Towards identifying the dynamic cellular patterns underlying early Arabidopsis floral development

A major challenge in developmental biology is to understand how multicellular tissues are organised into complex shapes. The various genetic, hormonal and mechanical events that drive morphogenesis must act by altering the properties of groups of cells in a coordinated manner through time and space. To gain a clear understanding of these events, we generate digital reconstructions of growing Arabidopsis owers, and use these to precisely quantify cellular properties during the early stages of ower development. Our goal is to then analyse these data with the appropriate mathematical methodology, in order to determine precisely which cellular properties (and in what measure) best characterises the emerging differentiation states that are essential to morphogenesis. We propose to identify and characterize cellular patterns based on measured cellular properties, linking their spatio-temporal behaviour to the observed changes induced by organogenesis. Our experiments begin with imaging the ower from multiple angles. These images are then fused to generate a high-resolution reconstruction, which is then segmented. By imaging the same ower bud over several days and by identifying cell lineages between time points, we generate 4-D data on the development of the ower. From these data, several spatial and spatio-temporal cell properties like volume, volumetric growth or strain were extracted. We have adopted a graph- based approach to organise the data. The 3D tissue observed at successive dates/time points is transformed into a graph whose vertices represent cells and edges represent either cell spatial neighborhood or temporal relations between cells based on lineage. This graph thus contains all the spatio-temporal information about the ower under study. While developing the methods to analyse these growing tissues, we have opted to initially simplify the task in two ways, by restricting the study to the earliest morphogenetic events in the ower (stages 1-3), and by examining only the outermost cell layer, the L1. This rich spatio-temporal information is used in two ways to study the events underlying ower development. Firstly, we applied a supervised approach to explore the properties of specific groups of cells, identified either by morphology or by gene expression. Secondly, we applied an unsupervised approach to identify cellular patterns. More specifically, a clustering method was applied to all the cells of one (or several) observed tissue sequence in order to identify homogeneous regions corresponding to specific cell behaviours. One important long-term goal is to determine how these cellular patterns diverge in mutants presenting a different phenotype, and to identify shifts or changes in properties within these groups or the presence or absence of certain groups. I will detail my approach and present preliminary results of my analyses. (Résumé d'auteur

Sequential pattern mining for discovering gene interactions and their contextual information from biomedical texts

International audienceBackgroundDiscovering gene interactions and their characterizations from biological text collections is a crucial issue in bioinformatics. Indeed, text collections are large and it is very difficult for biologists to fully take benefit from this amount of knowledge. Natural Language Processing (NLP) methods have been applied to extract background knowledge from biomedical texts. Some of existing NLP approaches are based on handcrafted rules and thus are time consuming and often devoted to a specific corpus. Machine learning based NLP methods, give good results but generate outcomes that are not really understandable by a user.ResultsWe take advantage of an hybridization of data mining and natural language processing to propose an original symbolic method to automatically produce patterns conveying gene interactions and their characterizations. Therefore, our method not only allows gene interactions but also semantics information on the extracted interactions (e.g., modalities, biological contexts, interaction types) to be detected. Only limited resource is required: the text collection that is used as a training corpus. Our approach gives results comparable to the results given by state-of-the-art methods and is even better for the gene interaction detection in AIMed.ConclusionsExperiments show how our approach enables to discover interactions and their characterizations. To the best of our knowledge, there is few methods that automatically extract the interactions and also associated semantics information. The extracted gene interactions from PubMed are available through a simple web interface at https://bingotexte.greyc.fr/ webcite. The software is available at https://bingo2.greyc.fr/?q=node/22 webcite

Short-Term cost impact of compliance with clinical practice guidelines for initial sarcoma treatment

Background: The impact of compliance to clinical practice guidelines (CPG) on outcomes and/or costs of care has not been completely clarified.Objective: To estimate relationships between medical expenditures and compliance to CPG for initial sarcoma treatment.Research design: Selected cohorts of patients diagnosed with sarcoma in 2005 and 2006, and treated at the University hospital and/or the cancer centre of the Rhône-Alpes region, France (n=90). Main outcome measurements were: patient characteristics, compliance with CPG, health outcomes, and costs. Data were mainly extracted from patient records. The logarithm of treatment costs was modelled using linear and Tobit regressions.Results: Rates of compliance with CPG were 86%, 66%, 88%, 89%, and 95% for initial diagnosis, primary surgical excision, wide surgical excision, chemotherapy, and radiotherapy, respectively. Total average costs reached €24,439, with €1,784, €11,225, €10,360, and €1,016 for diagnosis, surgery (primary and wide surgical excisions), chemotherapy, and radiotherapy, respectively. Compliance of diagnosis with CPG decreased the cost of diagnosis, whereas compliance of primary surgical excision increased the cost of chemotherapy. Compliance of chemotherapy with CPG decreased the cost of radiotherapy.Conclusion: Since chemotherapy is one of the major cost drivers, these results support that compliance with guidelines increases medical care expenditures in short term.Oncology; Sarcoma; Cost; Clinical guidelines; Efficacy; Medical Practices; Government Policy; Regulation; Public Health

Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria

Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts’ recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally

Diagnosis of Non-Celiac Gluten Sensitivity (NCGS)

Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts’ recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally

Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease

Celiac disease (CD) is an enteropathy resulting from an abnormal immune response to gluten-derived peptides in genetically susceptible individuals. This immune response is initiated by intestinal transport of intact peptide 31-49 (p31-49) and 33-mer gliadin peptides through an unknown mechanism. We show that the transferrin receptor CD71 is responsible for apical to basal retrotranscytosis of gliadin peptides, a process during which p31-49 and 33-mer peptides are protected from degradation. In patients with active CD, CD71 is overexpressed in the intestinal epithelium and colocalizes with immunoglobulin (Ig) A. Intestinal transport of intact p31-49 and 33-mer peptides was blocked by polymeric and secretory IgA (SIgA) and by soluble CD71 receptors, pointing to a role of SIgA–gliadin complexes in this abnormal intestinal transport. This retrotranscytosis of SIgA–gliadin complexes may promote the entry of harmful gliadin peptides into the intestinal mucosa, thereby triggering an immune response and perpetuating intestinal inflammation. Our findings strongly implicate CD71 in the pathogenesis of CD

Variability of extracellular vesicle release during storage of red blood cell concentrates is associated with differential membrane alterations, including loss of cholesterol-enriched domains

Transfusion of red blood cell concentrates is the most common medical procedure to treat anaemia. However, their storage is associated with development of storage lesions, including the release of extracellular vesicles. These vesicles affect in vivo viability and functionality of transfused red blood cells and appear responsible for adverse post-transfusional complications. However, the biogenesis and release mechanisms are not fully understood. We here addressed this issue by comparing the kinetics and extents of extracellular vesicle release as well as red blood cell metabolic, oxidative and membrane alterations upon storage in 38 concentrates. We showed that extracellular vesicle abundance increased exponentially during storage. The 38 concentrates contained on average 7 × 1012 extracellular vesicles at 6 weeks (w) but displayed a ∼40-fold variability. These concentrates were subsequently classified into 3 cohorts based on their vesiculation rate. The variability in extracellular vesicle release was not associated with a differential red blood cell ATP content or with increased oxidative stress (in the form of reactive oxygen species, methaemoglobin and band3 integrity) but rather with red blood cell membrane modifications, i.e., cytoskeleton membrane occupancy, lateral heterogeneity in lipid domains and transversal asymmetry. Indeed, no changes were noticed in the low vesiculation group until 6w while the medium and the high vesiculation groups exhibited a decrease in spectrin membrane occupancy between 3 and 6w and an increase of sphingomyelin-enriched domain abundance from 5w and of phosphatidylserine surface exposure from 8w. Moreover, each vesiculation group showed a decrease of cholesterol-enriched domains associated with a cholesterol content increase in extracellular vesicles but at different storage time points. This observation suggested that cholesterol-enriched domains could represent a starting point for vesiculation. Altogether, our data reveal for the first time that the differential extent of extracellular vesicle release in red blood cell concentrates did not simply result from preparation method, storage conditions or technical issues but was linked to membrane alterations

Feline low-grade alimentary lymphoma: an emerging entity and a potential animal model for human disease

BackgroundLow-grade alimentary lymphoma (LGAL) is characterised by the infiltration of neoplastic T-lymphocytes, typically in the small intestine. The incidence of LGAL has increased over the last ten years and it is now the most frequent digestive neoplasia in cats and comprises 60 to 75% of gastrointestinal lymphoma cases. Given that LGAL shares common clinical, paraclinical and ultrasonographic features with inflammatory bowel diseases, establishing a diagnosis is challenging. A review was designed to summarise current knowledge of the pathogenesis, diagnosis, prognosis and treatment of feline LGAL. Electronic searches of PubMed and Science Direct were carried out without date or language restrictions.ResultsA total of 176 peer-reviewed documents were identified and most of which were published in the last twenty years. 130 studies were found from the veterinary literature and 46 from the human medicine literature. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. The pathophysiology of feline LGAL still needs to be elucidated, not least the putative roles of infectious agents, environmental factors as well as genetic events. The most common therapeutic strategy is combination treatment with prednisolone and chlorambucil, and prolonged remission can often be achieved. Developments in immunohistochemical analysis and clonality testing have improved the confidence of clinicians in obtaining a correct diagnosis between LGAL and IBD. The condition shares similarities with some diseases in humans, especially human indolent T-cell lymphoproliferative disorder of the gastrointestinal tract.ConclusionsThe pathophysiology of feline LGAL still needs to be elucidated and prospective studies as well as standardisation of therapeutic strategies are needed. A combination of conventional histopathology and immunohistochemistry remains the current gold-standard test, but clinicians should be cautious about reclassifying cats previously diagnosed with IBD to lymphoma on the basis of clonality testing. Importantly, feline LGAL could be considered to be a potential animal model for indolent digestive T-cell lymphoproliferative disorder, a rare condition in human medicine