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author:("duchesne, A.")
1.  Retention of asbestos fibres in lungs of workers with asbestosis, asbestosis and lung cancer, and mesothelioma in Asbestos township. 
OBJECTIVE: To conduct a mineralogical study on the particles retained in the necropsied lungs of a homogenous group of asbestos miners and millers from Asbestos township (and a local reference population) and to consider the hypothesis that there is a difference in size between fibres retained in the lungs of patients with asbestosis with and without lung cancer. METHODS: Samples of lung tissue were obtained from 38 patients with asbestosis without lung cancer, 25 with asbestosis and lung cancer, and 12 with mesothelioma, from necropsied Quebec chrysotile miners and millers from Asbestos township. Fibre concentrations in the lungs of these patients were compared with those in tissue from necropsies carried out on a local reference population: men who had died of either accidental death or acute myocardial infarction between 1990 and 1992. 23 were born before 1940 and 26 after 1940. RESULTS: Geometric mean (GM) concentrations were higher in cases than in the controls for chrysotile fibres 5 to 10 microns long in patients with asbestosis with or without lung cancer; for tremolite fibres 5 to 10 microns long in all patients; for crocidolite, talc, or anthophyllite fibres 5 to 10 microns long in patients with mesothelioma; for chrysotile and tremolite fibres > or = 10 microns long in patients with asbestosis; and crocidolite, talc, or anthophyllite fibres > or = 10 microns long in patients with mesothelioma. However, median concentrations of each type of fibre in the lungs did not show any significant differences between the three disease groups. Average length to diameter ratios of the fibres were calculated to be larger in patients with asbestosis and lung cancer than in those without lung cancer for crocidolite fibres > or = 10 microns long, for chrysotile, amosite, and tremolite fibres 5 to 10 microns long, and for chrysotile and crocidolite fibres < 5 microns long. However, there was no statistical difference in the median length to diameter ratios for any type of fibres across the disease groups when they were calculated in each patient. Cumulative smoking index (pack-years) was higher in the group with asbestosis and lung cancer but was not statistically different from the two other disease groups. CONCLUSION: Lung cancers occurred in workers with asbestosis from Asbestos township who had an equal concentration of retained fibres but a tendency to a higher length to diameter ratio of amphiboles. These workers had a 29% higher average cumulative smoking index.
PMCID: PMC1128612  PMID: 8994398
2.  Histoplasmosis and subcutaneous nodules in a kidney transplant recipient: erythema nodosum versus fungal panniculitis 
Erythema nodosum (EN)-like lesions are a rare occurrence after solid organ transplantation. Differential diagnosis includes infective panniculitis, which can be a feature of progressive disseminated histoplasmosis (PDH), an uncommon but severe form affecting primarily immunocompromised hosts. We report on a fatal case of PDH, which presented as fungal panniculitis masquerading as EN in a renal allograft recipient 25 years after transplantation. We discuss the clinical, histopathological, and microbiological characteristics of this rare complication, with focus on its distinction from EN. This case emphasizes the central role of biopsy in transplant recipients presenting with cutaneous lesions, and the importance of clinicopathologic correlation and complementary microbiological investigations.
doi:10.1111/tid.12052
PMCID: PMC3618553  PMID: 23331504
histoplasmosis; progressive disseminated histoplasmosis; solid organ transplantation; renal transplant; kidney transplant; erythema nodosum; fungal panniculitis; infective panniculitis; granulomatous panniculitis
3.  Interlaboratory studies and initiatives developing standards for proteomics 
Proteomics  2013;13(6):10.1002/pmic.201200532.
Proteomics is a rapidly transforming interdisciplinary field of research that embraces a diverse set of analytical approaches to tackle problems in fundamental and applied biology. This view-point article highlights the benefits of interlaboratory studies and standardization initiatives to enable investigators to address many of the challenges found in proteomics research. Among these initiatives, we discuss our efforts on a comprehensive performance standard for characterizing PTMs by MS that was recently developed by the Association of Biomolecular Resource Facilities (ABRF) Proteomics Standards Research Group (sPRG).
doi:10.1002/pmic.201200532
PMCID: PMC3863631  PMID: 23319436
LC-MS/MS; Mass spectrometry-based proteomics; Phosphopeptides; Post-translational modifications; Protein identification
4.  Impact of ploidy level on the distribution of Pokey element insertions in the Daphnia pulex complex 
Mobile DNA  2014;5:1.
Background
Transposable elements (TEs) play a major role in genome evolution. Their capacity to move and/or multiply in the genome of their host may have profound impacts on phenotypes and dramatic consequences on genome structure. The population dynamics and distribution of TEs are influenced by their mode of transposition, the availability of niches in host genomes, and host population dynamics. Theories predict an increase in the number of TE insertions following hybridization or polyploidization. Evolution of TEs in hybrids and polyploids has mostly been studied in plants; few studies have examined the impacts of hybridization and/or polyploidization on TEs in animals. Hybrids and polyploids have arisen multiple times in the Daphnia pulex complex and are thought to reproduce by obligate parthenogenesis. Our study examines the effects of ploidy level on polymorphism and number of Pokey element insertions in diploid and polyploid hybrid isolates from the Daphnia pulex complex.
Results
The polymorphism of Pokey insertion sites did not depend solely on either the ploidy level or the genetic background of their host; therefore, it may be the result of interactions between these parameters and other parameters such as Pokey activity, selection and/or drift. No significant effect of ploidy level was found on the number of Pokey insertions using TE display and qPCR. However, the load of Pokey insertion sites and the number of unique insertion sites were slightly (but not significantly) higher in polyploids than in diploids.
Conclusions
These results suggest a lack of increase in the number of Pokey insertions following polyploidization but higher availability of Pokey insertion sites in polyploids than in diploids. Compared to previous TE display and qPCR results, the load of Pokey insertions in hybrid diploids was higher than in non-hybrid sexual and asexual diploids, which suggests an increase in the density of Pokey insertions following hybridization.
doi:10.1186/1759-8753-5-1
PMCID: PMC3882798  PMID: 24382139
Daphnia pulex; Hybrids; Insertion site polymorphism; Load; Pokey; Polyploids; Transposable element
5.  Poleward Expansion of the White-Footed Mouse (Peromyscus leucopus) under Climate Change: Implications for the Spread of Lyme Disease 
PLoS ONE  2013;8(11):e80724.
The white-footed mouse (Peromyscus leucopus) is an important reservoir host for Borrelia burgdorferi, the pathogen responsible for Lyme disease, and its distribution is expanding northward. We used an Ecological Niche Factor Analysis to identify the climatic factors associated with the distribution shift of the white-footed mouse over the last 30 years at the northern edge of its range, and modeled its current and potential future (2050) distributions using the platform BIOMOD. A mild and shorter winter is favouring the northern expansion of the white-footed mouse in Québec. With more favorable winter conditions projected by 2050, the distribution range of the white-footed mouse is expected to expand further northward by 3° latitude. We also show that today in southern Québec, the occurrence of B. burgdorferi is associated with high probability of presence of the white-footed mouse. Changes in the distribution of the white-footed mouse will likely alter the geographical range of B. burgdorferi and impact the public health in northern regions that have yet to be exposed to Lyme disease.
doi:10.1371/journal.pone.0080724
PMCID: PMC3832455  PMID: 24260464
6.  CD20-Targeted T Cells after Stem Cell Transplantation for High Risk and Refractory Non-Hodgkin’s Lymphoma 
A phase I trial of infusing anti-CD3 × anti-CD20 bispecific antibody (CD20Bi) armed activated T cells (aATC) was conducted in high-risk/refractory non-Hodgkin’s lymphoma patients to determine whether aATC infusions are safe, affect immune recovery, and induce an antilymphoma effect. Ex vivo expanded ATC from 12 patients were armed with anti-CD20 bispecific antibody, cryopreserved, and infused after autologous stem cell transplantation (SCT). Patients underwent SCT after high-dose chemotherapy, and aATC infusions were started on day +4. The patients received 1 infusion of aATC per week for 4 weeks after SCT with doses of 5,10,15, and 20 × 109. aATC infusions were safe and did not impair engraftment. The major side effects were chills, fever, hypotension, and fatigue. The mean number of IFN-γ Enzyme-linked Immunosorbent Spots (ElSpots) directed at CD20 positive lymphoma cells (DAUDI, P = .0098) and natural killer cell targets (K562, P < .0051) and the mean specific cytotoxicity directed at DAUDI (P = .037) and K562 (P = .002) from pre-SCT to post-SCT were significantly higher. The increase in IFN-γ EliSpots from pre-SCT to post-SCT in patients who received armed ATC after SCT were significantly higher than those in patients who received SCT alone (P = .02). Serum IL-7, IL-15, Macrophage inflammatory protein (MIP)-1 beta, IP-10, MIP-1α, and Monokine induced by gamma interferone increased within hours after infusion. Polyclonal and specific antibodies were near normal 3 months after SCT. aATC infusions were safe and increased innate and specific antilymphoma cell immunity without impairing antibody recovery after SCT.
doi:10.1016/j.bbmt.2013.03.010
PMCID: PMC3794673  PMID: 23529012
Non-Hodgkin lymphoma; Activated T cells; Bispecific antibody; Autologous stem cell; transplantation
7.  Structure and optical function of amorphous photonic nanostructures from avian feather barbs: a comparative small angle X-ray scattering (SAXS) analysis of 230 bird species 
Non-iridescent structural colours of feathers are a diverse and an important part of the phenotype of many birds. These colours are generally produced by three-dimensional, amorphous (or quasi-ordered) spongy β-keratin and air nanostructures found in the medullary cells of feather barbs. Two main classes of three-dimensional barb nanostructures are known, characterized by a tortuous network of air channels or a close packing of spheroidal air cavities. Using synchrotron small angle X-ray scattering (SAXS) and optical spectrophotometry, we characterized the nanostructure and optical function of 297 distinctly coloured feathers from 230 species belonging to 163 genera in 51 avian families. The SAXS data provided quantitative diagnoses of the channel- and sphere-type nanostructures, and confirmed the presence of a predominant, isotropic length scale of variation in refractive index that produces strong reinforcement of a narrow band of scattered wavelengths. The SAXS structural data identified a new class of rudimentary or weakly nanostructured feathers responsible for slate-grey, and blue-grey structural colours. SAXS structural data provided good predictions of the single-scattering peak of the optical reflectance of the feathers. The SAXS structural measurements of channel- and sphere-type nanostructures are also similar to experimental scattering data from synthetic soft matter systems that self-assemble by phase separation. These results further support the hypothesis that colour-producing protein and air nanostructures in feather barbs are probably self-assembled by arrested phase separation of polymerizing β-keratin from the cytoplasm of medullary cells. Such avian amorphous photonic nanostructures with isotropic optical properties may provide biomimetic inspiration for photonic technology.
doi:10.1098/rsif.2012.0191
PMCID: PMC3427513  PMID: 22572026
biophotonics; organismal structural colours; amorphous nanostructures; non-iridescence; single scattering; self-assembly
8.  Elastic Coupling of Nascent apCAM Adhesions to Flowing Actin Networks 
PLoS ONE  2013;8(9):e73389.
Adhesions are multi-molecular complexes that transmit forces generated by a cell’s acto-myosin networks to external substrates. While the physical properties of some of the individual components of adhesions have been carefully characterized, the mechanics of the coupling between the cytoskeleton and the adhesion site as a whole are just beginning to be revealed. We characterized the mechanics of nascent adhesions mediated by the immunoglobulin-family cell adhesion molecule apCAM, which is known to interact with actin filaments. Using simultaneous visualization of actin flow and quantification of forces transmitted to apCAM-coated beads restrained with an optical trap, we found that adhesions are dynamic structures capable of transmitting a wide range of forces. For forces in the picoNewton scale, the nascent adhesions’ mechanical properties are dominated by an elastic structure which can be reversibly deformed by up to 1 µm. Large reversible deformations rule out an interface between substrate and cytoskeleton that is dominated by a number of stiff molecular springs in parallel, and favor a compliant cross-linked network. Such a compliant structure may increase the lifetime of a nascent adhesion, facilitating signaling and reinforcement.
doi:10.1371/journal.pone.0073389
PMCID: PMC3765355  PMID: 24039928
9.  Giant-cell tumor of bone, anti-RANKL therapy 
BoneKEy Reports  2012;1:149.
Giant-cell tumor of bone (GCTB) is a rare osteolytic tumor of the bone. Although classified as a benign tumor, GCTB is characterized by local aggressiveness and risk of local recurrence. In addition, GTCB can in some cases lead to the development of so-called 'benign' chest metastases. Surgical resection by intralesional curettage with high-speed burring and polymethylmethacrylate cement is the standard treatment for resectable tumors. In cases of metastatic or unresectable disease (when planned surgical procedure is impossible or would result in severe morbidity), medical treatments such as cytotoxic chemotherapy or interferon-α have limited efficacy. Bisphosphonates have been proposed as a therapeutic option to reduce osteoclast activity. In bone, various pathological states may result from an imbalance in the RANK (receptor activator of nuclear factor kappa-B)/RANKL (receptor activator of nuclear factor kappa-B ligand)/OPG (osteoprotegerin) pathway. Involvement of the RANKL pathway in pathogenesis of GCTB was first proposed in 2000. Denosumab is a fully human monoclonal antibody that binds and inhibits RANKL, thereby preventing the activation of the RANK pathway. As it showed the possibility to counteract osteoclast activation in GCTB and prevent the known physiopathological role of RANKL, denosumab has been under evaluation in the clinic as a treatment for GCTB since 2005. Results of a first Phase II trial demonstrate the therapeutic potential of denosumab to inhibit progressive bone destruction and metastatic progression in patients with unsalvageable giant-cell tumor (GCT), and have also provided key insights into the biology of GCT. Denosumab is currently a therapeutic option for patients with unresectable GCTB but its place in the global therapeutic strategy has not yet been defined.
doi:10.1038/bonekey.2012.149
PMCID: PMC3868728  PMID: 24363925
10.  Diagnostic and Therapeutic Challenges in a Liver Transplant Recipient with Central Nervous System Invasive Aspergillosis 
This is a case report of central nervous system (CNS) invasive aspergillosis (IA) in a liver transplant recipient, which illustrates the utility of enzyme-based diagnostic tools for the timely and accurate diagnosis of IA, the treatment challenges and poor outcomes associated with CNS IA in liver transplant recipients.
doi:10.1016/j.diagmicrobio.2012.05.001
PMCID: PMC3396754  PMID: 22676861
11.  Importance of therapeutic patient education in ichthyosis: results of a prospective single reference center study 
Background
Ichthyoses are a heterogeneous group of rare genodermatoses. Patients and their families face difficulties related to daily care and management that may be aggravated by social isolation.
Objectives
To evaluate the impact of therapeutic educational programs in improving the knowledge of ichthyosis patients, and their relatives, about their disease.
Patients and methods
We organized a two sessions-program of “know-how” dedicated to the overall management of ichthyoses. These sessions were conducted based on a tool specifically designed for the study, which addressed our various areas of expertise through a collective game. The participants (patients and their parents and siblings) were divided into groups, and the questions were tailored according to the participants’ age. The program was conceived as a knowledge reinforcement program that took place during a weekend of education and rest, organized away from healthcare structures. Our aim was to facilitate the program in a neutral place to encourage respite care and to ensure the availability of a multidisciplinary healthcare team.
Results
After the reinforcement session, children aged from 6 to 12 years and their families acquired the targeted know-how and social skills.
Conclusion
Benefits of TPE in the management of ichthyoses are the following: (1) the trust between patients their families and the caregivers was strengthened; (2) the context of the program encouraged self-expression, answered questions and provided mutual aid; and (3) the more self-sufficient families could better manage emergencies.
doi:10.1186/1750-1172-8-113
PMCID: PMC3751792  PMID: 23902898
Genodermatoses; Therapeutic patient education; Children; Adults; Ichthyosis; Collective program
12.  Mitochondrial Capture Misleads about Ecological Speciation in the Daphnia pulex Complex 
PLoS ONE  2013;8(7):e69497.
The North American ecological species Daphniapulicaria and Daphniapulex are thought to have diverged from a common ancestor by adaptation to sympatric but ecologically distinct lake and pond habitats respectively. Based on mtDNA relationships, European D. pulicaria is considered a different species only distantly related to its North American counterpart, but both species share a lactate dehydrogenase (Ldh) allele F supposedly involved in lake adaptation in North America, and the same allele is also carried by the related Holarctic Daphniatenebrosa. The correct inference of the species’ ancestral relationships is therefore critical for understanding the origin of their adaptive divergence. Our species tree inferred from unlinked nuclear loci for D. pulicaria and D. pulex resolved the European and North American D. pulicaria as sister clades, and we argue that the discordant mtDNA gene tree is best explained by capture of D. pulex mtDNA by D. pulicaria in North America. The Ldh gene tree shows that F-class alleles in D. pulicaria and D. tenebrosa are due to common descent (as opposed to introgression), with D. tenebrosa alleles paraphyletic with respect to D. pulicaria alleles. That D. tenebrosa still segregates the ancestral and derived amino acids at the two sites distinguishing the pond and lake alleles suggests that D. pulicaria inherited the derived states from the D. tenebrosa ancestry. Our results suggest that some adaptations restricting the gene flow between D. pulicaria and D. pulex might have evolved in response to selection in ancestral environments rather than in the species’ current sympatric habitats. The Arctic (D. tenebrosa) populations are likely to provide important clues about these issues.
doi:10.1371/journal.pone.0069497
PMCID: PMC3711805  PMID: 23869244
13.  Global efficiency of local immunization on complex networks 
Scientific Reports  2013;3:2171.
Epidemics occur in all shapes and forms: infections propagating in our sparse sexual networks, rumours and diseases spreading through our much denser social interactions, or viruses circulating on the Internet. With the advent of large databases and efficient analysis algorithms, these processes can be better predicted and controlled. In this study, we use different characteristics of network organization to identify the influential spreaders in 17 empirical networks of diverse nature using 2 epidemic models. We find that a judicious choice of local measures, based either on the network's connectivity at a microscopic scale or on its community structure at a mesoscopic scale, compares favorably to global measures, such as betweenness centrality, in terms of efficiency, practicality and robustness. We also develop an analytical framework that highlights a transition in the characteristic scale of different epidemic regimes. This allows to decide which local measure should govern immunization in a given scenario.
doi:10.1038/srep02171
PMCID: PMC3707349  PMID: 23842121
14.  ABRF-sPRG 2013 Study: Development and Characterization of a Proteomics Normalization Standard Consisting of 1000 Stable Isotope Labeled Peptides and a Qualitative Stability Study of Peptides from the ABRF-sPRG 2012 Study 
The Proteomics Standards Research Group (sPRG) is reporting the first year progress in a two-year sPRG 2012-2013 study which focuses on the generation of a standard that can be used for interassay, interspecies, and interlaboratory normalization in both label-free and stable isotope label-based quantitative proteomics analysis. The standard has been formulated as two mixtures: 1000 stable isotope 13C/15N-labeled synthetic tryptic peptides alone, and peptides mixed with a tryptic digest from a HEK 293 cell lysate. The sequences of the synthetic peptides were derived from approximately 400 proteins and were conserved across proteomes of the most commonly analyzed species: Homo sapiens, Mus musculus and Rattus norvegicus. The selected peptides represent the full range of hydrophobicities and isoelectric points typical to tryptic peptides from complex proteomic samples. The standard was designed to represent proteins of various concentrations, spanning three orders of magnitude. This year we focused our efforts on selection of appropriate protein and peptide candidates, peptide synthesis, quality assessment and LC-MS evaluation by several sPRG member laboratories. The sPRG study design and initial results of a thorough characterization of the standard using a variety of instrumental configurations and bioinformatics approaches will be presented in this talk.
The sPRG is hopeful that the designed formulation will become a valuable resource in various mass spectrometry-based proteomic applications, including quantitative and differential profiling, as well as general benchmarking (e.g. chromatographic retention time). The sPRG plans to start recruiting study participants in April 2013, complete the study by the end of the year 2013, and present the results at the ABRF 2014 meeting. The sPRG encourages proteomics laboratories to participate in the study and sign in at www.abrf.org/sprg.
The second half of the session will discuss the qualitative stability study performed using purified synthetic peptides containing a variety of modifications selected from the 2012 sPRG ABRF sample. The stability of the selected synthetic peptides was evaluated by the sPRG using different storage conditions over a three-month period. After storage at either at room temperature, +4°C or −80°C for one week, one month, or three months. Quantitative LC-MS/MS analysis was used to monitor the stability and degradation of the peptides, and to determine the effect of modifications and storage conditions on peptide degradation rates. The data presented have been built on the quantitative study that was presented at both the 2012 ABRF and ASMS conferences. All forms of degraded peptides were separated and identified using nano-LC tandem mass spectrometry on a Thermo Scientific Q-Exactive hybrid mass spectrometer. Integrated extracted ion chromatograms were used to measure relative amounts of degradation to identify which pathways are most prevalent during storage.
PMCID: PMC3635292
15.  [No title available] 
The Proteomics Standards Research Group (sPRG) is reporting the first year progress in a two-year sPRG 2012–2013 study which focuses on the generation of a standard that can be used for interassay, interspecies, and interlaboratory normalization in both label-free and stable isotope label-based quantitative proteomics analysis. The standard has been formulated as two mixtures: 1000 stable isotope 13C/15N-labeled synthetic tryptic peptides alone, and peptides mixed with a tryptic digest from a HEK 293 cell lysate. The sequences of the synthetic peptides were derived from approximately 400 proteins and were conserved across proteomes of the most commonly analyzed species: Homo sapiens, Mus musculus and Rattus norvegicus. The selected peptides represent the full range of hydrophobicities and isoelectric points typical to tryptic peptides from complex proteomic samples. The standard was designed to represent proteins of various concentrations, spanning three orders of magnitude. This year we focused our efforts on selection of appropriate protein and peptide candidates, peptide synthesis, quality assessment and LC-MS evaluation by several sPRG member laboratories. The sPRG study design and initial results of a thorough characterization of the standard using a variety of instrumental configurations and bioinformatics approaches will be presented in this talk.
The sPRG is hopeful that the designed formulation will become a valuable resource in various mass spectrometry-based proteomic applications, including quantitative and differential profiling, as well as general benchmarking (e.g. chromatographic retention time). The sPRG plans to start recruiting study participants in April 2013, complete the study by the end of the year 2013, and present the results at the ABRF 2014 meeting. The sPRG encourages proteomics laboratories to participate in the study and sign in at www.abrf.org/sprg.
The second half of the session will discuss the qualitative stability study performed using purified synthetic peptides containing a variety of modifications selected from the 2012 sPRG ABRF sample. The stability of the selected synthetic peptides was evaluated by the sPRG using different storage conditions over a three-month period. After storage at either at room temperature, +4°C or -80°C for one week, one month, or three months. Quantitative LC-MS/MS analysis was used to monitor the stability and degradation of the peptides, and to determine the effect of modifications and storage conditions on peptide degradation rates. The data presented have been built on the quantitative study that was presented at both the 2012 ABRF and ASMS conferences. All forms of degraded peptides were separated and identified using nano-LC tandem mass spectrometry on a Thermo Scientific Q-Exactive hybrid mass spectrometer. Integrated extracted ion chromatograms were used to measure relative amounts of degradation to identify which pathways are most prevalent during storage.
PMCID: PMC3635369
16.  Optimizing Treatment Regimes to Hinder Antiviral Resistance in Influenza across Time Scales 
PLoS ONE  2013;8(3):e59529.
The large-scale use of antivirals during influenza pandemics poses a significant selection pressure for drug-resistant pathogens to emerge and spread in a population. This requires treatment strategies to minimize total infections as well as the emergence of resistance. Here we propose a mathematical model in which individuals infected with wild-type influenza, if treated, can develop de novo resistance and further spread the resistant pathogen. Our main purpose is to explore the impact of two important factors influencing treatment effectiveness: i) the relative transmissibility of the drug-resistant strain to wild-type, and ii) the frequency of de novo resistance. For the endemic scenario, we find a condition between these two parameters that indicates whether treatment regimes will be most beneficial at intermediate or more extreme values (e.g., the fraction of infected that are treated). Moreover, we present analytical expressions for effective treatment regimes and provide evidence of its applicability across a range of modeling scenarios: endemic behavior with deterministic homogeneous mixing, and single-epidemic behavior with deterministic homogeneous mixing and stochastic heterogeneous mixing. Therefore, our results provide insights for the control of drug-resistance in influenza across time scales.
doi:10.1371/journal.pone.0059529
PMCID: PMC3612110  PMID: 23555694
17.  Integrated Proteomics and Metabolomics of Arabidopsis Acclimation to Gene-Dosage Dependent Perturbation of Isopropylmalate Dehydrogenases 
PLoS ONE  2013;8(3):e57118.
Maintaining metabolic homeostasis is critical for plant growth and development. Here we report proteome and metabolome changes when the metabolic homeostasis is perturbed due to gene-dosage dependent mutation of Arabidopsis isopropylmalate dehydrogenases (IPMDHs). By integrating complementary quantitative proteomics and metabolomics approaches, we discovered that gradual ablation of the oxidative decarboxylation step in leucine biosynthesis caused imbalance of amino acid homeostasis, redox changes and oxidative stress, increased protein synthesis, as well as a decline in photosynthesis, which led to rearrangement of central metabolism and growth retardation. Disruption of IPMDHs involved in aliphatic glucosinolate biosynthesis led to synchronized increase of both upstream and downstream biosynthetic enzymes, and concomitant repression of the degradation pathway, indicating metabolic regulatory mechanisms in controlling glucosinolate biosynthesis.
doi:10.1371/journal.pone.0057118
PMCID: PMC3606340  PMID: 23533573
18.  Family burden in inherited ichthyosis: creation of a specific questionnaire 
Background
The concept of individual burden, associated with disease, has been introduced recently to determine the “disability” caused by the pathology in the broadest sense of the word (psychological, social, economic, physical). Inherited ichthyosis belong to a large heterogeneous group of Mendelian Disorders of Cornification. Skin symptoms have a major impact on patients’ Quality of Life but little is known about the burden of the disease on the families of patients.
Objectives
To develop and validate a specific burden questionnaire for the families of patients affected by ichthyosis.
Methods
Two steps were required. First, the creation of the questionnaire which followed a strict methodological process involving a multidisciplinary team and families. Secondarily, the validation of the questionnaire, including the assessment of its reliability, external validity, reproducibility and sensitivity, was carried out on a population of patients affected by autosomal recessive congenital ichthyosis. A population of parents of patients affected by ichthyosis was enrolled to answer the new questionnaire in association with the Short Form Q12 questionnaire (SF-12) and a clinical severity score was filled for each patient.
Results
Ninety four families were interviewed to construct the verbatim in order to create the questionnaire and a cognitive debriefing was realized. The concept of burden could be structured around five components: “economic”, “daily life”, “familial and personal relationship”, “work”, and “psychological impact”. As a result, “Family Burden Ichthyosis” (FBI) reproducible questionnaire of 25 items was created.
Forty two questionnaires were analyzable for psychometric validation. Reliability (Cronbach’s alpha coefficient = 0.89), reflected the good homogeneity of the questionnaire. The correlation between mental dimensions of the SF-12 and the FBI questionnaire was statistically significant which confirmed the external validity. The mean FBI score was 71.7 ± 18.8 and a significant difference in the FBI score was shown between two groups of severity underlining a good sensitivity of the questionnaire.
Conclusions
The internal and external validity of the “FBI” questionnaire was confirmed and it is correlated to the severity of ichtyosis. Ichthyoses, and other chronic pathologies, are difficult to assess by clinical or Quality of Life aspects alone as their impact can be multidimensional. “FBI” takes them all into consideration in order to explain every angle of the handicap generated.
doi:10.1186/1750-1172-8-28
PMCID: PMC3599730  PMID: 23414570
Global burden disease; Quality of life; Ichthyosis; Burden questionnaire
19.  The Timing and Targeting of Treatment in Influenza Pandemics Influences the Emergence of Resistance in Structured Populations 
PLoS Computational Biology  2013;9(2):e1002912.
Antiviral resistance in influenza is rampant and has the possibility of causing major morbidity and mortality. Previous models have identified treatment regimes to minimize total infections and keep resistance low. However, the bulk of these studies have ignored stochasticity and heterogeneous contact structures. Here we develop a network model of influenza transmission with treatment and resistance, and present both standard mean-field approximations as well as simulated dynamics. We find differences in the final epidemic sizes for identical transmission parameters (bistability) leading to different optimal treatment timing depending on the number initially infected. We also find, contrary to previous results, that treatment targeted by number of contacts per individual (node degree) gives rise to more resistance at lower levels of treatment than non-targeted treatment. Finally we highlight important differences between the two methods of analysis (mean-field versus stochastic simulations), and show where traditional mean-field approximations fail. Our results have important implications not only for the timing and distribution of influenza chemotherapy, but also for mathematical epidemiological modeling in general. Antiviral resistance in influenza may carry large consequences for pandemic mitigation efforts, and models ignoring contact heterogeneity and stochasticity may provide misleading policy recommendations.
Author Summary
Resistance of influenza to common antiviral agents carries the possibility of causing large morbidity and mortality through failure of treatment and should be taken into account when planning public health interventions focused on stopping transmission. Here we present a mathematical model of influenza transmission which incorporates heterogeneous contact structure and stochastic transmission events. We find scenarios when treatment either induces large levels of resistance or no resistance at identical values of transmission rates depending on the number initially infected. We also find, contrary to previous results, that targeted treatment causes more resistance at lower treatment levels than non-targeted treatment. Our results have important implications for the timing and distribution of antivirals in epidemics and highlight important differences in how transmission is modeled and where assumptions made in previous models cause them to lead to erroneous conclusions.
doi:10.1371/journal.pcbi.1002912
PMCID: PMC3567146  PMID: 23408880
20.  Evolution of a transposon in Daphnia hybrid genomes 
Mobile DNA  2013;4:7.
Background
Transposable elements play a major role in genome evolution. Their capacity to move and/or multiply in the genome of their host may have profound impacts on phenotypes, and may have dramatic consequences on genome structure. Hybrid and polyploid clones have arisen multiple times in the Daphnia pulex complex and are thought to reproduce by obligate parthenogenesis. Our study examines the evolution of a DNA transposable element named Pokey in the D. pulex complex.
Results
Portions of Pokey elements inserted in the 28S rRNA genes from various Daphnia hybrids (diploids and polyploids) were sequenced and compared to sequences from a previous study to understand the evolutionary history of the elements. Pokey sequences show a complex phylogenetic pattern. We found evidence of recombination events in numerous Pokey alleles from diploid and polyploid hybrids and also from non-hybrid diploids. The recombination rate in Pokey elements is comparable to recombination rates previously estimated for 28S rRNA genes in the congener, Daphnia obtusa. Some recombinant Pokey alleles were encountered in Daphnia isolates from multiple locations and habitats.
Conclusions
Phylogenetic and recombination analyses showed that recombination is a major force that shapes Pokey evolution. Based on Pokey phylogenies, reticulation has played and still plays an important role in shaping the diversity of the D. pulex complex. Horizontal transfer of Pokey seems to be rare and hybrids often possess Pokey elements derived from recombination among alleles encountered in the putative parental species. The insertion of Pokey in hotspots of recombination may have important impacts on the diversity and fitness of this transposable element.
doi:10.1186/1759-8753-4-7
PMCID: PMC3575242  PMID: 23384095
Daphnia pulex; Transposable element; Pokey; Hybrids; Recombination
21.  Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration 
Cell  2012;148(1-2):175-188.
SUMMARY
Little is known about how neutrophils and other cells establish a single zone of actin assembly during migration. A widespread assumption is that the leading edge prevents formation of additional fronts by generating long-range diffusible inhibitors or by sequestering essential polarity components. We use morphological perturbations, cell severing experiments, and computational simulations to show that diffusion-based mechanisms are not sufficient for long-range inhibition by the pseudopod. Instead, plasma membrane tension could serve as a long-range inhibitor in neutrophils. We find that membrane tension doubles during leading edge protrusion, and increasing tension is sufficient for long-range inhibition of actin assembly and Rac activation. Furthermore, reducing membrane tension causes uniform actin assembly. We suggest that tension, rather than diffusible molecules generated or sequestered at the leading edge, is the dominant source of long-range inhibition that constrains the spread of the existing front and prevents the formation of secondary fronts.
doi:10.1016/j.cell.2011.10.050
PMCID: PMC3308728  PMID: 22265410
22.  Pazopanib for the treatment of soft-tissue sarcoma 
Pazopanib is a multikinase inhibitor which potently inhibits the activity of major receptor tyrosine kinases, including vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, platelet-derived growth factor receptor-a, platelet-derived growth factor receptor-a, and c-Kit. Approved by the Food and Drug Administration in 2009 in the United States for the treatment of metastatic renal cell carcinoma, pazopanib has been tested in advanced or metastatic soft-tissue sarcoma. Unlike other tyrosine kinase inhibitors, a statistically significant efficacy in phase II but also in randomized phase III studies has been shown. In comparison with sunitinib or sorafenib, pazopanib has a similar toxicity profile and is generally well tolerated. This review details the development of this new therapeutic class in the treatment of metastatic soft-tissue sarcomas.
doi:10.2147/CPAA.S33195
PMCID: PMC3508654  PMID: 23204874
soft-tissue sarcoma; pazopanib; tyrosine kinase inhibitor
23.  Smoke Extracts and Nicotine, but not Tobacco Extracts, Potentiate Firing and Burst Activity of Ventral Tegmental Area Dopaminergic Neurons in Mice 
Neuropsychopharmacology  2011;36(11):2244-2257.
Nicotine prominently mediates the behavioral effects of tobacco consumption, either through smoking or when taking tobacco by snuff or chew. However, many studies question the exclusive role of nicotine in these effects. The use of preparations containing all the components of tobacco, such as tobacco and smoke extracts, may be more suitable than nicotine alone to investigate the behavioral effects of smoking and tobacco intake. In the present study, the electrophysiological effects of tobacco and smoke on ventral tegmental area dopaminergic (DA) neurons were examined in vivo in anesthetized wild-type (WT), β2-nicotinic acetylcholine receptor (nAChR) knockout (β2−/−), α4−/−, and α6−/− mice and compared with those of nicotine alone. In WT mice, smoke and nicotine had similar potentiating effects on DA cell activity, but the action of tobacco on neuronal firing was weak and often inhibitory. In particular, nicotine triggered strong bursting activity, whereas no bursting activity was observed after tobacco extract (ToE) administration. In β2−/− mice, nicotine or extract elicited no modification of the firing patterns of DA cells, indicating that extract acts predominantly through nAChRs. The differences between DA cell activation profiles induced by tobacco and nicotine alone observed in WT persisted in α6−/− mice but not in α4−/− mice. These results would suggest that tobacco has lower addiction-generating properties compared with either nicotine alone or smoke. The weak activation and prominent inhibition obtained with ToEs suggest that tobacco contains compounds that counteract some of the activating effects of nicotine and promote inhibition on DA cell acting through α4β2*-nAChRs. The nature of these compounds remains to be elucidated. It nevertheless confirms that nicotine is the main substance involved in the tobacco addiction-related activation of mesolimbic DA neurons.
doi:10.1038/npp.2011.112
PMCID: PMC3176561  PMID: 21716264
nicotine; VTA; dopaminergic cell; tobacco addiction; in vivo; nicotinic receptor; addiction & substance abuse; dopamine; neurophysiology; neuropharmacology; nicotinic receptor; smoke; tobacco; nicotine; ventral tegmental area
24.  Human Papillomavirus (HPV) DNA Triage of Women with Atypical Squamous Cells of Undetermined Significance with cobas 4800 HPV and Hybrid Capture 2 Tests for Detection of High-Grade Lesions of the Uterine Cervix 
Journal of Clinical Microbiology  2012;50(4):1240-1244.
The triage of women with high-risk (HR) human papillomavirus (HPV)-positive smears for atypical squamous cells of undetermined significance (ASC-US) to colposcopy is now an integrated option in clinical guidelines. The performance of cobas 4800 HPV and that of Hybrid Capture 2 (HC2) for HR HPV DNA detection in cervical samples in PreservCyt were compared in 396 women referred to colposcopy for ASC-US. Of these, 316 did not have cervical intraepithelial neoplasia (CIN), 47 had CIN1, 29 had CIN2 or CIN3 (CIN2+), and 4 had CIN of unknown grade. HR HPV was detected in 129 (32.6%) and 149 (37.6%) samples with HC2 and cobas 4800 HPV, respectively (P = 0.15). The clinical sensitivities and specificities for detecting CIN2+ were 89.7% (95% confidence interval [CI], 72.8 to 97.2%) and 66.7% (95% CI, 61.7 to 71.3%) with cobas 4800 HPV and 93.1% (95% CI, 77.0 to 99.2%) and 72.2% (95% CI 67.4 to 76.5%) with HC2. The performance of cobas 4800 HPV was similar to that of HC2 for identifying women with ASC-US who would benefit the most from colposcopy.
doi:10.1128/JCM.06656-11
PMCID: PMC3318562  PMID: 22301023
25.  PHYMYCO-DB: A Curated Database for Analyses of Fungal Diversity and Evolution 
PLoS ONE  2012;7(9):e43117.
Background
In environmental sequencing studies, fungi can be identified based on nucleic acid sequences, using either highly variable sequences as species barcodes or conserved sequences containing a high-quality phylogenetic signal. For the latter, identification relies on phylogenetic analyses and the adoption of the phylogenetic species concept.
Such analysis requires that the reference sequences are well identified and deposited in public-access databases. However, many entries in the public sequence databases are problematic in terms of quality and reliability and these data require screening to ensure correct phylogenetic interpretation.
Methods and Principal Findings
To facilitate phylogenetic inferences and phylogenetic assignment, we introduce a fungal sequence database. The database PHYMYCO-DB comprises fungal sequences from GenBank that have been filtered to satisfy stringent sequence quality criteria. For the first release, two widely used molecular taxonomic markers were chosen: the nuclear SSU rRNA and EF1-α gene sequences. Following the automatic extraction and filtration, a manual curation is performed to remove problematic sequences while preserving relevant sequences useful for phylogenetic studies. As a result of curation, ∼20% of the automatically filtered sequences have been removed from the database. To demonstrate how PHYMYCO-DB can be employed, we test a set of environmental Chytridiomycota sequences obtained from deep sea samples.
Conclusion
PHYMYCO-DB offers the tools necessary to: (i) extract high quality fungal sequences for each of the 5 fungal phyla, at all taxonomic levels, (ii) extract already performed alignments, to act as ‘reference alignments’, (iii) launch alignments of personal sequences along with stored data. A total of 9120 SSU rRNA and 672 EF1-α high-quality fungal sequences are now available.
The PHYMYCO-DB is accessible through the URL http://phymycodb.genouest.org/.
doi:10.1371/journal.pone.0043117
PMCID: PMC3441585  PMID: 23028445

Results 1-25 (124)