bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Flavivirus Population Diversity by RNA Interference
Authors: Brackney Doug E. , Schirtzinger Erin E. , Harrison Thomas D. , Ebel Gregory D. , Hanley Kathryn A.
Published: January 2015

To test the hypothesis that RNA interference (RNAi) imposes diversifying selection on RNA virus genomes, we quantified West Nile virus (WNV) quasispecies diversity after passage in
Drosophila
cells in which RNAi was left intact, depleted, or stimulated against WNV. As predicted, WNV diversity was significantly lower in RNAi-depleted cells and significantly greater in RNAi-stimulated cells relative to that in controls. These findings reveal that an innate immune defense can shape viral population structure.
DNA Vaccine Molecular Adjuvants SP-D-BAFF and SP-D-APRIL Enhance Anti-gp120 Immune Response and Increase HIV-1 Neutralizing Antibody Titers
Authors: Gupta Sachin , Clark Emily S. , Termini James M. , Boucher Justin , Kanagavelu Saravana , LeBranche Celia C. , Abraham Sakhi , Montefiori David C. , Khan Wasif N. , Stone Geoffrey W.
Published: January 2015

Broadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNA-protein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1.

IMPORTANCE
Recent identification of antibodies that neutralize most HIV-1 strains has revived hopes and efforts to create novel vaccines that can effectively stimulate HIV-1 neutralizing antibodies. However, the multiple immune evasion properties of HIV have hampered these efforts. These include the instability of the gp120 trimer, the inaccessibility of the conserved sequences, highly variable protein sequences, and the loss of HIV-1-specific antibody-producing cells during development. We have shown previously that tumor necrosis factor (TNF) superfamily ligands, including BAFF and APRIL, can be multitrimerized using the lung protein SP-D (surfactant protein D), enhancing immune responses. Here we show that DNA or DNA-protein vaccines encoding BAFF or APRIL multitrimers, IL-12p70, and membrane-bound HIV-1 Env gp140 induced tier 1 and tier 2 neutralizing antibodies in a mouse model. BAFF and APRIL enhanced the immune reaction, improved antibody binding, and increased the numbers of anti-HIV-1 antibody-secreting cells. Adaptation of this vaccine design may prove useful in designing preventive HIV-1 vaccines for humans.
Cotranslational Coat Protein-Mediated Inhibition of Potyviral RNA Translation
Authors: Besong-Ndika Jane , Ivanov Konstantin I. , Hafrèn Anders , Michon Thierry , Mäkinen Kristiina
Published: January 2015

Potato virus A
(PVA) is a single-stranded positive-sense RNA virus and a member of the family
Potyviridae
. The PVA coat protein (CP) has an intrinsic capacity to self-assemble into filamentous virus-like particles, but the mechanism responsible for the initiation of viral RNA encapsidation
in vivo
remains unclear. Apart from virion assembly, PVA CP is also involved in the inhibition of viral RNA translation. In this study, we show that CP inhibits PVA RNA translation in a dose-dependent manner, through a mechanism involving the CP-encoding region. Analysis of this region, however, failed to identify any RNA secondary structure(s) preferentially recognized by CP, suggesting that the inhibition depends on CP-CP rather than CP-RNA interactions. In agreement with this possibility, insertion of an in-frame stop codon upstream of the CP sequence led to a marked decrease in the inhibition of viral RNA translation. Based on these results, we propose a model in which the cotranslational interactions between excess CP accumulating in
trans
and CP translated from viral RNA in
cis
are required to initiate the translational repression. This model suggests a mechanism for how viral RNA can be sequestered from translation and specifically selected for encapsidation at the late stages of viral infection.

IMPORTANCE
The main functions of the CP during potyvirus infection are to protect viral RNA from degradation and to transport it locally, systemically, and from host to host. Although virion assembly is a key step in the potyviral infectious cycle, little is known about how it is initiated and how viral RNA is selected for encapsidation. The results presented here suggest that CP-CP rather than CP-RNA interactions are predominantly involved in the sequestration of viral RNA away from translation. We propose that the cotranslational nature of these interactions may represent a mechanism for the selection of viral RNA for encapsidation. A better understanding of the mechanism of virion assembly may lead to development of crops resistant to potyviruses at the level of viral RNA encapsidation, thereby reducing the detrimental effects of potyvirus infections on food production.
Nectin-Like Interactions between Poliovirus and Its Receptor Trigger Conformational Changes Associated with Cell Entry
Authors: Strauss Mike , Filman David J. , Belnap David M. , Cheng Naiqian , Noel Roane T. , Hogle James M.
Published: January 2015

Poliovirus infection is initiated by attachment to a receptor on the cell surface called Pvr or CD155. At physiological temperatures, the receptor catalyzes an irreversible expansion of the virus to form an expanded form of the capsid called the 135S particle. This expansion results in the externalization of the myristoylated capsid protein VP4 and the N-terminal extension of the capsid protein VP1, both of which become inserted into the cell membrane. Structures of the expanded forms of poliovirus and of several related viruses have recently been reported. However, until now, it has been unclear how receptor binding triggers viral expansion at physiological temperature. Here, we report poliovirus in complex with an enzymatically partially deglycosylated form of the 3-domain ectodomain of Pvr at a 4-Å resolution, as determined by cryo-electron microscopy. The interaction of the receptor with the virus in this structure is reminiscent of the interactions of Pvr with its natural ligands. At a low temperature, the receptor induces very few changes in the structure of the virus, with the largest changes occurring within the footprint of the receptor, and in a loop of the internal protein VP4. Changes in the vicinity of the receptor include the displacement of a natural lipid ligand (called “pocket factor”), demonstrating that the loss of this ligand, alone, is not sufficient to induce particle expansion. Finally, analogies with naturally occurring ligand binding in the nectin family suggest which specific structural rearrangements in the virus-receptor complex could help to trigger the irreversible expansion of the capsid.

IMPORTANCE
The cell-surface receptor (Pvr) catalyzes a large structural change in the virus that exposes membrane-binding protein chains. We fitted known atomic models of the virus and Pvr into three-dimensional experimental maps of the receptor-virus complex. The molecular interactions we see between poliovirus and its receptor are reminiscent of the nectin family, by involving the burying of otherwise-exposed hydrophobic groups. Importantly, poliovirus expansion is regulated by the binding of a lipid molecule within the viral capsid. We show that receptor binding either causes this molecule to be expelled or requires it, but that its loss is not sufficient to trigger irreversible expansion. Based on our model, we propose testable hypotheses to explain how the viral shell becomes destabilized, leading to RNA uncoating. These findings give us a better understanding of how poliovirus has evolved to exploit a natural process of its host to penetrate the membrane barrier.
Mammalian Adaptive Mutations of the PA Protein of Highly Pathogenic Avian H5N1 Influenza Virus
Authors: Yamaji Reina , Yamada Shinya , Le Mai Q. , Ito Mutsumi , Sakai-Tagawa Yuko , Kawaoka Yoshihiro
Published: January 2015

Highly pathogenic H5N1 influenza A viruses continue to circulate among avian species and cause sporadic cases of human infection. Therefore, the threat of a pandemic persists. However, the human cases of H5N1 infection have been limited mainly to individuals in close contact with infected poultry. These findings suggest that the H5N1 viruses need to acquire adaptive mutations to gain a replicative advantage in mammalian cells to break through the species barrier. Many amino acid mutations of the polymerase complex have been reported to enhance H5N1 virus growth in mammalian cells; however, the mechanism for H5N1 virus of adaptation to humans remains unclear. Here, we propose that the PA of an H5N1 influenza virus isolated from a human in Vietnam (A/Vietnam/UT36285/2010 [36285]) increased the ability of an avian H5N1 virus (A/chicken/Vietnam/TY31/2005 [Ck/TY31]) to grow in human lung epithelial A549 cells. The five PA amino acid substitutions V44I, V127A, C241Y, A343T, and I573V, which are rare in H5N1 viruses from human and avian sources, enhanced the growth capability of this virus in A549 cells. Moreover, these mutations increased the pathogenicity of the virus in mice, suggesting that they contribute to adaptation to mammalian hosts. Intriguingly, PA-241Y, which 36285 encodes, is conserved in more than 90% of human seasonal H1N1 viruses, suggesting that PA-241Y contributes to virus adaptation to human lung cells and mammalian hosts.

IMPORTANCE
Many amino acid substitutions in highly pathogenic H5N1 avian influenza viruses have been shown to contribute to adaptation to mammalian hosts. However, no naturally isolated H5N1 virus has caused extensive human-to-human transmission, suggesting that additional, as-yet unidentified amino acid mutations are needed for adaptation to humans. Here, we report that five amino acid substitutions in PA (V44I, V127A, C241Y, A343T, and I573V) contribute to the replicative efficiency of H5N1 viruses in human lung cells and to high virulence in mice. These results are helpful for assessing the pandemic risk of isolates and further our understanding of the mechanism of H5N1 virus adaptation to mammalian hosts.
Analysis of HIV-1 Gag Protein Interactions via Biotin Ligase Tagging
Authors: Ritchie Christopher , Cylinder Isabel , Platt Emily J. , Barklis Eric
Published: January 2015

We have examined the interactions of wild-type (WT) and matrix protein-deleted (ΔMA) HIV-1 precursor Gag (PrGag) proteins in virus-producing cells using a biotin ligase-tagging approach. To do so, WT and ΔMA PrGag proteins were tagged with the
Escherichia coli
promiscuous biotin ligase (BirA*), expressed in cells, and examined. Localization patterns of PrGag proteins and biotinylated proteins overlapped, consistent with observations that BirA*-tagged proteins biotinylate neighbor proteins that are in close proximity. Results indicate that BirA*-tagged PrGag proteins biotinylated themselves as well as WT PrGag proteins in
trans
. Previous data have shown that the HIV-1 Envelope (Env) protein requires an interaction with MA for assembly into virions. Unexpectedly, ΔMA proteins biotinylated Env, whereas WT BirA*-tagged proteins did not, suggesting that the presence of MA made Env inaccessible to biotinylation. We also identified over 50 cellular proteins that were biotinylated by BirA*-tagged PrGag proteins. These included membrane proteins, cytoskeleton-associated proteins, nuclear transport factors, lipid metabolism regulators, translation factors, and RNA-processing proteins. The identification of these biotinylated proteins offers new insights into HIV-1 Gag protein trafficking and activities and provides new potential targets for antiviral interference.

IMPORTANCE
We have employed a novel strategy to analyze the interactions of the HIV-1 structural Gag proteins, which involved tagging wild-type and mutant Gag proteins with a biotin ligase. Expression of the tagged proteins in cells allowed us to analyze proteins that came in close proximity to the Gag proteins as they were synthesized, transported, assembled, and released from cells. The tagged proteins biotinylated proteins encoded by the HIV-1
pol
gene and neighbor Gag proteins, but, surprisingly, only the mutant Gag protein biotinylated the HIV-1 Envelope protein. We also identified over 50 cellular proteins that were biotinylated, including membrane and cytoskeletal proteins and proteins involved in lipid metabolism, nuclear import, translation, and RNA processing. Our results offer new insights into HIV-1 Gag protein trafficking and activities and provide new potential targets for antiviral interference.
HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies
Authors: Lynch Rebecca M. , Wong Patrick , Tran Lillian , O'Dell Sijy , Nason Martha C. , Li Yuxing , Wu Xueling , Mascola John R.
Published: January 2015

Broadly neutralizing antibodies (bNAbs) have been isolated from selected HIV-1-infected individuals and shown to bind to conserved sites on the envelope glycoprotein (Env). However, circulating plasma virus in these donors is usually resistant to autologous isolated bNAbs, indicating that during chronic infection, HIV-1 can escape from even broadly cross-reactive antibodies. Here, we evaluate if such viral escape is associated with an impairment of viral replication. Antibodies of the VRC01 class target the functionally conserved CD4 binding site and share a structural mode of gp120 recognition that includes mimicry of the CD4 receptor. We examined naturally occurring VRC01-sensitive and -resistant viral strains, as well as their mutated sensitive or resistant variants, and tested point mutations in the backbone of the VRC01-sensitive isolate YU2. In several cases, VRC01 resistance was associated with a reduced efficiency of CD4-mediated viral entry and diminished viral replication. Several mutations, alone or in combination, in the loop D or β23-V5 region of Env conferred a high level of resistance to VRC01 class antibodies, suggesting a preferred escape pathway. We further mapped the VRC01-induced escape pathway
in vivo
using Envs from donor 45, from whom antibody VRC01 was isolated. Initial escape mutations, including the addition of a key glycan, occurred in loop D and were associated with impaired viral replication; however, compensatory mutations restored full replicative fitness. These data demonstrate that escape from VRC01 class antibodies can diminish viral replicative fitness, but compensatory changes may explain the limited impact of neutralizing antibodies during the course of natural HIV-1 infection.

IMPORTANCE
Some antibodies that arise during natural HIV-1 infection bind to conserved regions on the virus envelope glycoprotein and potently neutralize the majority of diverse HIV-1 strains. The VRC01 class of antibodies blocks the conserved CD4 receptor binding site interaction that is necessary for viral entry, raising the possibility that viral escape from antibody neutralization might exert detrimental effects on viral function. Here, we show that escape from VRC01 class antibodies can be associated with impaired viral entry and replication; however, during the course of natural infection, compensatory mutations restore the ability of the virus to replicate normally.
Heterologous Production of Curcuminoids
Authors: Rodrigues J. L. , Prather K. L. J. , Kluskens L. D. , Rodrigues L. R.
Published: January 2015

Curcuminoids, components of the rhizome of turmeric, show several beneficial biological activities, including anticarcinogenic, antioxidant, anti-inflammatory, and antitumor activities. Despite their numerous pharmaceutically important properties, the low natural abundance of curcuminoids represents a major drawback for their use as therapeutic agents. Therefore, they represent attractive targets for heterologous production and metabolic engineering. The understanding of biosynthesis of curcuminoids in turmeric made remarkable advances in the last decade, and as a result, several efforts to produce them in heterologous organisms have been reported. The artificial biosynthetic pathway (e.g., in
Escherichia coli
) can start with the supplementation of the amino acid tyrosine or phenylalanine or of carboxylic acids and lead to the production of several natural curcuminoids. Unnatural carboxylic acids can also be supplemented as precursors and lead to the production of unnatural compounds with possibly novel therapeutic properties. In this paper, we review the natural conversion of curcuminoids in turmeric and their production by
E. coli
using an artificial biosynthetic pathway. We also explore the potential of other enzymes discovered recently or already used in other similar biosynthetic pathways, such as flavonoids and stilbenoids, to increase curcuminoid yield and activity.
Ecology and Biotechnology of Selenium-Respiring Bacteria
Authors: Nancharaiah Y. V. , Lens P. N. L.
Published: January 2015

In nature, selenium is actively cycled between oxic and anoxic habitats, and this cycle plays an important role in carbon and nitrogen mineralization through bacterial anaerobic respiration. Selenium-respiring bacteria (SeRB) are found in geographically diverse, pristine or contaminated environments and play a pivotal role in the selenium cycle. Unlike its structural analogues oxygen and sulfur, the chalcogen selenium and its microbial cycling have received much less attention by the scientific community. This review focuses on microorganisms that use selenate and selenite as terminal electron acceptors, in parallel to the well-studied sulfate-reducing bacteria. It overviews the significant advancements made in recent years on the role of SeRB in the biological selenium cycle and their ecological role, phylogenetic characterization, and metabolism, as well as selenium biomineralization mechanisms and environmental biotechnological applications.
Yeast Prions: Structure, Biology, and Prion-Handling Systems
Authors: Wickner Reed B. , Shewmaker Frank P. , Bateman David A. , Edskes Herman K. , Gorkovskiy Anton , Dayani Yaron , Bezsonov Evgeny E.
Published: January 2015

A prion is an infectious protein horizontally transmitting a disease or trait without a required nucleic acid. Yeast and fungal prions are nonchromosomal genes composed of protein, generally an altered form of a protein that catalyzes the same alteration of the protein. Yeast prions are thus transmitted both vertically (as genes composed of protein) and horizontally (as infectious proteins, or prions). Formation of amyloids (linear ordered β-sheet-rich protein aggregates with β-strands perpendicular to the long axis of the filament) underlies most yeast and fungal prions, and a single prion protein can have any of several distinct self-propagating amyloid forms with different biological properties (prion variants). Here we review the mechanism of faithful templating of protein conformation, the biological roles of these prions, and their interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling systems, and other cellular factors governing prion generation and propagation. Human amyloidoses include the PrP-based prion conditions and many other, more common amyloid-based diseases, several of which show prion-like features. Yeast prions increasingly are serving as models for the understanding and treatment of many mammalian amyloidoses. Patients with different clinical pictures of the same amyloidosis may be the equivalent of yeasts with different prion variants.
Forme Fruste of HLH (haemophagocytic lymphohistiocytosis): diagnostic and therapeutic challenges
Authors: Inoue Susumu , Mangat Chetna , Rafe'e Yaseen , Sharman Mahesh
Published: January 2015

Infants and young children often present with a persistent febrile episode, sick appearance and negative infectious disease work-up. These patients present serious diagnostic and therapeutic problems to those who provide medical care, particularly since these children are clinically sick. We present a 13 month old child who presented with this clinical challenge. She was ultimately thought to have an incomplete form of HLH with underlying pathophysiology of hypercytokinemia, but also could have been a case of incomplete form of Kawasaki disease. She responded to IVIG, but this does not differentiate one diagnosis from another. Unfortunately we failed to obtain tests to exclude genetic etiologies of HLH, which would be important for predicting severity and risks of future recurrence. We wish to present this case so that one should do a thorough work up to establish a firm diagnosis of HLH and to search for genetic causes of this disorder.
‘The nodule that disappeared’ spontaneous regression of an eyelid noduloulcerative lesion mimicking the features of a basal cell carcinoma
Authors: Young-Zvandasara Tafadzwa , Popiela Magdalena , Shuttleworth Garry
Published: January 2015

We describe a case of a clinically apparent basal cell carcinoma (BCC) with spontaneous regression. Histological confirmation of the diagnosis was not possible, and an immunological basis for regression is presumed. The understanding of such immunologically mediated regression of BCCs could provide future therapeutic targeting and research is ongoing.
Blood pressure and hypertension in athletes: a systematic review
Authors: Berge H M , Isern C B , Berge E
Published: January 2015

Objective

Hypertension is reported to be the most prevalent risk factor for cardiovascular disease in elite athletes. We aimed to review blood pressure (BP) and prevalence of hypertension in different elite athletes, and study whether there was an association between high BP and left ventricular hypertrophy (LVH).

Methods

A systematic review of studies reporting BP in athletes using search strategies developed for PubMed and EMBASE, including only studies with ≥100 participants. We collected data on BP, prevalence of hypertension, LVH and methods of BP measurement.

Results

Of 3723 records identified, 51 met the inclusion criteria. These included men and women (n=138 390), aged mostly between 18 and 40 years, from varied sports disciplines. Mean systolic BP varied from 109±11 to 138±7 mm Hg and mean diastolic BP from 57±12 to 92±10 mm Hg. Strength-trained athletes had higher BP than endurance-trained athletes (131.3±5.3/77.3±1.4 vs 118.6±2.8/71.8±1.2 mm Hg, p<0.05), and there was a trend towards a higher BP in athletes training ≥10 h compared with others (121.8±3.8/73.8±2.5 vs 117.6±3.3/66.8±6.9, p=0.058), but overall there was no significant difference in BP between athletes and controls. The prevalence of hypertension varied from 0% to 83%. Some studies showed an association between high BP and LVH. Measurement methods were poorly standardised.

Conclusions

BP and prevalence of hypertension in athletes varied considerably partly because of variations in methodology, but type and intensity of training may contribute towards higher BP. High BP may be associated with LVH.
Sports injuries and illnesses in the Sochi 2014 Olympic Winter Games
Authors: Soligard Torbjørn , Steffen Kathrin , Palmer-Green Debbie , Aubry Mark , Grant Marie-Elaine , Meeuwisse Willem , Mountjoy Margo , Budgett Richard , Engebretsen Lars
Published: January 2015

Background

Systematic surveillance of injuries and illnesses is the foundation for developing preventive measures in sport.

Aim

To analyse the injuries and illnesses that occurred during the XXII Olympic Winter Games, held in Sochi in 2014.

Methods

We recorded the daily occurrence (or non-occurrence) of injuries and illnesses (1) through the reporting of all National Olympic Committee (NOC) medical teams and (2) in the polyclinic and medical venues by the Sochi 2014 medical staff.

Results

NOC and Sochi 2014 medical staff reported 391 injuries and 249 illnesses among 2780 athletes from 88 NOCs, equalling incidences of 14 injuries and 8.9 illnesses per 100 athletes over an 18-day period of time. Altogether, 12% and 8% of the athletes incurred at least one injury or illness, respectively. The percentage of athletes injured was highest in aerial skiing, snowboard slopestyle, snowboard cross, slopestyle skiing, halfpipe skiing, moguls skiing, alpine skiing, and snowboard halfpipe. Thirty-nine per cent of the injuries were expected to prevent the athlete from participating in competition or training. Women suffered 50% more illnesses than men. The rate of illness was highest in skeleton, short track, curling, cross-country skiing, figure skating, bobsleigh and aerial skiing. A total of 159 illnesses (64%) affected the respiratory system, and the most common cause of illness was infection (n=145, 58%).

Conclusions

Overall, 12% of the athletes incurred at least one injury during the games, and 8% an illness, which is similar to prior Olympic Games. The incidence of injuries and illnesses varied substantially between sports.
Protocol for a human in vivo model of acute cigarette smoke inhalation challenge in smokers with COPD: monitoring the nasal and systemic immune response using a network biology approach
Authors: Ross Clare L , Galloway-Phillipps Neil , Armstrong Paul C , Mitchell Jane A , Warner Timothy D , Brearley Christopher , Ito Mari , Tunstall Tanushree , Elkin Sarah , Kon Onn Min , Hansel Trevor T , Paul-Clark Mark J
Published: January 2015

Introduction

Cigarette smoke contributes to a diverse range of diseases including chronic obstructive pulmonary disease (COPD), cardiovascular disorders and many cancers. There currently is a need for human challenge models, to assess the acute effects of a controlled cigarette smoke stimulus, followed by serial sampling of blood and respiratory tissue for advanced molecular profiling. We employ precision sampling of nasal mucosal lining fluid by absorption to permit soluble mediators measurement in eluates. Serial nasal curettage was used for transcriptomic analysis of mucosal tissue.

Methods and analysis

Three groups of strictly defined patients will be studied: 12 smokers with COPD (GOLD Stage 2) with emphysema, 12 matched smokers with normal lung function and no evidence of emphysema, and 12 matched never smokers with normal spirometry. Patients in the smoking groups are current smokers, and will be given full support to stop smoking immediately after this study. In giving a controlled cigarette smoke stimulus, all patients will have abstained from smoking for 12 h, and will smoke two cigarettes with expiration through the nose in a ventilated chamber. Before and after inhalation of cigarette smoke, a series of samples will be taken from the blood, nasal mucosal lining fluid and nasal tissue by curettage. Analysis of plasma nicotine and metabolites in relation to levels of soluble inflammatory mediators in nasal lining fluid and blood, as well as assessing nasal transcriptomics, ex vivo blood platelet aggregation and leucocyte responses to toll-like receptor agonists will be undertaken.

Implications

Development of acute cigarette smoke challenge models has promise for the study of molecular effects of smoking in a range of pathological processes.

Ethics and dissemination

This study was approved by the West London National Research Ethics Committee (12/LO/1101). The study findings will be presented at conferences and will be reported in peer-reviewed journals.
Help-seeking intentions and subsequent 12-month mental health service use in Chinese primary care patients with depressive symptoms
Authors: Chin Weng Yee , Chan Kit T Y , Lam Cindy L K , Lam T P , Wan Eric Y F
Published: January 2015

Objective

To identify the factors associated with 12-month mental health service use in primary care patients with depressive symptoms.

Design

Cross-sectional followed by 12-month cohort study.

Setting and participants

10 179 adult patients were recruited from the waiting rooms of 59 primary care clinics across Hong Kong to complete a questionnaire which screened for depression. 518 screened-positive participants formed the cohort and were telephoned at 3, 6 and 12 months to monitor mental health service use.

Primary and secondary outcomes

▸ Help-seeking preferences;

▸ Intention to seek help from a healthcare professional;

▸ 12-month mental health service use.

Results

At baseline, when asked who they would seek help from if they thought they were depressed, respondents preferred using friends and family (46.5%) over a psychiatrist (24.9%), psychologist (22.8%) or general practitioner (GP; 19.9%). The presence of depressive symptoms was associated with a lower intention to seek help from family and friends but had no effect on intention to seek help from a healthcare professional. Over 12 months, 24.3% of the screened-positive cohort reported receiving services from a mental health professional. Factors associated with service use included identification of depression by the GP at baseline, having a past history of depression or other mental illness, and being a public sector patient. Having a positive intention to seek professional help or more severe depressive symptoms at baseline was not associated with a greater likelihood of receiving treatment.

Conclusions

Mental health service use appears to be very low in this setting with only one in four primary care patients with depressive symptoms receiving treatment from a psychiatrist, GP or psychologist over a year. To help reduce the burden of illness, better detection of depressive disorders is needed especially for patients who may be undertreated such as those with no prior diagnosis of depression and those with more severe symptoms.
Specialist integrated haematological malignancy diagnostic services: an Activity Based Cost (ABC) analysis of a networked laboratory service model
Authors: Dalley C , Basarir H , Wright J G , Fernando M , Pearson D , Ward S E , Thokula P , Krishnankutty A , Wilson G , Dalton A , Talley P , Barnett D , Hughes D , Porter N R , Reilly J T , Snowden J A
Published: January 2015

Aims

Specialist Integrated Haematological Malignancy Diagnostic Services (SIHMDS) were introduced as a standard of care within the UK National Health Service to reduce diagnostic error and improve clinical outcomes. Two broad models of service delivery have become established: ‘co-located’ services operating from a single-site and ‘networked’ services, with geographically separated laboratories linked by common management and information systems. Detailed systematic cost analysis has never been published on any established SIHMDS model.

Methods

We used Activity Based Costing (ABC) to construct a cost model for our regional ‘networked’ SIHMDS covering a two-million population based on activity in 2011.

Results

Overall estimated annual running costs were £1 056 260 per annum (£733 400 excluding consultant costs), with individual running costs for diagnosis, staging, disease monitoring and end of treatment assessment components of £723 138, £55 302, £184 152 and £94 134 per annum, respectively. The cost distribution by department was 28.5% for haematology, 29.5% for histopathology and 42% for genetics laboratories. Costs of the diagnostic pathways varied considerably; pathways for myelodysplastic syndromes and lymphoma were the most expensive and the pathways for essential thrombocythaemia and polycythaemia vera being the least.

Conclusions

ABC analysis enables estimation of running costs of a SIHMDS model comprised of ‘networked’ laboratories. Similar cost analyses for other SIHMDS models covering varying populations are warranted to optimise quality and cost-effectiveness in delivery of modern haemato-oncology diagnostic services in the UK as well as internationally.
Political party affiliation, political ideology and mortality
Authors: Pabayo Roman , Kawachi Ichiro , Muennig Peter
Published: January 2015

Background

Ecological and cross-sectional studies have indicated that conservative political ideology is associated with better health. Longitudinal analyses of mortality are needed because subjective assessments of ideology may confound subjective assessments of health, particularly in cross-sectional analyses.

Methods

Data were derived from the 2008 General Social Survey-National Death Index data set. Cox proportional analysis models were used to determine whether political party affiliation or political ideology was associated with time to death. Also, we attempted to identify whether self-reported happiness and self-rated health acted as mediators between political beliefs and time to death.

Results

In this analysis of 32 830 participants and a total follow-up time of 498 845 person-years, we find that political party affiliation and political ideology are associated with mortality. However, with the exception of independents (adjusted HR (AHR)=0.93, 95% CI 0.90 to 0.97), political party differences are explained by the participants’ underlying sociodemographic characteristics. With respect to ideology, conservatives (AHR=1.06, 95% CI 1.01 to 1.12) and moderates (AHR=1.06, 95% CI 1.01 to 1.11) are at greater risk for mortality during follow-up than liberals.

Conclusions

Political party affiliation and political ideology appear to be different predictors of mortality.
Higher effort–reward imbalance and lower job control predict exit from the labour market at the age of 61 years or younger: evidence from the English Longitudinal Study of Ageing
Authors: Hintsa T , Kouvonen A , McCann M , Jokela M , Elovainio M , Demakakos P
Published: January 2015

Background

We examined whether higher effort–reward imbalance (ERI) and lower job control are associated with exit from the labour market.

Methods

There were 1263 participants aged 50–74 years from the English Longitudinal Study on Ageing with data on working status and work-related psychosocial factors at baseline (wave 2; 2004–2005), and working status at follow-up (wave 5; 2010–2011). Psychosocial factors at work were assessed using a short validated version of ERI and job control. An allostatic load index was formed using 13 biological parameters. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Exit from the labour market was defined as not working in the labour market when 61 years old or younger in 2010–2011.

Results

Higher ERI OR=1.62 (95% CI 1.01 to 2.61, p=0.048) predicted exit from the labour market independent of age, sex, education, occupational class, allostatic load and depression. Job control OR=0.60 (95% CI 0.42 to 0.85, p=0.004) was associated with exit from the labour market independent of age, sex, education, occupation and depression. The association of higher effort OR=1.32 (95% CI 1.01 to 1.73, p=0.045) with exit from the labour market was independent of age, sex and depression but attenuated to non-significance when additionally controlling for socioeconomic measures. Reward was not related to exit from the labour market.

Conclusions

Stressful work conditions can be a risk for exiting the labour market before the age of 61 years. Neither socioeconomic position nor allostatic load and depressive symptoms seem to explain this association.
Extensive cerebral microbleeds predict parenchymal haemorrhage and poor outcome after intravenous thrombolysis
Authors: Yan Shenqiang , Jin Xinchun , Zhang Xuting , Zhang Sheng , Liebeskind David S , Lou Min
Published: January 2015

Purpose

Thrombolysis-related haemorrhagic transformation (HT) subtypes may have different prognostic implications. We aimed to analyse the impact of cerebral microbleeds (CMBs) burden on HT subtypes and outcome after intravenous thrombolysis.

Methods

We retrospectively examined clinical and radiological data from 333 consecutive patients with acute ischaemic stroke who underwent susceptibility-weighted imaging before intravenous thrombolysis. Logistic regression analysis was used to determine the impact of CMBs on HT subtypes and neurological outcome.

Results

We observed 596 CMBs in 119 (39.7%) patients on initial gradient-recalled echo scans. HT occurred in 88 (29.3%) patients, among which 62 were haemorrhagic infarction and 26 were parenchymal haemorrhage (PH). Logistic regression analysis indicated that the presence of extensive (≥3) CMBs was independently associated with PH (OR 6.704; 95% CI 2.054 to 21.883; p=0.002) and poor clinical outcome (OR 2.281; 95% CI 1.022 to 5.093; p=0.044).

Conclusions

The presence of extensive (≥3) CMBs increased the risk of PH 24 h after intravenous thrombolysis, and predicted poor clinical outcome independently.
Exercise-based rehabilitation for heart failure: systematic review and meta-analysis
Authors: Sagar Viral A , Davies Edward J , Briscoe Simon , Coats Andrew J S , Dalal Hasnain M , Lough Fiona , Rees Karen , Singh Sally , Taylor Rod S
Published: January 2015

Objective

To update the Cochrane systematic review of exercise-based cardiac rehabilitation (CR) for heart failure.

Methods

A systematic review and meta-analysis of randomised controlled trials was undertaken. MEDLINE, EMBASE and the Cochrane Library were searched up to January 2013. Trials with 6 or more months of follow-up were included if they assessed the effects of exercise interventions alone or as a component of comprehensive CR programme compared with no exercise control.

Results

33 trials were included with 4740 participants predominantly with a reduced ejection fraction (<40%) and New York Heart Association class II and III. Compared with controls, while there was no difference in pooled all-cause mortality between exercise CR with follow-up to 1 year (risk ratio (RR) 0.93; 95% CI 0.69 to 1.27, p=0.67), there was a trend towards a reduction in trials with follow-up beyond 1 year (RR 0.88; 0.75 to 1.02, 0.09). Exercise CR reduced the risk of overall (RR 0.75; 0.62 to 0.92, 0.005) and heart failure-specific hospitalisation (RR 0.61; 0.46 to 0.80, 0.0004) and resulted in a clinically important improvement in the Minnesota Living with Heart Failure questionnaire (mean difference: −5.8 points, −9.2 to −2.4, 0.0007). Univariate meta-regression analysis showed that these benefits were independent of the type and dose of exercise CR, and trial duration of follow- up, quality or publication date.

Conclusions

This updated Cochrane review shows that improvements in hospitalisation and health-related quality of life with exercise-based CR appear to be consistent across patients regardless of CR programme characteristics and may reduce mortality in the longer term. An individual participant data meta-analysis is needed to provide confirmatory evidence of the importance of patient subgroup and programme level characteristics (eg, exercise dose) on outcome.
Professor of animal welfare
Authors: Wolfensohn Sarah
Published: January 2015

Sarah Wolfensohn is still surprised to hear herself being introduced as ‘professor’ since it had not been in her career plan. Here, she explains how she came to be professor of animal welfare at the University of Surrey's vet school
Hermitian realizations of κ-Minkowski space–time
Authors: Kovačević Domagoj , Meljanac Stjepan , Samsarov Andjelo , Škoda Zoran
Published: January 2015

General realizations, star products and plane waves for κ-Minkowski space–time are considered. Systematic construction of general Hermitian realization is presented, with special emphasis on noncommutative plane waves and Hermitian star product. Few examples are elaborated and possible physical applications are mentioned.
Nobel Prizes in Physics and Chemistry 2014: Celebrating the International Year of Light 2015, commemorating the Old Quantum Theory
Authors: Shi Yu
Published: January 2015

2015 is the International Year of Light and Light-based Technologies (IYL), while the physics and chemistry Nobel Prizes 2014 are both about light. The work leading to the two prizes share the same basic theoretical foundation: when an electron jumps from a higher energy level to a lower energy level, the energy difference is transformed into a photon. This basic way of light generation is a key part of the Old Quantum Theory. Interestingly, the date of announcing the 2014 Nobel Prize for physics coincided with the birthdays of Niels Bohr and, especially, of Planck's blackbody radiation formula. In connection with the two 2014 Nobel Prizes, we recall the development of the Old Quantum Theory by Planck, Einstein and Bohr.
An algorithm to classify rational 3-tangles
Authors: Kwon B.
Published: January 2015

A 3-tangle T is the disjoint union of three properly embedded arcs in the unit 3-ball; it is called rational if there is a homeomorphism of pairs from (B3, T) to (D2 × I, {x1, x2, x3} × I). Two rational 3-tangles T and T′ are isotopic if there is an orientation-preserving self-homeomorphism h : (B3, T) → (B3, T′) that is the identity map on the boundary. In this paper, we give an algorithm to check whether or not two rational 3-tangles are isotopic by using a modified version of Dehn's method for classifying simple closed curves on surfaces.
Economic Robustness Analysis of Adaptive Chart Schemes for Monitoring the Total Nonconformities Number in Inspection Units
Authors: Lupo Toni
Published: January 2015

In recent years, a variety of enhanced schemes for the c chart have been developed aimed at the effectiveness improving of the related statistical process control (SPC) procedures. However, the performance of such chart schemes can be very sensitive to values assumed for some operating and cost parameters, in particular to the considered process shift magnitude arising from out-of-control conditions. In such a circumstance, the effectiveness of such chart schemes can be subjected to substantial reductions when they are implemented in operative contexts given that, in practice, such value is unknown and it can be very difficult to accurately estimate. For this reason, in the present paper it is developed an economic optimization approach able to find out the optimal configurations of the main adaptive c chart schemes. Subsequently, economic performances of such configurations are compared in order to derive information on their relative economic robustness, considering the difference between the estimated process shift magnitude and the actual one as influential factor and costs arising from the related SPC operations as performance comparison index. In addition, also a sensitivity analysis based on a [Formula: see text] fractional factorial design scheme, to investigate on influence of several operating and cost parameters on charts economic robustness, is carried out and the related considerations are given. The obtained results show that the parameters having the most impact on economic robustness, when the out-of-control process shift is not accurately estimated, are the cost associated with the production of non-conforming parts and the failure rate of the manufacturing system.
An Approach for the Fast Calculation Method of Pareto Solutions of a Two-objective Network
Authors: Takahashi Natsumi , Akiba Tomoaki , Nomura Shuhei , Yamamoto Hisashi
Published: January 2015

The shortest path problem is a kind of optimization problem and its aim is to find the shortest path connecting two specific nodes in a network, where each edge has its distance. When considering not only the distances between the nodes but also some other information, the problem is formulated as a multi-objective shortest path problem that involves multiple conflicting objective functions. The multi-objective shortest path problem is a kind of optimization problem of multi-objective network. In the general cases, multi-objectives are rarely optimized by a solution. So, to solve the multi-objective shortest path problem leads to obtaining Pareto solutions. An algorithm for this problem has been proposed by using the extended Dijkstra's algorithm. However, this algorithm for obtaining Pareto solutions has many useless searches for paths. In this study, we consider two-objective shortest path problem and propose efficient algorithms for obtaining the Pareto solutions. Our proposed algorithm can reduce more search space than existing algorithms, by solving a single-objective shortest path problem. The results of the numerical experiments suggest that our proposed algorithms reduce the computing time and the memory size for obtaining the Pareto solutions.
Buckling Analysis of the Discrete Planar Cosserat Rod
Authors: Kocsis Attila
Published: January 2015

In this paper, a discrete model of the planar Cosserat rod is presented. Based on the calculus of variations, the equilibrium equations of the model are derived for potential forces and hyperelastic material. Buckling of the structure under axial loading is thoroughly studied assuming linear elasticity. Dimensionless stiffness parameters are introduced, and analytical solutions are given for the critical loads and the corresponding buckled shapes of the model. Classification of the axially loaded structure is accomplished based on the number, sign, and physical admissibility of its buckling loads. It is revealed that the model can possess several buckling modes under tension.
Dynamic Characteristics of Inflatable Reflectors with Consideration of Assembly of Gores
Authors: San Bing Bing , Yin Li Wei , Zhu Zhao Quan
Published: January 2015

This paper focuses on the dynamic characteristics of reflectors considering the effects of assembly of gores. A model is established to properly predict the assembled shape of planar gores, and nonlinear finite element method and subspace iteration method are adopted to analyze the dynamic characteristics of reflectors. A comparative study is carried out based on the dynamic analysis with ideal reflector and assembled reflector to illustrate the impacts of assembly on mode shapes and natural frequencies of the reflectors. The results show that the presence of assembly of gores and seaming tapes has significant effects on mode shapes and natural frequencies of reflectors, which will influence the shape control of reflectors.