Redirecting splicing with bifunctional oligonucleotides

Abstract: Ectopic modulators of alternative splicing are important tools to study the function of splice variants and for correcting mis-splicing events that cause human diseases. Such modulators can be bifunctional oligonucleotides made of an antisense portion that determines target specificity, and a nonhybridizing tail that recruits proteins or RNA/protein complexes that affect splice site selection (TOSS and TOES, respectively, for targeted oligonucleotide silencer of splicing and targeted oligonucleotide enhancer of splicing). The use of TOSS and TOES has been restricted to a handful of targets. To generalize the applicability and demonstrate the robustness of TOSS, we have tested this approach on more than 50 alternative splicing events. Moreover, we have developed an algorithm that can design active TOSS with a success rate of 80%. To produce bifunctional oligonucleotides capable of stimulating splicing, we built on the observation that binding sites for TDP-43 can stimulate splicing and improve U1 snRNP binding when inserted downstream from 50 splice sites. A TOES designed to recruit TDP-43 improved exon 7 inclusion in SMN2. Overall, our study shows that bifunctional oligonucleotides can redirect splicing on a variety of genes, justifying their inclusion in the molecular arsenal that aims to alter the production of splice variants

Developing common protocols to measure tundra herbivory across spatial scales

Understanding and predicting large-scale ecological responses to global environmental change requires comparative studies across geographic scales with coordinated efforts and standardized methodologies. We designed, applied and assessed standardized protocols to measure tundra herbivory at three spatial scales: plot, site (habitat), and study area (landscape). The plot and site-level protocols were tested in the field during summers 2014-2015 at eleven sites, nine of them comprising warming experimental plots included in the International Tundra Experiment (ITEX). The study area protocols were assessed during 2014-2018 at 24 study areas across the Arctic. Our protocols provide comparable and easy-to-implement methods for assessing the intensity of invertebrate herbivory within ITEX plots and for characterizing vertebrate herbivore communities at larger spatial scales. We discuss methodological constraints and make recommendations for how these protocols can be used and how sampling effort can be optimized to obtain comparable estimates of herbivory, both at ITEX sites and at large landscape scales. The application of these protocols across the tundra biome will allow characterizing and comparing herbivore communities across tundra sites and at ecologically relevant spatial scales, providing an important step towards a better understanding of tundra ecosystem responses to large-scale environmental change.CGB was funded by the Estonian Research Council (grant IUT 20-28), and the European Regional Development Fund (Centre of Excellence EcolChange). JDMS was supported by the Research Council of Norway (262064). OG and LB were supported by the French Polar Institute (program “1036 Interactions”) and PRC CNRS Russie 396 (program “ICCVAT”). DSH, NL, MAG, JB and JDR were supported by the Natural Sciences and Engineering Research Council (Canada). NL, MAG, JB and JDR were supported by the Polar Continental Shelf Program. NL was supported by the Canada Research Chair program and the Canada Foundation for Innovation. NL and JB were supported by Environment Canada and Polar Knowledge Canada. NL and MAG were supported by the Government of Nunavut, the Igloolik Community, and Université de Moncton. NL, MAG and JB were supported by the Northern Scientific Training Program. JMA was funded by Carl Tryggers stiftelse för vetenskaplig forskning and Qatar Petroleum (QUEX-CAS-QP-RD-18_19). IHM-S was funded by the UK Natural Environmental Research Council Shrub Tundra (NE/M016323/1) grant. ISJ was funded by the University of Iceland Research Fund. Fieldwork in Yamal peninsula (Erkuta, Sabetta and Belyi) for DE, NS and AS was supported by the Russian Foundation for Basic Research (No: 18-05-60261 and No: 18-54-15013), Fram Centre project YaES (No: 362259), the Russian Center of Development of the Arctic, and the “Yamal-LNG” company. Fieldwork in Utqiaġvik was supported by the U.S. Fish and Wildlife Service. Fieldwork in Svalbard was supported by the Norwegian Research Council (AFG No: 246080/E10), the Norwegian Polar Institute, Climate-ecological Observatory for Arctic Tundra – COAT, the Svalbard Environmental protection fund (project number 15/20), and the University Centre in Svalbard (UNIS) and the AB-338/AB-838 students of 2018. Sampling at Billefjorden was supported by GACR 17- 20839S

Sillery et l'industrie du bois au XIXe siècle

Notre thèse réalise un tour d’horizon des activités matérielles et communautaires qui se déroulèrent dans la municipalité de Sillery au XIXe siècle. Intégrée au contexte mercantile de cette époque de l’histoire du Québec en tant que colonie britannique, Sillery connut, surtout entre 1810 et 1880, une prospérité et un accroissement de population dûs aux activités reliées à l’industrie du bois. L’implantation de cette structure industrielle y créa un milieu ouvrier et un milieu patronal distincts, qui nous semblèrent intéressants à étudier. Nous attachant d’abord à situer géographiquement la municipalité et la paroisse, nous mimes l’accent sur la relation entre la topographie et les différences de niveau social. Un aperçu de la situation historique nous permit ensuite de décrire l’évolution de cette municipalité au cours du XIXe ciècle. Enfin, nous fîmes un examen des langues parlées et des religions pratiquées. Nous connaissions alors mieux les lieux et les hommes. La première partie du corps du travail, les activités matérielles, étudie ensuite les deux industries majeures de l’époque: le flottage du bois dans les anses jusqu’à son expédition et la construction de navires. En premier chapitre, le flottage du bois se divise en une description du chantier, suivie d’un compte-rendu des étapes du flottage, des métiers, des rivalités au travail et finalement, des profils de quelques grands marchands de bois. Le second chapitre, intitulé la construction des navires, décrit les étapes de leur construction, les matériaux et les modèles fabriqués, les métiers. Puis il esquisse le portrait de quelques grands constructeurs. Le deuxième partie concerne les activités communautaires. Nous observons d’abord la vie domestique à travers l’habitation et les biens de consommation, tels que la nourriture, les transports, les vêtements les services. Le second chapitre propose un examen de la vie scolaire et municipale. Puis, troisièmement, les activités religieuses et de loisir (fêtes, cérémonies, jeux, sports...) viennent compléter cette étude de la vie collective. L’examen des activités communautaires démontre l’existence de deux groupes sociaux formés par l’industrialisation: les marchands-bourgeois et les ouvriers-prolétaires. En conclusion, les résultats de notre recherche révèlent le vrai visage de la société de Sillery au XIXe siècle: celui de deux communautés séparées, non pas par la nationalité ou la langue parlée, mais par un fossé économique infranchissable

L'incidence des politiques culturelles sur le développement des musées nationaux Canada-Québec depuis 1950

Cette thèse tente de mettre au point certains instruments de mesure qui détermineront l’incidence de la dimension identitaire des politiques culturelles sur le développement des musées nationaux au Canada et au Québec depuis 1950. Nous avons démontré que la promotion de l’identité collective est la motivation principale d’un État face à l’adoption d’une politique culturelle, et que lorsque deux gouvernements nationaux mettent de l’avant des composantes identitaires divergentes sur un territoire juridique partagé il en résulte des zones conflictuelles. Nous avons développé en première partie des définitions théoriques et un schéma conceptuel des politiques culturelles et muséales. En deuxième et troisième parties, nous analysons le développement des politiques culturelles et des musées nationaux canadien et québécois. L’incidence de la dimension identitaire des politiques culturelles s’est avérée mesurable pour les deux cas étudiés. Le Musée canadien des civilisations s’apparente au musée emblématique, avec une approche spatiotemporelle périodisée et une vision multiculturelle linéaire. Le Musée de la civilisation utilise une approche thématique circulaire et propose une image transculturelle de l’identité québécoise

Benefits of improving processes in cancer care with a care pathway-based electronic medical record

International audiencePurposeWe analyzed the intermediate and longer term changes in patients’ waiting times following the implementation of an electronic medical record (EMR) dedicated to ambulatory treatment in both medical and radiation oncology.Methods and materialsA pre-post study design was developed to assess improvements in patients’ waiting times, defined as the number of days between key steps in patient management preceding the first treatment. The postperiod began 1 year after the EMR go-live to allow for a preliminary period of adjustment to the new EMR. The EMR under study was closely integrated into the clinicians’ workflow, being designed as a care pathway information system to provide real-time support to the coordination of the entirety of care processes involving all the care personnel.ResultsThe large majority of the waiting-time indicators decreased over time, with decreases ranging from 2 to 28 days. However, an important time lag was necessary to see an improvement, to the extent that better access was only observed in the final months of the postperiod.ConclusionThe study highlights the potential to design EMR applications that capitalize on tight workflow integration, both in medical and radiation oncology, to deal with the fundamentally collaborative nature of cancer care delivery