bluuebunny/crossref_metadata_2025 huggingface dataset:
WORKING WITH BUSINESS LEADERS AND THEIR TEAMS
Authors: Sandler Catherine
Published: April 2010

abstract

Two topics are addressed in this article. Firstly, the author explores some of the connections between Isabel Menzies Lyth's work on organizations and her own practice as a psychodynamically‐oriented consultant and coach working with business leaders and their teams. In particular, the author explores the relevance of Isabel's ideas about anxiety in the context of the 2008–09 economic crisis. Almost all the companies with which the author was working were impacted by the recession. This brought to the fore the challenges faced by leaders as they navigate their organizations through a period of great uncertainty. A vignette is provided about a client company at which the author helped the CEO and Board to contain and manage their own anxiety and that of their staff in order to optimize performance during the downturn. Secondly, the author shares some reflections on her experience of Isabel as an analyst. She highlights Isabel's ‘fairly unanxious’ personality as a powerful therapeutic element in the analysis, describing how Isabel's calm, self‐possessed and undemonstrative manner could help others, including the author, to contain their own anxiety and move forward.
GOVERNMENT AND THE PERVERSE SOCIAL DEFENCE
Authors: Hoggett Paul
Published: April 2010

abstract

Part of Isabel Menzies Lyth's legacy is the concept of social defence. This article examines the perverse social defence, recently hypothesized by Susan Long, and deploys the concept in a critical exploration of aspects of the modernization of the public services in the UK. It is argued that the ‘targets and indicators’ culture constitutes a perverse defence which fosters the development of anas ifrelationship between government and reality. The article explores the damaging impact of this defence upon the capacity of government and society to stay in touch with the suffering generated by increasing social inequalities.
SOME THOUGHTS ON SUPERVISION
Authors: Leader Darian
Published: April 2010

abstract

The practice of supervision is increasingly seen today as a pedagogic activity in which knowledge and skills are transmitted from one party to another. Debates around supervision, however, have historically been concerned with a number of other issues, most notably transference and countertransference. We examine the central arguments of these debates in the psychoanalytic tradition, and discuss some of the theoretical and clinical consequences that follow from them. Taking unconscious dynamics into account forces us to recognize that supervision cannot be seen as a ‘neutral’ exercise of accumulating knowledge, but rather confronts both supervisee and supervisor with significant questions about their own position and self‐image.
Flood‐related disaster vulnerability: an impending crisis of megacities in Asia
Authors: Adikari Y. , Osti R. , Noro T.
Published: April 2010

The megacities around the world have been located in fertile river basins since the beginning of civilization. In recent years, population has been increasing drastically; as a result, people migrate to cities and live in vulnerable and marginal areas, thus giving rise to slums. Therefore, we would like to point out why and how megacities in Asia are vulnerable to flood. The vulnerability of the cities, especially the slums, is shaped by forces such as global changes, internal migration patterns, development practices and political instability, which constantly reshape the risk of floods, which may be frequent and disastrous. Hence, development choices with a strong scientific background, especially in the cities prone to monsoon, are necessary to protect development, and not only floods but all disaster risks should be regulated and mainstreamed into the development planning of cities.
DNA barcoding exposes a case of mistaken identity in the fern horticultural trade
Authors: PRYER KATHLEEN M. , SCHUETTPELZ ERIC , HUIET LAYNE , GRUSZ AMANDA L. , ROTHFELS CARL J. , AVENT TONY , SCHWARTZ DAVID , WINDHAM MICHAEL D.
Published: April 2010

Using cheilanthoid ferns, we provide an example of how DNA barcoding approaches can be useful to the horticultural community for keeping plants in the trade accurately identified. We use plastid rbcL, atpA, and trnG‐R sequence data to demonstrate that a fern marketed as Cheilanthes wrightii (endemic to the southwestern USA and northern Mexico) in the horticultural trade is, in fact, Cheilanthes distans (endemic to Australia and adjacent islands). Public and private (accessible with permission) databases contain a wealth of DNA sequence data that are linked to vouchered plant material. These data have uses beyond those for which they were originally generated, and they provide an important resource for fostering collaborations between the academic and horticultural communities. We strongly advocate the barcoding approach as a valuable new technology available to the horticulture industry to help correct plant identification errors in the international trade.
Psychosocial Determinants of Work‐to‐Family Conflict among Knowledge Workers with Boundaryless Work
Authors: Albertsen Karen , Persson Roger , Garde Anne H. , Rugulies Reiner
Published: April 2010

The aims of the present study were to investigate (1) whether antecedents of work‐to‐family conflict identified in previous research have similar effects among knowledge workers, whether work environmental factors, particularly relevant for boundaryless work and not explored previously, affect work‐to‐family conflict in this group, and (2) whether the workplace culture (family friendliness and demands on availability) has a main effect on work‐to‐family conflict and moderates the effects of the work environmental factors. A sample of 396 Danish knowledge workers selected from a national, representative cohort study was followed up after 12 months. Data were analysed with a multiple GLM procedure with and without adjustment for baseline values. The results identified adjustment behavior toward deadlines as an important precursor for the development of conflicts. Further, a family‐friendly workplace culture protected against conflicts and moderated the effect of influence at work. Well‐known antecedents, such as quantitative demands and number of work hours, were further confirmed as relevant also in this specific context. It is concluded that a workload of a suitable size, sustainable behavior related to deadlines, and a family‐friendly workplace culture could potentially improve the likelihood that employees feel confident that they perform successfully both at work and at home.
An Experimental Investigation of the Effects of Acknowledging False Negative and False Positive Errors on Clients' Cancer Screening Intentions: The Lesser of Two Evils?
Authors: Shiloh Shoshana
Published: April 2010

Two studies investigated people's motivations for testing, and the influence of awareness of test inaccuracies, on their intentions to undergo cancer screening tests. Study 1 used a between‐subjects design in which participants stated their intentions regarding one of several screening tests with equal accuracy but with either false negative, false positive, or unspecified errors. Study 2 used a within‐subjects design in which participants indicated their intentions regarding each of those screening tests. In Study 1, intentions for testing were relatively high, affected by instrumental (illness prevention) motivations, and unaffected by type of error acknowledged. Individuals with higher emotional (reassurance seeking) motivations had lower intentions to uptake tests with false positive errors. In Study 2, intentions to uptake all tests were lower compared to Study 1, and were affected by emotional motivations. Participants preferred a test with unspecified errors over tests with specified errors, and, when forced to choose, preferred tests with false negative over false positive errors. Findings are discussed in relation to Error Management Theory and Self‐Regulation Theory, emphasising the need to recognise motivations, affect, and framing as important factors in informed screening decisions.
Effect of fluorine flow and deposition temperature on physical characteristics and stability of fluorine-doped siloxane-based low-dielectric-constant material
Authors: Cheng Yi-Lung , Wu Jiung , Chiu Tai-Jung
Published: April 2010

The effects of SiF4 flow rate and deposition temperature on the physical properties and stability of fluorine-doped organo-silica-glass (OFSG) films were investigated. The porosity of the as-deposited OFSG dielectrics declines as the flow rate of SiF4 gas and the deposition temperature increase, increasing the dielectric constant. However, newly formed Si–F bonds have less electronic polarizability, reducing the dielectric constant. These traded-off properties yield a minimum dielectric constant of the OFSG film deposited at 250 °C with a SiF4 flow rate of 100 SCCM (SCCM denotes cubic centimeter per minute at STP). The stability of Si–F bonds in the OFSG films is related to the deposition conditions. OFSG films deposited a higher SiF4 flow rate (>400 SCCM) or a lower deposition temperature (<300 °C) have lower thermal stability and are less well protected against moisture because of the instability of Si–F bonds. Therefore, more attention should be paid to the conditions for depositing fluorine-doped OFSG dielectrics.
Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML
Authors: Zhang Xiao-Wei , Yan Xiao-Jing , Zhou Zi-Ren , Yang Fei-Fei , Wu Zi-Yu , Sun Hong-Bin , Liang Wen-Xue , Song Ai-Xin , Lallemand-Breitenbach Valérie , Jeanne Marion , Zhang Qun-Ye , Yang Huai-Yu , Huang Qiu-Hua , Zhou Guang-Biao , Tong Jian-Hua , Zhang Yan , Wu Ji-Hui , Hu Hong-Yu , de Thé Hugues , Chen Sai-Juan , Chen Zhu
Published: April 2010

Arsenic on the Fingers

Arsenic, an ancient drug used in traditional Chinese medicine, has attracted wide interest because it has therapeutic activity in patients with acute promyelocytic leukemia (APL). The drug acts by promoting degradation of an oncogenic protein, PML-RARα, a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor α, which is found specifically in APL cells and helps drive their growth.

Zhang
et al.

(p.
240
; see the Perspective by

Kogan

) now explain how arsenic initiates the molecular events leading to PML-RARα degradation. Arsenic was found to bind directly to cysteine residues within zinc finger domains of PML. Arsenic binding then induced oligomerization of PML, which in turn enhanced its association with an enzyme that helps catalyze SUMOylation, a posttranslational modification that can target proteins for degradation.
Why Copy Others? Insights from the Social Learning Strategies Tournament
Authors: Rendell L. , Boyd R. , Cownden D. , Enquist M. , Eriksson K. , Feldman M. W. , Fogarty L. , Ghirlanda S. , Lillicrap T. , Laland K. N.
Published: April 2010

It Pays to Be a Copy Cat

Does it pay to copy what others do?

Rendell
et al.

(p.
208
) elected to copy Robert Axelrod's 1979 tournament in which strategies for playing the iterated prisoner's dilemma game were pitted against each other until an overall winner emerged—the tit-for-tat strategy. In the 2008 tournament, 100 social learning strategies designed to cope with a changing environment competed against each other; the winning strategy involved sampling the behaviors of other players periodically, rather than exploring the environment alone.
Increased Silver Activity for Direct Propylene Epoxidation via Subnanometer Size Effects
Authors: Lei Y. , Mehmood F. , Lee S. , Greeley J. , Lee B. , Seifert S. , Winans R. E. , Elam J. W. , Meyer R. J. , Redfern P. C. , Teschner D. , Schlögl R. , Pellin M. J. , Curtiss L. A. , Vajda S.
Published: April 2010

Silver Cluster Catalysts for Propylene Oxide

The formation of ethylene oxide—in which an oxygen atom bridges the double bond of ethylene—can be made directly and efficiently from ethylene and oxygen with the aid of silver catalysts (typically comprising a small silver cluster on aluminum oxide). Similar approaches are not so successful for making propylene oxide—an important starting material for polyurethane plastics, which are made from chlorinated intermediates.

Lei
et al.

(p.
224
) report that silver trimers, Ag
3
, deposited on alumina are active for direct propylene oxide formation at low temperatures with only a low level of formation of CO
2
by-product, unlike larger particles that form from these clusters at higher temperatures. Density functional calculations suggest that the open-shell nature of the clusters accounts for the improved reactivity.
Probing the Nanoscale
Authors: Cook Robert F.
Published: April 2010

Probes that can now measure a variety of nanomechanical properties provide opportunities for new science and devices.
The Barometer of Life
Authors: Stuart S. N. , Wilson E. O. , McNeely J. A. , Mittermeier R. A. , Rodríguez J. P.
Published: April 2010

A broader taxonomic base to threatened species assessments will enable better conservation and policy decisions.
Graphene Spreads the Heat
Authors: Prasher Ravi
Published: April 2010

Can graphite monolayers outcompete traditional heat-spreading materials in electronic devices?
Central Chile Finally Breaks
Authors: Madariaga Raul , Métois Marianne , Vigny Christophe , Campos Jaime
Published: April 2010

It has been known for 10 years that the site of the Maule mega-earthquake of 27 February 2010 was fully locked and ready to break.
Cancer Therapy Reform
Authors: Levinson Arthur D.
Published: April 2010

Last month, the U.S. Food and Drug Administration (FDA) announced that it plans to draft new guidelines for testing and approving the use of multidrug treatments for diseases. For cancer treatment, the need for this approach and its attendant guidelines are based on an advanced understanding of the disease that has emerged from 30 years of research. If we are to achieve breakthrough cancer therapies, current FDA regulations must change.
NSF Board Draws Flak for Dropping Evolution From
Indicators
Authors: Bhattacharjee Yudhijit
Published: April 2010

The 2010 edition of
Science and Engineering Indicators
omits any mention of evolution and the big bang in its chapter on public attitudes toward science and technology because they forced the public to "conflate knowledge and beliefs."
Did Modern Humans Get Smart Or Just Get Together?
Authors: Culotta Elizabeth
Published: April 2010

The first archaeological signs of art and symbolism may mark new heights of social interaction rather than a cognitive leap.
Conquering by Copying
Authors: Pennisi Elizabeth
Published: April 2010

A computer tournament has revealed the benefit of copying someone else's actions over solving a problem solo, a finding that has implications for cultural evolution.
A Winning Combination
Authors: Pennisi Elizabeth
Published: April 2010

The pair of graduate students who designed the winning computer program in a recent social-learning tournament (
see main text
) obsessively spent hundreds of hours perfecting their social-learning strategy.
Characterization
of fHbp
,
nhba
(
gna2132
),
nadA
,
porA
, and Sequence Type in Group B Meningococcal Case Isolates Collected in England and Wales during January 2008 and Potential Coverage of an Investigational Group B Meningococcal Vaccine
Authors: Lucidarme Jay , Comanducci Maurizio , Findlow Jamie , Gray Stephen J. , Kaczmarski Edward B. , Guiver Malcolm , Vallely Pamela J. , Oster Philipp , Pizza Mariagrazia , Bambini Stefania , Muzzi Alessandro , Borrow Ray
Published: April 2010

Invasive disease caused by meningococcal capsular groups A, C, W-135, and Y is now preventable by means of glycoconjugate vaccines that target their respective polysaccharide capsules. The capsule of group B meningococci (MenB) is poorly immunogenic and may induce autoimmunity. Vaccines based on the major immunodominant surface porin, PorA, are effective against clonal epidemics but, thus far, have a limited scope of coverage against the wider MenB population at large. In an alternative approach, the first-generation, investigational, recombinant MenB (rMenB) plus outer membrane vesicle (OMV) (rMenB-OMV) vaccine contains a number of relatively conserved surface proteins, fHBP, NHBA (previously GNA2132), and NadA, alongside PorA P1.4-containing OMVs from the New Zealand MeNZB vaccine. MenB currently accounts for approximately 90% of cases of meningococcal disease in England and Wales. To assess potential rMenB-OMV vaccine coverage of pathogenic MenB isolates within this region, all English and Welsh MenB case isolates from January 2008 (
n
= 87) were genetically characterized with respect to fHBP, NHBA, NadA, and PorA. Alleles for
fHbp
,
nhba
, and
porA
were identified in all of the isolates, of which 22% were also found to harbor
nadA
alleles. On the basis of genotypic data and predicted immunological cross-reactivity, the potential level of rMenB-OMV vaccine coverage in England and Wales ranges from 66% to 100%.
Comparison of Three Anthrax Toxin Neutralization Assays
Authors: Ngundi Miriam M. , Meade Bruce D. , Lin Tsai-Lien , Tang Wei-Jen , Burns Drusilla L.
Published: April 2010

Different types of anthrax toxin neutralization assays have been utilized to measure the antibody levels elicited by anthrax vaccines in both nonclinical and clinical studies. In the present study, we sought to determine whether three commonly used toxin neutralization assays—J774A.1 cell-, RAW 264.7 cell-, and CHO cell-based assays—yield comparable estimates of neutralization activities for sera obtained after vaccination with anthrax vaccines composed of recombinant protective antigen (rPA). In order to compare the assays, sera were assayed alongside a common reference serum sample and the neutralization titers were expressed relative to the titer for the reference sample in each assay. Analysis of sera from rabbits immunized with multiple doses of the rPA vaccine showed that for later bleeds, the quantitative agreement between the assays was good; however, for early bleeds, some heterogeneity in relative neutralization estimates was observed. Analysis of serum samples from rabbits, nonhuman primates, and humans immunized with the rPA vaccine showed that the relative neutralization estimates obtained in the different assays agreed to various extents, depending on the species of origin of the sera examined. We identified differences in the magnitudes of the Fc receptor-mediated neutralization associated with the J774A.1 cell- and RAW 264.7 cell-based assays, which may account for some of the species dependence of the assays. The differences in the relative neutralization estimates among the assays were relatively small and were always less than 2.5-fold. However, because toxin neutralization assays will likely be used to establish the efficacies of new anthrax vaccines, our findings should be considered when assay outputs are interpreted.
Evaluation of the C.Diff Quik Chek Complete Assay, a New Glutamate Dehydrogenase and A/B Toxin Combination Lateral Flow Assay for Use in Rapid, Simple Diagnosis of
Clostridium difficile
Disease
Authors: Sharp Susan E. , Ruden Lila O. , Pohl Julie C. , Hatcher Patricia A. , Jayne Linda M. , Ivie W. Michael
Published: April 2010

The diagnosis of
Clostridium difficile
infection continues to be a challenge for many clinical microbiology laboratories. A new lateral flow assay, the C.Diff Quik Chek Complete assay, which tests for the presence of both glutamate dehydrogenase (GDH) and
C.
difficile
toxins A and B, was evaluated for its ability to diagnose
C.
difficile
disease. The results of this assay were compared to those of both PCR and toxigenic culture. The results showed that this assay allows 88% of specimens to be accurately screened as either positive (both tests positive) or negative (both tests negative) for the presence of toxigenic
C.
difficile
in less than 30 min and with minimal hands-on time. Use of a random-access PCR for the analysis of specimens with discrepant results (one test positive and the other negative) allows the easy, rapid, and highly sensitive (100%; 95% confidence interval [CI], 89.6 to 100%) and specific (99.6%; 95% CI, 97.3 to 99.9%) diagnosis of
C.
difficile
disease. The use of this algorithm would save institutional costs, curtail unnecessary isolation days, reduce the nosocomial transmission of disease, and increase the quality of care for patients.
Use of Fine-Needle Aspiration for Diagnosis of
Mycobacterium ulcerans
Infection
Authors: Cassisa Viviane , Chauty Annick , Marion Estelle , Ardant Marie Françoise , Eyangoh Sara , Cottin Jane , Aubry Jacques , Koussemou Hugues , Lelièvre Bénédicte , Férec Séverine , Tekaia Fredj , Johnson Christian , Marsollier Laurent
Published: April 2010

Noninvasive methods for the bacteriological diagnosis of early-stage
Mycobacterium ulcerans
infection are not available. It was recently shown that fine-needle aspiration (FNA) could be used for diagnosing
M. ulcerans
infection in ulcerative lesions. We report that FNA is an appropriate sampling method for diagnosing
M. ulcerans
infection in nonulcerative lesions.
Risk Factors and Outcomes Associated with Acquisition of Colistin-Resistant KPC-Producing
Klebsiella pneumoniae
: a Matched Case-Control Study
Authors: Zarkotou Olympia , Pournaras Spyros , Voulgari Evangelia , Chrysos Georgios , Prekates Athanassios , Voutsinas Dionysios , Themeli-Digalaki Katerina , Tsakris Athanassios
Published: April 2010

A matched 1:3 case-control study investigated factors predicting colistin-resistant versus colistin-susceptible KPC-producing
Klebsiella pneumoniae
acquisition and its impact on patient outcomes. Case patients were more often admitted from other institutions (
P =
0.019) and had longer therapy with β-lactam/β-lactamase inhibitors (
P
= 0.002) and higher overall mortality (
P
= 0.05). All 52 study isolates were clonally related, suggesting horizontal dissemination. None of these parameters independently predicted colistin resistance, which probably occurred in a susceptible KPC-KP strain that was subsequently disseminated horizontally.
Development of a Loop-Mediated Isothermal Amplification Assay for Rapid Detection of Subgroup J Avian Leukosis Virus
Authors: Zhang Xiaotao , Liao Ming , Jiao Peirong , Luo Kaijian , Zhang Henan , Ren Tao , Zhang Guihong , Xu Chenggang , Xin Chaoan , Cao Weisheng
Published: April 2010

Infection of breeder flocks in China with subgroup J avian leukosis virus (ALV-J) has increased recently. In this study, we have developed a loop-mediated isothermal amplification (LAMP) assay for rapid detection of ALV-J from culture isolates and clinical samples. The ALV-J-specific LAMP assay efficiently amplified the target gene within 45 min at 63°C using only a simple laboratory water bath. To determine the specificity of the LAMP assay, various subgroup ALVs and other related viruses were detected. A ladder pattern on gel electrophoresis was observed for ALV-J isolates but not for other viruses. To evaluate the sensitivities of the LAMP assay and conventional PCR, the NX0101 isolate plasmid DNA was amplified by them. The detection limit of the LAMP assay was 5 target gene copies/reaction, which was up to 20 times higher than that of conventional PCR. To evaluate the application of the LAMP assay for detection of ALV-J in clinical samples, 49 samples suspected of ALV infection from breeder flocks were tested by the LAMP assay and PCR. Moreover, virus isolation from these samples was also performed using cell culture. The positive-sample ratios were 21/49 (43%) by conventional PCR, 26/49 (53%) by the LAMP assay, and 19/46 (41%) by virus isolation. Additionally, a positive LAMP reaction can be visually ascertained by the observation of turbidity or a color change after addition of SYBR green I dye. Consequently, the LAMP assay is a simple, rapid, and sensitive diagnostic method and can potentially be developed for rapid detection of ALV-J infection in the field.
Wide Variation in the Multiplicity of HIV-1 Infection among Injection Drug Users
Authors: Bar Katharine J. , Li Hui , Chamberland Annie , Tremblay Cecile , Routy Jean Pierre , Grayson Truman , Sun Chuanxi , Wang Shuyi , Learn Gerald H. , Morgan Charity J. , Schumacher Joseph E. , Haynes Barton F. , Keele Brandon F. , Hahn Beatrice H. , Shaw George M.
Published: April 2010

Recent studies indicate that sexual transmission of human immunodeficiency virus type 1 (HIV-1) generally results from productive infection by only one virus, a finding attributable to the mucosal barrier. Surprisingly, a recent study of injection drug users (IDUs) from St. Petersburg, Russia, also found most subjects to be acutely infected by a single virus. Here, we show by single-genome amplification and sequencing in a different IDU cohort that 60% of IDU subjects were infected by more than one virus, including one subject who was acutely infected by at least 16 viruses. Multivariant transmission was more common in IDUs than in heterosexuals (60% versus 19%; odds ratio, 6.14; 95% confidence interval [CI], 1.37 to 31.27;
P
= 0.008). These findings highlight the diversity in HIV-1 infection risks among different IDU cohorts and the challenges faced by vaccines in protecting against this mode of infection.
Dimeric Architecture of the Hendra Virus Attachment Glycoprotein: Evidence for a Conserved Mode of Assembly
Authors: Bowden Thomas A. , Crispin Max , Harvey David J. , Jones E. Yvonne , Stuart David I.
Published: April 2010

Hendra virus is a negative-sense single-stranded RNA virus within the
Paramyxoviridae
family which, together with Nipah virus, forms the
Henipavirus
genus. Infection with bat-borne Hendra virus leads to a disease with high mortality rates in humans. We determined the crystal structure of the unliganded six-bladed β-propeller domain and compared it to the previously reported structure of Hendra virus attachment glycoprotein (HeV-G) in complex with its cellular receptor, ephrin-B2. As observed for the related unliganded Nipah virus structure, there is plasticity in the Glu579-Pro590 and Lys236-Ala245 ephrin-binding loops prior to receptor engagement. These data reveal that henipaviral attachment glycoproteins undergo common structural transitions upon receptor binding and further define the structural template for antihenipaviral drug design. Our analysis also provides experimental evidence for a dimeric arrangement of HeV-G that exhibits striking similarity to those observed in crystal structures of related paramyxovirus receptor-binding glycoproteins. The biological relevance of this dimer is further supported by the positional analysis of glycosylation sites from across the paramyxoviruses. In HeV-G, the sites lie away from the putative dimer interface and remain accessible to α-mannosidase processing on oligomerization. We therefore propose that the overall mode of dimer assembly is conserved for all paramyxoviruses; however, while the geometry of dimerization is rather closely similar for those viruses that bind flexible glycan receptors, significant (up to 60°) and different reconfigurations of the subunit packing (associated with a significant decrease in the size of the dimer interface) have accompanied the independent switching to high-affinity protein receptor binding in Hendra and measles viruses.
Endocytosis of Murine Norovirus 1 into Murine Macrophages Is Dependent on Dynamin II and Cholesterol
Authors: Perry Jeffrey W. , Wobus Christiane E.
Published: April 2010

Although noroviruses cause the vast majority of nonbacterial gastroenteritis in humans, little is known about their life cycle, including viral entry. Murine norovirus (MNV) is the only norovirus to date that efficiently infects cells in culture. To elucidate the productive route of infection for MNV-1 into murine macrophages, we used a neutral red (NR) infectious center assay and pharmacological inhibitors in combination with dominant-negative (DN) and small interfering RNA (siRNA) constructs to show that clathrin- and caveolin-mediated endocytosis did not play a role in entry. In addition, we showed that phagocytosis or macropinocytosis, flotillin-1, and GRAF1 are not required for the major route of MNV-1 uptake. However, MNV-1 genome release occurred within 1 h, and endocytosis was significantly inhibited by the cholesterol-sequestering drugs nystatin and methyl-β-cyclodextrin, the dynamin-specific inhibitor dynasore, and the dominant-negative dynamin II mutant K44A. Therefore, we conclude that the productive route of MNV-1 entry into murine macrophages is rapid and requires host cholesterol and dynamin II.
A Novel Bicistronic High-Capacity Gutless Adenovirus Vector That Drives Constitutive Expression of Herpes Simplex Virus Type 1 Thymidine Kinase and Tet-Inducible Expression of Flt3L for Glioma Therapeutics
Authors: Puntel Mariana , Muhammad A. K. M. G. , Candolfi Marianela , Salem Alireza , Yagiz Kader , Farrokhi Catherine , Kroeger Kurt M. , Xiong Weidong , Curtin James F. , Liu Chunyan , Bondale Niyati S. , Lerner Jonathan , Pechnick Robert N. , Palmer Donna , Ng Philip , Lowenstein Pedro R. , Castro Maria G.
Published: April 2010

Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Conditional cytotoxic/immune-stimulatory gene therapy (Ad-TK and Ad-Flt3L) elicits tumor regression and immunological memory in rodent GBM models. Since the majority of patients enrolled in clinical trials would exhibit adenovirus immunity, which could curtail transgene expression and therapeutic efficacy, we used high-capacity adenovirus vectors (HC-Ads) as a gene delivery platform. Herein, we describe for the first time a novel bicistronic HC-Ad driving constitutive expression of herpes simplex virus type 1 thymidine kinase (HSV1-TK) and inducible
Tet-
mediated expression of Flt3L within a single-vector platform. We achieved anti-GBM therapeutic efficacy with no overt toxicities using this bicistronic HC-Ad even in the presence of systemic Ad immunity. The bicistronic HC-Ad-TK/TetOn-Flt3L was delivered into intracranial gliomas in rats. Survival, vector biodistribution, neuropathology, systemic toxicity, and neurobehavioral deficits were assessed for up to 1 year posttreatment. Therapeutic efficacy was also assessed in animals preimmunized against Ads. We demonstrate therapeutic efficacy, with vector genomes being restricted to the brain injection site and an absence of overt toxicities. Importantly, antiadenoviral immunity did not inhibit therapeutic efficacy. These data represent the first report of a bicistronic vector platform driving the expression of two therapeutic transgenes, i.e., constitutive HSV1-TK and inducible Flt3L genes. Further, our data demonstrate no promoter interference and optimum gene delivery and expression from within this single-vector platform. Analysis of the efficacy, safety, and toxicity of this bicistronic HC-Ad vector in an animal model of GBM strongly supports further preclinical testing and downstream process development of HC-Ad-TK/TetOn-Flt3L for a future phase I clinical trial for GBM.
Enhancerless Cytomegalovirus Is Capable of Establishing a Low-Level Maintenance Infection in Severely Immunodeficient Host Tissues but Fails in Exponential Growth
Authors: Podlech Jürgen , Pintea Rares , Kropp Kai A. , Fink Annette , Lemmermann Niels A. W. , Erlach Katja C. , Isern Elena , Angulo Ana , Ghazal Peter , Reddehase Matthias J.
Published: April 2010

Major immediate-early transcriptional enhancers are genetic control elements that act, through docking with host transcription factors, as a decisive regulatory unit for efficient initiation of the productive virus cycle. Animal models are required for studying the function of enhancers paradigmatically in host organs. Here, we have sought to quantitatively assess the establishment, maintenance, and level of
in vivo
growth of enhancerless mutants of murine cytomegalovirus in comparison with those of an enhancer-bearing counterpart in models of the immunocompromised or immunologically immature host. Evidence is presented showing that enhancerless viruses are capable of forming restricted foci of infection but fail to grow exponentially.
Virus Cell-to-Cell Transmission
Authors: Mothes Walther , Sherer Nathan M. , Jin Jing , Zhong Peng
Published: April 2010

Viral infections spread based on the ability of viruses to overcome multiple barriers and move from cell to cell, tissue to tissue, and person to person and even across species. While there are fundamental differences between these types of transmissions, it has emerged that the ability of viruses to utilize and manipulate cell-cell contact contributes to the success of viral infections. Central to the excitement in the field of virus cell-to-cell transmission is the idea that cell-to-cell spread is more than the sum of the processes of virus release and entry. This implies that virus release and entry are efficiently coordinated to sites of cell-cell contact, resulting in a process that is distinct from its individual components. In this review, we will present support for this model, illustrate the ability of viruses to utilize and manipulate cell adhesion molecules, and discuss the mechanism and driving forces of directional spreading. An understanding of viral cell-to-cell spreading will enhance our ability to intervene in the efficient spreading of viral infections.
The ABCs of Rhinoviruses, Wheezing, and Asthma
Authors: Gern James E.
Published: April 2010

Human rhinoviruses (HRVs) were discovered as common cold pathogens over 50 years ago. Recent advances in molecular viral diagnostics have led to an appreciation of their role in more-significant respiratory illnesses, including bronchiolitis in infancy, childhood pneumonia, and acute exacerbations of chronic respiratory diseases such as asthma, chronic obstructive lung disease, and cystic fibrosis. Until a few years ago, only two groups of HRVs (A and B) had been recognized. However, full and partial sequencing of HRVs led to the discovery of a third species of HRV (HRV-C) that has distinct structural and biologic features. Risk factors and pathogenic mechanisms for more-severe HRV infections are being defined, and yet fundamental questions persist about mechanisms relating this common pathogen to allergic diseases and asthma. The close relationship between HRV infections and asthma suggests that antiviral treatments could have a major impact on the morbidity associated with this chronic respiratory disease.
Suppressor of Cytokine Signaling 3 Suppresses Hepatitis C Virus Replication in an mTOR-Dependent Manner
Authors: Shao Run-Xuan , Zhang Leiliang , Peng Lee F. , Sun Eileen , Chung Woo Jin , Jang Jae Yong , Tsai Wei-Lun , Hyppolite Guibenson , Chung Raymond T.
Published: April 2010

We and others have observed that hepatic levels of suppressor of cytokine signaling 3 (SOCS3) are significantly higher in persons with chronic hepatitis C, particularly those who are nonresponders to interferon (IFN) treatment, than in healthy individuals. However, the relationship between SOCS3 and hepatitis C virus (HCV) replication remains unclear. Given its putative role, we hypothesized that SOCS3 is permissive for viral replication. We therefore used the OR6 cell line, which harbors a genotype 1b full-length HCV replicon, and the genotype 2a full-length HCV strain JFH1 infection system to analyze the effects of SOCS3 overexpression and short hairpin RNA (shRNA)-mediated knockdown on HCV replication. We further analyzed the role of mTOR in the effects of SOCS3 by treating selected cells with rapamycin. OR6 cells and JFH1-infected Huh7.5.1 cells expressed significantly less SOCS3 than control cells. Furthermore, inhibition of HCV replication with the HCV protease inhibitor BILN 2061 restored SOCS3 protein levels. SOCS3 overexpression in OR6 cells and JFH1-infected Huh7.5.1 cells resulted in significantly lower HCV replication than that in the control cells, despite SOCS3-related inhibition of STAT1 phosphorylation and type I IFN signaling. In contrast, JFH1-infected cells with stable SOCS3 knockdown expressed higher levels of HCV proteins and RNA than did control cells. SOCS3-targeting shRNA also knocked down mTOR and phospho-mTOR. The mTOR inhibitor rapamycin reversed the inhibitory effects of SOCS3. In independent investigations, SOCS3 unexpectedly suppressed HCV replication in an mTOR-dependent manner. These findings suggest that increased SOCS3 levels consistently observed in chronic IFN nonresponders may reflect a compensatory host antiviral response to persistent infection and that manipulation of SOCS3/mTOR may offer benefit against HCV infection.
Persistence of Viremia and Production of Neutralizing Antibodies Differentially Regulated by PolymorphicAPOBEC3andBAFF-RLoci in Friend Virus-Infected Mice
Authors: Tsuji-Kawahara Sachiyo , Chikaishi Tomomi , Takeda Eri , Kato Maiko , Kinoshita Saori , Kajiwara Eiji , Takamura Shiki , Miyazawa Masaaki
Published: April 2010

Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. TheRfv3gene influences the persistence of viremia and production of virus-neutralizing antibodies in mice infected with Friend mouse retrovirus complex (FV). This locus has been mapped within a narrow segment of mouse chromosome 15 harboring theAPOBEC3andBAFF-Rloci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of theAPOBEC3allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derivedAPOBEC3exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at theAPOBEC3locus affect the production of neutralizing antibodies remain unclear. Here we show that theAPOBEC3genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derivedAPOBEC3still produce FV-neutralizing antibodies in the presence of primed T helper cells. Instead, higher viral loads at a very early stage of FV infection caused by either a lack of the B6-derivedAPOBEC3or a lack of the wild-typeBAFF-Rresulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in theAPOBEC3- orBAFF-R-deficient mice. In contrast to mice deficient in the B6-derivedAPOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functionalBAFF-Rallele exhibited sustained viremia, indicating that the polymorphisms at theBAFF-Rlocus may better explain theRfv3-defining phenotype of persistent viremia.
Novel RecombinantMycobacterium bovisBCG, Ovine Atadenovirus, and Modified Vaccinia Virus Ankara Vaccines Combine To Induce Robust Human Immunodeficiency Virus-Specific CD4 and CD8 T-Cell Responses in Rhesus Macaques
Authors: Rosario Maximillian , Hopkins Richard , Fulkerson John , Borthwick Nicola , Quigley Máire F. , Joseph Joan , Douek Daniel C. , Greenaway Hui Yee , Venturi Vanessa , Gostick Emma , Price David A. , Both Gerald W. , Sadoff Jerald C. , Hanke Tomáš
Published: April 2010

Mycobacterium bovisbacillus Calmette-Guérin (BCG), which elicits a degree of protective immunity against tuberculosis, is the most widely used vaccine in the world. Due to its persistence and immunogenicity, BCG has been proposed as a vector for vaccines against other infections, including HIV-1. BCG has a very good safety record, although it can cause disseminated disease in immunocompromised individuals. Here, we constructed a recombinant BCG vector expressing HIV-1 clade A-derived immunogen HIVA using the recently described safer and more immunogenic BCG strain AERAS-401 as the parental mycobacterium. Using routine ex vivo T-cell assays, BCG.HIVA401as a stand-alone vaccine induced undetectable and weak CD8 T-cell responses in BALB/c mice and rhesus macaques, respectively. However, when BCG.HIVA401was used as a priming component in heterologous vaccination regimens together with recombinant modified vaccinia virus Ankara-vectored MVA.HIVA and ovine atadenovirus-vectored OAdV.HIVA vaccines, robust HIV-1-specific T-cell responses were elicited. These high-frequency T-cell responses were broadly directed and capable of proliferation in response to recall antigen. Furthermore, multiple antigen-specific T-cell clonotypes were efficiently recruited into the memory pool. These desirable features are thought to be associated with good control of HIV-1 infection. In addition, strong and persistent T-cell responses specific for the BCG-derived purified protein derivative (PPD) antigen were induced. This work is the first demonstration of immunogenicity for two novel vaccine vectors and the corresponding candidate HIV-1 vaccines BCG.HIVA401and OAdV.HIVA in nonhuman primates. These results strongly support their further exploration.
Viral Nucleic Acids in Live-Attenuated Vaccines: Detection of Minority Variants and an Adventitious Virus
Authors: Victoria Joseph G. , Wang Chunlin , Jones Morris S. , Jaing Crystal , McLoughlin Kevin , Gardner Shea , Delwart Eric L.
Published: April 2010

Metagenomics and a panmicrobial microarray were used to examine eight live-attenuated viral vaccines. Viral nucleic acids in trivalent oral poliovirus (OPV), rubella, measles, yellow fever, varicella-zoster, multivalent measles/mumps/rubella, and two rotavirus live vaccines were partially purified, randomly amplified, and pyrosequenced. Over half a million sequence reads were generated covering from 20 to 99% of the attenuated viral genomes at depths reaching up to 8,000 reads per nucleotides. Mutations and minority variants, relative to vaccine strains, not known to affect attenuation were detected in OPV, mumps virus, and varicella-zoster virus. The anticipated detection of endogenous retroviral sequences from the producer avian and primate cells was confirmed. Avian leukosis virus (ALV), previously shown to be noninfectious for humans, was present as RNA in viral particles, while simian retrovirus (SRV) was present as genetically defective DNA. Rotarix, an orally administered rotavirus vaccine, contained porcine circovirus-1 (PCV1), a highly prevalent nonpathogenic pig virus, which has not been shown to be infectious in humans. Hybridization of vaccine nucleic acids to a panmicrobial microarray confirmed the presence of endogenous retroviral and PCV1 nucleic acids. Deep sequencing and microarrays can therefore detect attenuated virus sequence changes, minority variants, and adventitious viruses and help maintain the current safety record of live-attenuated viral vaccines.
Human Bocavirus Capsid Structure: Insights into the Structural Repertoire of the
Parvoviridae
Authors: Gurda Brittney L. , Parent Kristin N. , Bladek Heather , Sinkovits Robert S. , DiMattia Michael A. , Rence Chelsea , Castro Alejandro , McKenna Robert , Olson Norm , Brown Kevin , Baker Timothy S. , Agbandje-McKenna Mavis
Published: April 2010

Human bocavirus (HBoV) was recently discovered and classified in the
Bocavirus
genus (family
Parvoviridae
, subfamily
Parvovirinae
) on the basis of genomic similarity to bovine parvovirus and canine minute virus. HBoV has been implicated in respiratory tract infections and gastroenteric disease in children worldwide, yet despite numerous epidemiological reports, there has been limited biochemical and molecular characterization of the virus. Reported here is the three-dimensional structure of recombinant HBoV capsids, assembled from viral protein 2 (VP2), at 7.9-Å resolution as determined by cryo-electron microscopy and image reconstruction. A pseudo-atomic model of HBoV VP2 was derived from sequence alignment analysis and knowledge of the crystal structure of human parvovirus B19 (genus
Erythrovirus
). Comparison of the HBoV capsid structure to that of parvoviruses from five separate genera demonstrates strong conservation of a β-barrel core domain and an α-helix, from which emanate several loops of various lengths and conformations, yielding a unique surface topology that differs from the three already described for this family. The highly conserved core is consistent with observations for other single-stranded DNA viruses, and variable surface loops have been shown to confer the host-specific tropism and the diverse antigenic properties of this family.
Torrential upper gastrointestinal bleeding from ‘downhill’ oesophageal varices complicating long term central venous access for total parenteral nutrition
Authors: Lim Eu Jin , Stella Damien L , Russell David M
Published: April 2010

Oesophageal varices usually develop in the setting of portal hypertension secondary to chronic liver disease. However, superior vena cava (SVC) obstruction can result in ‘downhill’ varices forming in the upper oesophagus. A case of torrential upper gastrointestinal bleeding from SVC obstruction due to chronic central venous access for home total parenteral nutrition is described. It is suggested that in patients presenting with gastrointestinal bleeding in the setting of SVC obstruction, ‘downhill’ varices should be suspected. The current literature is discussed regarding management of such varices. It is recommended that endoscopic variceal surveillance be carried out in patients with known SVC obstruction.
The impact of social norm change strategies on smokers' quitting behaviours
Authors: Zhang Xueying , Cowling David W , Tang Hao
Published: April 2010

Objective

Using a social norm change paradigm model that reflects the California Tobacco Control Program's (CTCP) priorities, we compare the strength of the relationship of the social norm constructs to key smoking behavioural outcomes.

Methods

Social norm constructs that correspond to CTCP's priority areas were created from selected California Adult Tobacco Survey knowledge, attitude and belief questions using confirmatory factor analysis. We then examined the relationship between these constructs and quitting behaviours using logistic regression.

Results

The secondhand smoke (SHS) and countering pro-tobacco influences'(CPTI) constructs followed a dose-response curve with quitting behaviours. Respondents who rated high on the SHS construct were about 70% more likely to have made a recent quit attempt in the last 12 months and about 100% more likely to intend to quit in the next 6 months than respondents who rated low on the SHS construct. For CPTI, respondents who rated high on this construct were 67% more likely to have made a recent quit attempt in the last 12 months and 62% more likely to have intentions to quit in the next 6 months than respondents who rated low on the CPTI construct.

Conclusion

Social norm change constructs represent CTCP's priorities and are strongly related to desired individual behaviour outcomes. This analysis provides strong support for the framework underlying CTCP—namely, that changing social norms affects behaviour change at the individual level through changing population-level smoking-related behaviours.