bluuebunny/crossref_metadata_2025 huggingface dataset:
MNB/DYRK1A as a multiple regulator of neuronal development
Authors: Tejedor Francisco J. , Hämmerle Barbara
Published: November 2010

MNB/DYRK1A is a member of the dual‐specificity tyrosine phosphorylation‐regulated kinase (DYRK) family that has been strongly conserved across evolution. There are substantial data implicating MNB/DYRK1A in brain development and adult brain function, as well as in neurodegeneration and Down syndrome pathologies. Here we review our current understanding of the neurodevelopmental activity of MNB/DYRK1A. We discuss how MNB/DYRK1A fulfils several sequential roles in neuronal development and the molecular mechanisms possibly underlying these functions. We also summarize the evidence behind the hypotheses to explain how the imbalance in MNB/DYRK1A gene dosage might be implicated in the neurodevelopmental alterations associated with Down syndrome. Finally, we highlight some research directions that may help to clarify the mechanisms and functions of MNB/DYRK1A signalling in the developing brain.
Activation, regulation, and inhibition of DYRK1A
Authors: Becker Walter , Sippl Wolfgang
Published: November 2010

Dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. Higher than normal levels of DYRK1A are associated with the pathology of neurodegenerative diseases and have been implicated in some neurobiological alterations of Down syndrome, such as mental retardation. It is therefore important to understand the molecular mechanisms that control the activity of DYRK1A. Here we review the current knowledge about the initial self‐activation of DYRK1A by tyrosine autophosphorylation and propose that this mechanism presents an ancestral feature of the CMGC group of kinases. However, tyrosine phosphorylation does not appear to regulate the enzymatic activity of DYRK1A. Control of DYRK1A may take place on the level of gene expression, interaction with regulatory proteins and regulated nuclear translocation. Finally, we compare the properties of small molecule inhibitors that target DYRK1A and evaluate their potential application and limitations. The β‐carboline alkaloid harmine is currently the most selective and potent inhibitor of DYRK1A and has proven very useful in cellular assays.
Incumbent Responsiveness to Female Challengers
Authors: LUCAS JENNIFER
Published: November 2010

How do congressional incumbents respond to challengers, particularly female challengers? This article extends recent research on the effect of congressional challengers on legislative agenda setting by analyzing the symbolic effect of a female challenger on bill sponsorship and cosponsorship of women's issue legislation. The results indicate incumbents who ran against female challengers in the previous election are more likely to respond to that constituency through their legislative activities. However, in practice, there may be few significant policy effects, as incumbents challenged by female opponents are more likely to cosponsor, rather than sponsor, women's issue legislation.

¿Cómo responden los miembros del Congreso a los candidatos y especialmente a las candidatas que les disputan su reelección? Este artículo amplía investigaciones recientes sobre el efecto de la presión electoral sobre distritos seguros en la definición de la agenda. Lo hace analizando el efecto simbólico que produce la presión electoral de candidatas femeninas en distritos cuyo representante actual ha sido reelegido varias veces enfocándose en qué tanto dicho representante patrocina o copatrocina proyectos de ley favorables a las mujeres. Los resultados indican que los representantes que contendieron contra mujeres en elecciones previas están más inclinados a responder al electorado femenino a través de sus actividades legislativas. En la práctica, sin embargo, puede haber pocos efectos políticos significativos, ya que los representantes están más inclinados a copatrocinar que a patrocinar leyes que favorecen a las mujeres.
How Abortion Became a Partisan Issue: Media Coverage of the Interest Group‐Political Party Connection
Authors: CARMINES EDWARD G. , GERRITY JESSICA C. , WAGNER MICHAEL W.
Published: November 2010

That Democrats are widely perceived as a pro‐choice party while Republicans are generally perceived as a pro‐life party seems apparent to even the most casual observer of American politics. Yet, this perception was not always as clear as it is today. Our understanding of the partisan evolution of the abortion issue in the United States is informed by previous research demonstrating that changes in the abortion issue at both the elite and mass level conform to Carmines and Stimson's issue evolution model of partisan dynamics. However, an important piece of this puzzle remains unresolved—how does the issue differentiation between the parties get communicated from elite party actors to the mass public? Analyzing over 30 years of several sources of news coverage on abortion, we show that over time, news stories revealed a closer link between particular interest groups and political parties, with the Republican Party becoming aligned with pro‐life interest groups while the Democrats were identified with pro‐choice groups. We posit that media coverage of the interaction between interest groups and political parties on abortion highlighted the issue's increasing political relevance in the minds of the American public and helped to communicate the parties' evolving issue positions to the wider electorate.

Que el partido demócrata está a favor del aborto mientras que el partido republicano está en contra parece obvio aún para cualquier observador de la política estadounidense. A pesar de esto, esta división no siempre fue tan clara como lo es ahora. Nuestra comprensión de la evolución del tópico del aborto en los partidos de los Estados Unidos está fundada en investigaciones previas que demuestran que los cambios en el tema del aborto, tanto en la elite como el público, se ajustan al modelo de evolución de las dinámicas partidistas de Carmines and Stimson. Sin embargo, una pieza importante de este rompecabezas queda sin resolver—¿cómo se comunican las diferencias entre las posturas partidistas sobre diversos asuntos, desde las elites partidistas al público en general? Analizando varias fuentes sobre la cobertura de noticias del aborto por cerca de 30 años, demostramos que a través del tiempo las noticias revelan un vínculo más cercano entre grupos de intereses particulares y los partidos políticos, con el partido republicano favoreciendo a los grupos de interés pro‐vida y los demócratas a los grupos pro‐aborto. Proponemos que la cobertura de los medios sobre la interacción entre los grupos de interés y los partidos políticos sobre el aborto puso de manifiesto la creciente relevancia del tópico en las mentes del público estadounidense y ayudó a comunicar al electorado cómo evolucionaron las posiciones de los partidos.
Environmental justice in the UK: uncertainty, ambiguity and the law
Authors: Pedersen Ole W
Published: November 2010

This paper examines the concept of environmental justice with particular reference to its development in the UK. The paper analyses the empirical evidence behind environmental justice and argues that, while the body of evidence is compelling, it simultaneously highlights a number of limitations. Moreover, the paper offers an analysis of the multiple responses taken at official and non-governmental organisation levels to environmental justice. The paper argues that often these responses are vague and diverse, and run the risk of rendering environmental justice, as a concept, ineffective. Finally, the paper discusses what role the law may be able to play in shaping environmental justice debates in the UK.
Transition of adolescents with cystic fibrosis from paediatric to adult care
Authors: Towns Susan Joy , Bell Scott Cameron
Published: November 2010

Transition to adult health care for adolescents with complex chronic illness such as cystic fibrosis (CF) is a challenge for the health care system with increasing numbers of young people requiring lifelong adult health care due to improvements in early diagnosis, treatment and survival. The changing face of CF and current guidelines for transition to adult care will be reviewed with a discussion and case study illustrating effective transition. Key features include (i) early preparation, planning and facilitating self‐management skills; (ii) engaging all involved by a coordinated approach, including young people with CF, their families and the paediatric and adult teams; (iii) detailed communication, including comprehensive written referral report and documentation of prior complications of CF; (iv) feedback between the paediatric and the adult health care teams; and (v) ongoing audit of the transition process. The barriers to effective transition will be examined in the context of challenges faced by the paediatric centres, the development and resourcing of appropriate adult services, difficulties for the young person and their family as well as integrating the health care system overall. While acknowledging the development and evaluation of models of care for transition services with CF, continued evaluation of transition services can provide an evidence base to ensure effective systems with allocation of resources, inform training of health professionals and meet the needs of young people with CF and other chronic illnesses as they navigate the health care system.

Please cite this paper as: Towns SJ and Bell SC. Transition of adolescents with cystic fibrosis from Paediatric to Adult care. Clin Respir J 2011; 5: 64–75.
What If Industrial–Organizational Psychology Decided to Take Workplace Decisions Seriously?
Authors: Dalal Reeshad S. , Bonaccio Silvia , Highhouse Scott , Ilgen Daniel R. , Mohammed Susan , Slaughter Jerel E.
Published: November 2010

The major premise of this article is that increased exposure to—and increased application of—theories, methods, and findings from the judgment and decision-making (JDM) field will aid industrial–organizational psychology and organizational behavior (IOOB) researchers and practitioners in studying workplace decisions. To this end, we first provide evidence of the lack of cross-fertilization between JDM and IOOB and then provide an overview of the JDM research literature. Next, with the aid of a panel of prominent IOOB scholars who share JDM interests, we discuss the philosophical and methodological traditions in IOOB and JDM, the areas in which IOOB has already been enriched by JDM as well as the areas in which it might be further enriched in the future, ways of increasing cross-fertilization from JDM to IOOB, and ways in which IOOB can in turn contribute to JDM. Through this focal article, we hope to spark conversation and ultimately engender more cross-fertilization between JDM and IOOB.
Taking Workplace Decisions Seriously: This Conversation Has Been Fruitful!
Authors: Bonaccio Silvia , Dalal Reeshad S. , Highhouse Scott , Ilgen Daniel R. , Mohammed Susan , Slaughter Jerel E.
Published: November 2010

We are gratified by the large number of commentaries to our focal article (Dalal, Bonaccio, et al., 2010) that advocated greater integration of industrial–organizational psychology and organizational behavior (IOOB) with the field of judgment and decision making (JDM). The commentaries were uniformly constructive and civil. Our disagreements with the commentaries are mild and are limited primarily to the roles of external validity, internal validity, and laboratory experiments in IOOB. For the majority of our response, we attempt to build on the views expressed in the commentaries and to articulate some thoughts regarding the future. We structure our response according to the following themes: barriers to cross-fertilization between IOOB and JDM, areas of existing and potential JDM-to-IOOB cross-fertilization, areas of potential IOOB-to-JDM cross-fertilization, and ways to increase (and ideally institutionalize) cross-fertilization. We hope our focal article and our response to the commentaries will help to ignite exciting basic research and important practical applications associated with decision making in the workplace.
75 Years After Likert: Thurstone Was Right!
Authors: Drasgow Fritz , Chernyshenko Oleksandr S. , Stark Stephen
Published: November 2010

For over three-quarters of a century researchers and practitioners have analyzed rating scale data using methods that assume a dominance response process wherein an individual high on the trait assessed is assumed to answer positively with high probability. This approach derives from Likert's famous 1932 approach to the development and analysis of rating scales. In this paper, we argue that Likert scaling and related methods are misguided. Instead, we propose that methods that have evolved from Thurstone (1927, 1928, 1929) scaling provide a better representation of the choice process underlying rating scale judgments. These methods hypothesize an ideal point response process where the probability of endorsement is assumed to be directly related to the proximity of the statement to the individual's standing on the assessed trait. We review some research showing the superiority of ideal point methods for personality assessment and then describe several settings in which ideal point methods should provide tangible improvements over traditional approaches to assessment.
Biomarkers in Atrial Fibrillation, Ventricular Arrhythmias, and Sudden Cardiac Death
Authors: Mountantonakis Stavros , Deo Rajat
Published: November 2010

Cardiac arrhythmias including atrial fibrillation, ventricular tachycardia, and ventricular fibrillation are important causes of cardiovascular morbidity and mortality. Although they usually occur in the setting of structural heart disease, these arrhythmias can be the primary manifestation of subclinical cardiovascular disease and have deleterious consequences including stroke, heart failure, and death. Investigational efforts have focused on developing risk stratification algorithms and diagnostic methods to identify patients who are most likely to sustain cardiac arrhythmias and benefit from early pharmacologic and interventional therapies. This review highlights important clinical and translational studies that identify potential biological markers to predict the onset of cardiac arrhythmias and their complications. Particular focus is placed on mechanisms involving the neurohormonal system, inflammation, the renin–angiotensin–aldosterone system, and metabolic pathways.
Thrombolytics and Myocardial Infarction
Authors: Kunadian Vijayalakshmi , Gibson C. Michael
Published: November 2010

Coronary artery disease is the single leading cause of death in the United States. Occlusion of the coronary artery was identified to be the cause of myocardial infarction almost a century ago. Following a series of investigations, streptokinase was discovered and demonstrated to be beneficial for the treatment of patients with acute myocardial infarction in terms of reducing short‐ and long‐term mortality. Newer agents including tissue plasminogen activators such as alteplase, reteplase, tenecteplase were developed subsequently. In the present era, thrombolytic therapy and primary percutaneous coronary intervention has revolutionized the way patients with acute myocardial infarction are managed resulting in significant reduction in cardiovascular death. This article provides an overview of the various thrombolytic agents utilized in the management of patients with acute myocardial infarction.
Subcutaneous embryonal rhabdomyosarcoma in a dog: cytologic, immunocytochemical, histologic, and ultrastructural features
Authors: Avallone Giancarlo , Pinto da Cunha Nazaré , Palmieri Chiara , Della Salda Leonardo , Stefanello Damiano , Roccabianca Paola , Caniatti Mario
Published: November 2010

Abstract: A subcutaneous mass on the left antebrachium of an 11‐year‐old intact female English Pointer dog was evaluated presurgically by cytologic examination and immunocytochemical staining. The sample consisted of discrete, variably sized, markedly pleomorphic neoplastic cells that expressed vimentin with diffuse cytoplasmic staining, desmin with focal paranuclear staining, and myoglobin with diffuse cytoplasmic staining, consistent with a diagnosis of rhabdomyosarcoma. Lymphocytic and histiocytic markers were negative. Aspirates of the enlarged ipsilateral prescapular lymph node were positive for metastatic disease. Surgical excision of the tumor and lymph node were followed by histologic and electron microscopic examination. Histomorphologic appearance of neoplastic cells from the mass and the lymph node paralleled cytologic findings; the histologic diagnosis was round cell variant of embryonal rhabdomyosarcoma. By ultrastructural evaluation, cells contained numerous mitochondria and masses of cytoplasmic tangled myofilaments, features typical of rhabdomyoblasts. The dog received doxorubicin (30 mg/m2) every 3 weeks for 5 treatments. Local recurrence developed 6 months after resection but was not treated. Despite a guarded prognosis and untreated local recurrence, the dog was still alive 18 months after surgery. Cytologic evaluation and immunocytochemical staining were pivotal for the presurgical diagnosis of rhabdomyosarcoma.
Crevicular Porphyromonas gingivalis‐specific immunoglobulin A levels in healthy and periodontitis‐affected Thai cohorts
Authors: Choonharuangdej Suwan , Chutinet Aurasri , Kuphasuk Yosvimol
Published: November 2010

Abstract Aim:  Immunoglobulin A is a key humoral immune component involved in defense mechanisms against infections. Periodontitis, the chronic inflammatory disease causing periodontal destruction, adversely affects adults worldwide, including Thailand. As the development of periodontitis is partly mediated by immune components, levels of total and Porphyromonas gingivalis‐specific immunoglobulin A in gingival crevicular fluid of Thai cohorts were studied.

Methods:  Gingival crevicular fluid was collected from 24 patients with severe generalized chronic periodontitis and 22 healthy controls. The amount and concentration of total and Porphyromonas gingivalis‐specific immunoglobulin A in each gingival crevicular fluid sample were determined by enzyme‐linked immunosorbent assay.

Results:  The control group contained the highest concentrations of both types of gingival crevicular fluid–immunoglobulin A, but the lowest levels of these antibodies were found in the deep sites of the periodontitis group. Moreover, the concentrations of gingival crevicular fluid–immunoglobulin A and the degree of periodontitis severity appeared to have an inverse relationship. There was no significant difference in the amounts of gingival crevicular fluid–immunoglobulin A in the control and periodontitis groups.

Conclusions:  This study supports the hypothesis that high concentrations of specific gingival crevicular fluid–immunoglobulin A antibodies directed against Porphyromonas gingivalis, a potent periodontic microorganism, could retard periodontitis development.
Fabrication techniques for three-dimensional metamaterials in the midinfrared
Authors: Wendt J. R. , Burckel D. B. , Ten Eyck G. A. , Ellis A. R. , Brener I. , Sinclair M. B.
Published: November 2010

The authors have developed two versions of a flexible fabrication technique known as membrane projection lithography that can produce nearly arbitrary patterns in “212 D” and fully three-dimensional (3D) structures. The authors have applied this new technique to the fabrication of split ring resonator-based metamaterials in the midinfrared. The technique utilizes electron beam lithography for resolution, pattern design flexibility, and alignment. The resulting structures are nearly three orders of magnitude smaller than equivalent microwave structures that were first used to demonstrate a negative index material. The fully 3D structures are highly isotropic and exhibit both electrically and magnetically excited resonances for incident transverse electromagnetic waves.
Performance and reliability analysis of p-type metal-oxide-semiconductor field effect transistors with various combinations of Ru and Al gate metal
Authors: Park Hong Bae , Park Chang Seo , Kang Chang Yong , Song Seung-Chul , Lee Byoung Hun , Kim Tea Wan , Jang Tae-Young , Kim Dong-Hyoub , Jeong Jae Kyeong , Choi Rino
Published: November 2010

Device performance and reliability characteristics of various types of Ru–Al-based metal gates on HfSiO gate dielectrics were investigated for p-type metal-oxide-semiconductor field effect transistor (pMOSFET) applications. Using the high work function of Ru and a dipole formed by Al atoms in a gate dielectric, the threshold voltage of the pMOSFET could be controlled successfully. However, the excessive diffusion of Al atoms generated more interface states and bulk trapping in the high-k dielectric layer and degraded the device performances and reliability characteristics. It was also found that the carefully tailored sequence of deposition and composition of Ru and Al metals can be used to prevent the excessive diffusion of Al atoms.
Cytochrome P450 Compound I: Capture, Characterization, and C-H Bond Activation Kinetics
Authors: Rittle Jonathan , Green Michael T.
Published: November 2010

The Power Behind P450

Drugs, toxins and a range of metabolic substrates are detoxified in the liver by family of iron-containing enzymes called cytochrome P450. The iron component transfers oxygen to compounds that are often highly resistant to chemical reaction, but we know very little about the mechanism of this vital detoxification process.
Rittle and Green
(p.
933
; see the Perspective by

Sligar

) have managed to capture the P450 reaction intermediate by freezing a solution of the enzyme as it reacts with an oxidant. Spectroscopic techniques and kinetic studies then revealed an iron(IV)oxo intermediate that passes its oxygen along to the substrate with remarkable speed.
Amazonia Through Time: Andean Uplift, Climate Change, Landscape Evolution, and Biodiversity
Authors: Hoorn C. , Wesselingh F. P. , ter Steege H. , Bermudez M. A. , Mora A. , Sevink J. , Sanmartín I. , Sanchez-Meseguer A. , Anderson C. L. , Figueiredo J. P. , Jaramillo C. , Riff D. , Negri F. R. , Hooghiemstra H. , Lundberg J. , Stadler T. , Särkinen T. , Antonelli A.
Published: November 2010

The Making of Amazonian Diversity

The biodiversity of the Amazon Basin is legendary, but the processes by which it has been generated have been debated. In the late 20th century the prevalent view was that the engine of diversity was repeated contraction and expansion of forest refugia during the past 3 million years or so.

Hoorn
et al.

(p.
927
) analyze findings from a diverse range of disciplines, including molecular phylogeny, ecology, sedimentology, structural geology, and palaeontology, to offer an overview of the entire history of this region during the Cenozoic era (66 million years ago). The uplift of the Andes was a pivotal event in the evolution of Amazonian landscapes because it continually altered river drainage patterns, which in turn put a variety of pressures on organisms to adapt to changing conditions in a multiplicity of ways. Hence, the diversity of the modern biota of the Amazon has more ancient origins than previously thought.
Optogenetic Control of Cardiac Function
Authors: Arrenberg Aristides B. , Stainier Didier Y. R. , Baier Herwig , Huisken Jan
Published: November 2010

A Steady Beat

A regular heartbeat depends on steady function of the cardiac pacemaker. The early embryonic heart is neither as steady nor as organized as the mature heart.

Arrenberg
et al.

(p.
971
) used zebrafish engineered to express light-sensitive proteins to locate and manipulate the function of the cardiac pacemaker. By controlling the activity of small patches of cells with light beams, the authors monitored the development of the young heart, showing how the cardiac pacemaker develops during embryogenesis.
Coupling of Nitrous Oxide and Methane by Global Atmospheric Chemistry
Authors: Prather Michael J. , Hsu Juno
Published: November 2010

Lingering Atmospheric Perturbations

Nitrous oxide and methane are chemically active greenhouse gases whose atmospheric abundances are greatly influenced by anthropogenic emissions.
Prather and Hsu
(p.
952
) used an atmospheric chemistry model to show how nitrous oxide emissions lower the concentration of tropospheric methane through a chain of chemical reactions that include stratospheric ozone depletion, changes in solar ultraviolet radiation fluxes, altered fluxes of ozone transport from the stratosphere to the troposphere, and increases in the amount of tropospheric hydroxyl radicals. This mechanism acts on a 108-year-long time scale—10 times longer than the atmospheric residence time of methane.
Anomalous Strength Characteristics of Tilt Grain Boundaries in Graphene
Authors: Grantab Rassin , Shenoy Vivek B. , Ruoff Rodney S.
Published: November 2010

Perfect Imperfections

Graphene is composed of six-atom rings, but will include a number of five- and seven-atom rings as defects. Using simulations,

Grantab
et al.

(p.
946
) show that more defects do not necessarily lead to greater deterioration of mechanical properties. Mismatches caused by differences in the orientation of neighboring crystals are divided into low- and high-angle grain boundaries, and typically it is the lower-angle boundaries that are stronger. In graphene, by contrast, the larger-angle boundaries, which consist of higher-defect densities, are better able to accommodate the strain and prevent failure that originates in the breakup of the seven-member graphene rings. This suggests ways for synthesizing imperfect graphene sheets that will have mechanical properties that are close to those of perfect graphene.
Prion-Like Behavior of Amyloid-β
Authors: Kim Jungsu , Holtzman David M.
Published: November 2010

Can Alzheimer's disease arise through pathogenic transmission of a protein aggregate?
Fertility Goddesses as Trojan Horses
Authors: Govers Francine , Angenent Gerco C.
Published: November 2010

In flowering plants, fertilization and fungal infection depend on the same type of receptor proteins.
Irremediable Complexity?
Authors: Gray Michael W. , Lukeš Julius , Archibald John M. , Keeling Patrick J. , Doolittle W. Ford
Published: November 2010

Complex cellular machines may have evolved through a ratchet-like process called constructive neutral evolution.
Ralph Hall Bids to Lead Science Panel
Authors: Mervis Jeffrey
Published: November 2010

In an election that saw Republicans gain control of the U.S. House of Representatives, it's perhaps fitting that the presumptive new chair of the House science committee, Representative Ralph Hall (R–TX), is a former Democrat.
The Promise and Pitfalls of a Cancer Breakthrough
Authors: Marshall Eliot
Published: November 2010

A landmark clinical trial reported last week that screening for small tumors with advanced x-ray imaging led to a significant drop in lung cancer deaths (20% fewer) among smokers and ex-smokers, compared with screening with standard chest x-rays.
Earth-Observation Summit Endorses Global Data Sharing
Authors: Stone Richard
Published: November 2010

A veritable orchestra of Earth-observation systems is intended to make reams of data available and relevant to decision-makers. At a summit last week, initiatives were unveiled to monitor land-cover changes and forest carbon stocks.
Affordable 'Exomes' Fill Gaps in a Catalog of Rare Diseases
Authors: Kaiser Jocelyn
Published: November 2010

A flurry of reports this year on new genes for rare diseases caused by a defect in a single gene takes advantage of cheap, next-generation DNA-sequencing technologies that make it possible to sequence the 1% of the genome that codes for proteins, known as exons.
Collapse? What Collapse? Societal Change Revisited
Authors: Lawler Andrew
Published: November 2010

Old notions about how societies fail are at odds with new data painting a more nuanced, complicated—and possibly hopeful—view of human adaptation to change.
Taking the Sting Out of Acid Rain
Authors: Malakoff David
Published: November 2010

As a landmark U.S. law turns 20, success marks the acid rain control program, but the cap-and-trade market it created is in turmoil.
Characterization of Gene Use and Efficacy of Mouse Monoclonal Antibodies toStreptococcus pneumoniaeSerotype 8
Authors: Yano Masahide , Pirofski Liise-anne
Published: November 2010

Streptococcus pneumoniaeis the most common cause of community-acquired pneumonia in the United States and globally. Despite the availability of pneumococcal capsular polysaccharide (PPS) and protein conjugate-based vaccines, the prevalence of antibiotic-resistant pneumococcal strains, serotype (ST) replacement in nonconjugate vaccine strains, and uncertainty as to whether the PPS vaccine that is used in adults protects against pneumonia emphasize the need for continued efforts to understand the nature of protective PPS antibody responses. In this study, we generated mouse monoclonal antibodies (MAbs) to a conjugate consisting of the PPS of serotype 8 (PPS8)S. pneumoniaeand tetanus toxoid. Thirteen MAbs, including four IgMs that bound to PPS8 and phosphorylcholine (PC) and five IgMs and four IgG1s that bound to PPS8 but not PC, were produced, and their nucleotide sequences, epitope and fine specificity, and efficacy against lethal challenge with ST8S. pneumoniaewere determined. MAbs that bound to PPS8 exhibited gene use that was distinct from that exhibited by MAbs that bound to PC. Only PPS8-binding MAbs that did not bind PC were protective in mice. All 13 MAbs used germ line variable-region heavy (VH) and light (VL) chain genes, with no evidence of somatic hypermutation. Our data reveal a relationship between PPS specificity and VHgene use and MAb efficacy in mice. These findings provide insight into the relationship between antibody molecular structure and function and hold promise for the development of novel surrogates for pneumococcal vaccine efficacy.
Comparison of Real-Time Multiplex Human Papillomavirus (HPV) PCR Assays with INNO-LiPA HPV Genotyping Extra Assay
Authors: Else Elizabeth A. , Swoyer Ryan , Zhang Yuhua , Taddeo Frank J. , Bryan Janine T. , Lawson John , Van Hyfte Inez , Roberts Christine C.
Published: November 2010

Real-time type-specific multiplex human papillomavirus (HPV) PCR assays were developed to detect HPV DNA in samples collected for the efficacy determination of the quadrivalent HPV (type 6, 11, 16, and 18) L1 virus-like particle (VLP) vaccine (Gardasil). Additional multiplex (L1, E6, and E7 open reading frame [ORF]) or duplex (E6 and E7 ORF) HPV PCR assays were developed to detect high-risk HPV types, including HPV type 31 (HPV31), HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, and HPV59. Here, we evaluated clinical specimen concordance and compared the limits of detection (LODs) between multiplex HPV PCR assays and the INNO-LiPA HPV Genotyping Extra assay, which detects 28 types, for the 14 HPV types common to both of these methods. Overall HPV detection agreement rates were >90% for swabs and >95% for thin sections. Statistically significant differences in detection were observed for HPV6, HPV16, HPV18, HPV35, HPV39, HPV45, HPV56, HPV58, and HPV59 in swabs and for HPV45, HPV58, and HPV59 in thin sections. Where
P
was <0.05, discordance was due to detection of more HPV-positive samples by the multiplex HPV PCR assays. LODs were similar for eight HPV types, significantly lower in multiplex assays for five HPV types, and lower in INNO-LiPA for HPV6 only. LODs were under 50 copies for all HPV types, with the exception of HPV39, HPV58, and HPV59 in the INNO-LiPA assay. The overall percent agreement for detection of 14 HPV types between the type-specific multiplex HPV PCR and INNO-LiPA genotyping assays was good. The differences in positive sample detection favored multiplex HPV PCR, suggesting increased sensitivity of HPV DNA detection by type-specific multiplex HPV PCR assays.
Clinical Features of Group B
Streptococcus
Prosthetic Joint Infections and Molecular Characterization of Isolates
Authors: Corvec S. , Illiaquer M. , Touchais S. , Boutoille D. , van der Mee-Marquet N. , Quentin R. , Reynaud A. , Lepelletier D. , Bémer P.
Published: November 2010

Twelve group B
Streptococcus
(GBS) prosthetic joint infection (PJI) cases are reported. The mean patient age was 55 years. Eleven infections were caused by GBS alone. The associated isolates belonged to phylogenetic lineages different from those that cause neonatal meningitis. The clinical outcome was favorable for the eight patients for whom follow-up data were available.
Comparison of Conventional, Nested, and Real-Time Quantitative PCR for Diagnosis of Scrub Typhus
Authors: Kim Dong-Min , Park Geon , Kim Hyong Sun , Lee Joo Young , Neupane Ganesh Prasad , Graves Stephen , Stenos John
Published: November 2010

Orientia tsutsugamushi
is the causative agent of scrub typhus. For the diagnosis of scrub typhus, we investigated the performances of conventional PCR (C-PCR), nested PCR (N-PCR), and real-time quantitative PCR (Q-PCR) targeting the
O. tsutsugamushi
-specific 47-kDa gene. To compare the detection sensitivities of the three techniques, we used two template systems that used plasmid DNA (plasmid detection sensitivity), including a partial region of the 47-kDa gene, and genomic DNA (genomic detection sensitivity) from a buffy coat sample of a single patient. The plasmid detection sensitivities of C-PCR, N-PCR, and Q-PCR were 5 × 10
4
copies/μl, 5 copies/μl, and 50 copies/μl, respectively. The results of C-PCR, N-PCR, and Q-PCR performed with undiluted genomic DNA were negative, positive, and positive, respectively. The genomic detection sensitivities of N-PCR and Q-PCR were 64-fold and 16-fold (crossing point [Cp], 37.7; 426 copies/μl), respectively. For relative quantification of
O. tsutsugamushi
bacteria per volume of whole blood, we performed real-time DNA PCR analysis of the human
GAPDH
gene, along with the
O. tsutsugamushi
47-kDa gene. At a 16-fold dilution, the copy number and genomic equivalent (GE) of
GAPDH
were 1.1 × 10
5
copies/μl (Cp, 22.64) and 5.5 × 10
4
GEs/μl, respectively. Therefore, the relative concentration of
O. tsutsugamushi
at a 16-fold dilution was 0.0078 organism/one white blood cell (WBC) and 117 organisms/μl of whole blood, because the WBC count of the patient was 1.5 × 10
4
cells/μl of whole blood. The sensitivities of C-PCR, N-PCR, and Q-PCR performed with blood samples taken from patients within 4 weeks of onset of fever were 7.3% (95% confidence interval [CI], 1.6 to 19.9), 85.4% (95% CI, 70.8 to 94.4), and 82.9% (95% CI, 67.9 to 92.8), respectively. All evaluated assays were 100% specific for
O. tsutsugamushi
. In conclusion, given its combined sensitivity, specificity, and speed, Q-PCR is the preferred assay for the diagnosis of scrub typhus.
Phylogenetic Patterns of Human Respiratory Picornavirus Species, Including the Newly Identified Group C Rhinoviruses, during a 1-Year Surveillance of a Hospitalized Patient Population in Italy
Authors: Piralla Antonio , Baldanti Fausto , Gerna Giuseppe
Published: November 2010

Human rhinovirus species C (HRV-C) was the second most common HRV species detected in hospitalized patients in Italy with acute respiratory disease during a 1-year surveillance period. Sequencing of the picornavirus VP4/VP2 region allowed molecular typing of HRV-A and HRV-B and provisional typing of HRV-C.
Spatial Configuration of Hepatitis E Virus Antigenic Domain
Authors: Xing Li , Wang Joseph C. , Li Tian-Cheng , Yasutomi Yasuhiro , Lara James , Khudyakov Yury , Schofield Darren , Emerson Suzanne U. , Purcell Robert H. , Takeda Naokazu , Miyamura Tatsuo , Cheng R. Holland
Published: November 2010

Hepatitis E virus (HEV) is a human pathogen that causes acute hepatitis. When an HEV capsid protein containing a 52-amino-acid deletion at the C terminus and a 111-amino-acid deletion at the N terminus is expressed in insect cells, the recombinant HEV capsid protein can self-assemble into a T=1 virus-like particle (VLP) that retains the antigenicity of the native HEV virion. In this study, we used cryoelectron microscopy and image reconstruction to show that anti-HEV monoclonal antibodies bind to the protruding domain of the capsid protein at the lateral side of the spikes. Molecular docking of the HEV VLP crystal structure revealed that Fab224 covered three surface loops of the recombinant truncated second open reading frame (ORF2) protein (PORF2) at the top part of the spike. We also determined the structure of a chimeric HEV VLP and located the inserted B-cell tag, an epitope of 11 amino acids coupled to the C-terminal end of the recombinant ORF2 protein. The binding site of Fab224 appeared to be distinct from the location of the inserted B-cell tag, suggesting that the chimeric VLP could elicit immunity against both HEV and an inserted foreign epitope. Therefore, the T=1 HEV VLP is a novel delivery system for displaying foreign epitopes at the VLP surface in order to induce antibodies against both HEV and the inserted epitope.
The Bovine Herpesvirus 4 Bo10 Gene Encodes a Nonessential Viral Envelope Protein That Regulates Viral Tropism through both Positive and Negative Effects
Authors: Machiels Bénédicte , Lété Céline , de Fays Katalin , Mast Jan , Dewals Benjamin , Stevenson Philip G. , Vanderplasschen Alain , Gillet Laurent
Published: November 2010

All gammaherpesviruses encode a glycoprotein positionally homologous to the Epstein-Barr virus gp350 and the Kaposi's sarcoma-associated herpesvirus (KSHV) K8.1. In this study, we characterized the positional homologous glycoprotein of bovine herpesvirus 4 (BoHV-4), encoded by the Bo10 gene. We identified a 180-kDa gene product, gp180, that was incorporated into the virion envelope. A Bo10 deletion virus was viable but showed a growth deficit associated with reduced binding to epithelial cells. This seemed to reflect an interaction of gp180 with glycosaminoglycans (GAGs), since compared to the wild-type virus, the Bo10 mutant virus was both less infectious for GAG-positive (GAG
+
) cells and more infectious for GAG-negative (GAG
−
) cells. However, we could not identify a direct interaction between gp180 and GAGs, implying that any direct interaction must be of low affinity. This function of gp180 was very similar to that previously identified for the murid herpesvirus 4 gp150 and also to that of the Epstein-Barr virus gp350 that promotes CD21
+
cell infection and inhibits CD21
−
cell infection. We propose that such proteins generally regulate virion attachment both by binding to cells and by covering another receptor-binding protein until they are displaced. Thus, they regulate viral tropism both positively and negatively depending upon the presence or absence of their receptor.
Rabies Virus (RV) Glycoprotein Expression Levels Are Not Critical for Pathogenicity of RV
Authors: Wirblich Christoph , Schnell Matthias J.
Published: November 2010

Previous comparisons of different rabies virus (RV) strains suggested an inverse relationship between pathogenicity and the amount of glycoprotein produced in infected cells. In order to provide more insight into this relationship, we pursued an experimental approach that allowed us to alter the glycoprotein expression level without altering the glycoprotein sequence, thereby eliminating the contribution of amino acid changes to differences in viral virulence. To this end, we constructed an infectious clone of the highly pathogenic rabies virus strain CVS-N2c and replaced its cognate glycoprotein gene with synthetic versions in which silent mutations were introduced to replace wild-type codons with the most or least frequently used synonymous codons. A recombinant N2c variant containing the fully codon-optimized G gene and three variants carrying a partially codon-deoptimized G gene were recovered on mouse neuroblastoma cells and shown to express 2- to 3-fold more and less glycoprotein, respectively, than wild-type N2c. Pathogenicity studies in mice revealed the WT-N2c virus to be the most pathogenic strain. Variants containing partially codon-deoptimized glycoprotein genes or the codon-optimized gene were less pathogenic than WT-N2c but still caused significant mortality. We conclude that the expression level of the glycoprotein gene does have an impact on pathogenicity but is not a dominant factor that determines pathogenicity. Thus, strategies such as changes in codon usage that aim solely at altering the expression level of the glycoprotein gene do not suffice to render a pathogenic rabies virus apathogenic and are not a viable and safe approach for attenuation of a pathogenic strain.
Higher Level of Replication Efficiency of 2009 (H1N1) Pandemic Influenza Virus than Those of Seasonal and Avian Strains: Kinetics from Epithelial Cell Culture and Computational Modeling
Authors: Mitchell Hugh , Levin Drew , Forrest Stephanie , Beauchemin Catherine A. A. , Tipper Jennifer , Knight Jennifer , Donart Nathaniel , Layton R. Colby , Pyles John , Gao Peng , Harrod Kevin S. , Perelson Alan S. , Koster Frederick
Published: November 2010

The pathogenicity and transmission of influenza A viruses are likely determined in part by replication efficiency in human cells, which is the net effect of complex virus-host interactions. H5N1 avian, H1N1 seasonal, and H1N1 2009 pandemic influenza virus strains were compared by infecting human differentiated bronchial epithelial cells in air-liquid interface cultures at relatively low virus particle/cell ratios. Differential equation and computational models were used to characterize the
in vitro
kinetic behaviors of the three strains. The models were calibrated by fitting experimental data in order to estimate difficult-to-measure parameters. Both models found marked differences in the relative values of
p
, the virion production rate per cell, and
R
0
, an index of the spread of infection through the monolayer, with the values for the strains in the following rank order (from greatest to least): pandemic strain, followed by seasonal strain, followed by avian strain, as expected. In the differential equation model, which treats virus and cell populations as well mixed,
R
0
and
p
varied proportionately for all 3 strains, consistent with a primary role for productivity. In the spatially explicit computational model,
R
0
and
p
also varied proportionately except that
R
0
derived for the pandemic strain was reduced, consistent with constrained viral spread imposed by multiple host defenses, including mucus and paracrine antiviral effects. This synergistic experimental-computational strategy provides relevant parameters for identifying and phenotyping potential pandemic strains.
Oxidative Stress Induces Reactivation of Kaposi's Sarcoma-Associated Herpesvirus and Death of Primary Effusion Lymphoma Cells
Authors: Li Xudong , Feng Jiaying , Sun Ren
Published: November 2010

Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL) cells are predominantly infected with latent Kaposi's sarcoma-associated herpesvirus (KSHV), presenting a barrier to the destruction of tumor cells. Latent KSHV can be reactivated to undergo lytic replication. Here we report that in PEL cells, oxidative stress induced by upregulated reactive oxygen species (ROS) can lead to KSHV reactivation or cell death. ROS are upregulated by NF-κB inhibition and are required for subsequent KSHV reactivation. Disruption of the intracellular redox balance through depletion of the antioxidant glutathione or inhibition of the antioxidant enzyme catalase also induces KSHV reactivation, suggesting that hydrogen peroxide induces reactivation. In addition, p38 signaling is required for KSHV reactivation induced by ROS. Furthermore, treatment of PEL cells with a higher concentration of the NF-κB inhibitor than that used for inducing KSHV reactivation further upregulates ROS and induces massive cell death. ROS, but not p38 signaling, are required for PEL cell death induced by NF-κB inhibition as well as by glutathione depletion. Importantly, anticancer drugs, such as cisplatin and arsenic trioxide, also induce KSHV reactivation and PEL cell death in a ROS-dependent manner. Our study thus establishes a critical role for ROS and oxidative stress in the regulation of KSHV reactivation and PEL cell death. Disrupting the cellular redox balance may be a potential strategy for treating KSHV-associated lymphoma.
Norovirus P Particle, a Novel Platform for Vaccine Development and Antibody Production
Authors: Tan Ming , Huang Pengwei , Xia Ming , Fang Ping-An , Zhong Weiming , McNeal Monica , Wei Chao , Jiang Wen , Jiang Xi
Published: November 2010

The norovirus P particle is an octahedral nanoparticle formed by 24 copies of the protrusion (P) domain of the norovirus capsid protein. This P particle is easily produced in
Escherichia coli
, extremely stable, and highly immunogenic. There are three surface loops per P domain, making a total of 72 loops per particle, and these are potential sites for foreign antigen presentation for immune enhancement. To prove this concept, a small peptide (His tag, 7 amino acids [aa]) and a large antigen (rotavirus VP8, 159 aa) were inserted into one of the loops. Neither insertion affects P particle formation, while both antigens were presented well on the P particle surface. The immune-enhancement effect of the P particle was demonstrated by significantly increased antibody titers induced by the P particle-presented antigens compared to the titers induced by free antigens. In addition, the measured neutralization antibody titers and levels of protection against rotavirus shedding in mice immunized with the VP8 chimeric P particles were significantly higher than those of mice immunized with the free VP8 antigen. Sera from P particle-VP8 chimera-vaccinated animals also blocked norovirus virus-like particle (VLP) binding to the histo-blood group antigen (HBGA) receptors. From these data, the P particle appears to be an excellent vaccine platform for antigen presentation. The readily available three surface loops and the great capacity for foreign antigen insertion make this platform attractive for wide application in vaccine development and antibody production. The P particle-VP8 chimeras may serve as a dual vaccine against both rotavirus and norovirus.
Noncytotoxic Inhibition of Viral Infection through eIF4F-Independent Suppression of Translation by 4EGi-1
Authors: McMahon Robert , Zaborowska Izabela , Walsh Derek
Published: November 2010

The eukaryotic initiation factor eIF4F recruits ribosomes to capped mRNAs while eIF2 mediates start codon recognition to initiate protein synthesis. Increasing interest in targeting translation to suppress tumor growth has led to the development of new classes of inhibitors, including 4EGi-1, which disrupts eIF4F complexes. However, the full effects of this inhibitor and its potential uses in the treatment of other disease states remain unclear. Here, we show that overall rates of protein synthesis in primary human cells were affected only modestly by eIF4F disruption using the mTOR inhibitor Torin1, yet were highly sensitive to 4EGi-1. Translational suppression occurred even at concentrations of 4EGi-1 that were below those required to significantly alter eIF4F levels but were instead found to increase the association of ribosomal complexes containing inactive eIF2α. Although highly stable in culture, the effects of 4EGi-1 on both cellular protein synthesis and ribosome association were readily reversible upon inhibitor removal. In addition, despite potently inhibiting translation, prolonged exposure to 4EGi-1 had only modest effects on cell morphology and protein abundance without affecting viability or stress tolerance to any significant degree, although differential effects on heat shock protein (hsp) expression highlighted distinct 4EGi-1-sensitive modes of hsp induction. In contrast, 4EGi-1 potently suppressed poxvirus replication as well as both reactivation and lytic phases of herpesvirus infection. These findings identify a novel way in which 4EGi-1 affects the host cell's protein synthesis machinery and demonstrate its potential as a noncytotoxic inhibitor of diverse forms of viral infection.