of the anthrax toxin; it was selected based on its superior functional activity in the toxin neutralization activity (TNA) assay. MDX-1303 has demonstrated efficacy in the postexposure and therapeutic settings in New Zealand White rabbits, cynomolgus monkeys, and African green monkeys. This phase I study sought to characterize the safety, tolerability, immunogenicity, and pharmacokinetics (PK)/pharmacodynamics (PD) of MDX-1303 in healthy human subjects. Cohorts of 3 to 10 subjects were administered MDX-1303 as either a single intravenous (i.v.) dose at dose levels of 0.3, 1, 3, 10, and 20 mg/kg of body weight or as a single intramuscular (i.m.) dose at 100 mg. Forty-six subjects were enrolled, and 16 (35%) of these subjects experienced one or more grade 1 adverse events considered to be related to treatment with MDX-1303. There were no grade 2 to 4 adverse events or serious adverse events (SAEs) considered to be related to treatment. The mean half-life of MDX-1303 ranged from 22 to 33 days across the i.v. administration cohorts and was approximately 32 days following i.m. administration. Systemic exposure following 100-mg i.m. administration was within the range of exposure following 1-mg/kg i.v. administration with a relative bioavailability of approximately 65%. MDX-1303 was generally well tolerated, and no anti-MDX-1303 antibodies were detected following a single dose.
Improved Antimicrobial Host Defense in Mice following Poly-(1,6)-β-
d
-Glucopyranosyl-(1,3)-β-
d
-Glucopyranose Glucan Treatment by a Gender-Dependent Immune Mechanism
Authors: Newsome Courtni T. , Flores Estefany , Ayala Alfred , Gregory Stephen , Reichner Jonathan S.
Published: October 2011

Clinical trials with biological modifiers targeting specific inflammatory mediators associated with severe sepsis have shown no or limited survival benefit. The approach taken in studies reported here was to limit the point source of intra-abdominal infection by potentiating innate immune function, thereby lessening the severity of sepsis and improving survival. Soluble beta-glucans, glucose polymers of the fungal cell wall, have been shown to stimulate innate immune host defense in animal and human studies when administered prior to an infectious challenge. We evaluated the effects of poly-(1,6)-β-
d
-glucopyranosyl-(1,3)-β-
d
-glucopyranose glucan (PGG glucan) on overall survival when administered intraperitoneally after the onset of polymicrobial infection by cecal ligation and puncture (CLP). Since gender-dependent differences in host immune response to infection have been reported, male and female mice were prospectively stratified for PGG glucan treatment. Outbred CD-1 mice were administered 10 mg/kg of body weight PGG glucan or the polysaccharide control, dextran, 1 h after CLP. Six hours after CLP, blood samples were obtained for cytokine measurements. Surprisingly, a gender-dependent effect on the response to PGG glucan was revealed. PGG glucan enhanced survival in female mice over a 10-day period, but survival in males was improved for only 24 h. In female mice, PGG glucan reduced interleukin-6 (IL-6) and IL-10 levels and reduced the bacterial burden in the liver. Ovariectomy abrogated the response to PGG glucan. Together, the translational potential of these findings is the indicated use of PGG glucan given locally, rather than intravenously, for improved source control during the management of sepsis. This therapy does not require prophylactic beta-glucan administration.
Plasma Antibody Profiles as Diagnostic Biomarkers for Tuberculosis
Authors: Khan Imran H. , Ravindran Resmi , Krishnan Viswanathan V. , Awan Irum Nawaz , Rizvi Syed Kumail , Saqib Muhammad Arif , Shahzad Mirza Imran , Tahseen Sabira , Ireton Greg , Goulding Celia W. , Felgner Phil , DeRiemer Kathy , Khanum Azra , Luciw Paul A.
Published: October 2011

Two billion people are infected with
Mycobacterium tuberculosis
, the etiological agent of tuberculosis (TB), worldwide. Ten million to 20 million of the infected individuals develop disease per year. TB is a treatable disease, provided that it is diagnosed in a timely manner. The current TB diagnostic methods are subjective, inefficient, or not cost-effective. Antibody-based blood tests can be used efficiently and cost-effectively for TB diagnosis. A major challenge is that different TB patients generate antibodies against different antigens. Therefore, a multiplex immunoassay approach is needed. We have developed a multiplex panel of 28
M. tuberculosis
antigen-coated microbeads. Plasma samples were obtained from over 300 pulmonary TB patients and healthy controls in a country where TB is endemic, Pakistan. Multiplex data were analyzed using computational tools by multivariate statistics, classification algorithms, and cluster analysis. The results of antibody profile-based detection, using 16 selected antigens, closely correlated with those of the sputum-based diagnostic methods (smear microscopy and culture) practiced in countries where TB is endemic. Multiplex microbead immunoassay had a sensitivity and specificity of approximately 90% and 80%, respectively. These antibody profiles could potentially be useful for the diagnosis of nonpulmonary TB, which accounts for approximately 20% of cases of disease. Since an automated, high-throughput version of this multiplex microbead immunoassay could analyze thousands of samples per day, it may be useful for the diagnosis of TB in millions of patients worldwide.
Molecular Detection and Species-Specific Identification of Medically Important Aspergillus Species by Real-Time PCR in Experimental Invasive Pulmonary Aspergillosis
Authors: Walsh Thomas J. , Wissel Mark C. , Grantham Kevin J. , Petraitiene Ruta , Petraitis Vidmantas , Kasai Miki , Francesconi Andrea , Cotton Margaret P. , Hughes Johanna E. , Greene Lora , Bacher John D. , Manna Pradip , Salomoni Martin , Kleiboeker Steven B. , Reddy Sushruth K.
Published: October 2011

Diagnosis of invasive pulmonary aspergillosis (IPA) remains a major challenge to clinical microbiology laboratories. We developed rapid and sensitive quantitative PCR (qPCR) assays for genus- and species-specific identification of
Aspergillus
infections by use of TaqMan technology. In order to validate these assays and understand their potential diagnostic utility, we then performed a blinded study of bronchoalveolar lavage (BAL) fluid specimens from well-characterized models of IPA with the four medically important species. A set of real-time qPCR primers and probes was developed by utilizing unique ITS1 regions for genus- and species-specific detection of the four most common medically important
Aspergillus
species (
Aspergillus fumigatus
,
A. flavus
,
A. niger
, and
A. terreus
). Pan-
Aspergillus
and species-specific qPCRs with BAL fluid were more sensitive than culture for detection of IPA caused by
A. fumigatus
in untreated (
P
< 0.0007) and treated (
P
≤ 0.008) animals, respectively. For infections caused by
A. terreus
and
A. niger
, culture and PCR amplification from BAL fluid yielded similar sensitivities for untreated and treated animals. Pan-
Aspergillus
PCR was more sensitive than culture for detection of
A. flavus
in treated animals (
P
= 0.002). BAL fluid pan-
Aspergillus
and species-specific PCRs were comparable in sensitivity to BAL fluid galactomannan (GM) assay. The copy numbers from the qPCR assays correlated with quantitative cultures to determine the pulmonary residual fungal burdens in lung tissue. Pan-
Aspergillus
and species-specific qPCR assays may improve the rapid and accurate identification of IPA in immunocompromised patients.
Indications that Live Poultry Markets Are a Major Source of Human H5N1 Influenza Virus Infection in China
Authors: Wan Xiu-Feng , Dong Libo , Lan Yu , Long Li-Ping , Xu Cuiling , Zou Shumei , Li Zi , Wen Leying , Cai Zhipeng , Wang Wei , Li Xiaodan , Yuan Fan , Sui Hongtao , Zhang Ye , Dong Jie , Sun Shanhua , Gao Yan , Wang Min , Bai Tian , Yang Lei , Li Dexin , Yang Weizhong , Yu Hongjie , Wang Shiwen , Feng Zijian , Wang Yu , Guo Yuanji , Webby Richard J. , Shu Yuelong
Published: October 2011

Human infections of H5N1 highly pathogenic avian influenza virus have continued to occur in China without corresponding outbreaks in poultry, and there is little conclusive evidence of the source of these infections. Seeking to identify the source of the human infections, we sequenced 31 H5N1 viruses isolated from humans in China (2005 to 2010). We found a number of viral genotypes, not all of which have similar known avian virus counterparts. Guided by patient questionnaire data, we also obtained environmental samples from live poultry markets and dwellings frequented by six individuals prior to disease onset (2008 and 2009). H5N1 viruses were isolated from 4 of the 6 live poultry markets sampled. In each case, the genetic sequences of the environmental and corresponding human isolates were highly similar, demonstrating a link between human infection and live poultry markets. Therefore, infection control measures in live poultry markets are likely to reduce human H5N1 infection in China.
The Cargo-Binding Domain of Transportin 3 Is Required for Lentivirus Nuclear Import
Authors: Logue Eric C. , Taylor Kayleigh T. , Goff Peter H. , Landau Nathaniel R.
Published: October 2011

Lentiviruses, unlike the gammaretroviruses, are able to infect nondividing cells by transiting through nuclear pores to access the host genomic DNA. Several nuclear import and nuclear pore components have been implicated as playing a role in nuclear import, including transportin 3 (TNPO3), a member of the importin-β family of nuclear import proteins. We demonstrated that TNPO3 was required by several lentiviruses, with simian immunodeficiency virus mac239 (SIVmac239) and equine infectious anemia virus (EIAV) the most dependent and human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV) the least. Analysis of HIV-1/SIVmac239 chimeric viruses showed that dependence on TNPO3 mapped to the SIVmac239 capsid. Mutation of a single amino acid, A76V in the SIVmac239 capsid, rendered the virus TNPO3 independent and resistant to mCPSF6-358, a truncated splicing factor that prevents HIV-1 nuclear import. Using a complementation assay based on 293T cells that express a TNPO3-targeted short hairpin RNA (shRNA), we showed that the
Drosophila
TNPO3 homologue can substitute for its human counterpart and that it mapped a key functional domain of TNPO3 to the carboxy-terminal cargo-binding domain. Within the cargo-binding domain, two hydrophobic motifs were required for TNPO3-dependent infection. The mutated TNPO3 proteins maintained their ability to localize to the nucleus, suggesting that their inability to restore lentivirus infection resulted from an inability to bind to a host or viral cargo protein.
ISG56 and IFITM1 Proteins Inhibit Hepatitis C Virus Replication
Authors: Raychoudhuri Amit , Shrivastava Shubham , Steele Robert , Kim Hangeun , Ray Ranjit , Ray Ratna B.
Published: October 2011

Hepatitis C virus (HCV) often leads to persistent infection. Interferon (IFN) and IFN-stimulated genes (ISGs) are amplified during HCV infection but fail to eliminate virus from the liver in a large number of infected patients. We have observed previously that HCV infection induces IFN-β production in immortalized human hepatocytes (IHH) as early as 24 h after infection, although virus replication is not inhibited. To gain insights on possible countermeasures of virus for the suppression of host antiviral response, the cellular transcriptional profiles of ISGs were examined after various treatments of IHH. The majority of ISGs were upregulated in IFN-treated IHH from the level for mock-treated cells. However, the comparison of ISG expression in IFN-treated IHH and IFN-pretreated, HCV genotype 2a-infected IHH indicated that virus infection suppresses the upregulation of a subset of effector molecules, including ISG56 and IFITM1. Similar results were observed for HCV-infected Huh7 cells. Subsequent study suggested that the exogenous expression of ISG56 or IFITM1 inhibits HCV replication in IHH or Huh7 cells, and the knockdown of these genes enhanced HCV replication. Further characterization revealed that the overexpression of these ISGs does not block HCV pseudotype entry into Huh7 cells. Taken together, our results demonstrated that ISG56 and IFITM1 serve as important molecules to restrict HCV infection, and they may have implications in the development of therapeutic modalities.
Modeling of Human Cytomegalovirus Maternal-Fetal Transmission in a Novel Decidual Organ Culture
Authors: Weisblum Yiska , Panet Amos , Zakay-Rones Zichria , Haimov-Kochman Ronit , Goldman-Wohl Debra , Ariel Ilana , Falk Haya , Natanson-Yaron Shira , Goldberg Miri D. , Gilad Ronit , Lurain Nell S. , Greenfield Caryn , Yagel Simcha , Wolf Dana G.
Published: October 2011

Human cytomegalovirus (HCMV) is the leading cause of congenital infection, associated with severe birth defects and intrauterine growth retardation. The mechanism of HCMV transmission via the maternal-fetal interface is largely unknown, and there are no animal models for HCMV. The initial stages of infection are believed to occur in the maternal decidua. Here we employed a novel decidual organ culture, using both clinically derived and laboratory-derived viral strains, for the
ex vivo
modeling of HCMV transmission in the maternal-fetal interface. Viral spread in the tissue was demonstrated by the progression of infected-cell foci, with a 1.3- to 2-log increase in HCMV DNA and RNA levels between days 2 and 9 postinfection, the expression of immediate-early and late proteins, the appearance of typical histopathological features of natural infection, and dose-dependent inhibition of infection by ganciclovir and acyclovir. HCMV infected a wide range of cells in the decidua, including invasive cytotrophoblasts, macrophages, and endothelial, decidual, and dendritic cells. Cell-to-cell viral spread was revealed by focal extension of infected-cell clusters, inability to recover infectious extracellular virus, and high relative proportions (88 to 93%) of cell-associated viral DNA. Intriguingly, neutralizing HCMV hyperimmune globulins exhibited inhibitory activity against viral spread in the decidua even when added at 24 h postinfection—providing a mechanistic basis for their clinical use in prenatal prevention. The
ex vivo
-infected decidual cultures offer unique insight into patterns of viral tropism and spread, defining initial stages of congenital HCMV transmission, and can facilitate evaluation of the effects of new antiviral interventions within the maternal-fetal interface milieu.
Rift Valley Fever Virus Vaccine Lacking the NSs and NSm Genes Is Safe, Nonteratogenic, and Confers Protection from Viremia, Pyrexia, and Abortion following Challenge in Adult and Pregnant Sheep
Authors: Bird Brian H. , Maartens Louis H. , Campbell Shelley , Erasmus Baltus J. , Erickson Bobbie R. , Dodd Kimberly A. , Spiropoulou Christina F. , Cannon Deborah , Drew Clifton P. , Knust Barbara , McElroy Anita K. , Khristova Marina L. , Albariño César G. , Nichol Stuart T.
Published: October 2011

Rift Valley fever virus (RVFV) is a mosquito-borne human and veterinary pathogen causing large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Safe and effective vaccines are critically needed, especially those that can be used in a targeted one-health approach to prevent both livestock and human disease. We report here on the safety, immunogenicity, and efficacy of the ΔNSs-ΔNSm recombinant RVFV (rRVFV) vaccine (which lacks the NSs and NSm virulence factors) in a total of 41 sheep, including 29 timed-pregnant ewes. This vaccine was proven safe and immunogenic for adult animals at doses ranging from 1.0 × 10
3
to 1.0 × 10
5
PFU administered subcutaneously (s.c.). Pregnant animals were vaccinated with 1.0 × 10
4
PFU s.c. at day 42 of gestation, when fetal sensitivity to RVFV vaccine-induced teratogenesis is highest. No febrile reactions, clinical illness, or pregnancy loss was observed following vaccination. Vaccination resulted in a rapid increase in anti-RVFV IgM (day 4) and IgG (day 7) titers. No seroconversion occurred in cohoused control animals. A subset of 20 ewes progressed to full-term delivery after vaccination. All lambs were born without musculoskeletal, neurological, or histological birth defects. Vaccine efficacy was assessed in 9 pregnant animals challenged at day 122 of gestation with virulent RVFV (1.0 × 10
6
PFU intravenously). Following challenge, 100% (9/9) of the animals were protected, progressed to full term, and delivered healthy lambs. As expected, all 3 sham-vaccinated controls experienced viremia, fetal death, and abortion postchallenge. These results demonstrate that the ΔNSs-ΔNSm rRVFV vaccine is safe and nonteratogenic and confers high-level protection in sheep.
Adenosine A1-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment
Authors: Gao Xiang , Patzak Andreas , Sendeski Mauricio , Scheffer Peter G. , Teerlink Tom , Sällström Johan , Fredholm Bertil B. , Persson A. Erik G. , Carlström Mattias
Published: October 2011

Adenosine mediates tubuloglomerular feedback responses via activation of A1-receptors on the renal afferent arteriole. Increased preglomerular reactivity, due to reduced nitric oxide (NO) production or increased levels of ANG II and reactive oxygen species (ROS), has been linked to hypertension. Using A1-receptor knockout (A1−/−) and wild-type (A1+/+) mice we investigated the hypothesis that A1-receptors modulate arteriolar and blood pressure responses during NO synthase (NOS) inhibition or ANG II treatment. Blood pressure and renal afferent arteriolar responses were measured in nontreated mice and in mice with prolonged Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) or ANG II treatment. The hypertensive responses to l-NAME and ANG II were clearly attenuated in A1−/−mice. Arteriolar contractions to l-NAME (10−4mol/l; 15 min) and cumulative ANG II application (10−12to 10−6mol/l) were lower in A1−/−mice. Simultaneous treatment with tempol (10−4mol/l; 15 min) attenuated arteriolar responses in A1+/+but not in A1−/−mice, suggesting differences in ROS formation. Chronic treatment with l-NAME or ANG II did not alter arteriolar responses in A1−/−mice, but enhanced maximal contractions in A1+/+mice. In addition, chronic treatments were associated with higher plasma levels of dimethylarginines (asymmetrical and symmetrical) and oxidative stress marker malondialdehyde in A1+/+mice, and gene expression analysis showed reduced upregulation of NOS-isoforms and greater upregulation of NADPH oxidases. In conclusion, adenosine A1-receptors enhance preglomerular responses during NO inhibition and ANG II treatment. Interruption of A1-receptor signaling blunts l-NAME and ANG II-induced hypertension and oxidative stress and is linked to reduced responsiveness of afferent arterioles.
Theta oscillations reflect a putative neural mechanism for human sensorimotor integration
Authors: Cruikshank Leanna C. , Singhal Anthony , Hueppelsheuser Mark , Caplan Jeremy B.
Published: October 2011

Hippocampal theta oscillations (3–12 Hz) may reflect a mechanism for sensorimotor integration in rats (Bland BH. Prog Neurobiol 26: 1–54, 1986); however, it is unknown whether cortical theta activity underlies sensorimotor integration in humans. Rather, the mu rhythm (8–12 Hz) is typically found to desynchronize during movement. We measured oscillatory EEG activity for two conditions of an instructed delayed reaching paradigm. Conditions 1 and 2 were designed to differentially manipulate the contribution of the ventral visuomotor stream during the response initiation phase. We tested the hypothesis that theta activity would reflect changes in the relevant sensorimotor network: condition 2 engaged ventral stream mechanisms to a greater extent than condition 1. Theta oscillations were more prevalent during movement initiation and execution than during periods of stillness, consistent with a sensorimotor relevance for theta activity. Furthermore, theta activity was more prevalent at temporal sites in condition 2 than condition 1 during response initiation, suggesting that theta activity is present within the necessary sensorimotor network. Mu activity desynchronized more during condition 2 than condition 1, suggesting mu desynchronization is also specific to the sensorimotor network. In summary, cortical theta synchronization and mu desynchronization may represent broadly applicable rhythmic mechanisms for sensorimotor integration in the human brain.
Experimental Models of Cryptococcosis
Authors: Sabiiti Wilber , May Robin C. , Pursall E. Rhiannon
Published: October 2011

Cryptococcosis is a life-threatening fungal disease that infects around one million people each year. Establishment and progression of disease involves a complex interplay between the fungus and a diverse range of host cell types. Over recent years, numerous cellular, tissue, and animal models have been exploited to probe this host-pathogen interaction. Here we review the range of experimental models that are available for cryptococcosis research and compare the relative advantages and limitations of the different systems.
Increased Skin Papilloma Formation in Mice Lacking Glutathione Transferase GSTP
Authors: Henderson Colin J. , Ritchie Kenneth J. , McLaren Aileen , Chakravarty Probir , Wolf C. Roland
Published: October 2011

The glutathione S-transferase GSTP is overexpressed in many human cancers and chemotherapy-resistant cancer cells, where there is evidence that GSTP may have additional functions beyond its known catalytic role. On the basis of evidence that Gstp-deficient mice have a comparatively higher susceptibility to skin carcinogenesis, we investigated whether this phenotype reflected an alteration in carcinogen detoxification or not. For this study, Gstp−/− mice were interbred with Tg.AC mice that harbor initiating H-ras mutations in the skin. Gstp−/−/Tg.AC mice exposed to the proinflammatory phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) exhibited higher tumor incidence and multiplicity with a significant thickening of skin after treatment, illustrating hyperproliferative growth. Unexpectedly, we observed no difference in cellular proliferation or apoptosis or in markers of oxidative stress, although higher levels of the inflammatory marker nitrotyrosine were found in Gstp−/−/Tg.AC mice. Instead, gene set enrichment analysis of microarray expression data obtained from skin revealed a more proapoptotic and proinflammatory environment shortly after TPA treatment. Within 4 weeks of TPA treatment, Gstp−/−/Tg.AC mice displayed altered lipid/sterol metabolism and Wnt signaling along with aberrant processes of cytoskeletal control and epidermal morphogenesis at both early and late times. In extending the evidence that GSTP has a vital role in normal homeostatic control and cancer prevention, they also strongly encourage the emerging concept that GSTP is a major determinant of the proinflammatory character of the tumor microenvironment. This study shows that the GSTP plays a major role in carcinogenesis distinct from its role in detoxification and provides evidence that the enzyme is a key determinant of the proinflammatory tumor environment. Cancer Res; 71(22); 7048–60. ©2011 AACR.
EGFR-AKT-Smad Signaling Promotes Formation of Glioma Stem-like Cells and Tumor Angiogenesis by ID3-Driven Cytokine Induction
Authors: Jin Xun , Yin Jinlong , Kim Sung-Hak , Sohn Young-Woo , Beck Samuel , Lim Young Chang , Nam Do-Hyun , Choi Yun-Jaie , Kim Hyunggee
Published: October 2011

Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the pathobiological traits of glioblastoma and genesis of glioma stem-like cells (GSC), but the underlying mechanism is still unknown. Here, we show that epidermal growth factor receptor (EGFR) signaling regulates the proliferation, angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins (IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3 alone imparted GSC features to primary astrocytes derived from Ink4a/Arf-deficient mouse, and EGFR–ID3–IL-6 signaling axis gave rise to tumor cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5–driven induction of ID3, which led to a decrease in the tumorsphere forming ability of GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without obvious cytotoxic effects. However, these cells seemed to regain colonogenic ability after removal of the EGFR inhibitors. Together, the results delineate a novel integrative molecular mechanism in which the RTK-ID signaling pathway governs genesis and maintenance of GBM histopathologic features, such as GSCs-based tumor initiation, progression, and angiogenesis. Cancer Res; 71(22); 7125–34. ©2011 AACR.
β-Blockers and Survival among Danish Patients with Malignant Melanoma: A Population-Based Cohort Study
Authors: Lemeshow Stanley , Sørensen Henrik Toft , Phillips Gary , Yang Eric V. , Antonsen Sussie , Riis Anders H. , Lesinski Gregory B. , Jackson Rebecca , Glaser Ronald
Published: October 2011

Background: To study whether use of β-blockers increases survival in patients with malignant melanoma because experimental data suggest that catecholamine hormones may be involved in stimulating the aggressiveness of malignant melanoma.

Methods: A total of 4,179 patients diagnosed with malignant melanoma in Denmark with a median follow-up of 4.9 years and identified in the Danish Cancer Registry participated. Data on β-blocker use, comorbidity, and survival were obtained from medical and administrative databases. Cox proportional hazards models were used to estimate HRs for all-cause mortality with 95% CIs with adjustment for prognostic factors.

Results: A total of 372 (8.9%) patients with malignant melanoma were treated with β-blockers within 90 days of melanoma diagnosis. The median β-blocker duration for exposure within 90 days of melanoma diagnosis, more than 90 days, and no prior exposure was 7.6, 1.4, and 0 years, respectively. The patients receiving β-blockers were older, had more comorbidities, and more cardiovascular and psychotropic drug user than the patients receiving no β-blockers prior to melanoma diagnosis. After adjustment for age and comorbidity index, the HR for melanoma death was 0.87 (95% CI: 0.64–1.20) and for all-cause mortality was 0.81 (95% CI: 0.67–0.97).

Conclusion: Increased survival time of patients with melanoma receiving β-blockers suggests that this class of drugs may hold promise in treatment strategy for these patients.

Impact: The observations described here suggest that catecholamines may retard melanoma progression and that β-blockers may have unrecognized potential as a therapeutic intervention for melanoma. Cancer Epidemiol Biomarkers Prev; 20(10); 2273–9. ©2011 AACR.
Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer
Authors: Roylance Rebecca , Endesfelder David , Gorman Patricia , Burrell Rebecca A. , Sander Jil , Tomlinson Ian , Hanby Andrew M. , Speirs Valerie , Richardson Andrea L. , Birkbak Nicolai J. , Eklund Aron C. , Downward Julian , Kschischo Maik , Szallasi Zoltan , Swanton Charles
Published: October 2011

Background: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive breast cancer in contrast to ER-negative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes.

Methods: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome.

Results: There was increased CIN and clonal heterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.

Conclusions: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup.

Impact: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation. Cancer Epidemiol Biomarkers Prev; 20(10); 2183–94. ©2011 AACR.
Cancer Fatalism: Deterring Early Presentation and Increasing Social Inequalities?
Authors: Beeken Rebecca J. , Simon Alice E. , von Wagner Christian , Whitaker Katriina L. , Wardle Jane
Published: October 2011

Background: Fatalistic beliefs about cancer have been implicated in low uptake of screening and delay in presentation particularly in low socioeconomic status (SES) groups, but no studies have systematically evaluated interrelationships between SES, fatalism, and early detection behaviors. We explored whether (i) fatalism is associated with negative attitudes toward early detection, (ii) lower SES groups are more fatalistic, and (iii) SES differences in fatalism partly explain SES differences in attitudes toward early detection.

Methods: In a population-representative sample of adults in Britain using computer-based interviews in the home setting, respondents (N = 2,018) answered two questions to index fatalism (expectations of cancer survival and cure) and two items on early detection attitudes (the perceived value of early detection and fear of symptom reporting). SES was indexed with a social grade classification.

Results: Fatalism was associated with being less positive about early detection (β = −0.40, P < 0.001) and more fearful about seeking help for a suspicious symptom (β = 0.24, P < 0.001). Lower SES groups were more fatalistic (β = −0.21, P < 0.001). Path analyses suggest that SES differences in fatalism might explain SES differences in attitudes about early detection.

Conclusions: In this population sample, SES differences in fatalism partly explained SES differences in the perceived value of early detection and fear of symptom presentation.

Impact: Fatalistic beliefs about cancer should be targeted to promote early presentation of cancer and this may be particularly important for lower SES groups. Cancer Epidemiol Biomarkers Prev; 20(10); 2127–31. ©2011 AACR.
No Evidence for Human Papillomavirus in the Etiology of Colorectal Polyps
Authors: Burnett-Hartman Andrea N. , Newcomb Polly A. , Mandelson Margaret T. , Galloway Denise A. , Madeleine Margaret M. , Wurscher Michelle A. , Carter Joseph J. , Makar Karen W. , Potter John D. , Schwartz Stephen M.
Published: October 2011

Background: While some studies have reported detection of oncogenic human papillomavirus (HPV) in colorectal tumors, others have not.

Methods: We examined the association between oncogenic HPV infection and colorectal polyps in a case–control study of individuals with colorectal adenomas (n = 167), hyperplastic polyps (n = 87), and polyp-free controls (n = 250). We carried out real-time PCR for HPV-16 and -18 DNA, and SPF PCR covering 43 HPV types, on lesional and normal colorectal tissue samples. Plasma antibodies for oncogenic HPV types were assessed via a bead-based multiplex Luminex assay.

Results: HPV DNA was not found in any of the 609 successfully assayed colorectal tissue samples from adenomas, hyperplastic polyps, normal biopsies adjacent to polyps, or normal biopsies of the rectum of disease-free controls. Also, there was no association between HPV seropositivity for all oncogenic HPV types combined, for either polyp type, and for men or women. When analyses were restricted to participants without a history of polyps, among men [adenomas (n = 31), hyperplastic polyps (n = 28), and controls (n = 68)], there was an association between seropositivity and hyperplastic polyps when all oncogenic HPV types were combined (OR = 3.0; 95% CI: 1.1–7.9).

Conclusions: Overall, our findings do not support an etiologic relationship between HPV and colorectal adenomas or hyperplastic polyps; however, our finding suggesting an association between HPV seropositivity and hyperplastic polyps in men may warrant further investigations.

Impact: After stringent controls for contamination and three methods to assess HPV infection, we report no evidence for HPV in the etiology of colorectal neoplasia for either men or women. Cancer Epidemiol Biomarkers Prev; 20(10); 2288–97. ©2011 AACR.
Prognostic Significance of Cytoplasmic p27 Expression in Human Melanoma
Authors: Chen Guangdi , Cheng Yabin , Zhang Zhizhong , Martinka Magdalena , Li Gang
Published: October 2011

Background: The cyclin-dependent kinase inhibitor p27 plays important roles in cell proliferation, cell motility, and apoptosis. Interestingly, the nuclear and cytoplasmic p27 exert opposite biological functions. In this study, we investigated the prognostic impact of subcellular p27 expression.

Methods: We constructed melanoma tissue microarrays in a large series of melanoma patients, including 29 normal nevi, 52 dysplastic nevi, 270 primary melanomas, and 148 metastatic melanomas. The expression level of subcellular p27 in different stages of melanocytic lesions and its prognostic significance were evaluated.

Results: Compared with dysplastic nevi, nuclear p27 expression was remarkably reduced in primary melanomas and further reduced in metastatic melanoma (P < 0.001 for both), whereas cytoplasmic p27 expression is significantly increased from dysplastic nevi to primary melanomas (P = 0.032) and further increased in melanoma metastases (P = 0.037). Although loss of nuclear p27 expression is correlated with a worse 5-year survival of primary melanoma patients in Kaplan–Meier analysis (P = 0.046), it is not a prognostic factor by multivariate Cox regression analysis. On the contrary, Kaplan–Meier analysis showed that gain of cytoplasmic p27 was associated with a poor 5-year survival of metastatic melanoma patients (P < 0.001). Multivariate Cox regression analysis revealed that positive cytoplasmic p27 expression is an independent prognostic factor to predict metastatic melanoma patient outcome.

Conclusion: Cytoplasmic p27 may serve as a promising prognostic marker for metastatic melanoma.

Impact: Because there is no reliable prognostic marker for metastatic melanoma, our finding may have important clinical implications using cytoplasmic p27 as a prognostic biomarker for advanced melanoma. Cancer Epidemiol Biomarkers Prev; 20(10); 2212–21. ©2011 AACR.