NCube/papyrus huggingface dataset:
The role of DcR3 in systemic lupus erythematosus and islet β-Cell viability and function

Decoy receptor 3 (DcR3) is a member of the tumor necrosis factor (TNF) receptor family, and is widely expressed in human normal tissues and malignant tumors. It is a decoy receptor of three TNF family members, i.e., FasL, LIGHT and TL1A. The interaction of DcR3 and its ligands will not transmit signal into cells via DcR3 because DcR3 is a soluble protein without a transmembrane and intracellular segment. Thereby, DcR3 competitively inhibits signaling through three functional receptors, i.e., Fas, HVEM/LTbetaR and DR3. In previous studies, we found that DcR3 could modulate immune cell function, and protect islet viability. Herein, we generated DcR3 transgenic (Tg) mice driven by the human β-actin promoter to further investigate the function of DcR3. Interestingly, the DcR3 Tg mice developed a lupus-like syndrome at 6 months of age. They presented a variety of autoantibodies including anti-nucleus and anti-dsDNA antibodies. They also manifested renal, dermal, hepatic and hematopoietic lesions. Compared to lpr and gld mouse lupus models, DcR3 Tg mice more closely resembled human SLE in terms of Th2-biased immune response and anti-Sm antibody production. Furthermore, we found that DcR3-producing hematopoietic cell were sufficient to cause these pathological changes. Mechanistically, DcR3 may break T-cell homeostasis to interfere with peripheral tolerance, and then induce autoimmunity.    In humans, we detected high DcR3 levels in SLE patient sera. The high DcR3 levels were related to elevated IgE titer in some SLE patients, as was the case in the mouse model. Therefore, DcR3 may represent an important pathogenetic factor of human SLE.  Utilizing the DcR3 Tg mouse, we further elucidated the mechanism by which DcR3 protected islets from primary nonfunction (PNF). Blocking of LIGHT and TL1A signaling by DcR3 are involved in such protection. Moreover, by mRNA microarray we identified possible downstream molecules, which may mediate such protection. We confirmed that Adcyap1 and Bank1 played critical roles in mediating DcR3’s effect in islet protection.  Our studies resolved a puzzle about the relationship between the Fas/FasL apoptosis signaling pathway and the pathogenesis of human SLE. DcR3 can block Fas/FasL pathway even if there is no genetic mutation in Fas and FasL. DcR3 can simultaneously interfere with LIGHT and TL1A signaling to cause a more complex phenotype than the simple Fas or FasL mutation in patients. DcR3 can also be employed as a potential diagnostic parameter for SLE. The discovery of the mechanism of DcR3 in protecting islets allows us to explore novel therapeutic targets to protect islet graft.

Keyphrases: DcR3, transgenic, systemic lupus erythematosus, islet transplantation, primary nonfunction ( PNF)
L’effet de HOXB4 sur l’expansion et la différenciation des progéniteurs myéloïdes

Over-expression of the homeobox transcription factor HOXB4 results in a selective expansion of HSC in vitro and in vivo. However, the intracellular half-life of the protein is only one hour, which represents an important obstacle for its clinical use. Three HOXB4 mutants with single amino acid (AA) substitution in the first 31 AA have demonstrated increased intracellular stability of the protein. We evaluated the effect of wild type (wt) and mutant (m) HOXB4 on expansion and differentiation of myeloid progenitors. Ectopic expressions of wt- and m- HOXB4 had a comparable effect on the frequency of myeloid progenitors in semi-solid assay. However, the proliferative capacity of myeloid progenitors expressing wt-HOXB4 and 1423 m-HOXB4 was considerably better than that of control (GFP only) and other two mutants. Additionally, while all HOXB4 variants conferred similar self-renewal capacity to multipotent (GEMM) progenitors, the production of single-lineage granulocytic progenitors (CFU-G) was severely compromised when cells were expressing 1426 and 1427 m-HOXB4. Conversely, the cellularity of myeloid colonies was also diminished with these mutants suggesting, that both mutations affect certain biologic function(s) of wt-HOX4 in addition to increasing its stability. On the other hand, 1423 m-HOXB4 did not seem to lose any wt-HOXB4 functions tested in in vitro assays making this mutant an interesting target for further investigation.

Keyphrases: Wild type HOXB4, Mutated HOXB4, Myeloid progenitors
Comparaison entre deux stratégies transfusionnelles en postopératoire de chirurgie cardiaque pédiatrique

Anemia is frequent in pediatric patients following cardiac surgery. Despite frequent transfusions, the optimal hemoglobin threshold where benefits surpass risks is still unknown for these patients. Recently, Lacroix et al. showed that a restrictive transfusion strategy was not inferior to a liberal strategy concerning the development or progression of multiple organ dysfunction syndrome (MODS) and mortality in pediatric intensive care patients. In the absence of evidence, the aim of this study was to determine the impact of a restrictive versus a liberal transfusion strategy on new or progressive multiple organ dysfunction syndrome (MODS) in children following cardiac surgery. We conducted a subgroup analysis of the postoperative cardiac surgery patients of the Transfusion Requirements in Pediatric Intensive Care Unit (TRIPICU) study. Our study showed no statistically and clinically significant differences in the number of patients who acquired or worsened MODS, nor secondary outcomes between a restrictive and a liberal transfusion strategy. This subgroup analysis generates a research hypothesis that should be confirmed by a randomized controlled trial.

Keyphrases: Cardiopathie, Transfusion, Randomized controlled trial, Subgroupe analysis, Pediatric critical care, Cardiac surgery, Congenital heart disease, Red blood-cell, Hemoglobin, Trnafsusion treshold, Multiple organ dysfunction syndrome
Community remoteness and birth outcomes among First Nations in Quebec

OBJECTIVE: It is unknown whether Aboriginal birth outcomes may be affected by the degree of community remoteness. We assessed community remoteness and birth outcomes among Quebec First Nations. METHODS: We used Statistics Canada's vital data for the province of Quebec, 1991-2000. Postcode geo-coding linkage was used to identify all births in First Nations communities (reserves). Communities were grouped into four zones based on the degree of remoteness. Multilevel logistic regression was used to obtain the ORs adjusting for maternal characteristics. RESULTS: Preterm birth rates rose progressively from the most remote (5.2%) to the least remote (8.2%) zone (P<0.001). In contrast, infant mortality rose progressively from the least remote (6.9/1000) to the most remote (16.8/1000) zone (P<0.01). The excess infant mortality in the more remote zones could be largely explained by the high postneonatal mortality. Postnatal SIDS was 3 times higher in the most remote compared to the least remote zone. Perinatal mortality was highest in the most remote zone but the differences were not significant across the four zones. Similar patterns were observed after adjusting for maternal age, education, parity and marital status.   CONCLUSIONS: Despite lower rates of preterm deliveries, First Nations living in more remote communities suffered a substantially higher risk of infant death, especially postneonatal death, compared to First Nations living in less remote communities. There is a greater need for improving maternal and infant health in more remote Aboriginal communities.

Keyphrases: infant mortality, preterm birth, low birth weight, high birth weight, postneonatal death, First Nations, community remoteness, Aboriginal people
The importance of the Hedgehog signaling pathway at the level of the blood-brain barrier

The blood-brain barrier (BBB), composed of tightly bound endothelial cells (ECs), regulates the entry of blood-borne molecules and immune cells into the CNS. Recent studies indicate that the Hedgehog (Hh) signaling pathway in adult tissues plays an important role in vascular proliferation, differentiation and tissue repair. Using a lipid membrane raft-based proteomic approach, I have identified the Hedgehog (Hh) pathway as a signaling cascade involved in preserving and upkeeping BBB functions. My study shows that human astrocytes express and secrete Sonic Hh (Shh) and conversely, that human BBB-ECs bear the Hh receptor Patched-1 (Ptch-1), the signal transducer Smoothened (Smo) as well as transcription factors of the Gli family. Furthermore, activation of the Hh pathway in BBB-ECs restricts the passage of soluble tracers in vitro. By blocking the Hh signaling in vitro and by using Shh knock-out (-/-) embryonic mice, I demonstrate a reduced expression of TJ molecules claudin-5, occludin and ZO-1. Hh activation also decreases the surface expression of cell adhesion molecules ICAM-1 and VCAM-1, and decreases BBB-ECs secretion of pro-inflammatory chemokines IL-8/CXCL8 and monocytes chemoattractant protein 1 MCP-1/CCL2, resulting in a reduction of migrating CD4+ lymphocytes across human BBB-EC monolayers. In vitro treatment with inflammatory cytokines TNF-α and IFN-γ, upregulates the production of astrocytic Shh and the BBB-EC surface expression of Ptch-1 and Smo. In active Multiple Sclerosis (MS) lesions, in which the BBB is disrupted, Shh expression is drastically upregulated in hypertrophic astrocytes, while Ptch-1 and Smo expression is down-regulated or left unchanged, suggesting that a deregulation in the Hh signaling pathway may prevent the barrier stabilizing properties of Hh. Our data demonstrate an anti-inflammatory and BBB-promoting effect of astrocyte-secreted Hh and suggest that a pro-inflammatory environment disrupt the BBB by impacting, at least in part, on Hh signaling in brain ECs.

Keyphrases: lipid membrane raft, blood-brain barrier, tight junction, Sonic hedgehog, Sonic Hedgehog, astrocyte, astrocyte, endothelial cell, Multiple sclerosis, neuroimmunology, neuroimmunologie, permeability, Hedgehog signaling pathway
Étude des interactions entre les cellules progénitrices endothéliales et l’adiponectine

Adiponectin, an adipokine whose plasma levels are inversely correlated to metabolic syndrome components, protects against atherosclerosis and reduces myocardium infarction-associated risks. Endothelial progenitor cells (EPCs) are involved in vascular repair and their number is reduced in patients with cardiovascular disease. We hypothesized that positive effects of adiponectin against atherosclerosis are explained in part by its interaction with EPCs.     EPCs were obtained from healthy volunteers’ venous blood by mononuclear cell isolation and plating on collagen-coated dishes. Three subpopulations of EPCs were characterized by flow cytometry immunophenotyping. Expression of adiponectin receptors, AdipoR1, AdipoR2 and H-cadherin was evaluated by qPCR in EPCs and endothelial cells. Effects of recombinant adiponectin on apoptosis of EPCs and HUVECs were assessed. Expression of neutrophil elastase by EPCs and enzymatic activity on adiponectin processing were assessed.   Quantitative PCR of EPCs and HUVECs mRNA showed a higher expression of AdipoR1 compared to AdipoR2 and no expression of H-cadherin in EPCs. Expression of AdipoR1 in EPCs was confirmed by Western Blot. We demonstrated that early EPCs express neutrophil elastase. Adiponectin significantly increased survival of two subpopulations of EPCs in condition of serum deprivation but had no effects on HUVECs. Neutrophil elastase activity was confirmed in EPCs conditioned media.   Adiponectin protects some EPCs subpopulations against apoptosis and therefore could modulate their involvement in vascular repair. Neutrophil elastase activity of EPCs could locally modify adiponectin activity by its ability to generate the globular form of adiponectin.

Keyphrases: adipokine, atherosclerosis, apoptosis, vascular repair, neutrophil elastase
Performances de la puce exon et son application dans l’analyse de l’épissage alternatif associé à la métastase du cancer de sein

We demonstrate how the Affymetrix Exon Array, can be used to simultaneously profile gene expression level, and detect variations at the isoform level. We use a well studied set of brain and reference RNA samples previously used by the MicroArray Quality Control (MAQC) consortium study. We demonstrate a high concordance of gene expression measurements among three popular expression platforms – Affymetrix Exon Array, Illumina, and Affymetrix 3’ targeted array (U133A). More interestingly, we show that in many cases of discordant results, the effect can be explained by differential probe placements across platforms, and that the exact isoform change can only be captured by the Exon Array. Finally, we are able to detect hundreds of cases of splicing, transcript initiation, and termination differences between the brain and reference tissue samples. We propose that the Exon Array is a highly effective tool for transcript isoform profiling, and that it should be used in a variety of systems where such changes are known to be associated with diseases, such as neurological disorders and cancer. As application, we used the Affymetrix Exon Array to identify metastatis-specific alternative splicing in mouse model of breast cancer at the whole genome level. We utilize a well characterized series of three mouse mammary tumor lines exhibiting varying levels of metastatic potential. We catalogued 2623 transcripts which exhibit splicing aberrations during the progression of cancer. A genetic pathway analysis shows the half of them implicated in several cell activities, cancers and genetic disorders.

Keyphrases: Exon Array, Alternative splicing, Breast cancer, Gene pathway
Une heuristique à grand voisinage pour un problème de confection de tournée pour un seul véhicule avec cueillettes et livraisons et contrainte de chargement

In this work, we consider a new type of pickup and delivery routing problem with last- in-first-out loading constraints for a single vehicle with multiple stacks. This problem is motivated by similar problems reported in the literature. In the problem considered, items are collected and put on top of one of multiple stacks inside the vehicle, such that the total height of the items on each stack does not exceed a given threshold. The loading constraints state that if items i and j are in the same stack and item i is collected before item j, then i must be delivered after j. Furthermore, an item can be delivered only if it is on the top of a stack. An adaptive large neighborhood heuristic, based on recent studies in this field, is proposed to solve the problem. Numerical results are reported on many classical instances reported in the literature and also on some new ones.

Keyphrases: Vehicle Routing Problem, Pickup and delivery, Loading constraint, Traveling salesman problem
Rôle de la protéine ScFRK1 dans le développement du sac embryonnaire et son impact sur le guidage des tubes polliniques

The Solanum chacoense Fertilization-Related Kinase 1 (ScFRK1) is a member of plant MAPKKK that is specifically expressed in ovules. ScFRK1 mRNA levels accumulate predominantly in the egg apparatus cells of the embryo sac at mature stage and decrease rapidly following pollination. These results suggest both pre- and post-fertilization roles in ovule development. Although no expression could be detected in mature pollen, FRK1 mRNAs could be detected in pollen mother cells. Transgenic plants expressing sense or antisense ScFRK1 showed no abnormal phenotype in vegetative tissues but produced seedless fruits upon pollination. A microscope-based examination of developing female gametophytes revealed that its formation did not progress further than the functional megaspore stage in affected transgenic plants and, as the levels of ScFRK1 mRNA decreased, the percentage of normal embryo sacs declined. Surprisingly, even in severely affected plants producing no or very few embryo sacs, pollination led to the production of parthenocarpic fruits. Similarly, viable pollen production declined with decreasing levels of ScFRK1 and this could be linked to affected mitosis I. Since embryo sac integrity is a prerequisite for pollen tube guidance, we devised a semi-in vivo pollen tube growth system to assess the ability of the ScFRK1 mutant ovules to attract pollen tubes. As expected, guidance was severely affected, confirming the involvement of the egg apparatus cells as the source of attracting molecules. Attraction was also determined to be highly species-specific and developmentally-regulated with the acquisition of attraction competence on anthesis day.

Keyphrases: Embryo sac, Egg apparatus, Megagametogenesis, Pollen tube guidance, Solanum chacoense, Solanum chacoense, Solanaceae, MAPKKK, MAPKKK
Luther on love and law : a historical investigation of Martin Luther's application of scriptural authority to Church and State

This paper begins by citing some of the past century’s commentaries on Luther’s views on authority in government and the church as well as his views on human nature.  I will show where his critics place him in reference to the scholastic tradition as well as the Roman tradition within the church.  From here I will consider his writings themselves for the arguments that he made regarding the church and its source of authority as well as its proper relationship to the government, or temporal authority.  I will address Luther’s perspective on the church’s place in society as compares with the temporal authority’s role.  Finally I will present Luther’s writings in two specific situations concerning how the kingdom of God is built; more precisely, to what extent, if at all, the church is to depend upon the temporal authority for the establishment of the kingdom of God.  The aim of this paper is to reply to the charge of some critics that Luther depended on the temporal authority for the establishment of the church and the implication that he gave the temporal authority control over spiritual matters.  We will discover that Luther’s final source of authority comes from the Scriptures and the surprising effect that this has on his political philosophy is both to increase submission to the governing authorities as well as to increase freedom from the tyranny of false doctrine.

Keyphrases: Martin Luther, Bible, Church, State, John Neville Figgis, Kindom of God, Authority, Reformation, Law, Freedom, Gospel
Lumbar-sacral pedicle screw insertion with preoperative CT-based navigation

Objective:  The authors studied 135 consecutive patients following a lumbo-sacral fixation using pedicle screws and CT-based navigation to evaluate pedicle screw accuracy and clinical outcomes.   Methods: The series included 44 men and 91 women (mean age 61 years, range 24-90 years).  All 836 screws were planned with pre-operative CT-Scans in a navigation system (SNN, Surgical Navigation Network, Mississauga, Ontario, Canada) for diameter, length and direction.  Fixation included the lumbar spines only (55), the lumbo-sacral spine (73) or the thoraco-lumbo-sacral spine (7).  Pedicle perforation, screw length and spondylolisthesis were assessed on post-operative CT-Scan.  Pain was surveyed using self-rated scales, visual analogue scales, Oswestry and SF-36 questionnaires.  Bony union was assessed on post-operative follow-up radiographs.   Results: Pedicle perforation was found in 49/836 (5.9%) screws (2.4% laterally, 1.7% inferiorly, 1.1% superiorly, 0.7% medially).  The errors were minor (0.1-2mm, 46/49) or intermediate (2.1 – 4 mm, 3/49).  All intermediate errors were lateral.  There were no major errors (≥ 4.1mm).  Some screws were judged too long (66/836, 8%).  The average time to insert one screw with navigation was 19.1 minutes from application to removal of the reference frame. The amount of improvement at one year post-operation for self-rated leg and back pain were 72% and 48% respectively.  The improvement was stable over 2 years.  Above-level and below-level radiological degenerations were found in 44 patients (33%) and 3 patients respectively (2%) and occurred on average 22.2 ± 2.6 months after the surgery.  Fusions ending at L2 had the most degenerations (14/25, 56%).       Conclusion: CT-based preoperative navigation for lumbo-sacral pedicle screw insertion is accurate and associated with a good short term outcome, making it worth the investment of the additional time required.  Segmental degeneration may have a negative effect on radiological and clinical outcomes.

Keyphrases: CT-based spinal navigation, Spondylolisthesis, Transpedicular screws, Lumbar fusion, Segmental degeneration
Vers une meilleure caractérisation des sujets atteints d’asthme exacerbé au travail

Background: Work related asthma (WRA) refers to asthma that is induced or exacerbated by the workplace. Occupational asthma (OA) and work-exacerbated asthma (WEA) are difficult to distinguish in clinical practice since in both conditions workers complain of deterioration of their asthma while at work. In addition, physicians are often faced with subjects with work related respiratory symptoms (WRS) without being asthmatics. These subjects are often excluded from studies whose aim is to better characterize WRA.  Objectives: 1. To compare the diurnal variability of peak expiratory flow (PEF) during periods at and away from work between subjects with OA and WEA. 2. To assess the prevalence of subjects with work related respiratory symptoms but without asthma among subjects referred for possible WRA, and to compare their characteristics and work environment to subjects with WRA. Results: Work exposures induce a significant PEF variability in both OA and WEA. However, the magnitude of variability is higher in OA than in WEA during work exposures. Subjects with WRS without asthma represent a large proportion of the subjects referred for possible WRA.  Conclusions: WRA should be considered in all individuals who present with new-onset or worsening asthma. The similarity of the symptoms between subjects with WRA and WRS emphasizes the need to perform an extensive investigation.  This investigation should be based on a stepwise approach in which multiple objective testing improves the certainty of diagnosis and help to differentiate between OA and WEA.

Keyphrases: Work-related asthma, Occupational asthma, Work-exacerbated asthma, Peak expiratory flow, Work-related respiratory symptoms
Évaluation de la durée des effets aigus de l'exercice sur la cognition

Objective: The purpose of this study was to evaluate the effects of a brief bout of physical exercise on executive cognitive functions and to determine the duration of these effects.  Method: Forty-eight healthy, undergraduate male students were divided into two experimental groups and one control group. The experimental intervention was a 30 minutes aerobic exercise on a treadmill. Both groups completed the Stroop test either immediately after the exercise (group 1) or 10 minutes later (group 2). The control group performed the same cognitive task but without any exercise.  Results: Statistical analyses did not indicate an effect of exercise on cognitive functioning, whether the cognitive task was performed immediately or 10 minutes after the exercise.  Conclusion: One bout of exercise did not influence performance on a cognitive functions task. Results are discussed in terms of methodological limitations and future research implications.

Keyphrases: Cognition, Attention, Inhibition, Stroop, Acute exercise, Cognition, Attention, Inhibition, Stroop, Executive function