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1.  Models for preclinical studies in aging-related disorders: One is not for all 
Preclinical studies are essentially based on animal models of a particular disease. The primary purpose of preclinical efficacy studies is to support generalization of treatment–effect relationships to human subjects. Researchers aim to demonstrate a causal relationship between an investigational agent and a disease-related phenotype in such models. Numerous factors can muddle reliable inferences about such cause-effect relationships, including biased outcome assessment due to experimenter expectations. For instance, responses in a particular inbred mouse might be specific to the strain, limiting generalizability. Selecting well-justified and widely acknowledged model systems represents the best start in designing preclinical studies, especially to overcome any potential bias related to the model itself. This is particularly true in the research that focuses on aging, which carries unique challenges, mainly attributable to the fact that our already long lifespan makes designing experiments that use people as subjects extremely difficult and largely impractical.
PMCID: PMC4811343  PMID: 27042427
aging; animal models; rodents; swine; cardiovascular medicine; preclinical studies; frailty; multimorbidity
2.  Genetic Adaptation vs. Ecophysiological Plasticity of Photosynthetic-Related Traits in Young Picea glauca Trees along a Regional Climatic Gradient 
Assisted population migration (APM) is the intentional movement of populations within a species range to sites where future environmental conditions are projected to be more conducive to growth. APM has been proposed as a proactive adaptation strategy to maintain forest productivity and to reduce the vulnerability of forest ecosystems to projected climate change. The validity of such a strategy will depend on the adaptation capacity of populations, which can partially be evaluated by the ecophysiological response of different genetic sources along a climatic gradient. This adaptation capacity results from the compromise between (i) the degree of genetic adaptation of seed sources to their environment of origin and (ii) the phenotypic plasticity of functional trait which can make it possible for transferred seed sources to positively respond to new growing conditions. We examined phenotypic variation in morphophysiological traits of six seed sources of white spruce (Picea glauca [Moench] Voss) along a regional climatic gradient in Québec, Canada. Seedlings from the seed sources were planted at three forest sites representing a mean annual temperature (MAT) gradient of 2.2°C. During the second growing season, we measured height growth (H2014) and traits related to resources use efficiency and photosynthetic rate (Amax). All functional traits showed an adaptive response to the climatic gradient. Traits such as H2014, Amax, stomatal conductance (gs), the ratio of mesophyll to stomatal conductance, water use efficiency, and photosynthetic nitrogen-use efficiency showed significant variation in both physiological plasticity due to the planting site and seed source variation related to local genetic adaptation. However, the amplitude of seed source variation was much less than that related to plantation sites in the area investigated. The six seed sources showed a similar level of physiological plasticity. H2014, Amax and gs, but not carboxylation capacity (Vcmax), were correlated and decreased with a reduction of the average temperature of the growing season at seed origin. The clinal variation in H2014 and Amax appeared to be driven by CO2 conductance. The presence of locally adapted functional traits suggests that the use of APM may have advantages for optimizing seed source productivity in future local climates.
PMCID: PMC4737914  PMID: 26870067
white spruce; climate change; assisted migration; local adaptation; acclimation; functional traits; mesophyll conductance; photosynthetic capacity
3.  Advances in allergen-microarray technology for diagnosis and monitoring of allergy: The MeDALL allergen-chip 
Methods (San Diego, Calif.)  2013;66(1):106-119.
Allergy diagnosis based on purified allergen molecules provides detailed information regarding the individual sensitization profile of allergic patients, allows monitoring of the development of allergic disease and of the effect of therapies on the immune response to individual allergen molecules. Allergen microarrays contain a large variety of allergen molecules and thus allow the simultaneous detection of allergic patients’ antibody reactivity profiles towards each of the allergen molecules with only minute amounts of serum. In this article we summarize recent progress in the field of allergen microarray technology and introduce the MeDALL allergen-chip which has been developed for the specific and sensitive monitoring of IgE and IgG reactivity profiles towards more than 170 allergen molecules in sera collected in European birth cohorts. MeDALL is a European research program in which allergen microarray technology is used for the monitoring of the development of allergic disease in childhood, to draw a geographic map of the recognition of clinically relevant allergens in different populations and to establish reactivity profiles which are associated with and predict certain disease manifestations. We describe technical advances of the MeDALL allergen-chip regarding specificity, sensitivity and its ability to deliver test results which are close to in vivo reactivity. In addition, the usefulness and numerous advantages of allergen microarrays for allergy research, refined allergy diagnosis, monitoring of disease, of the effects of therapies, for improving the prescription of specific immunotherapy and for prevention are discussed.
PMCID: PMC4687054  PMID: 24161540
Allergen-microarray; Sensitivity; Blocking antibodies; Allergy-diagnosis; Recombinant allergen; Immunoglobulin E; Immunoglobulin G
4.  Organellar Genomes of White Spruce (Picea glauca): Assembly and Annotation 
Genome Biology and Evolution  2015;8(1):29-41.
The genome sequences of the plastid and mitochondrion of white spruce (Picea glauca) were assembled from whole-genome shotgun sequencing data using ABySS. The sequencing data contained reads from both the nuclear and organellar genomes, and reads of the organellar genomes were abundant in the data as each cell harbors hundreds of mitochondria and plastids. Hence, assembly of the 123-kb plastid and 5.9-Mb mitochondrial genomes were accomplished by analyzing data sets primarily representing low coverage of the nuclear genome. The assembled organellar genomes were annotated for their coding genes, ribosomal RNA, and transfer RNA. Transcript abundances of the mitochondrial genes were quantified in three developmental tissues and five mature tissues using data from RNA-seq experiments. C-to-U RNA editing was observed in the majority of mitochondrial genes, and in four genes, editing events were noted to modify ACG codons to create cryptic AUG start codons. The informatics methodology presented in this study should prove useful to assemble organellar genomes of other plant species using whole-genome shotgun sequencing data.
PMCID: PMC4758241  PMID: 26645680
gymnosperms; white spruce; organelle; genome assembly; sequencing; ABySS
5.  The hidden burden of adult allergic rhinitis: UK healthcare resource utilisation survey 
The affliction of allergic rhinitis (AR) has been trivialised in the past. Recent initiatives by the European Academy of Allergy & Clinical Immunology and by the EU parliament seek to rectify that situation. The aim of this study was to provide a comprehensive picture of the burden and unmet need of AR patients.
This was a cross-sectional, online, questionnaire-based study (June–July 2011) including symptomatic seasonal AR (SAR) patients (≥18 years) from a panel. SAR episode pattern, severity, medication/co-medication usage, residual symptoms on treatment, number of healthcare visits, absenteeism and presenteeism were collected.
One thousand patients were recruited (mild: n = 254; moderate/severe: n = 746). Patients with moderate/severe disease had significantly more symptomatic episodes/year (8.0 vs 6.0/year; p = 0.025) with longer episode-duration (12.5 vs 9.8 days; p = 0.0041) and more commonly used ≥2 AR therapies (70.5 vs 56.1 %; OR 1.87; p = 0.0001), looking for better and faster nasal and ocular symptom relief. The reported symptom burden was high irrespective of treatment, and significantly (p < 0.0001) higher in the moderate/severe group. Patients with moderate/severe AR were more likely to visit their GP (1.61 vs 1.19 times/year; OR: 1.49; p = 0.0061); due to dissatisfaction with therapy in 35.4 % of cases. Patients reported SAR-related absenteeism from work on 4.1 days/year (total cost to UK: £1.25 billion/year) and noted presenteeism for a mean of 37.7 days/year (vs 21.0 days/year; OR 1.71; p = 0.0048). Asthma co-morbid patients reported the need to increase their reliever- (1 in 2 patients) and controller-medication (1 in 5 patients) if they did not take their rhinitis medication.
This study differentiated between patients with mild and moderate/severe AR, demonstrating a burden of poorly controlled symptoms and high co-medication use. The deficiency in obtaining symptom control with what are currently considered firstline treatments suggests the need for a novel therapeutic approach.
Electronic supplementary material
The online version of this article (doi:10.1186/s13601-015-0083-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4650835  PMID: 26583068
Allergic rhinitis; UK; Symptom episode; Co-medication; Absenteeism; Presenteeism
6.  Genetic Adaptation to Climate in White Spruce Involves Small to Moderate Allele Frequency Shifts in Functionally Diverse Genes 
Genome Biology and Evolution  2015;7(12):3269-3285.
Understanding the genetic basis of adaptation to climate is of paramount importance for preserving and managing genetic diversity in plants in a context of climate change. Yet, this objective has been addressed mainly in short-lived model species. Thus, expanding knowledge to nonmodel species with contrasting life histories, such as forest trees, appears necessary. To uncover the genetic basis of adaptation to climate in the widely distributed boreal conifer white spruce (Picea glauca), an environmental association study was conducted using 11,085 single nucleotide polymorphisms representing 7,819 genes, that is, approximately a quarter of the transcriptome.
Linear and quadratic regressions controlling for isolation-by-distance, and the Random Forest algorithm, identified several dozen genes putatively under selection, among which 43 showed strongest signals along temperature and precipitation gradients. Most of them were related to temperature. Small to moderate shifts in allele frequencies were observed. Genes involved encompassed a wide variety of functions and processes, some of them being likely important for plant survival under biotic and abiotic environmental stresses according to expression data. Literature mining and sequence comparison also highlighted conserved sequences and functions with angiosperm homologs.
Our results are consistent with theoretical predictions that local adaptation involves genes with small frequency shifts when selection is recent and gene flow among populations is high. Accordingly, genetic adaptation to climate in P. glauca appears to be complex, involving many independent and interacting gene functions, biochemical pathways, and processes. From an applied perspective, these results shall lead to specific functional/association studies in conifers and to the development of markers useful for the conservation of genetic resources.
PMCID: PMC4700950  PMID: 26560341
environmental gradient; genetic basis of adaptation; genomics of adaptation; population genomics; white spruce
7.  A common language to assess allergic rhinitis control: results from a survey conducted during EAACI 2013 Congress 
The concept of control is gaining importance in the field of allergic rhinitis (AR), with a visual analogue scale (VAS) score being a validated, easy and attractive tool to evaluate AR symptom control. The doctors’ perception of a VAS score as a good tool for evaluating AR symptom control is unknown, as is the level of AR control perceived by physicians who treat patients.
307 voluntarily selected physicians attending the annual (2013) European Academy of Allergy and Clinical Immunology (EAACI) meeting completed a digital survey. Delegates were asked to (1) estimate how many AR patients/week they saw during the season, (2) estimate the proportion of patients they considered to have well-, partly- and un-controlled AR, (3) communicate how they gauged this control and (4) assess how useful they would find a VAS as a method of gauging control. 257 questionnaires were filled out completely and analysed.
EAACI delegates reported seeing 46.8 [standard deviation (SD) 68.5] AR patients/week during the season. They estimated that 38.7 % (SD 24.0), 34.2 % (SD 20.2) and 20.0 % (SD 16.34) of their AR patients had well-controlled (no AR symptoms), partly-controlled (some AR symptoms), or un-controlled-(moderate/severe AR symptoms) disease despite taking medication [remainder unknown (7.1 %)]. However, AR control was assessed in many ways, including symptom severity (74 %), frequency of day- and night-time symptoms (67 %), activity impairment (57 %), respiratory function monitoring (nasal and/or lung function; 40 %) and incidence of AR exacerbations (50 %). 91 % of delegates felt a simple VAS would be a useful tool to gauge AR symptom control.
A substantial portion of patients with AR are perceived as having uncontrolled or partly controlled disease even when treated. A simple VAS score is considered a useful tool to monitor AR control.
Electronic supplementary material
The online version of this article (doi:10.1186/s13601-015-0080-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4621924  PMID: 26509001
Allergic rhinitis; Control; Digital; Survey; Visual analogue scale; VAS
8.  Characterization of Rhinitis According to the Asthma Status in Adults Using an Unsupervised Approach in the EGEA Study 
PLoS ONE  2015;10(8):e0136191.
The classification of rhinitis in adults is missing in epidemiological studies.
To identify phenotypes of adult rhinitis using an unsupervised approach (data-driven) compared with a classical hypothesis-driven approach.
983 adults of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) were studied. Self-reported symptoms related to rhinitis such as nasal symptoms, hay fever, sinusitis, conjunctivitis, and sensitivities to different triggers (dust, animals, hay/flowers, cold air…) were used. Allergic sensitization was defined by at least one positive skin prick test to 12 aeroallergens. Mixture model was used to cluster participants, independently in those without (Asthma-, n = 582) and with asthma (Asthma+, n = 401).
Three clusters were identified in both groups: 1) Cluster A (55% in Asthma-, and 22% in Asthma+) mainly characterized by the absence of nasal symptoms, 2) Cluster B (23% in Asthma-, 36% in Asthma+) mainly characterized by nasal symptoms all over the year, sinusitis and a low prevalence of positive skin prick tests, and 3) Cluster C (22% in Asthma-, 42% in Asthma+) mainly characterized by a peak of nasal symptoms during spring, a high prevalence of positive skin prick tests and a high report of hay fever, allergic rhinitis and conjunctivitis. The highest rate of polysensitization (80%) was found in participants with comorbid asthma and allergic rhinitis.
This cluster analysis highlighted three clusters of rhinitis with similar characteristics than those known by clinicians but differing according to allergic sensitization, and this whatever the asthma status. These clusters could be easily rebuilt using a small number of variables.
PMCID: PMC4550236  PMID: 26309034
10.  Less Pollen-Mediated Gene Flow for More Signatures of Glacial Lineages: Congruent Evidence from Balsam Fir cpDNA and mtDNA for Multiple Refugia in Eastern and Central North America 
PLoS ONE  2015;10(4):e0122815.
The phylogeographic structure and postglacial history of balsam fir (Abies balsamea), a transcontinental North American boreal conifer, was inferred using mitochondrial DNA (mtDNA) and chloroplast DNA (cpDNA) markers. Genetic structure among 107 populations (mtDNA data) and 75 populations (cpDNA data) was analyzed using Bayesian and genetic distance approaches. Population differentiation was high for mtDNA (dispersed by seeds only), but also for cpDNA (dispersed by seeds and pollen), indicating that pollen gene flow is more restricted in balsam fir than in other boreal conifers. Low cpDNA gene flow in balsam fir may relate to low pollen production due to the inherent biology of the species and populations being decimated by recurrent spruce budworm epidemics, and/or to low dispersal of pollen grains due to their peculiar structural properties. Accordingly, a phylogeographic structure was detected using both mtDNA and cpDNA markers and population structure analyses supported the existence of at least five genetically distinct glacial lineages in central and eastern North America. Four of these would originate from glacial refugia located south of the Laurentide ice sheet, while the last one would have persisted in the northern Labrador region. As expected due to reduced pollen-mediated gene flow, congruence between the geographic distribution of mtDNA and cpDNA lineages was higher than in other North American conifers. However, concordance was not complete, reflecting that restricted but nonetheless detectable cpDNA gene flow among glacial lineages occurred during the Holocene. As a result, new cpDNA and mtDNA genome combinations indicative of cytoplasmic genome capture were observed.
PMCID: PMC4388536  PMID: 25849816
11.  Comparison of two methods to report potentially avoidable hospitalizations in France in 2012: a cross-sectional study 
Potentially avoidable hospitalizations represent an indirect measure of access to effective primary care. However many approaches have been proposed to measure them and results may differ considerably. This work aimed at examining the agreement between the Weissman and Ansari approaches in order to measure potentially avoidable hospitalizations in France.
Based on the 2012 French national hospital discharge database (Programme de Médicalisation des Systèmes d’Information), potentially avoidable hospitalizations were measured using two approaches proposed by Weissman et al. and by Ansari et al. Age- and sex-standardised rates were calculated in each department. The two approaches were compared for diagnosis groups, type of stay, severity, age, sex, and length of stay.
The number and age-standardised rate of potentially avoidable hospitalizations estimated by the Weissman et al. and Ansari et al. approaches were 742,474 (13.3 cases per 1,000 inhabitants) and 510,206 (9.0 cases per 1,000 inhabitants), respectively. There are significant differences by conditions groups, age, length of stay, severity level, and proportion of medical stays between the Weissman and Ansari methods.
Regarding potentially avoidable hospitalizations in France in 2012, the agreement between the Weissman and Ansari approaches is poor. The method used to measure potentially avoidable hospitalizations is critical, and might influence the assessment of accessibility and performance of primary care.
PMCID: PMC4316643  PMID: 25608760
Diagnosis-related groups; International classification of disease; Potentially avoidable hospitalizations; PMSI; France
13.  Variations in foliar monoterpenes across the range of jack pine reveal three widespread chemotypes: implications to host expansion of invasive mountain pine beetle 
The secondary compounds of pines (Pinus) can strongly affect the physiology, ecology and behaviors of the bark beetles (Coleoptera: Curculionidae, Scolytinae) that feed on sub-cortical tissues of hosts. Jack pine (Pinus banksiana) has a wide natural distribution range in North America (Canada and USA) and thus variations in its secondary compounds, particularly monoterpenes, could affect the host expansion of invasive mountain pine beetle (Dendroctonus ponderosae), which has recently expanded its range into the novel jack pine boreal forest. We investigated monoterpene composition of 601 jack pine trees from natural and provenance forest stands representing 63 populations from Alberta to the Atlantic coast. Throughout its range, jack pine exhibited three chemotypes characterized by high proportions of α-pinene, β-pinene, or limonene. The frequency with which the α-pinene and β-pinene chemotypes occurred at individual sites was correlated to climatic variables, such as continentality and mean annual precipitation, as were the individual α-pinene and β-pinene concentrations. However, other monoterpenes were generally not correlated to climatic variables or geographic distribution. Finally, while the enantiomeric ratios of β-pinene and limonene remained constant across jack pine's distribution, (−):(+)-α-pinene exhibited two separate trends, thereby delineating two α-pinene phenotypes, both of which occurred across jack pine's range. These significant variations in jack pine monoterpene composition may have cascading effects on the continued eastward spread and success of D. ponderosae in the Canadian boreal forest.
PMCID: PMC4436562  PMID: 26042134
Pinus banksiana; Pinaceae; jack pine; monoterpenes; Dendroctonus ponderosae; mountain pine beetle
14.  Genomic selection accuracies within and between environments and small breeding groups in white spruce 
BMC Genomics  2014;15(1):1048.
Genomic selection (GS) may improve selection response over conventional pedigree-based selection if markers capture more detailed information than pedigrees in recently domesticated tree species and/or make it more cost effective. Genomic prediction accuracies using 1748 trees and 6932 SNPs representative of as many distinct gene loci were determined for growth and wood traits in white spruce, within and between environments and breeding groups (BG), each with an effective size of Ne ≈ 20. Marker subsets were also tested.
Model fits and/or cross-validation (CV) prediction accuracies for ridge regression (RR) and the least absolute shrinkage and selection operator models approached those of pedigree-based models. With strong relatedness between CV sets, prediction accuracies for RR within environment and BG were high for wood (r = 0.71–0.79) and moderately high for growth (r = 0.52–0.69) traits, in line with trends in heritabilities. For both classes of traits, these accuracies achieved between 83% and 92% of those obtained with phenotypes and pedigree information. Prediction into untested environments remained moderately high for wood (r ≥ 0.61) but dropped significantly for growth (r ≥ 0.24) traits, emphasizing the need to phenotype in all test environments and model genotype-by-environment interactions for growth traits. Removing relatedness between CV sets sharply decreased prediction accuracies for all traits and subpopulations, falling near zero between BGs with no known shared ancestry. For marker subsets, similar patterns were observed but with lower prediction accuracies.
Given the need for high relatedness between CV sets to obtain good prediction accuracies, we recommend to build GS models for prediction within the same breeding population only. Breeding groups could be merged to build genomic prediction models as long as the total effective population size does not exceed 50 individuals in order to obtain high prediction accuracy such as that obtained in the present study. A number of markers limited to a few hundred would not negatively impact prediction accuracies, but these could decrease more rapidly over generations. The most promising short-term approach for genomic selection would likely be the selection of superior individuals within large full-sib families vegetatively propagated to implement multiclonal forestry.
PMCID: PMC4265403  PMID: 25442968
Genomic selection; Genotype-by-environment interactions; Relatedness; Somatic embryogenesis; Spruce
15.  Chronic respiratory diseases and risk factors in 12 regions of the Russian Federation 
Estimation suggests that at least 4 million people die, annually, as a result of chronic respiratory disease (CRD). The Global Alliance against Chronic Respiratory Diseases (GARD) was formed following a mandate from the World Health Assembly to address this serious and growing health problem.
To investigate the prevalence of CRD in Russian symptomatic patients and to evaluate the frequency of major risk factors for CRD in Russia.
A cross-sectional, population-based epidemiological study using the GARD questionnaire on adults from 12 regions of the Russian Federation. Common respiratory symptoms and risk factors were recorded. Spirometry was performed in respondents with suspected CRD. Allergic rhinitis (AR) and chronic bronchitis (CB) were defined by the presence of related symptoms according to the Allergic Rhinitis and its Impact on Asthma and the Global Initiative for Obstructive Lung Disease guidelines; asthma was defined based on disease symptoms; chronic obstructive pulmonary disease (COPD) was defined as a post-bronchodilator forced expiratory volume per 1 second/forced vital capacity ratio <0.7 in symptomatic patients, following the Global Initiative for Obstructive Lung Disease guidelines.
The number of questionnaires completed was 7,164 (mean age 43.4 years; 57.2% female). The prevalence of asthma symptoms was 25.7%, AR 18.2%, and CB 8.6%. Based on patient self-reported diagnosis, 6.9% had asthma, 6.5% AR, and 22.2% CB. The prevalence of COPD based on spirometry in patients with respiratory symptoms was estimated as 21.8%.
The prevalence of respiratory diseases and risk factors was high in Russia when compared to available data. For bronchial asthma and AR, the prevalence for related symptoms was higher than self-reported previous diagnosis.
PMCID: PMC4166963  PMID: 25246783
chronic respiratory diseases; GARD; Russia; prevalence
16.  Operational definitions of asthma in recent epidemiological studies are inconsistent 
The best combination of questions to define asthma in epidemiological asthma studies is not known. We summarized the operational definitions of asthma used in prevalence studies and empirically assess how asthma prevalence estimates vary depending on the definition used.
We searched the Thomson Reuters ISI Web of knowledge and included (1) cross-sectional studies (2) on asthma prevalence (3) conducted in the general population and (4) containing an explicit definition of asthma. The search was limited to the 100 most-cited papers or published since January 2010. For each paper, we recorded the asthma definition used and other variables. Then we applied the definitions to the data of the Portuguese National Asthma survey (INAsma) and of the 2005–2006 National Health and Nutrition Examination Survey (NHANES) computing asthma prevalence estimates for the different definitions.
Of 1738 papers retrieved, 117 were included for analysis. Lifetime asthma, diagnosed asthma and current asthma were defined in 8, 12 and 29 different ways, respectively. By applying definitions of current asthma on INAsma and NHANES data, the prevalence ranged between 5.3%-24.4% and 1.1%-17.2%, respectively.
There is considerable heterogeneity in the definitions of asthma used in epidemiological studies leading to highly variable estimates of asthma prevalence. Studies to inform a standardized operational definition are needed. Meanwhile, we propose a set of questions to be reported when defining asthma in epidemiological studies.
PMCID: PMC4136946  PMID: 25136441
Asthma; Definition; Epidemiology; Prevalence; Review
17.  A Picea abies Linkage Map Based on SNP Markers Identifies QTLs for Four Aspects of Resistance to Heterobasidion parviporum Infection 
PLoS ONE  2014;9(7):e101049.
A consensus linkage map of Picea abies, an economically important conifer, was constructed based on the segregation of 686 SNP markers in a F1 progeny population consisting of 247 individuals. The total length of 1889.2 cM covered 96.5% of the estimated genome length and comprised 12 large linkage groups, corresponding to the number of haploid P. abies chromosomes. The sizes of the groups (from 5.9 to 9.9% of the total map length) correlated well with previous estimates of chromosome sizes (from 5.8 to 10.8% of total genome size). Any locus in the genome has a 97% probability to be within 10 cM from a mapped marker, which makes the map suited for QTL mapping. Infecting the progeny trees with the root rot pathogen Heterobasidion parviporum allowed for mapping of four different resistance traits: lesion length at the inoculation site, fungal spread within the sapwood, exclusion of the pathogen from the host after initial infection, and ability to prevent the infection from establishing at all. These four traits were associated with two, four, four and three QTL regions respectively of which none overlapped between the traits. Each QTL explained between 4.6 and 10.1% of the respective traits phenotypic variation. Although the QTL regions contain many more genes than the ones represented by the SNP markers, at least four markers within the confidence intervals originated from genes with known function in conifer defence; a leucoanthocyanidine reductase, which has previously been shown to upregulate during H. parviporum infection, and three intermediates of the lignification process; a hydroxycinnamoyl CoA shikimate/quinate hydroxycinnamoyltransferase, a 4-coumarate CoA ligase, and a R2R3-MYB transcription factor.
PMCID: PMC4103950  PMID: 25036209
18.  Relationship between genome and epigenome - challenges and requirements for future research 
BMC Genomics  2014;15(1):487.
Understanding the links between genetic, epigenetic and non-genetic factors throughout the lifespan and across generations and their role in disease susceptibility and disease progression offer entirely new avenues and solutions to major problems in our society. To overcome the numerous challenges, we have come up with nine major conclusions to set the vision for future policies and research agendas at the European level.
PMCID: PMC4073504  PMID: 24942464
Genome; Epigenome; Microbiome; Environment
19.  Evolution of gene structure in the conifer Picea glauca: a comparative analysis of the impact of intron size 
BMC Plant Biology  2014;14:95.
A positive relationship between genome size and intron length is observed across eukaryotes including Angiosperms plants, indicating a co-evolution of genome size and gene structure. Conifers have very large genomes and longer introns on average than most plants, but impacts of their large genome and longer introns on gene structure has not be described.
Gene structure was analyzed for 35 genes of Picea glauca obtained from BAC sequencing and genome assembly, including comparisons with A. thaliana, P. trichocarpa and Z. mays. We aimed to develop an understanding of impact of long introns on the structure of individual genes. The number and length of exons was well conserved among the species compared but on average, P. glauca introns were longer and genes had four times more intronic sequence than Arabidopsis, and 2 times more than poplar and maize. However, pairwise comparisons of individual genes gave variable results and not all contrasts were statistically significant. Genes generally accumulated one or a few longer introns in species with larger genomes but the position of long introns was variable between plant lineages. In P. glauca, highly expressed genes generally had more intronic sequence than tissue preferential genes. Comparisons with the Pinus taeda BACs and genome scaffolds showed a high conservation for position of long introns and for sequence of short introns. A survey of 1836 P. glauca genes obtained by sequence capture mostly containing introns <1 Kbp showed that repeated sequences were 10× more abundant in introns than in exons.
Conifers have large amounts of intronic sequence per gene for seed plants due to the presence of few long introns and repetitive element sequences are ubiquitous in their introns. Results indicate a complex landscape of intron sizes and distribution across taxa and between genes with different expression profiles.
PMCID: PMC4108047  PMID: 24734980
Genome size; Pinus taeda; BAC; Repeat elements; Gymnosperms; Gene expression
20.  Sublingual immunotherapy: World Allergy Organization position paper 2013 update 
We have prepared this document, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update”, according to the evidence-based criteria, revising and updating chapters of the originally published paper, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2009”, available at Namely, these comprise: “Mechanisms of sublingual immunotherapy;” “Clinical efficacy of sublingual immunotherapy” – reporting all the data of all controlled trials published after 2009; “Safety of sublingual immunotherapy” – with the recently published Grading System for adverse reactions; “Impact of sublingual immunotherapy on the natural history of respiratory allergy” – with the relevant evidences published since 2009; “Efficacy of SLIT in children” – with detailed analysis of all the studies; “Definition of SLIT patient selection” – reporting the criteria for eligibility to sublingual immunotherapy; “The future of immunotherapy in the community care setting”; “Methodology of clinical trials according to the current scientific and regulatory standards”; and “Guideline development: from evidence-based medicine to patients' views” – including the evolution of the methods to make clinical recommendations.
Additionally, we have added new chapters to cover a few emerging crucial topics: “Practical aspects of schedules and dosages and counseling for adherence” – which is crucial in clinical practice for all treatments; “Perspectives and new approaches” – including recombinant allergens, adjuvants, modified allergens, and the concept of validity of the single products. Furthermore, “Raising public awareness about sublingual immunotherapy”, as a need for our patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion, are also reported in detail.
PMCID: PMC3983904  PMID: 24679069
Sublingual immunotherapy; Allergen-specific immunotherapy; Mechanisms of SLIT; Safety of SLIT; Efficacy of SLIT; Clinical trials methodology in SLIT
21.  The bud break process and its variation among local populations of boreal black spruce 
Phenology of local populations can exhibit adaptations to the current environmental conditions resulting from a close interaction between climate and genotype. The bud break process and its variations among populations were analyzed in greenhouse by monitoring the growth resumption in black spruce [Picea mariana (Mill.) BSP] seedlings originating from seeds of five stands across the closed boreal forest in Quebec, Canada. Bud break lasted 15 days and occurred earlier and quicker in northern provenances. Provenance explained between 10.2 and 32.3% of the variance in bud break, while the families accounted for a smaller but still significant part of the variance. The late occurrence of one phenological phase corresponded to a delayed occurrence of the others according to linear relationships. A causal model was proposed in the form of a chain of events with each phase of bud break being related to the previous and successive one, while no link was observed between non-adjacent phases. The adaptation of black spruce populations along the latitudinal gradient points toward a strategy based on rapid physiological processes triggered by temperature increase inducing high metabolic activity. The variation observed in bud break reflects an evolutionary trade-off between maximization of security and taking advantage of the short growing season. This work provides evidence of the phenological adaptations of black spruce to its local environmental conditions while retaining sizeable genetic diversity within populations. Because of the multigenic nature of phenology, this diversity should provide some raw material for adaptation to changing local environmental conditions.
PMCID: PMC4211384  PMID: 25389430
adaptation; cold climate; genecology; genetic diversity; phenology; temperature
22.  The Phylogeny and Biogeographic History of Ashes (Fraxinus, Oleaceae) Highlight the Roles of Migration and Vicariance in the Diversification of Temperate Trees 
PLoS ONE  2013;8(11):e80431.
The cosmopolitan genus Fraxinus, which comprises about 40 species of temperate trees and shrubs occupying various habitats in the Northern Hemisphere, represents a useful model to study speciation in long-lived angiosperms. We used nuclear external transcribed spacers (nETS), phantastica gene sequences, and two chloroplast loci (trnH-psbA and rpl32-trnL) in combination with previously published and newly obtained nITS sequences to produce a time-calibrated multi-locus phylogeny of the genus. We then inferred the biogeographic history and evolution of floral morphology. An early dispersal event could be inferred from North America to Asia during the Oligocene, leading to the diversification of the section Melioides sensus lato. Another intercontinental dispersal originating from the Eurasian section of Fraxinus could be dated from the Miocene and resulted in the speciation of F. nigra in North America. In addition, vicariance was inferred to account for the distribution of the other Old World species (sections Sciadanthus, Fraxinus and Ornus). Geographic speciation likely involving dispersal and vicariance could also be inferred from the phylogenetic grouping of geographically close taxa. Molecular dating suggested that the initial divergence of the taxonomical sections occurred during the middle and late Eocene and Oligocene periods, whereas diversification within sections occurred mostly during the late Oligocene and Miocene, which is consistent with the climate warming and accompanying large distributional changes observed during these periods. These various results underline the importance of dispersal and vicariance in promoting geographic speciation and diversification in Fraxinus. Similarities in life history, reproductive and demographic attributes as well as geographical distribution patterns suggest that many other temperate trees should exhibit similar speciation patterns. On the other hand, the observed parallel evolution and reversions in floral morphology would imply a major influence of environmental pressure. The phylogeny obtained and its biogeographical implications should facilitate future studies on the evolution of complex adaptive characters, such as habitat preference, and their possible roles in promoting divergent evolution in trees.
PMCID: PMC3837005  PMID: 24278282
23.  Impact of active and passive smoking as risk factors for asthma and COPD in women presenting to primary care in Syria: first report by the WHO-GARD survey group 
The burden of chronic respiratory disease (CRD) is alarming. International studies suggest that women with CRD are undersurveyed and underdiagnosed by physicians worldwide. It is unclear what the prevalence of CRD is in the general population of Syria, particularly among women, since there has never been a survey on CRD in this nation. The purpose of this study was to investigate the impact of different patterns of smoking on CRD in women.
Materials and methods
We extracted data on smoking patterns and outcome in women from the Global Alliance Against Chronic Respiratory Diseases survey. Using spirometric measurements before and after the use of inhaled bronchodilators, we tracked the frequency of CRD in females active and passive narghile or cigarette smokers presenting to primary care. We administered the questionnaire to 788 randomly selected females seen during 1 week in the fiscal year 2009–2010 in 22 primary care centers in six different regions of Syria. Inclusion criteria were age >6 years, presenting for any medical complaint. In this cross-sectional study, three groups of female subjects were evaluated: active smokers of cigarettes, active smokers of narghiles, and passive smokers of either cigarettes or narghiles. These three groups were compared to a control group of female subjects not exposed to active or passive smoking.
Exposure to active cigarette smoke but not narghile smoke was associated with doctor-diagnosed chronic obstructive pulmonary disease (COPD). However, neither cigarette nor narghile active smoking was associated with increased incidence of spirometrically diagnosed COPD. Paradoxically, exposure to passive smoking of either cigarettes or narghiles resulted in association with airway obstruction, defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 70% according to the Global initiative for chronic Obstructive Lung Disease criteria; association with FEV1 < 80% predicted, evidencing moderate to severe GOLD spirometric grade, and doctor-diagnosed COPD. Physicians tend to underdiagnose COPD in women who present to primary care clinics. Whereas around 15% of enrolled women had evidence of COPD with FEV1/FVC < 70% after bronchodilators, only 4.8% were physician-diagnosed. Asthma did not appear to be a significant spirometric finding in these female subjects, although around 11% had physician-diagnosed asthma. One limitation is FEV1/FVC < 70% could have also resulted from uncontrolled asthma. The same limitation has been reported by the Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar (PLATINO) study.
Contrary to popular belief in developing countries, women exposed to tobacco smoke, whether active or passive, and whether by cigarettes or narghiles, like men are at increased risk for the development of COPD, although cultural habits and taboos may decrease the risk of active smoking in some women.
These findings will be considered for country and region strategy for noncommunicable diseases, to overcome underdiagnosis of CRD in women, fight widespread female cigarette and narghile smoking, and promote behavioral research in this field.
PMCID: PMC3794890  PMID: 24124359
passive smoking; women; COPD; asthma; narghile; water pipe; behavior
24.  The Landscape of Nucleotide Polymorphism among 13,500 Genes of the Conifer Picea glauca, Relationships with Functions, and Comparison with Medicago truncatula 
Genome Biology and Evolution  2013;5(10):1910-1925.
Gene families differ in composition, expression, and chromosomal organization between conifers and angiosperms, but little is known regarding nucleotide polymorphism. Using various sequencing strategies, an atlas of 212k high-confidence single nucleotide polymorphisms (SNPs) with a validation rate of more than 92% was developed for the conifer white spruce (Picea glauca). Nonsynonymous and synonymous SNPs were annotated over the corresponding 13,498 white spruce genes representative of 2,457 known gene families. Patterns of nucleotide polymorphisms were analyzed by estimating the ratio of nonsynonymous to synonymous numbers of substitutions per site (A/S). A general excess of synonymous SNPs was expected and observed. However, the analysis from several perspectives enabled to identify groups of genes harboring an excess of nonsynonymous SNPs, thus potentially under positive selection. Four known gene families harbored such an excess: dehydrins, ankyrin-repeats, AP2/DREB, and leucine-rich repeat. Conifer-specific sequences were also generally associated with the highest A/S ratios. A/S values were also distributed asymmetrically across genes specifically expressed in megagametophytes, roots, or in both, harboring on average an excess of nonsynonymous SNPs. These patterns confirm that the breadth of gene expression is a contributing factor to the evolution of nucleotide polymorphism. The A/S ratios of Medicago truncatula genes were also analyzed: several gene families shared between P. glauca and M. truncatula data sets had similar excess of synonymous or nonsynonymous SNPs. However, a number of families with high A/S ratios were found specific to P. glauca, suggesting cases of divergent evolution at the functional level.
PMCID: PMC3814201  PMID: 24065735
Picea; Medicago; nucleotide polymorphism; synonymous and nonsynonymous substitutions; expression profiles; selection
25.  Air pollution and asthma control in the Epidemiological study on the Genetics and Environment of Asthma 
The associations between exposure to air pollution and asthma control are not well known. The objective is to assess the association between long term exposure to NO2, O3 and PM10 and asthma control in the EGEA2 study (2003–2007).
Modeled outdoor NO2, O3 and PM10 estimates were linked to each residential address using the 4-km grid air pollutant surface developed by the French Institute of Environment for 2004. Asthma control was assessed in 481 subjects with current asthma using a multidimensional approach following the 2006–2009 GINA guidelines. Multinomial and ordinal logistic regressions were conducted adjusted on sex, age, BMI, education, smoking and use of inhaled corticosteroids. The association between air pollution and the three domains of asthma control (symptoms, exacerbations and lung function) was assessed. Odds Ratios (ORs) are reported per Inter Quartile Range (IQR).
Median concentrations (μg.m−3) were 32(IQR 25–38) for NO2 (n=465), 46(41–52) for O3 and 21(18–21) for PM10 (n=481). In total, 44%, 29% and 27% had controlled, partly-controlled and uncontrolled asthma. The ordinal ORs for O3 and PM10 with asthma control were 1.69(95%CI 1.22–2.34) and 1.35(95%CI 1.13–1.64) respectively. When including both pollutants in the same model, both associations persisted. Associations were not modified by sex, smoking status, use of inhaled corticosteroids, atopy, season of examination or BMI. Both pollutants were associated with each of the three main domains of control.
The results suggest that long-term exposure to PM10 and O3 is associated with uncontrolled asthma in adults, defined by symptoms, exacerbations and lung function. Abstract Word count: 250 Key words: air pollution, asthma, asthma control
PMCID: PMC3943770  PMID: 21690606
Adult; Air Pollutants; adverse effects; analysis; Asthma; epidemiology; etiology; genetics; Case-Control Studies; Cross-Sectional Studies; Environmental Exposure; adverse effects; analysis; Environmental Monitoring; Follow-Up Studies; France; epidemiology; Hospitalization; statistics & numerical data; Humans; Logistic Models; Lung; physiopathology; Nitrous Acid; adverse effects; analysis; Ozone; adverse effects; analysis; Residence Characteristics; Respiratory Tract Diseases; complications; epidemiology; genetics; Seasons; Severity of Illness Index; air pollution; asthma; asthma control

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