NCube/papyrus huggingface dataset:
Rôle de la somatostatine dans la plasticité synaptique des interneurones somatostatinergiques de l’hippocampe

The CA1 region of the hippocampus includes a population of GABAergic interneurons expressing somatostatin (SOM-INs). This type of interneurons displays a long-term potentiation (LTP) dependant on type 1a metabotropic glutamate receptors (mGluR1a) at their excitatory synapses from pyramidal cells (PC). It was recently demonstrated that mGluR1a dependent LTP can be induce by contextual fear learning showing an important role of this LTP in learning and memory. However, the implication of the peptide somatostatin (SST) in this LTP remains unknown. In the present study, the role of SST in mGluR1 dependent LTP and the effect of exogenous somatostatin-14 (SST-14) onto excitatory synapses of SOM-INs were investigated. To do this, transgenic mice expressing enhanced yellow fluorescent protein (eYFP) under the control of the promoter of SST were used. Patch clamp recordings and pharmacological approaches were used with these mice. Results suggested that application of exogenous SST-14 induces a LTP through type 1-5 somatostatin receptors (SST1-5) of excitatory synapses of SOM-INs but does not affect synapses of PC or parvalbumin-expressing interneurons (PV-INs). This LTP induced by SST-14 was independent of N-methyl-D-aspartate receptor (NMDAR) and mGluR1a, activity dependent, and prevented by blocking GABAA receptors. Furthermore, mGluR1a dependent LTP was prevented by inhibition of SST1-5 and by depletion of SST by cysteamine treatment, suggesting a role of endogenous SST in LTP. Our results indicate that endogenous SST may contribute to Hebbian LTP at excitatory synapses by controlling GABAA inhibition. SST would then have a role in regulating SOM-INs LTP that may be important for hippocampus dependent memory processes.

Keyphrases: Somatotropin-release inhibitory factor –SRIF, Patch clamp, GABAergic interneurons, Hebbian LTP, SST1-5, GABAA inhibition
Investigating why dissemination of scientific evidence fails to persuade antivaxxers : a transdisciplinary review

Most Americans are not concerned about vaccines. However, a small but vocal minority is, and a growing number of parents are receiving vaccine mandate exemptions for their children on the basis of religion or “personal belief.” Vaccine refusal can have disastrous consequences: in some communities, childhood vaccination coverage has dived well below the threshold required for “herd immunity,” allowing diseases like measles to stage a forceful comeback. Vaccine hesitancy and refusal are often attributed to a lack of knowledge or lack of understanding of scientific “facts” on the part of antivaxxers. Most public health interventions that aim to promote vaccination rely on disseminating trustworthy scientific knowledge and see science communication as a one-way process of diffusion of scientific evidence. If antivaxxers knew how safe, effective, and necessary vaccines are, the theory goes, they would vaccinate more. Unfortunately, literature across disciplines suggests that such passive, community-wide education interventions are mostly ineffective at persuading antivaxxers to adopt pro-vaccination attitudes and behaviours. Why?  Inspired by Edgar Morin’s principles of transdisciplinarity, Thomas Kuhn’s theory of scientific revolutions, and Trisha Greenhalgh’s meta-narrative review methodology, I examine the publications of different seminal authors across disciplines that directly or indirectly provide an answer to this question. I distinguish three main approaches, which differ as to their general explanation of why interventions based on simple dissemination of scientific evidence fail. The first explanation is that antivaxxers lack the scientific literacy that is necessary to understand the scientific evidence that is presented to them. The second is that antivaxxers’ resistance to scientific evidence can be explained by the numerous cognitive biases and “rules of thumb” that lead individuals to make systematic errors in judgment and thus deviate from the rational choice theory decision-making ideal. The third narrative stresses sociocultural influences. According to cultural cognition theory, culture influences risk perceptions through the mechanisms of cognitive biases and heuristics. These three narratives about vaccine hesitancy and refusal are thoroughly examined in order to provide a cross-disciplinary synthesis of factors that may explain the failure of education-based public health interventions to persuade antivaxxers.

Keyphrases: knowledge translation, knowledge transfer, science of science communication, science communication, antivaxxers, vaccination, scientific literacy, cognitive biases, cultural theory of risk, cultural cognition
Promesses et trahisons, suivi de La trahison dans Les Portes du sang de Michel Del Castillo

This Master’s thesis explores the modalities of a narrative structure declined in several singular points of view, which multiplies the variations on the theme of betrayal, when it is felt, for a human being, on the affective level. It also explores the question of transmission in a relationship where an adult allows a child to develop his own personality. In the creative part of my thesis, the « novel » entitled Promesses et trahisons recounts the relation between a music master and his young pupil. The reader discovers the successes and the setbacks in this exclusive relationship through three different points of view. After the confession of the student, who remembers as an adult his past history, we have access to the diary of the master presented as an archival document. Another point of view completes the story in the form of a letter, signed by a third party, before an epilogue, which will shed a final light on the plot. The book that inspired the essay section of my thesis is entitled Les Portes du sang. In it, the author, Michel Del Castillo, explores a mother-son relationship (adult and child) through several testimonials, which in turn a narrator tries to contrast and corroborate in order to reveal the elusive personality of the character responsible for her son’s feeling of betrayal. In both cases, one finds a quest for identity whose mystery persists beyond the text.

Keyphrases: Confession, Trahison, Promesse, Michel Del Castillo, Intimate story, Betrayal, Promise
Pattern-based refactoring in model-driven engineering

Model-Driven Engineering (MDE) is a software engineering paradigm that uses models as first-class concepts from which validation, code, testing, and documentation are derived. This paradigm involves various artifacts such as models, meta-models, or model transformation programs. In an industrial context, these artifacts are increasingly complex. In particular, their maintenance is time and resources consuming. In order to reduce the complexity of artifacts and the cost of their maintenance, many researchers have been interested in refactoring these artifacts to improve their quality. In this thesis, we propose to study refactoring in MDE holistically, by its application to these different artifacts. First, we use specific design patterns, as an example of prior knowledge, applied to model transformations to enable refactoring. We first proceed with a detecting phase of design patterns, with different forms and levels of completeness. The detected occurrences thus form refactoring opportunities that will be exploited to implement more desirable and/or more complete forms of these design patterns. In the absence of prior knowledge, such as design patterns, we propose an approach based on genetic programming, to learn transformation rules, capable of detecting refactoring opportunities and correcting them. As an alternative to prior knowledge, our approach uses examples of pairs of artifacts before and after refactoring, in order to learn refactoring rules. We illustrate this approach on model refactoring.

Keyphrases: Software engineering, Model-driven Engineering, Refactoring, Design Pattern, Model Transformation, Learning by Example, Refactorisation
Méthodes de décomposition basées sur la relaxation lagrangienne : cas du problème de transport avec coûts fixes

Our research topic focuses on solving the fixed charge transportation problem (FCTP). The classic transportation problem is to determine the optimal distribution pattern in a network. The network is divided into two subsets of vertices : the origins characterized by a supply and the destinations characterized by a demand. Each arc connecting an origin and a destination has a variable cost associated with it. The objective is to satisfy all demands while minimizing the sum of variable transportation costs. In FCTP, there are also fixed costs associated with all arcs, in addition to all others things that describe a typical transportation problem. So, each arc is associated a variable cost and a fixed cost which is considered if and only if the arc is used. The objective is now to minimize the total sum of costs, variable and fixed. The FCTP therefore confronts us with a different and more complex model. The resolution complexity is even increased for large instances. In this thesis, we study and present a new resolution method for large FCTP instances. This is a lagrangian decomposition method which uses lagrangian relaxation and a subgradient algorithm to find a lower bound to the global problem. We have integrated into the method a lagrangian heuristic, including a “slope scaling” procedure in order to improve our sub-gradient algorithm and the final result of the method. At the end of our resolution process, we find, for some large instances, a way to improve the solution proposed by CPLEX for the FCTP by giving as parameter to CPLEX the final solution of our method.

Keyphrases: Fixed charge transportation problem, Decomposition method, Lagrangian relaxation, Sub-gradient algorithm, Heuristics
Recherche de biomarqueurs d’activité ostéoclastique pour prévenir les fractures de stress chez les chevaux de course

Every year racehorses die from complete catastrophic fractures in training and racing. Supra-physiological cyclic loads during exercise cause bone microcracks not discernible with current imaging in vivo. Osteoclasts recruited to the sites of the damage induce focal bone lysis and osteopenia by excessive resorption, creating a stress riser area susceptible to complete fracture. However, the biological impact of osteoclasts in stress fractures is not entirely understood. Our objectives were to establish in vitro cultures of equine osteoclasts, to correlate osteoclast numbers with the tartrate-resistant acid phosphatase 5b isoform (TRACP-5b), to correlate bone resorption with the TRACP-5b and the C-terminal telopeptide of type I collagen (CTX-I), as well as to investigate the effects of inflammatory factors on osteoclast activity.   Following equine sternal bone marrow aspirations, hematopoietic stem cells were isolated, stored in a cell bank, thawed, differentiated into osteoclasts, with or without equine bone slices, and they finally underwent inflammatory stimulation (IL-1β or LPS). CTX-I and TRACP 5b were assayed by ELISAs. Osteoclasts stained with tartrate resistant acid phosphatase were counted and bone resorption areas stained with toluidine blue were measured. In the osteoclast cultures, the TRACP 5b increased (p < 0.0001) with time and correlated (r = 0.63, p < 0.001) with osteoclast number. In the osteoclast-bone cultures, both CTX-I (p = 0.0018) and TRACP-5b (p = 0.02) increased with time, correlated with each other (r = 0.64, p < 0.002) and both correlated with bone resorption (r = 0.85, p < 0.001 and r = 0.82, p < 0.001, respectively). The inflammatory stimuli had no significant effects. Equine osteoclasts and bone resorption were successfully induced on equine bone from sternal bone marrow aspiration. For the first time CTX-I and TRACP-5b were measured in equine osteoclast cultures. In vitro, CTX-I is a biomarker of equine bone resorption and TRACP-5b a biomarker of equine osteoclast number and bone resorption. Further investigations are required to measure the serum TRACP-5b capacity to detect excessive skeletal resorption in racehorses.

Keyphrases: Cheval, CTX-I, TRACP-5b, Osteoclast, Horse, Racehorse, Stress fracture, Bone resorption, Bone biomarker
Efficacité des isoxazolines pour traiter le réservoir principal de l’agent de la maladie de Lyme, la souris Peromyscus leucopus

Lyme disease is the most common vector-borne disease in North America; the risk caused by the disease is partly due to its tick vector’s tenacity and limited number of approaches to reduce its abundance in the environment. Few existing methods efficiently and safely target the principal host for the bacteria, white-footed mice Peromyscus leucopus.The objective of this thesis was to evaluate the efficacy of a new family of antiparasitic drug, isoxazolines, when passively administered as an oral bait to micromammals in endemic site for Lyme disease. Oral baits were distributed during the summer of 2018 and 2019 on five selected sites in the Thousand Islands National Park. Density of ticks in the environment was estimated using drag sampling while small mammal trapping allowed biodiversity and infestation (number of ticks per mouse) to be assess. Impact of isoxazoline used (sarolaner or fluralaner), biodiversity and characteristics of environment (type of forests, temperature, humidity) were also evaluated. Linear mixed models were fitted to determine the impact of measured variables and treatment on infestation level and density of questing nymphs. Results show a significant reduction in tick load for mice captured on treatment plots compared to control plots for 3 out of 5 sites. However, we did not observe a significant reduction in the density of questing nymphs, probably due to the limited duration of the study. Density of nymphs followed interannual variation and was best explained by humidity levels at the time of sampling and plot-level host biodiversity. Peromyscus spp. infestation was linked to the sex (male being more infested) and body length of the mice, high density of questing larvae, year and month of capture and treatment applied to the microsite. Fluralaner showed to be more efficient at reducing mice average tick load. This study was the first to use oral sarolaner to treat the most important reservoir for the Lyme disease agent in the environment. Our protocol did not significantly reduce questing nymphs in the environment for the duration of this study but could potentially diminish Lyme disease human risk with long term use through reduced Peromyscus infestation.

Keyphrases: Isoxazolines, Maladie vectorielle, Borrelia burgdoferi, Ixodes scapularis, Peromyscus leucopus, Lyme disease, Tick-borne disease, Thousand Islands, Micromammals
Évaluation de la stabilisation de la rupture du ligament croisé crânial canin par la suture latérale : une étude de cinématique 3D in-vitro

The impact of surgical correction of cranial cruciate ligament rupture (CCLR) on 3D kinematics has not been thoroughly evaluated in dogs. The success of current techniques remains limited, as illustrated by suboptimal weightbearing and progression of osteoarthritis. The inability to restore the stifle’s 3D kinematics might be a key element in understanding these suboptimal outcomes. The objective of this study was to evaluate the impact of lateral suture stabilization (LSS) on the 3D kinematics of the canine stifle joint. We hypothesized that LSS would not restore 3D kinematics in our model.  Ten pelvic limbs collected from euthanized large dogs (25-40 kg) were tested with a previously validated apparatus that simulates trot. Three experimental conditions were compared: (a) intact stifle; (b) unstable stifle following cranial cruciate ligament transection (CCLt) and (c) CCLt stabilized by LSS. Three-dimensional kinematics were collected through 5 gait cycles and curves were analyzed using a Wilcoxon signed-rank test.  LSS restored baseline kinematics for the entire stance phase for cranial and lateromedial translation, sagittal flexion, and abduction. It restored distraction over 90% of the stance phase. Internal rotation was limited, but not restored. This in vitro study had limitations, as it used a simplified model of stifle motion and weight-bearing. The results of this study demonstrate that LSS can restore physiologic 3D kinematics largely comparable to those of healthy stifles. Suboptimal outcome in patients following CCLR stabilization by LSS may therefore result from causes other than immediate postoperative abnormal 3D kinematics.

Keyphrases: Canin, Cranial cruciate ligament rupture, Canine, Veterinary surgery, Lateral suture stabilization, Three-dimensional kinematics
Découvertes de nouveaux mécanismes de résistance au Topotecan, un inhibiteur des topoisomérases, chez Leishmania infantum

Leishmania, a protozoan parasite, causes a neglected tropical disease that is fatal if left untreated. In recent years, the effectiveness of the drugs used to tackle leishmaniasis has decreased dramatically due to the emergence of drug resistant parasites. Even though Topetecan (TPT), currently employed as an anti-tumoral drug, has shown strong anti-leishmanial activity (its EC50 being measured in nanomoles), its efficiency may be compromised by the resistance developped by the parasites, similarly to the resistance already recorded by tumoral cells to the drug.  In this study, the mecanisms of resistance to TPT by Leishmania infantum were caracterised at the molecular level. The whole genome of parasites resistant to TPT (16 x EC50) (TPT700.1, TPT700.2, TPT700.3) was sequenced. The role of various genetic elements in the resistance mecanisms was confirmed via a complementation by episomal nucleofection in the wild type and was studied with the help of computational models.   Neither amplications nor deletions were identified and only a minor variation in the chromosome number was observed. However, a non-synonymous single nucleotide polymorphism was identified in the gene coding the large subunit of topoisomerase IB, TPT’s target, within each of the resistant mutant parasites confering variable levels of resistance (TPT700.1 F187Y > TPT700.3 W232R > TPT700.2 G191A > wild type). Furthermore, in sillico models highlighted the proximity of these amino acid substitutions to the catalytic site of topoisomerase IB and also to the binding pockets of TPT.  In conclusion, these results suggest that a point mutation in the large subunit of TOP IB is sufficient to confer high levels of resistance (about 24 x EC50) to TPT700.1F187Y, TPT700.2G191A and TPT700.3 W232R. Therefore, TPT can be considered a pharmacological tool to study resistance in Leishmania.

Keyphrases: Leishmania, Mutation, Topoisomerase, Drug resistance, Single-nucleotide polymorphism
Effets de la trazodone sur le comportement et le cortisol sérique du gnou bleu (Connochaetes taurinus)

Trazodone is a dose-dependant serotonin antagonist and agonist used in human and veterinary medicine to treat anxiety-related conditions. Trauma has been identified as the leading cause of morbidity and mortality in several wild ruminant species and can be exacerbated by stress. In a recent study in domestic goats, trazodone reduced activity levels without adverse effects. Trazodone could allow for safer capture and handling in ruminant species. The objectives of the present study were to identify a dose of trazodone that decreases activity levels in captive blue wildebeest (Connochaetes taurinus), to evaluate its effects on serum cortisol levels following a routine veterinary procedure, and its safety. A pilot study using ethograms identified a 15 mg/kg oral dose of trazodone as effective to reduce activity levels. Over 6 hours, this dose resulted in a 111% increase in time spent sleeping/resting (P=0.0003), a 41% increase in time spent lying down (P=0.0016), a 64% reduction in time spent moving (P=0.005), and a 65% reduction in time spent being vigilant (P=0.026). Systemic absorption of trazodone was identified when plasma concentrations were measured after 2 hours (95 ± 48 µg/L). Serum cortisol levels during a routine venipuncture event were not significantly different following trazodone adminstration (P > 0.05). Mild hyporexia was the only adverse effect noted at 15 mg/kg and was absent at a 12 mg/kg dose. Trazodone appears safe and promising to decrease activity in the blue wildebeest and might thus have a positive effect on wild ruminant welfare and the safety of veterinary procedures.

Keyphrases: Connochaetes taurinus, cortisol, blue wildebeest, stress, trazodone
Optimisation de l’anesthésie du lapin (Oryctolagus cuniculus) par l’application des principes du Enhanced Recovery After Surgery (ERAS)

Adapting ERAS guideline principles to rabbit anesthesia could improve their risk of perioperative mortality which remains elevated. The development of a reversible IM protocol could hasten recovery and decrease complications. The objectives of this thesis were 1) to investigate the relationship between oxygen administration and ventilation, 2) to define PK-PD parameters of IV midazolam and its antagonist flumazenil in rabbits. In a prospective, randomized, blinded study, 25 New Zealand White rabbits (4 males, 21 females; 3.1–5.9 kg; 1 year old) were anesthetized with IM alfaxalone (4 mg/kg), dexmedetomidine (0.1 mg/kg) and midazolam (0.2 mg/kg) and randomized to a 5 (n = 8) or 10 (n = 17) minutes waiting period between drug injection and oxygen (100%) or medical air administration (facemask, 1 L/minute). Immediately before (PREoxy/air5/10) and 2 minutes after oxygen or medical air (POSToxy/air5/10), respiratory rate (fR), pH, PaCO2, PaO2 were investigated. Hypoxemia (PaO2 < 88 mmHg) was observed at all PRE times. PREoxy5 [71 (61–81) mmHg]; PREoxy10 [58 (36–80) mmHg] and PREair10 [48 (32–64) mmHg]. Hypoxemia persisted when breathing air: POSTair10 [49 (33–66) mmHg]. Oxygen administration corrected hypoxemia but was associated with decreased fR (> 70%; p = 0.016, both groups) and hypercapnia (p = 0.016, both groups). fR was unchanged breathing air (p = 0.5). PaCO2 was higher when breathing oxygen than air (p < 0.001). Early oxygen administration resolved anesthesia-induced hypoxemia, but worsened hypoventilation indicating that hypoxic respiratory drive is an important contributor to ventilation using the studied drug combination. In a prospective, randomized, blinded, crossover study, 15 New Zealand White rabbits (7 males, 8 females; 2.73 – 4.65 kg, 1 year old) received IV midazolam (1.2 mg/kg) followed by IV flumazenil (FLU; 0.05 mg/kg) or saline control (SAL; equal volume) to reverse loss of righting reflex (LORR). Midazolam was injected (T0). Treatment (FLU/SAL) injected 30 seconds after LORR. Arterial blood samples were collected and analyzed using liquid chromatography/mass spectrometry. Time to return of righting reflex (ReRR) compared between groups. FLU terminal half-life, plasma clearance and volume of distribution were 26.3 min [95%CI: 23.3–29.3], 18.74 mL/min/kg [16.47–21.00] and 0.63 L/kg [0.55–0.71], respectively. ReRR was 25 times faster in FLU (23 [8–44] seconds) versus SAL (576 [130–1141] seconds; p<0.001, 95%CI [425–914 seconds]). Return of sedation (LORR) occurred in both groups (4/13 in FLU; 7/13 in SAL) at 1540 [858–2328] seconds. Flumazenil quickly and reliably reversed sedation from midazolam injection. However, the potential resedation after flumazenil administration warrants careful monitoring in the recovery period.

Keyphrases: Gaz sanguin, Rabbit, Anesthesia, Early Recovery After Surgery, Eras, Flumazenil, Righting reflex, Pre-oxygenation, Hypoxemia, Blood gas