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1.  Serological Evidence for Non-Lethal Exposures of Mongolian Wild Birds to Highly Pathogenic Avian Influenza H5N1 Virus 
PLoS ONE  2014;9(12):e113569.
Surveillance for highly pathogenic avian influenza viruses (HPAIV) in wild birds is logistically demanding due to the very low rates of virus detection. Serological approaches may be more cost effective as they require smaller sample sizes to identify exposed populations. We hypothesized that antigenic differences between classical Eurasian H5 subtype viruses (which have low pathogenicity in chickens) and H5N1 viruses of the Goose/Guangdong/96 H5 lineage (which are HPAIV) may be used to differentiate populations where HPAIVs have been circulating, from those where they have not. To test this we performed hemagglutination inhibition assays to compare the reactivity of serum samples from wild birds in Mongolia (where HPAIV has been circulating, n = 1,832) and Europe (where HPAIV has been rare or absent, n = 497) to a panel of reference viruses including classical Eurasian H5 (of low pathogenicity), and five HPAIV H5N1 antigens of the Asian lineage A/Goose/Guangdong/1/96. Antibody titres were detected against at least one of the test antigens for 182 Mongolian serum samples (total seroprevalence of 0.10, n = 1,832, 95% adjusted Wald confidence limits of 0.09–0.11) and 25 of the European sera tested (total seroprevalence of 0.05, n = 497, 95% adjusted Wald confidence limits of 0.03–0.07). A bias in antibody titres to HPAIV antigens was found in the Mongolian sample set (22/182) that was absent in the European sera (0/25). Although the interpretation of serological data from wild birds is complicated by the possibility of exposure to multiple strains, and variability in the timing of exposure, these findings suggest that a proportion of the Mongolian population had survived exposure to HPAIV, and that serological assays may enhance the targeting of traditional HPAIV surveillance toward populations where isolation of HPAIV is more likely.
PMCID: PMC4266605  PMID: 25502318
2.  Circulation of Reassortant Influenza A(H7N9) Viruses in Poultry and Humans, Guangdong Province, China, 2013 
Emerging Infectious Diseases  2014;20(12):2034-2040.
Influenza A(H7N9) virus emerged in eastern China in February 2013 and continues to circulate in this region, but its ecology is poorly understood. In April 2013, the Guangdong Provincial Center for Disease Control and Prevention (CDC) implemented environmental and human syndromic surveillance for the virus. Environmental samples from poultry markets in 21 city CDCs (n = 8,942) and respiratory samples from persons with influenza-like illness or pneumonia (n = 32,342) were tested; viruses isolated from 6 environmental samples and 16 patients were sequenced. Sequence analysis showed co-circulation of 4 influenza A(H7N9) virus strains that evolved by reassortment with avian influenza A(H9N2) viruses circulating in this region. In addition, an increase in human cases starting in late 2013 coincided with an increase in influenza A H7 virus isolates detected by environmental surveillance. Co-circulation of multiple avian influenza viruses that can infect humans highlights the need for increased surveillance of poultry and potential environmental sources.
PMCID: PMC4257815  PMID: 25418838
influenza; H7N9; H9N2; emergence; reassortment; human; poultry; influenza A; H3N2; viruses; respiratory infections; Guangdong Province; China
3.  A Recommended Numbering Scheme for Influenza A HA Subtypes 
PLoS ONE  2014;9(11):e112302.
Comparisons of residues between sub-types of influenza virus is increasingly used to assess the zoonotic potential of a circulating strain and for comparative studies across subtypes. An analysis of N-terminal cleavage sites for thirteen subtypes of influenza A hemagglutinin (HA) sequences, has previously been described by Nobusawa and colleagues. We have expanded this analysis for the eighteen known subtypes of influenza. Due to differences in the length of HA, we have included strains from multiple clades of H1 and H5, as well as strains of H5 and H7 subtypes with both high and low pathogenicity. Analysis of known structures of influenza A HA enables us to define amino acids which are structurally and functionally equivalent across all HA subtypes using a numbering system based on the mature HA sequence. We provide a list of equivalences for amino acids which are known to affect the phenotype of the virus.
PMCID: PMC4229193  PMID: 25391151
4.  A Transparent and Transferable Framework for Tracking Quality Information in Large Datasets 
PLoS ONE  2014;9(11):e112249.
The ability to evaluate the validity of data is essential to any investigation, and manual “eyes on” assessments of data quality have dominated in the past. Yet, as the size of collected data continues to increase, so does the effort required to assess their quality. This challenge is of particular concern for networks that automate their data collection, and has resulted in the automation of many quality assurance and quality control analyses. Unfortunately, the interpretation of the resulting data quality flags can become quite challenging with large data sets. We have developed a framework to summarize data quality information and facilitate interpretation by the user. Our framework consists of first compiling data quality information and then presenting it through 2 separate mechanisms; a quality report and a quality summary. The quality report presents the results of specific quality analyses as they relate to individual observations, while the quality summary takes a spatial or temporal aggregate of each quality analysis and provides a summary of the results. Included in the quality summary is a final quality flag, which further condenses data quality information to assess whether a data product is valid or not. This framework has the added flexibility to allow “eyes on” information on data quality to be incorporated for many data types. Furthermore, this framework can aid problem tracking and resolution, should sensor or system malfunctions arise.
PMCID: PMC4224478  PMID: 25379884
5.  Low back pain among school teachers in Botswana, prevalence and risk factors 
Although low back pain (LBP) represents a common occupational problem, few epidemiological studies have investigated the prevalence and risk factors for LBP among school teachers, particularly in Africa. School teachers are known to represent an occupational group among which there appears to be a high prevalence of LBP. The objective of this study was, therefore, to conduct one of the first epidemiological investigations of LBP among teachers in Botswana.
A cross-sectional study was conducted among teachers in Botswana using self-administered questionnaires which were distributed to 3100 randomly selected school teachers and collected over a five-month period between July and November 2012. The questionnaire included low back pain information, demographic data, lifestyle, work-related characteristics and psychosocial factors. Data were analysed using Chi-squared and logistic regression models. The 12 month prevalence and LBP disability and associated risk factors were also analysed.
A total of 1747 teachers returned completed questionnaires, yielding a response rate of 56.3%. The 12-month prevalence of LBP was 55.7%, with 67.1% of them reporting minimal disability. The results of logistic regression analysis revealed that female gender [OR: 1.51, 95% CI: 1.14-2.00] and previous back injury [OR: 9.67, 95% CI: 4.94-18.93] were positively correlated to LBP. Awkward arm position [OR: 1.81, 95% CI: 1.24-2.62] and high psychological job demands [OR: 1.40, 95% CI: 1.02-1.93] were also significantly associated with LBP. Regular physical exercise was negatively associated with LBP [OR: 0.63, 95% CI: 0.43-0.93]. Female gender [OR: 2.67, 95% CI: 1.52-3.99] and previous back injury [OR: 3.01, 95% CI: 1.92-4.74] were also positively associated with LBP disability.
The prevalence of LBP appears to be high among school teachers in Botswana. A wide variety of LBP risk factors were identified in this study. Female gender and previous injury were both associated with LBP presence and disability. The complex nature of LBP risk factors found in this study suggests than no single specific preventative or intervention strategy will help in reducing these conditions. As such, to help reduce the prevalence, progression and burden of LBP among Botswana teachers, a greater emphasis should now be placed on ergonomics education, regular physical exercise and occupational stress.
PMCID: PMC4230345  PMID: 25358427
6.  Elevated Glucocorticoids during Ovine Pregnancy increase Appetite and produce Glucose Dysregulation and Adiposity in Their Granddaughters in response to ad libitum feeding at one year of age 
Synthetic glucocorticoids (sGC) are administered to women threatening preterm labor. We have shown multi-generational endocrine and metabolic effects of fetal sGC exposure. We hypothesized that sGC exposure would alter the second filial generation (F2) offspring neonatal leptin peak that controls development of appetitive behavior with metabolic consequences.
Study design
F0 nulliparous ewes were bred to a single ram. Beginning at day 103 of gestation (Term 150), dexamethasone (DEX) ewes received 4 injections of 2 mg DEX i.m, 12 h apart. Control ewes received saline. Ewes lambed naturally. At 22 months of age, F1 offspring were mated to produce F2 offspring. At 10 months of age F2 female offspring were placed on an ad libitum feeding challenge for 12 weeks.
DEX F2 female offspring did not show a post-natal leptin peak and their plasma cortisol concentration was elevated in the first days of life. During the feeding challenge DEX F2 offspring consumed 10 % more feed and gained 20 % more weight compared to control F2 offspring. At the end of the feeding challenge DEX F2 offspring had greater adiposity compared to control F2 offspring. F2 sGC offspring showed impaired insulin secretion in response to an IVGTT.
sGC administration to F0 mothers eliminates the neonatal leptin peak in F2 female offspring potentially by inhibition due to elevated cortisol in the DEX F2 offspring. F2 offspring showed increased appetite, weight gain and adiposity during an ad libitum feeding challenge accompanied by decreased insulin response to an IVGTT.
PMCID: PMC3786012  PMID: 23727517
synthetic glucocorticoids; fetal; sheep; appetite; leptin; multigenerational
7.  Genomewide Analysis of Reassortment and Evolution of Human Influenza A(H3N2) Viruses Circulating between 1968 and 2011 
Journal of Virology  2014;88(5):2844-2857.
Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and genomic evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the genomic evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the evolution of these viruses.
IMPORTANCE Each winter, influenza virus infects approximately 5 to 15% of the world's population, resulting in significant morbidity and mortality. Influenza A(H3N2) viruses evolve continuously by reassortment and genomic evolution. This leads to changes in antigenic recognition (antigenic drift) which make it necessary to update vaccines against influenza A(H3N2) viruses frequently. In this study, the relationship of genetic evolution to antigenic change spanning the entire period of A(H3N2) virus circulation was studied for the first time. The results presented in this study contribute to a better understanding of genetic evolution in correlation with antigenic evolution of influenza A(H3N2) viruses.
PMCID: PMC3958060  PMID: 24371052
9.  Excessive production and extreme editing of human metapneumovirus defective interfering RNA is associated with type I IFN induction 
The Journal of General Virology  2014;95(Pt 8):1625-1633.
Type I IFN production is one of the hallmarks of host innate immune responses upon virus infection. Whilst most respiratory viruses carry IFN antagonists, reports on human metapneumovirus (HMPV) have been conflicting. Using deep sequencing, we have demonstrated that HMPV particles accumulate excessive amounts of defective interfering RNA (DIs) rapidly upon in vitro passage, and that these are associated with IFN induction. Importantly, the DIs were edited extensively; up to 70 % of the original A and T residues had mutated to G or C, respectively. Such high editing rates of viral RNA have not, to our knowledge, been reported before. Bioinformatics and PCR assays indicated that adenosine deaminase acting on RNA (ADAR) was the most likely editing enzyme. HMPV thus has an unusually high propensity to generate DIs, which are edited at an unprecedented high frequency. The conflicting published data on HMPV IFN induction and antagonism are probably explained by DIs in virus stocks. The interaction of HMPV DIs with the RNA-editing machinery and IFN responses warrants further investigation.
PMCID: PMC4103063  PMID: 24760760
10.  Antigenic Variation of Clade 2.1 H5N1 Virus Is Determined by a Few Amino Acid Substitutions Immediately Adjacent to the Receptor Binding Site 
mBio  2014;5(3):e01070-14.
Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype are genetically highly variable and have diversified into multiple phylogenetic clades over the past decade. Antigenic drift is a well-studied phenomenon for seasonal human influenza viruses, but much less is known about the antigenic evolution of HPAI H5N1 viruses that circulate in poultry. In this study, we focused on HPAI H5N1 viruses that are enzootic to Indonesia. We selected representative viruses from genetically distinct lineages that are currently circulating and determined their antigenic properties by hemagglutination inhibition assays. At least six antigenic variants have circulated between 2003, when H5N1 clade 2.1 viruses were first detected in Indonesia, and 2011. During this period, multiple antigenic variants cocirculated in the same geographic regions. Mutant viruses were constructed by site-directed mutagenesis to represent each of the circulating antigenic variants, revealing that antigenic differences between clade 2.1 viruses were due to only one or very few amino acid substitutions immediately adjacent to the receptor binding site. Antigenic variants of H5N1 virus evaded recognition by both ferret and chicken antibodies. The molecular basis for antigenic change in clade 2.1 viruses closely resembled that of seasonal human influenza viruses, indicating that the hemagglutinin of influenza viruses from different hosts and subtypes may be similarly restricted to evade antibody recognition.
Highly pathogenic avian influenza (HPAI) H5N1 viruses are responsible for severe outbreaks in both commercial and backyard poultry, causing considerable economic losses and regular zoonotic transmissions to humans. Vaccination is used increasingly to reduce the burden of HPAI H5N1 virus in poultry. Influenza viruses can escape from recognition by antibodies induced upon vaccination or infection through genetic changes in the hemagglutinin protein. The evolutionary patterns and molecular basis of antigenic change in HPAI H5N1 viruses are poorly understood, hampering formulation of optimal vaccination strategies. We have shown here that HPAI H5N1 viruses in Indonesia diversified into multiple antigenic variants, that antigenic differences were due to one or a very few substitutions near the receptor binding site, and that the molecular basis for antigenic change was remarkably similar to that for seasonal human influenza viruses. These findings have consequences for future vaccination and surveillance considerations and contribute to the understanding of the antigenic evolution of influenza viruses.
PMCID: PMC4056550  PMID: 24917596
11.  Identification of a Pantoea Biosynthetic Cluster That Directs the Synthesis of an Antimicrobial Natural Product 
PLoS ONE  2014;9(5):e96208.
Fire Blight is a destructive disease of apple and pear caused by the enteric bacterial pathogen, Erwinia amylovora. E. amylovora initiates infection by colonizing the stigmata of apple and pear trees, and entering the plants through natural openings. Epiphytic populations of the related enteric bacterium, Pantoea, reduce the incidence of disease through competition and antibiotic production. In this study, we identify an antibiotic from Pantoea ananatis BRT175, which is effective against E. amylovora and select species of Pantoea. We used transposon mutagenesis to create a mutant library, screened approximately 5,000 mutants for loss of antibiotic production, and recovered 29 mutants. Sequencing of the transposon insertion sites of these mutants revealed multiple independent disruptions of an 8.2 kb cluster consisting of seven genes, which appear to be coregulated. An analysis of the distribution of this cluster revealed that it was not present in any other of our 115 Pantoea isolates, or in any of the fully sequenced Pantoea genomes, and is most closely related to antibiotic biosynthetic clusters found in three different species of Pseudomonas. This identification of this biosynthetic cluster highlights the diversity of natural products produced by Pantoea.
PMCID: PMC4010436  PMID: 24796857
12.  Sociodemographic Factors and Prejudice toward HIV and Hepatitis B/C Status in a Working-Age Population: Results from a National, Cross-Sectional Study in Japan 
PLoS ONE  2014;9(5):e96645.
In many countries, HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) infected individuals may face discrimination and mistreatment from coworkers. Effective interventions to reduce workplace discrimination are therefore needed to protect these vulnerable populations. The current study investigated potential associations between sociodemographic factors and prejudice toward HIV and HBV/HCV infected colleagues within a Japanese working population.
An online anonymous, nationwide internet survey was administered to a cross-section of approximately 3,000 individuals in Japan. The survey comprised 14 questions focusing on demographics (five items), basic HIV or HBV/HCV knowledge (eight items), and potential prejudice toward HIV or HBV/HCV infected colleagues (one item). The sociodemographic characteristics evaluated were sex, age, educational level, employment status, and individual income; with multiple logistic regression used for the analysis.
In total, 3,055 individuals were recruited for the HIV related survey and 3,129 for the HBV/HCV related survey. Older age was significantly and positively associated with prejudice toward HIV infected colleagues (p<0.01) and negatively associated with prejudice toward HBV/HCV infected colleagues (p<0.01). Statistically significant associations were not observed between other sociodemographic characteristics and potential prejudice toward HIV and HBV/HCV infected coworkers.
Overall, this study suggests that age may be associated with prejudice toward HIV and HBV/HCV infected colleagues among the working age population of Japan. As such, policy makers should consider the age of participants when formulating efforts to reduce prejudice toward HIV and HBV/HCV infected workers.
PMCID: PMC4008599  PMID: 24792095
13.  Automated Big Data Analysis in Bottom-up and Targeted Proteomics 
Similar to other data intensive sciences, analyzing mass spectrometry-based proteomics data involves multiple steps and diverse software using different algorithms and data formats and sizes. Besides that the distributed and evolving nature of the data in online repositories, another challenge is that a scientists have to deal with many steps of analysis pipelines. A documented data processing is also becoming an essential part for the overall reproducibility of the results. Thanks to different e-Science initiatives, scientific workflow engines have become a means for automated, sharable and reproducible data processing. While these are designed as general tools, they can be employed to solve different challenges that we are facing in handling our Big Data. Here we present three use cases: improving the performance of different spectral search engines by decomposing input data and recomposing the resulting files, building spectral libraries from more than 20 million spectra, and integrating information from multiple resources to select most appropriate peptides for targeted proteomics analyses. The three use cases demonstrate different challenges in exploiting proteomics data analysis. In the first we integrate local and cloud processing resources in order to obtain better performance resulting in more than 30-fold speed improvement. By considering search engines as legacy software our solution is applicable to multiple search algorithms. The second use case is an example of automated processing of many data files of different sizes and locations, starting with raw data and ending with the final, ready-to-use library. This demonstrates the robustness and fault tolerance when dealing with huge amount data stored in multiple files. The third use case demonstrates retrieval and integration of information and data from multiple online repositories. In addition to the diversity of data formats and Web interfaces, this use case also illustrates how to deal with incomplete data.
PMCID: PMC4162283
14.  In vivo reprogramming of astrocytes to neuroblasts in the adult brain 
Nature cell biology  2013;15(10):10.1038/ncb2843.
Adult differentiated cells can be reprogrammed into pluripotent stem cells or lineage-restricted proliferating precursors in culture; however, this has not been demonstrated in vivo. Here, we show that the single transcription factor SOX2 is sufficient to reprogram resident astrocytes into proliferative neuroblasts in the adult mouse brain. These induced adult neuroblasts (iANBs) persist for months and can be generated even in aged brains. When supplied with BDNF and noggin or when the mice are treated with a histone deacetylase inhibitor, iANBs develop into electrophysiologically mature neurons, which functionally integrate into the local neural network. Our results demonstrate that adult astrocytes exhibit remarkable plasticity in vivo, a feature that might have important implications in regeneration of the central nervous system using endogenous patient-specific glial cells.
PMCID: PMC3867822  PMID: 24056302
Anesthesiology  2010;112(4):834-841.
Brief isoflurane anesthesia induces neuroapoptosis in the developing rodent brain, but susceptibility of nonhuman primates to the apoptogenic action of isoflurane has not been studied. Therefore, we exposed postnatal day 6 (P6) rhesus macaques to a surgical plane of isoflurane anesthesia for 5 h, and studied the brains 3 h later for histopathological changes.
With the same intensity of physiological monitoring typical for human neonatal anesthesia, five P6 rhesus macaques were exposed for 5 h to isoflurane maintained between 0.7 and 1.5 end tidal Vol% (endotracheally intubated, mechanically ventilated), and five controls were exposed for 5 h to room air without further intervention. Three hours later, the brains were harvested and serially sectioned across the entire forebrain and midbrain, and stained immunohistochemically with antibodies to activated caspase-3 for detection and quantification of apoptotic neurons.
Quantitative evaluation of brain sections revealed a median of 32.5 (range, 18.0 to 48.2) apoptotic cells per mm3 of brain tissue in the isoflurane group and only 2.5 (range, 1.9 to 3.8) in the control group (difference significant at p = 0.008). Apoptotic neuronal profiles were largely confined to the cerebral cortex. In the control brains, they were sparse and randomly distributed, whereas in the isoflurane brains they were abundant and preferentially concentrated in specific cortical layers and regions.
The developing nonhuman primate brain is sensitive to the apoptogenic action of isoflurane, and displays a 13-fold increase in neuroapoptosis after 5 h exposure to a surgical plane of isoflurane anesthesia.
PMCID: PMC3962067  PMID: 20234312
17.  Unifying Viral Genetics and Human Transportation Data to Predict the Global Transmission Dynamics of Human Influenza H3N2 
PLoS Pathogens  2014;10(2):e1003932.
Information on global human movement patterns is central to spatial epidemiological models used to predict the behavior of influenza and other infectious diseases. Yet it remains difficult to test which modes of dispersal drive pathogen spread at various geographic scales using standard epidemiological data alone. Evolutionary analyses of pathogen genome sequences increasingly provide insights into the spatial dynamics of influenza viruses, but to date they have largely neglected the wealth of information on human mobility, mainly because no statistical framework exists within which viral gene sequences and empirical data on host movement can be combined. Here, we address this problem by applying a phylogeographic approach to elucidate the global spread of human influenza subtype H3N2 and assess its ability to predict the spatial spread of human influenza A viruses worldwide. Using a framework that estimates the migration history of human influenza while simultaneously testing and quantifying a range of potential predictive variables of spatial spread, we show that the global dynamics of influenza H3N2 are driven by air passenger flows, whereas at more local scales spread is also determined by processes that correlate with geographic distance. Our analyses further confirm a central role for mainland China and Southeast Asia in maintaining a source population for global influenza diversity. By comparing model output with the known pandemic expansion of H1N1 during 2009, we demonstrate that predictions of influenza spatial spread are most accurate when data on human mobility and viral evolution are integrated. In conclusion, the global dynamics of influenza viruses are best explained by combining human mobility data with the spatial information inherent in sampled viral genomes. The integrated approach introduced here offers great potential for epidemiological surveillance through phylogeographic reconstructions and for improving predictive models of disease control.
Author Summary
What explains the geographic dispersal of emerging pathogens? Reconstructions of evolutionary history from pathogen gene sequences offer qualitative descriptions of spatial spread, but current approaches are poorly equipped to formally test and quantify the contribution of different potential explanatory factors, such as human mobility and demography. Here, we use a novel phylogeographic method to evaluate multiple potential predictors of viral spread in human influenza dynamics. We identify air travel as the predominant driver of global influenza migration, whilst also revealing the contribution of other mobility processes at more local scales. We demonstrate the power of our inter-disciplinary approach by using it to predict the global pandemic expansion of H1N1 influenza in 2009. Our study highlights the importance of integrating evolutionary and ecological information when studying the dynamics of infectious disease.
PMCID: PMC3930559  PMID: 24586153
18.  Integrating influenza antigenic dynamics with molecular evolution 
eLife  2014;3:e01914.
Influenza viruses undergo continual antigenic evolution allowing mutant viruses to evade host immunity acquired to previous virus strains. Antigenic phenotype is often assessed through pairwise measurement of cross-reactivity between influenza strains using the hemagglutination inhibition (HI) assay. Here, we extend previous approaches to antigenic cartography, and simultaneously characterize antigenic and genetic evolution by modeling the diffusion of antigenic phenotype over a shared virus phylogeny. Using HI data from influenza lineages A/H3N2, A/H1N1, B/Victoria and B/Yamagata, we determine patterns of antigenic drift across viral lineages, showing that A/H3N2 evolves faster and in a more punctuated fashion than other influenza lineages. We also show that year-to-year antigenic drift appears to drive incidence patterns within each influenza lineage. This work makes possible substantial future advances in investigating the dynamics of influenza and other antigenically-variable pathogens by providing a model that intimately combines molecular and antigenic evolution.
eLife digest
Every year, seasonal influenza, commonly called flu, infects up to one in five people around the world, and causes up to half a million deaths. Even though the human immune system can detect and destroy the virus that causes influenza, people can catch flu many times throughout their lifetimes because the virus keeps evolving in an effort to avoid the immune system. This antigenic drift—so-called because the antigens displayed by the virus keep changing—also explains why influenza vaccines become less effective over time and need to be reformulated every year.
It is possible to determine which antigens are displayed by a new strain of the virus by observing how blood samples that respond to known strains respond to the new strain. This information about the “antigenic phenotype” of the virus can be plotted on an antigenic map in which strains with similar antigens cluster together. Gene sequencing has shown that there are four subtypes of the flu virus that commonly infect people; but the relationship between changes in antigenic phenotype and changes in gene sequences of the influenza virus is poorly understood.
Bedford et al. have now developed an approach to combine antigenic maps with genetic information about the four subtypes of the human flu virus. This revealed that the antigenic phenotype of H3N2—a subtype that is becoming increasingly common—evolved faster than the other three subtypes. Further, a correlation was observed between antigenic drift and the number of new influenza cases per year for each flu strain. This suggests that knowing which antigenic phenotypes are present at the start of flu season could help predict which strains of the virus will predominate later on.
The work of Bedford et al. provides a useful framework to study influenza, and could help to pinpoint which changes in viral genes cause the changes in antigens. This information could potentially speed up the development of new flu vaccines for each flu season.
PMCID: PMC3909918  PMID: 24497547
influenza; evolution; antigenic cartography; phylogenetics; Bayesian inference; multidimensional scaling; viruses
19.  The application of multiple reaction monitoring and multi-analyte profiling to HDL proteins 
HDL carries a rich protein cargo and examining HDL protein composition promises to improve our understanding of its functions. Conventional mass spectrometry methods can be lengthy and difficult to extend to large populations. In addition, without prior enrichment of the sample, the ability of these methods to detect low abundance proteins is limited. Our objective was to develop a high-throughput approach to examine HDL protein composition applicable to diabetes and cardiovascular disease (CVD).
We optimized two multiplexed assays to examine HDL proteins using a quantitative immunoassay (Multi-Analyte Profiling- MAP) and mass spectrometric-based quantitative proteomics (Multiple Reaction Monitoring-MRM). We screened HDL proteins using human xMAP (90 protein panel) and MRM (56 protein panel). We extended the application of these two methods to HDL isolated from a group of participants with diabetes and prior cardiovascular events and a group of non-diabetic controls.
We were able to quantitate 69 HDL proteins using MAP and 32 proteins using MRM. For several common proteins, the use of MRM and MAP was highly correlated (p < 0.01). Using MAP, several low abundance proteins implicated in atherosclerosis and inflammation were found on HDL. On the other hand, MRM allowed the examination of several HDL proteins not available by MAP.
MAP and MRM offer a sensitive and high-throughput approach to examine changes in HDL proteins in diabetes and CVD. This approach can be used to measure the presented HDL proteins in large clinical studies.
PMCID: PMC3900256  PMID: 24397693
High density lipoprotein; Proteomics; Multiple reaction monitoring; Multi-analyte panel; Diabetes; Cardiovascular disease
20.  Orphan nuclear receptor TLX regulates astrogenesis by modulating BMP signaling 
Neural stem cells (NSCs) are self-renewing multipotent progenitors that generate both neurons and glia. The precise control of NSC behavior is fundamental to the architecture and function of the central nervous system. We previously demonstrated that the orphan nuclear receptor TLX is required for postnatal NSC activation and neurogenesis in the neurogenic niche. Here, we show that TLX modulates bone morphogenetic protein (BMP)-SMAD signaling to control the timing of postnatal astrogenesis. Genes involved in the BMP signaling pathway, such as Bmp4, Hes1, and Id3, are upregulated in postnatal brains lacking Tlx. Chromatin immunoprecipitation and electrophoretic mobility shift assays reveal that TLX can directly bind the enhancer region of Bmp4. In accordance with elevated BMP signaling, the downstream effectors SMAD1/5/8 are activated by phosphorylation in Tlx mutant mice. Consequently, Tlx mutant brains exhibit an early appearance and increased number of astrocytes with marker expression of glial fibrillary acidic protein (GFAP) and S100B. Taken together, these results suggest that TLX tightly controls postnatal astrogenesis through the modulation of BMP-SMAD signaling pathway activity.
PMCID: PMC3989729  PMID: 24782704
nuclear receptor; TLX; neural stem cells; neurogenesis; astrogenesis; BMP-SMAD signaling
21.  Prevalence of tobacco smoking among school teachers in Botswana 
Tobacco Induced Diseases  2013;11(1):24.
Tobacco is a leading cause of death worldwide, and nearly 80% of all smokers live in low to middle income countries. Previous research has suggested that smoking rates vary by occupation, with relatively low rates commonly seen among educators. Despite this fact, little is known about the smoking habits of teachers in Botswana. The objective of this study, therefore, was to investigate prevalence and correlates of tobacco use among school teachers in Botswana.
The prevalence of smoking among school teachers in Botswana was found to be relatively low. Of the 1732 participants in the study, only 3.2% reported being current smokers, 5.3% were ex-smokers and 91.5% had never smoked. Smoking was more common among male teachers when compared to females, being 10.8% and 0.4%, respectively. Factors such as school level, marital status and body mass index were found to be positively associated with tobacco smoking, whereas age, length of employment and weekly working hours were not.
This study suggests that Botswana school teachers have a low prevalence of tobacco smoking. While this result may be attributed to tobacco control measures that have been put in place, there is still need to put in place systems to monitor compliance and programs to help those who want to quit smoking. Such protocols would represent a major step forward in further reducing the prevalence of smoking in the education profession.
PMCID: PMC4220795  PMID: 24283758
22.  Draft Genome Sequence of the Antibiotic-Producing Epiphytic Isolate Pantoea ananatis BRT175 
Genome Announcements  2013;1(6):e00902-13.
Pantoea is a member of the Enterobacteriaceae, whose members have been shown to produce novel antibiotics. Here, we report the 4.8-Mb genome sequence of Pantoea ananatis strain BRT175, an epiphytic isolate from strawberries that produces an antibiotic that is effective against the fire blight pathogen, Erwinia amylovora.
PMCID: PMC3820774  PMID: 24201193
23.  Draft Genome Sequence of the Antibiotic-Producing Cystic Fibrosis Isolate Pantoea agglomerans Tx10 
Genome Announcements  2013;1(5):e00904-13.
Pantoea agglomerans is an enteric bacterium that is capable of causing both plant and human disease. Here, we report the genome sequence of a cystic fibrosis isolate, P. agglomerans Tx10, which produces an antibiotic that is effective against Staphylococcus aureus.
PMCID: PMC3814576  PMID: 24179115
24.  Tobacco use among Australian dental hygiene students is declining, but more still needs to be done 
Tobacco Induced Diseases  2013;11(1):22.
While health care professionals have a responsibility to prevent and control the use of tobacco for improved health outcomes, it appears that some dental hygiene students continue to smoke. A survey of Australian dental hygiene students found that up to 16.3% smoke, although this prevalence rate decreased with each year of study. As future role models, it is essential that smoking cessation counselling is embedded in the dental curriculum to not only discourage their own habits, but so that they may promote the importance of being tobacco free to the wider population.
PMCID: PMC4015873  PMID: 24148282
Smoking; Tobacco; Students; Dental hygiene; Prevention
25.  Quantifying the Impact of Immune Escape on Transmission Dynamics of Influenza 
Science (New York, N.Y.)  2009;326(5953):726-728.
Influenza virus evades prevailing natural and vaccine-induced immunity by accumulating antigenic change in the haemagglutinin surface protein. Linking amino acid substitutions in haemagglutinin epitopes to epidemiology has been problematic because of the scarcity of data connecting these scales. We use experiments on equine influenza virus to address this issue, quantifying how key parameters of viral establishment and shedding increase the probability of transmission with genetic distance between previously immunizing virus and challenge virus. Qualitatively similar patterns emerge from analyses based on antigenic distance and from a published human influenza study. Combination of the equine data and epidemiological models allows us to calculate the effective reproductive number of transmission as a function of relevant genetic change in the virus, illuminating the probability of influenza epidemics as a function of immunity.
PMCID: PMC3800096  PMID: 19900931

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