bluuebunny/crossref_metadata_2025 huggingface dataset:
GmDREB2A;2, a Canonical DEHYDRATION-RESPONSIVE ELEMENT-BINDING PROTEIN2-Type Transcription Factor in Soybean, Is Posttranslationally Regulated and Mediates Dehydration-Responsive Element-Dependent Gene Expression
Authors: Mizoi Junya , Ohori Teppei , Moriwaki Takashi , Kidokoro Satoshi , Todaka Daisuke , Maruyama Kyonoshin , Kusakabe Kazuya , Osakabe Yuriko , Shinozaki Kazuo , Yamaguchi-Shinozaki Kazuko
Published: November 2012

Soybean (Glycine max) is an important crop around the world. Abiotic stress conditions, such as drought and heat, adversely affect its survival, growth, and production. The DEHYDRATION-RESPONSIVE ELEMENT-BINDING PROTEIN2 (DREB2) group includes transcription factors that contribute to drought and heat stress tolerance by activating transcription through the cis-element dehydration-responsive element (DRE) in response to these stress stimuli. Two modes of regulation, transcriptional and posttranslational, are important for the activation of gene expression by DREB2A in Arabidopsis (Arabidopsis thaliana). However, the regulatory system of DREB2 in soybean is not clear. We identified a new soybean DREB2 gene, GmDREB2A;2, that was highly induced not only by dehydration and heat but also by low temperature. GmDREB2A;2 exhibited a high transactivation activity via DRE and has a serine/threonine-rich region, which corresponds to a negative regulatory domain of DREB2A that is involved in its posttranslational regulation, including destabilization. Despite the partial similarity between these sequences, the activity and stability of the GmDREB2A;2 protein were enhanced by removal of the serine/threonine-rich region in both Arabidopsis and soybean protoplasts, suggestive of a conserved regulatory mechanism that involves the recognition of serine/threonine-rich sequences with a specific pattern. The heterologous expression of GmDREB2A;2 in Arabidopsis induced DRE-regulated stress-inducible genes and improved stress tolerance. However, there were variations in the growth phenotypes of the transgenic Arabidopsis, the induced genes, and their induction ratios between GmDREB2A;2 and DREB2A. Therefore, the basic function and regulatory machinery of DREB2 have been maintained between Arabidopsis and soybean, although differentiation has also occurred.
A superbright X-ray laboratory microsource empowered by a novel restoration algorithm
Authors: De Caro Liberato , Altamura Davide , Vittoria Fabio Alessio , Carbone Gerardina , Qiao Fen , Manna Liberato , Giannini Cinzia
Published: November 2012

The properties of nanoscale materials vary with the size and shape of the building blocks, which can be measured by (grazing-incidence) small-angle X-ray scattering along with the mutual positions of the nanoparticles. The accuracy in the determination of such parameters is dependent on the signal-to-noise ratio of the X-ray scattering pattern and on the visibility of the interference fringes. Here, a first-generation-synchrotron-class X-ray laboratory microsource was used in combination with a new restoration algorithm to probe nanoscale-assembled superstructures. The proposed algorithm, based on a maximum likelihood approach, allows one to deconvolve the beam-divergence effects from data and to restore, at least partially, missing data cut away by the beam stopper. It is shown that the combination of a superbright X-ray laboratory microsource with the data-restoring method allows a virtual enhancement of the instrument brilliance, improving signal-to-noise ratio and fringe visibility and reaching levels of performance comparable to third-generation synchrotron radiation beamlines.
NICE clinical guideline (CG152): the management of Crohn's disease in adults, children and young people
Authors: Mayberry J. F. , Lobo A. , Ford A. C. , Thomas A.
Published: November 2012

Background

The guideline offers best practice advice on the care of adults, children and young people with Crohn's disease.

Aim

To provide clinically effective and cost‐effective evidence‐based recommendations to guide clinical practice in a clinical guideline commissioned by the National Institute for Health and Clinical Excellence (NICE).

Methods

A systematic review of the evidence including critical appraisal, meta‐analysis and cost‐effectiveness modelling.

Results

Thirty‐one evidence‐based recommendations covering induction and maintenance therapy are available. Five key priorities for implementation are identified together with nine future research recommendations. Three guideline versions are available: short (containing just the recommendations), full (containing the full evidence base) and an Understanding NICE guidance for patients and carers. Algorithms have been produced together with a NICE pathway and implementation tools.

Conclusion

These are the first evidence‐based clinical and cost‐effectiveness guidelines for Crohn's disease in the United Kingdom.
Autoantibodies to erythropoietin receptor in patients with immune‐mediated diseases: relationship to anaemia with erythroid hypoplasia
Authors: Hara Akinori , Furuichi Kengo , Higuchi Masato , Iwata Yasunori , Sakai Norihiko , Kaneko Shuichi , Wada Takashi
Published: November 2012

The prevalence, clinical associations and pathogenic role of newly identified autoantibodies to the erythropoietin receptor (EPOR) in patients with anaemia were investigated. Sera from 203 patients with immune‐related or chronic kidney diseases were screened for anti‐EPOR antibodies by enzyme‐linked immunosorbent assay, and antibody specificity was evaluated by immunoprecipitating EPOR from AS‐E2 cells using purified immunoglobulin (Ig) fractions. In addition, the pathogenic role of anti‐EPOR antibodies was determined by examining their inhibitory effects on AS‐E2 cell proliferation. Clinical findings were compared between patients with and without anti‐EPOR antibodies, in all patients and those with systemic lupus erythematosus (SLE). Serum anti‐EPOR antibodies were detected in 52 patients. Purified IgG or IgM fractions from anti‐EPOR antibody‐positive sera immunoprecipitated EPOR and inhibited the EPO‐dependent proliferation of AS‐E2 cells in a dose‐dependent manner. Anti‐EPOR antibodies were associated with low haemoglobin concentrations and reticulocytopenia in all patients enrolled and those with SLE. Further, there was a negative correlation between the levels of anti‐EPOR antibodies and the number of bone marrow erythroblasts in patients who underwent bone marrow examinations. These findings suggest that EPOR autoantibodies are present in a subset of patients with anaemia and that impaired erythropoiesis can be mediated by anti‐EPOR antibodies, which functionally neutralize EPO activity.
The Role of Acetate in the Etiology of Symptomatic Hypotension
Authors: Keshaviah Prakash R.
Published: November 2012

Acetate, although widely used as the source of buffer in hemodialysis, has been implicated in the development of symptomatic hypotension and hypoxemia during dialysis. Studies of acetate infusion clearly indicate a vasodilatory effect. Acetate also increases cardiac output. If the increase in cardiac output is not adequate to compensate for the decrease in peripheral resistance, hypotension can result. Acetate infusion studies indicate a significant increase in oxygen consumption. This may be the most plausible explanation for dialysis‐induced hypoxemia. Correction of the hypoxemia with supplemental oxygen has been shown to reduce the incidence of hypotensive episodes and intradialytic symptoms. Studies comparing cardiovascular stability during acetate and bicarbonate dialysis indicate that bicarbonate dialysis is beneficial only when the fall in serum osmolality during dialysis is significant. If the fall in serum osmolality is blunted either with a high‐sodium dialysate or mannitol infusions, there is little difference between acetate and bicarbonate. From a practical viewpoint, high‐sodium dialysis is technically less complex and expensive than bicarbonate dialysis.
Systemic Associations of Dynamic Retinal Vessel Analysis: A Review of Current Literature
Authors: Lim Michelle , Sasongko Muhammad B. , Ikram Mohammad K. , Lamoureux Ecosse , Wang Jie Jin , Wong Tien Yin , Cheung Carol Y.
Published: November 2012

Endothelial dysfunction is a key pathogenic mechanism of CVD. The retinal microvascular network offers a unique, non‐invasive window to study endothelial function. Recently, dynamic measurement of retinal vessel caliber using flicker light stimulation has been used to evaluate potential endothelial dysfunction and other mechanisms in CVD. A variety of studies now indicate that retinal vasodilation during flicker light simulation is reduced in diabetes, hypertension, hyperlipidemia and obesity, and may be influenced by age and race/ethnicity. These data suggest that flicker light‐induced retinal vasodilation may be a unique and non‐invasive measure of endothelial dysfunction. This review focuses recent studies on systemic associations of flicker light‐induced retinal vasodilation, and discusses the potential for future research in this area.
A Simulation Integrated Investment Project Ranking and Selection Approach
Authors: YALCINKAYA Ozgur , ARMANERI Ozgur
Published: November 2012

Enterprises are confronted with several project alternatives that they assume to gain revenue in the future, but their own economical resources are limited to carry out all alternatives. Therefore, a decision process arises to prioritize and select among alternatives according to the predetermined goals and criteria to reach the maximum utilization. On the other hand, in project evaluation, the values of project parameters are often assumed to be known with complete certainty. However, project parameters normally change during a life cycle of the project, and it is necessary to consider uncertainty and risk phenomena while evaluating projects. Simulation-based project evaluation approaches enable to make more reliable investment decision since they permit to include future uncertainty and risk in analysis process. In this article, a novel simulation-based optimal decision approach is proposed for evaluating and comparing investment projects under uncertain and/or risky environments. The phases of the proposed approach are; (a) developing the effectiveness measure formulation of a project, (b) identifying and checking all controllable project parameters that affect the measure, (c) developing simulation model for the measure, and (d) performing the project ranking and selection procedures in order to rank and select the projects. Three ranking and selection procedures, previously used for comparing performances of the different production/service systems, are embedded in the proposed approach.
Coordination and Optimization: The Integrated Supply Chain Analysis with Non-Linear Price-Sensitive Demand
Authors: UDDIN Mohammed Forhad , SANO Kazushi
Published: November 2012

In this work, a supply chain with coordination mechanism consisting single vendor and buyer is considered. Further, instead of price sensitive linear or deterministic demand function, a price-sensitive non-linear demand function is introduced in this paper. To find the inventory cost, penalty cost and transportation cost, it is considered that the production and shipping functions of vendor are continuously harmonized and occur at the same rate. In this integrated supply chain, the Buyer’s Linear Program (LP), vendor’s Integer Program (IP) and coordinated Mixed Integer Program (MIP) models are formulated. Numerical examples presented in this research, which include the sensitivity of the key parameters to illustrate the models.  The solution procedures demonstrate that the individual profit as well as joint profit could be increased by coordination mechanism even though the demand function is non-linear. In addition, the results illustrate that Buyer’s selling price with consumers purchasing price could be decreased which may increase the demand of the end market. Finally, a conclusion is drawn in favor of the coordinated supply chain with non-linear price sensitive demand function.
Finding Most Vital Links over Time in a Flow Network
Authors: MOROWATI-SHALILVAND Shahram , MEHRI-TEKMEH Javad
Published: November 2012

This paper deals with finding most vital links of a network which carries flows over time (also called ”dynamic flows”). Given a network and a time horizon T, Single Most Vital Link Over Time (SMVLOT) problem looks for a link whose removal results in greatest decrease in the value of maximum flow over time (dynamic maximum flow) up to time horizon T between two terminal nodes. SMVLOT problem is formulated as a mixed binary linear programming problem. This formulation is extended to a general case called k-Most Vital Links Over Time (KMVLOT) problem, in which we look for finding those k links whose removal makes greatest decrease in the value of maximum flow over time. A Benders decomposition algorithm is proposed for solving SMVLOT and KMVLOT problems. For the case of SMVLOT problem, the proposed algorithm is improved to a fully combinatorial algorithm by adopting an iterative method for solving existing integer programming problem. However, our experimental results showed the superiority of proposed methods.
Electrically, Chemically, and Photonically Powered Torsional and Tensile Actuation of Hybrid Carbon Nanotube Yarn Muscles
Authors: Lima Márcio D. , Li Na , Jung de Andrade Mônica , Fang Shaoli , Oh Jiyoung , Spinks Geoffrey M. , Kozlov Mikhail E. , Haines Carter S. , Suh Dongseok , Foroughi Javad , Kim Seon Jeong , Chen Yongsheng , Ware Taylor , Shin Min Kyoon , Machado Leonardo D. , Fonseca Alexandre F. , Madden John D. W. , Voit Walter E. , Galvão Douglas S. , Baughman Ray H.
Published: November 2012

Nanotube Yarn Actuators

Actuators are used to convert heat, light, or electricity into a twisting or tensile motion, and are often described as artificial muscles. Most materials that show actuation either provide larger forces with small-amplitude motions, such as the alloy NiTi, or provide larger motions with much less force, such as polymeric materials. Other problems with such actuators can include slow response times and short lifetimes.

Lima
et al.

(p.
928
, see the Perspective by

Schulz

) show that a range of guest-filled, twist-spun carbon nanotube yarns can be used for linear or torsional actuation, can solve the problems of speed and lifetime, and do not require electrolytes for operation.
Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice
Authors: Luk Kelvin C. , Kehm Victoria , Carroll Jenna , Zhang Bin , O’Brien Patrick , Trojanowski John Q. , Lee Virginia M.-Y.
Published: November 2012

Synthetic Parkinson's

Parkinson's disease (PD) and related α-synucleinopathies are defined by the accumulation of α-synuclein (α-Syn)–containing intraneuronal inclusions—Lewy bodies (LBs) and Lewy neurites (LNs)—in association with the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and other brain regions. However, a cause-and-effect relationship between LB/LN formation and neurodegeneration remains unclear. Indeed, whether LB/LNs are toxic or represent a neuroprotective response has been contentious.

Luk
et al.

(p.
949
) injected α-Syn fibrils generated from recombinant mouse α-Syn protein into the dorsal striatum of wild-type mice and found that misfolded α-Syn caused the formation of PD-like LB/LNs and subsequent cell-to-cell transmission of pathologic α-Syn to anatomically interconnected regions, including the SNpc. Furthermore, the formation of LB/LNs and their accumulation in SNpc resulted in the progressive loss of these dopaminergic neurons, reduced dopamine innervations to the dorsal striatum, and culminated in motor deficits similar to PD. Thus, a synthetic misfolded wild-type protein (that is, α-Syn) was able to elicit and transmit disease pathology and neurodegeneration in healthy nontransgenic mice.
The Green Economy Post Rio+20
Authors: Barbier Edward B.
Published: November 2012

Sustainable development, a focus at the June United Nations meeting, requires critical endorsement and action by the G20.
Orbitofrontal Cortex Supports Behavior and Learning Using Inferred But Not Cached Values
Authors: Jones Joshua L. , Esber Guillem R. , McDannald Michael A. , Gruber Aaron J. , Hernandez Alex , Mirenzi Aaron , Schoenbaum Geoffrey
Published: November 2012

Experience Versus Models

There is an ongoing debate over what the orbitofrontal cortex contributes to behavior, learning, and decision-making.

Jones
et al.

(p.
953
) found that the orbitofrontal cortex was important for value-based computations when value must be inferred from an associative model of the task but not when value estimates based on previous experience are sufficient. This result calls into question the assumption that this region simply signals economic value. However, it would be consistent with a concept of the orbitofrontal cortex as being important for constructing model-based representations of the world that are orthogonal to value.
A Rab32-Dependent Pathway Contributes to
Salmonella
Typhi Host Restriction
Authors: Spanò Stefania , Galán Jorge E.
Published: November 2012

Removing Typhoid Restriction

Some bacterial pathogens exhibit exquisite host adaptation and can only infect a single host. For example,
Salmonella enterica
serovar Typhi (
S.
Typhi), the cause of typhoid fever, can only infect humans. The host restriction is manifested at the cellular level because
S.
Typhi is unable to survive within macrophages of species other than human.
Spanò and Galán
(p.
960
) found that expression of a single type-III secretion effector protein from a broad host
Salmonella
in S. Typhi, allowed this human-exclusive pathogen to survive within macrophages from a nonpermissive host. Furthermore,
S.
Typhi expressing this effector was able to replicate within mice, a nonpermissive host.
Cooperative Transcription Factor Complexes in Control
Authors: Martinez Gustavo J. , Rao Anjana
Published: November 2012

The cooperative binding of transcription factors regulates the differentiation of T cells as well as the generation and function of B cells and dendritic cells.
Billionaire Restores Funding for Novel Biomedical Network
Authors: Couzin-Frankel Jennifer
Published: November 2012

Casino magnate Sheldon Adelson is putting up roughly $20 million to $25 million this year to reenergize his medical foundation, which supports collaborative research into bold ideas in neuroscience and cancer. And Adelson hints that number may grow.
Nearly Buried, Mussels Get a Helping Hand
Authors: Stokstad Erik
Published: November 2012

North America is home to a record diversity of freshwater mussels with dazzling reproductive strategies and key ecological roles. But can they withstand the hard knocks of a modern world?
Performance Evaluation of the New Roche cobas AmpliPrep/cobas TaqMan HCV Test, Version 2.0, for Detection and Quantification of Hepatitis C Virus RNA
Authors: Pas S. , Molenkamp R. , Schinkel J. , Rebers S. , Copra C. , Seven-Deniz S. , Thamke D. , de Knegt R. J. , Haagmans B. L. , Schutten M.
Published: November 2012

To evaluate the analytical performance and explore the clinical applicability of the new Roche cobas AmpliPrep/cobas TaqMan HCV test, v2.0 (CAP/CTM v2.0), a platform comparison was performed on panels and diagnostic samples with the Roche cobas AmpliPrep/cobas TaqMan HCV test (CAP/CTM v1.0), the Siemens Versant HCV RNA 3.0 branched DNA (bDNA) test, the Abbott
m
2000 RealTi
m
e HCV assay (Real
time
assay), and the Siemens Versant HCV transcription-mediated amplification (TMA) test (TMA assay). The analytical performance of the CAP/CTM v2.0 on WHO and Acrometrix panels and clinical specimens of patients infected with HCV genotype 1, 2, 3, 4, 5, or 6 relative to that of the CAP/CTM v1.0 was significantly improved. In a qualitative comparison of the CAP/CTM v2.0 relative to the TMA assay on genotype 1 to 4 samples, the two tests proved to be almost equally sensitive. Response-guided therapy in one of five HCV genotype 4-infected patients previously tested with the CAP/CTM v1.0 would have significantly changed if tested with the CAP/CTM v2.0. In conclusion, the Roche CAP/CTM v2.0 has significantly better performance characteristics than the former CAP/CTM HCV v1.0 and the bDNA assay and performance characteristics comparable to those of the Real
time
assay.
Comparison of Broth Enhancement to Direct Plating for Screening of Rectal Cultures for Ciprofloxacin-Resistant Escherichia coli
Authors: Liss Michael A. , Nakamura Kristen K. , Peterson Ellena M.
Published: November 2012

A transrectal prostate biopsy is the most common procedure used to establish the diagnosis of prostate cancer. Prior to biopsy, patients are commonly given ciprofloxacin for prophylaxis. However, a complication of the procedure is infection with ciprofloxacin-resistant organisms, in particular resistant
Escherichia coli
. In order to identify patients carrying ciprofloxacin-resistant
E. coli
, so as to tailor their antibiotic prophylaxis, rectal swabs are screened using selective broth and/or solid medium. In our evaluation, we compared broth enrichment and direct plating techniques by using brain heart infusion broth and MacConkey agar containing 1 μg/ml or 10 μg/ml of ciprofloxacin. Of the 100 patients included in the study, 20 were colonized with ciprofloxacin-resistant organisms, 19 of which were
E. coli
. There was no significant difference (
P
> 0.1) between the culture methods or the ciprofloxacin concentrations in the medium when identifying patients with ciprofloxacin-resistant
E. coli
; however, broth enrichment using 1 μg/ml ciprofloxacin was the most sensitive at 100%, but it was the least specific. Direct plating of rectal swabs onto MacConkey agar containing 10 μg/ml of ciprofloxacin was 100% specific and missed only 1 positive specimen, with a sensitivity of 94.7%; this method was the most cost-effective. Therefore, direct plating of rectal swabs onto selective medium proved to be a sensitive and cost-effective approach in identifying patients colonized with ciprofloxacin-resistant
E. coli
.
Comparative Evaluation of the Nanosphere Verigene RV+ Assay and the Simplexa Flu A/B & RSV Kit for Detection of Influenza and Respiratory Syncytial Viruses
Authors: Alby Kevin , Popowitch Elena B. , Miller Melissa B.
Published: November 2012

Using retrospective (
n
= 200) and prospective (
n
= 150) nasopharyngeal specimens, we evaluated the Nanosphere Verigene RV+ and the Focus Diagnostics Simplexa Flu A/B & RSV tests. Overall, RV+ demonstrated sensitivities and specificities of 96.6% and 100% for influenza A virus, 100% and 99.7% for influenza B virus, and 100% and 100% for respiratory syncytial virus (RSV), while the Simplexa test sensitivities and specificities were 82.8 and 99.7%, 76.2 and 100%, and 94.6 and 100%, respectively.
Critical Role of MDA5 in the Interferon Response Induced by Human Metapneumovirus Infection in Dendritic Cells and
In Vivo
Authors: Baños-Lara M. Del Rocío , Ghosh Arpita , Guerrero-Plata Antonieta
Published: November 2012

Human metapneumovirus (hMPV) is a respiratory paramyxovirus of global clinical relevance. Despite the substantial knowledge generated during the last 10 years about hMPV infection, information regarding the activation of the immune response against this virus remains largely unknown. In this study, we demonstrated that the helicase melanoma differentiation-associated gene 5 (MDA5) is essential to induce the interferon response after hMPV infection in human and mouse dendritic cells as well as in an experimental mouse model of infection. Our findings
in vitro
and
in vivo
showed that MDA5 is required for the expression and activation of interferon (IFN) regulatory factors (IRFs). hMPV infection induces activation of IRF-3, and it regulates the expression of IRF-7. However, both IRF-3 and IRF-7 are critical for the production of type I and type III IFNs. In addition, our
in vivo
studies in hMPV-infected mice indicated that MDA5 alters viral clearance, enhances disease severity and pulmonary inflammation, and regulates the production of cytokines and chemokines in response to hMPV. These findings are relevant for a better understanding of the pathogenesis of hMPV infection.
Identification and Functional Analysis of the Novel ORF4 Protein Encoded by Porcine Circovirus Type 2
Authors: He Jialing , Cao Jingjing , Zhou Niu , Jin Yulan , Wu Jiusheng , Zhou Jiyong
Published: November 2012

Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated diseases in pigs. To date, viral proteins Cap, Rep, Rep′, and ORF3, encoded by the PCV2 genome, have been described. Here, transcription and translation of a novel viral gene within the PCV2 genome (designated ORF4) was determined and functionally analyzed
in vitro
and
in vivo
. Northern blot analysis indicated that the RNA transcribed from the ORF4 gene is about 180 bp in length and overlaps ORF3 in the same direction. Site-directed mutagenesis confirmed that the viral ORF4 protein is not essential for virus replication in PK-15 cells and in mice infected with an ORF4-deficient PCV2 (PCV2Δ). PCV2Δ triggered higher activity levels of caspase-3 and -8 than wild-type PCV2 (wPCV2) in PK-15 cells. The antigenic epitopes of two mouse monoclonal antibodies (MAbs) raised against the viral ORF4 protein were mapped to the same 19KSSASPR25 peptide. Expression of ORF4 was confirmed using the specific MAbs in wPCV2-infected PK-15 cells and mice. Mice infected with PCV2Δ had a higher serum viral load (genomic copies) and more severe lymphoid tissue damage in the spleen than those infected with wPCV2. Meanwhile, flow-cytometric analysis indicated that the PCV2Δ infection caused a significant decrease of CD4
+
and CD8
+
T lymphocytes. Our results demonstrate that ORF4 is a newly discovered viral protein that is not essential for PCV2 replication but plays a role in suppressing caspase activity and regulating CD4
+
and CD8
+
T lymphocytes during PCV2 infection.
A Vaccine Based on the Rhesus Cytomegalovirus UL128 Complex Induces Broadly Neutralizing Antibodies in Rhesus Macaques
Authors: Wussow Felix , Yue Yujuan , Martinez Joy , Deere Jesse D. , Longmate Jeff , Herrmann Andreas , Barry Peter A. , Diamond Don J.
Published: November 2012

Neutralizing antibodies (NAb) are important for interfering with horizontal transmission of human cytomegalovirus (HCMV) leading to primary and congenital HCMV infection. Recent findings have shown that a pentameric virion complex formed by the glycoproteins gH/gL, UL128, UL130, and UL131A (UL128C) is required for HCMV entry into epithelial/endothelial cells (Epi/EC) and is the target of potent NAb in HCMV-seropositive individuals. Using bacterial artificial chromosome technology, we have generated a modified vaccinia Ankara virus (MVA) that stably coexpresses all 5 rhesus CMV (RhCMV) proteins homologous to HCMV UL128C, termed MVA-RhUL128C. Coimmunoprecipitation confirmed the interaction of RhgH with the other 4 RhCMV subunits of the pentameric complex. All 8 RhCMV-naïve rhesus macaques (RM) vaccinated with MVA-RhUL128C developed NAb that blocked infection of monkey kidney epithelial cells (MKE) and rhesus fibroblasts. NAb titers induced by MVA-RhUL128C measured on both cell types at 2 to 6 weeks postvaccination were comparable to levels observed in naturally infected RM. In contrast, MVA expressing a subset of RhUL128C proteins or RhgB glycoprotein only minimally stimulated NAb that inhibited infection of MKE. In addition, following subcutaneous RhCMV challenge at 8 weeks postvaccination, animals vaccinated with MVA-RhUL128C showed reduced plasma viral loads. These results indicate that MVA expressing the RhUL128C induces NAb inhibiting RhCMV entry into both Epi/EC and fibroblasts and limits RhCMV replication in RM. This novel approach is the first step in developing a prophylactic HCMV vaccine designed to interfere with virus entry into major cell types permissive for viral replication, a required property of an effective vaccine.
Unusual Features of Vaccinia Virus Extracellular Virion Form Neutralization Resistance Revealed in Human Antibody Responses to the Smallpox Vaccine
Authors: Benhnia Mohammed Rafii-El-Idrissi , Maybeno Matthew , Blum David , Aguilar-Sino Rowena , Matho Michael , Meng Xiangzhi , Head Steven , Felgner Philip L. , Zajonc Dirk M. , Koriazova Lilia , Kato Shinichiro , Burton Dennis R. , Xiang Yan , Crowe James E. , Peters Bjoern , Crotty Shane
Published: November 2012

The extracellular virion form (EV) of vaccinia virus (VACV) is essential for viral pathogenesis and is difficult to neutralize with antibodies. Why this is the case and how the smallpox vaccine overcomes this challenge remain incompletely understood. We previously showed that high concentrations of anti-B5 antibodies are insufficient to directly neutralize EV (M. R. Benhnia, et al., J. Virol. 83:1201–1215, 2009). This allowed for at least two possible interpretations: covering the EV surface is insufficient for neutralization, or there are insufficient copies of B5 to allow anti-B5 IgG to cover the whole surface of EV and another viral receptor protein remains active. We endeavored to test these possibilities, focusing on the antibody responses elicited by immunization against smallpox. We tested whether human monoclonal antibodies (MAbs) against the three major EV antigens, B5, A33, and A56, could individually or together neutralize EV. While anti-B5 or anti-A33 (but not anti-A56) MAbs of appropriate isotypes were capable of neutralizing EV in the presence of complement, a mixture of anti-B5, anti-A33, and anti-A56 MAbs was incapable of directly neutralizing EV, even at high concentrations. This remained true when neutralizing the IHD-J strain, which lacks a functional version of the fourth and final known EV surface protein, A34. These immunological data are consistent with the possibility that viral proteins may not be the active component of the EV surface for target cell binding and infectivity. We conclude that the protection afforded by the smallpox vaccine anti-EV response is predominantly mediated not by direct neutralization but by isotype-dependent effector functions, such as complement recruitment for antibodies targeting B5 and A33.
Myxovirus Resistance Gene A (MxA) Expression Suppresses Influenza A Virus Replication in Alpha Interferon-Treated Primate Cells
Authors: Matzinger Shannon R. , Carroll Timothy D. , Dutra Joseph C. , Ma Zhong-Min , Miller Christopher J.
Published: November 2012

Alpha interferon (IFN-α) production is triggered when influenza virus RNA is detected by appropriate pattern recognition receptors in the host cell. IFN-α induces the expression of more than 300 interferon-stimulated genes (ISGs), and this blunts influenza virus replication. The human ISG MxA can inhibit influenza A virus replication in mouse cells by interfering with a step in the virus replication cycle after primary transcription of the negative-strand RNA genome to mRNA (J. Pavlovic, O. Haller, and P. Staeheli, J. Virol. 66:2564–2569, 1992). To determine the role of MxA in blocking human influenza A virus replication in primate cells, we manipulated MxA expression in rhesus kidney epithelial cells (LLC-MK
2
) and human lung carcinoma cells (A549). We found that IFN-α treatment prior to influenza virus infection suppressed virus replication and induced the expression of many ISGs, including MxA. However, IFN-α-mediated suppression of virus replication was abolished by small interfering RNA (siRNA) knockdown of MxA expression in IFN-treated cells. In addition, influenza virus replication was suppressed in Vero cells stably transfected with MxA. A strand-specific reverse transcription-PCR (RT-PCR) assay showed that positive-strand influenza virus mRNA and negative-strand genomic RNA (gRNA) accumulated to high levels at 8 h after infection in control Vero cells containing the empty vector. However, in Vero cells stably transfected with MxA positive-strand influenza virus mRNA, complementary positive-strand influenza virus genome RNA (cRNA) and influenza virus gRNA were drastically suppressed. Thus, in primate cells, MxA inhibits human seasonal influenza virus replication at a step prior to primary transcription of gRNA into mRNA. Taken together, these results demonstrate that MxA mediates control of influenza virus replication in primate cells treated with IFN-α.
Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment
Authors: Bartels Doug J. , Sullivan James C. , Zhang Eileen Z. , Tigges Ann M. , Dorrian Jennifer L. , De Meyer Sandra , Takemoto Darin , Dondero Elizabeth , Kwong Ann D. , Picchio Gaston , Kieffer Tara L.
Published: November 2012

The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC
50
]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC
50
) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.
Oligomeric Properties of Adeno-Associated Virus Rep68 Reflect Its Multifunctionality
Authors: Zarate-Perez Francisco , Mansilla-Soto Jorge , Bardelli Martino , Burgner John W. , Villamil-Jarauta Maria , Kekilli Demet , Samso Monserrat , Linden R. Michael , Escalante Carlos R.
Published: November 2012

The adeno-associated virus (AAV) encodes four regulatory proteins called Rep. The large AAV Rep proteins Rep68 and Rep78 are essential factors required in almost every step of the viral life cycle. Structurally, they share two domains: a modified version of the AAA
+
domain that characterizes the SF3 family of helicases and an N-terminal domain that binds DNA specifically. The combination of these two domains imparts extraordinary multifunctionality to work as initiators of DNA replication and regulators of transcription, in addition to their essential role during site-specific integration. Although most members of the SF3 family form hexameric rings
in vitro
, the oligomeric nature of Rep68 is unclear due to its propensity to aggregate in solution. We report here a comprehensive study to determine the oligomeric character of Rep68 using a combination of methods that includes sedimentation velocity ultracentrifugation, electron microscopy, and hydrodynamic modeling. We have determined that residue Cys151 induces Rep68 to aggregate
in vitro
. We show that Rep68 displays a concentration-dependent dynamic oligomeric behavior characterized by the presence of two populations: one with monomers and dimers in slow equilibrium and a second one consisting of a mixture of multiple-ring structures of seven and eight members. The presence of either ATP or ADP induces formation of larger complexes formed by the stacking of multiple rings. Taken together, our results support the idea of a Rep68 molecule that exhibits the flexible oligomeric behavior needed to perform the wide range of functions occurring during the AAV life cycle.
The Hemagglutinin Protein of Highly Pathogenic H5N1 Influenza Viruses Overcomes an Early Block in the Replication Cycle To Promote Productive Replication in Macrophages
Authors: Cline Troy D. , Karlsson Erik A. , Seufzer Bradley J. , Schultz-Cherry Stacey
Published: November 2012

Macrophages are known to be one of the first lines of defense against influenza virus infection. However, they may also contribute to severe disease caused by the highly pathogenic avian (HPAI) H5N1 influenza viruses. One reason for this may be the ability of certain influenza virus strains to productively replicate in macrophages. However, studies investigating the productive replication of influenza viruses in macrophages have been contradictory, and the results may depend on both the type of macrophages used and the specific viral strain. In this work, we investigated the ability of H1 to H16 viruses to productively replicate in primary murine alveolar macrophages and RAW264.7 macrophages. We show that only a subset of HPAI H5N1 viruses, those that cause high morbidity and mortality in mammals, can productively replicate in macrophages, as measured by the release of newly synthesized virus particles into the cell supernatant. Mechanistically, we found that these H5 strains can overcome a block early in the viral life cycle leading to efficient nuclear entry, viral transcription, translation, and ultimately replication. Studies with reassortant viruses demonstrated that expression of the hemagglutinin gene from an H5N1 virus rescued replication of H1N1 influenza virus in macrophages. This study is the first to characterize H5N1 influenza viruses as the only subtype of influenza virus capable of productive replication in macrophages and establishes the viral gene that is required for this characteristic. The ability to productively replicate in macrophages is unique to H5N1 influenza viruses and may contribute to their increased pathogenesis.
Sensitivity of forest plan value to parameters of simulated annealing
Authors: Strimbu Bogdan M. , Paun Mihaela
Published: November 2012

Simulated annealing (SA) is a heuristic technique popular in forest planning, providing solutions close to optimality in reduced computation time. The present study challenges the common approach used to establish the parameters of SA that mimic physical processes by proving that slow cooling or large initial temperatures do not necessarily lead to optimal solutions. The study has two objectives: (1) to identify the parameters (i.e., initial temperature and annealing rate) that could supply close to optimal results with reduced experimentation time and (2) to assess the impact of parameters determining SA performances. Using three forest inventory data sets from British Columbia, we investigated the influence of initial temperature, annealing rate, and numbers of runs on forest planning solutions using a replicated completely randomized design organized as a factorial experiment within a repeated-measures framework. The optimal solution seems to be little influenced by the number of runs; our findings indicate that the combination of initial temperature and rate of annealing is critical in obtaining superior results. Furthermore, the selection of the SA parameters seems to be dependent on the harvest age, which indicates that the parameters should be selected considering whether or not a stand is harvested more than once during the planning period.
Oral treatment with gallic acid and quercetin alleviates lindane-induced cardiotoxicity in rats
Authors: Padma Viswanadha Vijaya , Poornima Paramasivan , Prakash Chermakani , Bhavani Ramachandran
Published: November 2012

Lindane is a man-made organochlorine pesticide used for agricultural purposes. Since lindane-induced toxicity is mediated by free radical generation, this investigation was carried out to study the protective effects of gallic acid and quercetin against lindane-induced cardiotoxicity. Lindane (100 mg·(kg body mass)−1) was administered orally to rats for 30 days. Histological analysis revealed pathological changes in the heart of lindane-treated rats. Biochemical analysis of the lindane-treated animals showed elevated activity for serum marker enzymes, lipid peroxidation (LPO), and membrane-bound Ca2+ATPase, with a concomitant decrease in the level of non-enzymic antioxidant (GSH), enzymic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase (GPx), and glutathione-S-transferase (GST), and membrane-bound ATPases like Na+/K+ATPase and Mg2+ATPase in heart tissue. The results suggest that gallic acid and quercetin offer protection against lindane-induced myocardial damage, possibly through maintaining levels of endogenous antioxidant enzymes and membrane bound ATPase activity, as well as inhibiting lipid peroxidation.
Selection and estimation of sequential catch-at-age models
Authors: Gudmundsson Gudmundur , Gunnlaugsson Thorvaldur
Published: November 2012

Fish stock assessment by catch-at-age and survey data is affected by many stochastic elements: measurement errors; sampling variations; natural variations in mortality, catchability and migrations; technological and social effects on fishing intensity and selectivity. Estimation of simulated models shows that the bias in estimation by linear approximation of the Kalman filter or automatic approximation of the marginal likelihood function is much smaller than the errors produced by the stochastic elements. In time series modelling, they are represented by residuals in the equations. Strong simplifying assumptions about these effects are common in catch-at-age analysis, but estimation of models for Icelandic cod ( Gadus morhua ) and pollock ( Pollachius virens , herein referred to as saithe) demonstrates that the relative importance of different random elements can vary greatly between stocks. These assumptions include exact catch-at-age measurements, no irregular migrations or variations in natural mortality, separable fishing mortality rates, and no permanent variations in survey catchability. Inappropriate simplificactions can have a strong effect on stock estimates. It is possible and important to test simplifying assumptions by comparison with more general models. Estimation of the magnitude of natural mortality is also examined.
A random effects population dynamics model based on proportions-at-age and removal data for estimating total mortality
Authors: Trenkel Verena M. , Bravington Mark V. , Lorance Pascal
Published: November 2012

Catch curves are widely used to estimate total mortality for exploited marine populations. The usual population dynamics model assumes constant recruitment across years and constant total mortality. We extend this to include annual recruitment and annual total mortality. Recruitment is treated as an uncorrelated random effect, while total mortality is modelled by a random walk. Data requirements are minimal as only proportions-at-age and total catches are needed. We obtain the effective sample size for aggregated proportion-at-age data based on fitting Dirichlet-multinomial distributions to the raw sampling data. Parameter estimation is carried out by approximate likelihood. We use simulations to study parameter estimability and estimation bias of four model versions, including models treating mortality as fixed effects and misspecified models. All model versions were, in general, estimable, though for certain parameter values or replicate runs they were not. Relative estimation bias of final year total mortalities and depletion rates were lower for the proposed random effects model compared with the fixed effects version for total mortality. The model is demonstrated for the case of blue ling (Molva dypterygia) to the west of the British Isles for the period 1988 to 2011.
Impact and performance of Mediterranean fishing gear by side-scan sonar technology
Authors: Lucchetti Alessandro , Sala Antonello
Published: November 2012

An innovative approach with side-scan sonar was implemented to observe directly during towing operations the behaviour and the performance of hydraulic dredge, Rapido trawl, and two types of Mediterranean bottom trawls. The innovative aspect of the current paper is that a side-scan sonar was used alongside fishing operations when towing was in progress. Based on available literature, the type and level of the physical impact assessed were used to infer biological and ecological consequences caused by the fishing gear. The sonar used in real time can be applied to a wide range of research and management issues, such as the fishing gear impact on benthic ecosystems and the in situ fishing gear performance. We demonstrated that gear type and rigging, together with environmental conditions, are the main factors affecting the disturbance caused by fishing. Hydraulic dredges scrape the surface of the substratum and dig into it by resuspending large amounts of sediment. Rapido trawls used in muddy areas for common sole (Solea solea) dig deeper into the sediment, making furrows up to 10–13 cm deep. The most evident physical effects of trawling were the furrows produced by the otterboards, while other parts of the trawl created only faint marks.
New framework for volumetric constitutive behaviour of compacted unsaturated soils
Authors: Kodikara Jayantha
Published: November 2012

Volumetric behaviour is a fundamental consideration in unsaturated soil constitutive modelling. It is more complex than when the soil is saturated, as unsaturated soils exhibit a range of responses such as swelling and collapse under wetting and shrinkage and cracking during drying. While significant advances have been made, it is still difficult to generally explain all patterns of behaviour. This paper presents a new framework for modelling volumetric response of unsaturated soils with emphasis on compacted soils. The framework uses void ratio (e), moisture ratio (ew), and net stress (p) as the main constitutive variables and suction as a dependent variable. This choice of ewas a main constitutive variable is theoretically sound and is more attractive than the use of suction, which is relatively difficult to measure and displays significant hysteresis during drying and wetting. The framework incorporates the well-known compaction curve making it easily applicable to practical situations. Within the overall e–ew–p space, the operative space is constrained by three main surfaces; namely, loading–wetting state boundary surface, tensile failure surface, and the saturated plane. The conceptual basis for these state surfaces is described and the framework is qualitatively validated against observed behaviour of compacted soils.
Load tests on full-scale bored pile groups
Authors: Dai Guoliang , Salgado Rodrigo , Gong Weiming , Zhang Yanbei
Published: November 2012

The interactions between closely spaced piles in a pile group are complex. Very limited experimental data are available on the loading of full-scale bored pile groups. This paper reports the results of axial static load tests of both full-scale instrumented pile groups and single piles. The load tests aimed to ascertain the influence of number, length, and spacing of the piles on pile group load response. Experiments varied in the number of piles in the group, pile spacing, type of pile groups, and pile length. All piles had a diameter of 400 mm. Two-, four-, and nine-pile groups with pile lengths of 20 and 24 m were tested. As the isolated piles and some piles in the pile groups were instrumented, the load transfer and load–settlement curves of both piles in isolation and individual instrumented piles in the groups were obtained. The interaction coefficient for each pile in the group was back-calculated from the measured data. The interaction coefficients are shown to be dependent on pile proximity, as usually assumed in elastic analyses, but also on settlement and on the size of the group.