NCube/papyrus huggingface dataset:
Pratiques traditionnelles chez les sages-femmes autochtones du Nunavik et programme de formation

The Inuit of Hudson’s Bay in Nunavik (Quebec) have distinguished themselves from other indigenous communities by re-asserting their autonomy over the care of pregnant women within their community. A strong sense of self-determination led to the abandonment of the practice of transferring pregnant women for delivery at hospitals far from their village and, in 1986, to the creation of a program to train midwives locally. In addition, this program tries to reinstate traditional practices alongside the teaching of modern obstetrics in order to offer women services which are both of high quality and culturally suitable.  The aim of our study was to determine whether the training of indigenous midwives in Nunavik has helped to reconcile these two different approaches to teaching: one being the focus on traditional practices, and the other on standards of care.  A qualitative research method was used with data collected by means of interviews. Respondents included five Inuit midwives from within the three Hudson’s Bay communities having local birthing centres, as well as six student midwives from the Nunavik midwifery program.  Analysis of the data does not allow for confirmation of the reintegration of traditional knowledge in the practise of indigenous midwives. The results of this research reveal, in effect, a rarity of traditional practices being applied throughout the perinatal period (E.g. use of medicinal plants, positions used during delivery, various delivery manoeuvres). The beliefs or codes of conduct in respect to pregnancy seem to profit from a better transmission, but are not utilized equally within the communities.  In regards to the modern obstetrics component, the program appears to be in conformity with current Western requirements, having been recognized by the Order of the Midwives of Quebec since September, 2008. Moreover, both midwives and students are conscious of the need to receive quality training in their field. They would like to profit from a greater rigor in the teaching of theory, as well as more continuity in the process of apprenticeship. The difficulty found in the teaching of these dual types of knowledge (traditional and modern) thus seems to relate more particularly to the area of traditional practices. Inuit midwives and students wish to protect and promote their cultural inheritance, but more within the perspective of community responsibility that within the framework of a training scheme. A collaboration between the wishes of the communities, concerning the rehabilitation of their cultural inheritance, and the current reality of bio-medicine, remains paramount in order to continue to guarantee the safety and the quality of the services provided.

Keyphrases: Sage-femme, Midwifery, Perinatal care, Inuit from Nunavik, Traditional beliefs and practices, Training program, Qualitative method
Les sources d'incohérences des initiatives de financement du logement social au Nicaragua

Nicaragua suffers of a very important housing deficit. The bulk of it is due to the inability of the finance sector to attend low income families. Numerous initiatives were implemented by organization from the three societal sectors to alleviate this problem. Some were successful, others were not. Today, although the objectives set by these initiatives seems to respond the existing problem, the deficit keeps on deepening. This thesis offers to analyse the causes of the problem and to understand why the implemented initiatives are not functioning as they should. It emphasizes the lack of coordination existing and demonstrates that the whole sector functions in accordance with a silo approach which is itself indicative of a lack of housing finance policy coherence. Finally, it analyses the possible origin of such an organization and of the policy incoherence that brought it. Through this analysis it attempts to clarify the respective accountability of the Nicaraguan State and the ODA which is the main financing source of these programs.

Keyphrases: Microfinance, Microfinance, Housing finance, Silo approach, Public-private-civil relationship, Policy coherence, Aid effectiveness, State accountability
Etude des inhibiteurs d'entrée de CXCR4 : corécepteur d'entrée du virus de l'immunodéficience humaine

HIV entry into target cell is one of the main therapeutic goals in AIDS research.  One fusion inhibitor is actually used as therapeutics and one more entry  inhibitor targeting the CCR5 coreceptor was approved recently. The discovery  of inhibitors targeting the second HIV coreceptor CXCR4 with high antiviral  power versus low interference with natural functions of CXCR4 represents a  crucial issue in AIDS research.    In our study, antiviral properties and functional effect of different kinds of  molecules were tested: 1) peptides derivative mimicking CXCR4 domains 2)  SDF-1 derivative peptides and 3) T140 (a low molecular weight inhibitor)  derivative molecules. These molecules were investigated in HIV infection and  cellular migration.    The main goal of our study was to determine molecules having great antiviral  properties versus low interference on chemotactic response induced by the  natural ligand of CXCR4 (SDF-1).  Within the panel of molecules tested, some  have great potential to become lead compounds for inhibition of viral entry  through CXCR4.

Keyphrases: viral entry, HIV, entry inhibitors, CXCR4 coreceptor
La calnexine: un élément clé dans l'apoptose chez la levure Schizosaccharomyces pombe

Programmed Cell Death (PCD) is an essential process to the cells.  PCD was first characterized in cell development and can be separated in sub-groups depending of cell death characteristics observed.  Apoptosis is one of the PCD sub-groups that was first associated to complex organisms for its roles in cell development and in maintenance of tissues integrity.  The apoptotic pathway is characterized by specific morphological and signalization characteristics.  In the last ten years, numerous studies demonstrated the existence of apoptosis in unicellular organisms such as yeast.  This apoptotic program was extensively studied in the two yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe and share characteristics with the mammalian one.  However, yeast apoptosis is distinctive at many points as yeast do not encodes all the mammalian homologues of the apoptotic pathway.   Although yeast and mammalian apoptosis seems to differs, the interest about yeast apoptosis is growing given that yeast is an excellent and easily tractable model system.    External and internal stimuli can induce apoptosis by different ways.  Accumulation of unfolded or incompletely folded proteins in the endoplasmic reticulum (ER) causing ER stress is a well-known inducer of the apoptotic pathway.  Signalization of ER-stress induced apoptosis involves the same transducers than the UPR (Unfolded Protein Response) pathway.  It was recently shown that calnexin, a transmembrane chaperone of the ER, is implicated in ER-stress apoptosis in mammalian cells.  In this particular case, it was demonstrated that calnexin acts as a scaffold in the cleavage of the apoptotic protein Bap31 by caspase 8.     We demonstrated that ER stress and inositol deficiency, a precursor of many important signalization molecules, are two situations leading to apoptosis in the yeast S. pombe.  These two pathways leading to apoptosis seems to differ as only inositol deficiency is dependant of the yeast metacaspase Pca1p.  We also demonstrated that S. pombe calnexin, essential for cell viability of this yeast, takes part in these two apoptotic process.  ER stress induced apoptosis needs a calnexin anchors to the ER membrane to be efficient.  However, apoptosis induced by inositol starvation needs the calnexin C-terminal tail with the transmembrane domain to be delayed.  These two opposite actions from the same protein lead to the hypothesis that calnexin encodes both pro and anti-apoptotic functions.  By the discovery that calnexin is cleaved under normal culture conditions, a model was elaborated explaining the distinctive roles of calnexin in these two apoptotic pathways.  This model proposed a role of calnexin cleavage to apoptosis.

Keyphrases: UPR, ER stress, S. pombe, Inositol, Programmed Cell Death, Endoplasmic Reticulum, Apoptosis, Cleavage, Calnexin, Yeast
Mutagénèse semi-aléatoire au site actif de la DHFR humaine : création et caractérisation de variantes hautement résistantes au MTX

Human dihydrofolate reductase (hDHFR) is an enzyme that is essential to cell proliferation. It reduces dihydrofolate to tetrahydrofolate, an important cofactor involved in purine and thymidylate biosynthesis. hDHFR is a choice target for chemotherapeutic drugs like methotrexate (MTX), which specifically inhibits the enzyme, stopping cell proliferation and leading to cellular death. MTX is used for the treatment of many proliferative diseases, including cancers. Widespread use of MTX has lead to the development of resistance mechanisms appear which impair treatment efficiency. The present work focuses on a mechanism of resistance, namely mutations in hDHFR that reduce its affinity for MTX, to better understand the underlying mechanisms of inhibitor recognition at the active site of the enzyme. In parallel, we aim at identifying the most MTX-resistant variants to offer novel selectable markers for particular cell culture systems, such as hematopoietic cell culture, which offer important perspectives for cellular therapy. To study the role of different regions of the hDHFR active site, and to verify if a correlation exists between mutations in these regions and increased resistance to MTX, a combinatorial strategy was developed enabling the creation of several hDHFR variant libraries at active site residues located in proximity to bound MTX. The libraries were selected in vivo in a  bacterial system using culture media containing high concentration of the inhibitor. One library in particular, hDHFR 31/34/35, yielded a considerable number of highly MTX-resistant combinatorial hDHFR variants. The most interesting candidates were tested for their potential as selectable markers in various cell lines, including transduced hematopoietic cells. Complete protection from MTX-cytotoxicity was obtained for these cells following infection with the combinatorial variants. To better understand the molecular causes of MTX resistance, resolution of the crystal structures of variant proteins in presence of MTX was attempted. Resolution of the F31R/Q35E double variant revealed that the resistance phenotype was related to important differences in the active site relative to WT, possibly attributable to a dynamic motion effect. A more general comprehension of antifolate recognition and resistance was achieved by sequence and structural comparison of antifolate-resistant DHFR variants from different species.  Overall, our work contributes to the better understanding of enzyme-inhibitor interactions, which could provide new insights into the development of more efficient clinical therapies. In addition, this work has yielded novel drug-resistance genes useful as selectable markers for cellular biology.

Keyphrases: Human dihydrofolate reductase, Enzyme catalysis, Inhibition, Inhibition, Folate metabolism, Combinatorial mutagenesis, Antifolate resistance, Methotrexate, Selectable markers, Hematopoietic cells, X-ray crystallography
Directed evolution of human dihydrofolate reductase: towards a better understanding of binding at the active site

Human dihydrofolate reductase (hDHFR) is an essential enzyme for cellular proliferation and it has long been the target of antifolate drugs for the treatment of various types of cancer. Despite the clinical effectiveness of current antifolate treatments, new drugs are required to reduce the side-effects associated with their use. An essential requirement for design of new antifolates is a better understanding of how these drugs interact with their targets.  We applied directed evolution to identify mutant hDHFR variants with modified binding to some clinically relevant antifolates. A saturation mutagenesis approach was used to create genetic diversity at active-site residues of hDHFR and a new, efficient screening strategy was developed to identify the amino acids that preserved native activity and/or conferred antifolate resistance. The screening method consists in a high-throughput first-tier bacterial selection coupled with a second-tier in vitro assay that allows for rapid detection of the best variants among the leads, according to user-defined parameters. Many active, antifolate-resistant mutants of hDHFR were identified. Moreover, the approach has proven efficient in rapidly assessing kinetic (kcat) and inhibition parameters of the hDHFR variants (IC50). Structure-function relationship analysis based on kinetic investigation, available structural and functional data as well as modeling were performed. By monitoring which mutations have the greatest effect on binding, we have begun to build a molecular picture of the contacts involved in drug binding. By varying the drugs we test against, we gain a better understanding of the specific binding properties that determine ligand discrimination.

Keyphrases: human dihydrofolate reductase, methotrexate, drug-resistance, saturation and combinatorial mutagenesis, directed evolution, high-throughput screening, structure-function relationship, enzyme kinetics, molecular modeling
Environnement bâti et transport actif scolaire : le cas des écoles de proximité de la région de Montréal

Purpose The proportion of children actively commuting to school has decreased significantly but few studies have investigated factors that might affect school mobility. This research examines the influence of a wide range of factors (such as urban form characteristics, parent’s travel behaviours and parental perceptions) on school travel behaviour for children who live near school.  Methods The Tracy McMillan’s conceptual framework of an elementary-aged child’s trip to school was used. We objectively measured environmental attributes of three urban neighbourhoods and three suburban neighbourhoods in Montreal metropolitan area. Data of the Groupe de recherche Ville et mobilité regarding children trips to school, parental perceptions and parents’ travel behaviours were analysed.  Results A high proportion of children are actively commuting to school in the three urban neighbourhoods and in one suburban neighbourhood. Connectivity for pedestrians and cyclists and positive parental perception of school active transportation are positively associated with high proportion of walking and biking to school in these four neighbourhoods.  Conclusion Suburban neighbourhoods support active transportation only for children whereas urban neighbourhoods support active transportation for children and parents. Attributes of built environment in urban neighbourhoods seem to have a positive effect on parental perceptions and behaviours regarding walking and biking for school trips.

Keyphrases: Urban form, Children, Mobilité, School mobility, Walking, Biking, Parents, School Trips, Neighbourhood, Environmental audit, Travel behaviour
Impact d’une mutation ponctuelle stratégique de la protéine HOXB4 sur son pouvoir de régulation, de prolifération et de différenciation des CSH et des progéniteurs murins

Ex vivo hematopoietic stem cell expansion represents a most appealing option to improve bone marrow transplantation. Utilization of the unique hematopoietic stem cell (HSC) expansion abilities of the transcription factor HOXB4 for clinical applications is hampered by its short intracellular half-life. To overcome this difficulty, 3 different single amino-acid substitution mutants of HOXB4 with 3-4 fold increased half-life were generated and their biologic activity compared to that of wild type (wt) HOXB4 using in vitro and in vivo assays. We have shown that overexpression of mutated HOXB4 in HSC using an infection strategy did not impair their long term hematopoietic reconstitution potential in transplanted mice. We have found that cells overexpressing mutant HOXB4 had greater expansion in vitro in competitive and non-competitive designs than wt HOXB4. Moreover, in vivo peripheral blood and spleen repopulation had lymphoid and myeloid contributions closer to untransplanted animals with mutant than wt HOXB4. In addition, cells overexpressing mutant HOXB4 protein were detected much more rapidly and in greater proportion in peripheral blood than cells overexpressing the wt form. One of the mutated HOXB4 proteins (1426) did not promote the expansion of common myeloid progenitors in comparison to wt HOXB4. Finally, using intracellular protein modulation studies, we have shown that the effects of mutated and wt HOXB4 proteins in hematopoietic stem and progenitor cells were not completely due to a HOXB4 concentration effect.

Keyphrases: hematopoietic stem cells, HOXB4, HOXB4, Differentiation, Expansion, Expansion, Myeloid progenitors, Transplantation, Transplantation
Effet de l'atorvastatine et de l'amlodipine sur le remodelage vasculaire dans l'hypertension

Abstract Background and purpose Antihypertensive drugs such as the calcium channel blocker (CCB) amlodipine and cholesterol lowering agents such as statins exhibit pleiotropic effects. Amlodipine reduces aortic hypertrophy and hyperplasia in spontaneously hypertensive rat (SHR) by inducing a transient wave of apoptosis. Atorvastatin induces apoptosis of vascular smooth muscle cell (VSMC) in vitro, independently of cholesterol synthesis, an effect that remains to be shown in vivo. The present studies were designed to test the hypothesis that atorvastatin can induce vascular remodeling by VSMC apoptosis in vivo in SHR, and to test whether combined therapy with low dose amlodipine would provide synergistic effects on regression of aortic hypertrophy. Experimental approach 11-week old SHR were given atorvastatin and amlodipine, alone or in combination, for three or six weeks. Primary end-points were vascular remodeling and blood pressure. Secondary end-points included DNA fragmentation and content in the aorta, oxidative stress, cholesterol and serum total nitrite and nitrate (NOx) concentrations. Key results Treatment with atorvastatin did not modify vascular structure, although it significantly reduced oxidative stress after three weeks and blood pressure after six weeks. Amlodipine dose-dependently reduced blood pressure and aortic hypertrophy. Significant reduction of cellular hyperplasia was reached after 6 weeks with a low dose of amlodipine alone or after 3 weeks when atorvastatin was combined with low dose amlodipine. Conclusions and implications Our results do not support the notion that atorvastatin induces VSMC apoptosis in vivo, although the data suggest a possible interaction with amlodipine in reducing VSMC hyperplasia in the hypertensive aorta.

Keyphrases: Hypertension, Amlodipine, Vascular remodeling, Hypertension, Apoptosis, Spontaneously hypertensive rat, Atorvastatin, Amlodipine, Combination therapy
Classes Alléliques d’Haplotypes et Sélection Positive dans le Génome Humain

Natural selection eliminates detrimental and favors advantageous phenotypes. This process leaves characteristic signatures in the underlying genomic segments that can be recognized through deviations in the allelic or in haplotypic frequency spectra. We introduce a new way of looking at the genomic single nucleotide polymorphisms : the haplotype allelic classes (HAC). The model combine segregating sites and haplotypic informations in order to reveal useful characteristics of the data, providing an identifiable signature of recent positive selection that can be detected by comparison with the background distribution. We compare the HAC distribution's partition between the haplotypes carrying the selected allele and the remaining ones. Coalescence simulations are used to study the distributions under standard population models assuming neutrality, demographic scenarios and selection models. To test, in practice, the performance of HAC and the derived statistic in capturing deviation from neutrality due to selection, we analyzed the genetic variation in the locus of lactase persistence in the three HapMap populations.

Keyphrases: Positive selection, Statistical test, Genetic variability, Population genetics, Lactase, Lactase
Reactive Hyperemia as endothelial function determinant using plethysmography methods

Atherosclerotic diseases are mainly caused by coronary and peripheral blood vessel disorders. Endothelial dysfunction represents an early phase in these diseases, when patients are generally asymptomatic.  We developed a technique, based on near infrared spectroscopy (NIRS), for measurement of arterial blood flow variations in limbs during reactive hyperemia. The technique allows the study of the level of vascular impairment and probably quantifying the level of endothelial dysfunction at peripheral arteries.  The experiment was performed on two cohorts of 13 and 15 patients and was compared to strain gauge plethysmography (SGP) which is considered as gold standard.  Afterward, we characterized endothelial reaction during reactive hyperemia through blood flow variations by modeling the hyperemic curve. Preliminary studies have shown that the hyperemic response generally adopts a bimodal form. The first peak was attributed to myogenic reaction that is endothelial independent and the second one to local endothelial cells reaction. The quantification of the two hyperemic response components makes it possible to calculate an index of ‘health’ for local endothelial cells, named ηfactor.  The results showed a strong correlation (r = 0.91) of blood flow measurements between the developed method and the gold standard.  We concluded that NIRS is a precise technique for non-invasive measurement of blood flow. Moreover, we found a high repeatability (ICC = 0.9313) of the ηfactor in repeated measurements indicating its robustness. Nonetheless, more studies are required to validate the diagnosis value of the defined factor.   Key words: reactive hyperemia, myogenic response, endothelial dependent vasodilatation, nitric oxide, atherosclerosis, near infrared spectroscopy (NIRS)

Keyphrases: Reactive hyperemia, Myogenic response, Atherosclerosis, Nitric oxide, Near infrared spectroscopy