A compensation-based pricing scheme in marketswith non-convexities

A compensation-based pricing scheme is a market clearing mechanism that may be applied when a uniform, linear pricing scheme cannot support equilibrium allocations in the auction markets. We analyze extensions of our previously proposed pricing scheme [14] to include various possible representations of bids that reflect some non-convex costs and constraints. We conclude with a discussion on directions for future research.auction design, electricity market, non-convex bids, minimum profit condition, unit commitment constraints

Désordres de l'homéostasie lipidique durant le développement du diabète non-insulino dépendant chez le psammomys obesus

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

Targeting the IL-33/ST2 pathway in asthma : implications for development, exacerbation and treatment

Asthma is a term that encompasses a disease spectrum with different phenotypes that vary in severity and whose common characteristic is airflow limitation. Allergic asthma is the most common phenotype of asthma and is characterized by allergen induced inflammatory responses, airway hyperresponsiveness (AHR), and remodeling. The limitations of current treatment together with the prospect of curative therapies set the incentive for identifying novel targets for asthma treatment. The epithelium-derived cytokine interleukin-33 (IL-33) and its receptor ST2 are implicated in the initiation and progression of asthma by several genetic and experimental studies. This thesis investigates the role of the IL-33/ST2 pathway in asthma development, exacerbation and treatment, using mouse models of asthma. In paper I, we investigated the role of IL-33/ST2 signaling in promoting allergen-induced AHR, airway inflammation, and remodeling in a mouse model of asthma, in which wild-type and ST2-/- mice were exposed to intranasal instillations of house dust mite (HDM) extract. We revealed that ST2-dependent signaling is important for the development of AHR in the peripheral lung compartment and for the development of inflammatory responses including airway eosinophilia, induction of allergen-specific IgE, inflammation and goblet cell hyperplasia in the peripheral airways, and production of the cytokines IL-5, IL-13 and IL-33. In paper II, we tested the hypothesis that IL-33/ST2-dependent mast cell responses contribute to the development of AHR and airway inflammation, using a model where the lungs of mast cell deficient mice were engrafted with either wild-type or ST2-/- bone marrow derived mast cells, and subsequently exposed to HDM. Unexpectedly, we discovered a protective role for ST2-dependent mast cell responses in the development of AHR located in the peripheral lung. This protective effect appeared to be independent of airway inflammation but was associated with elevated levels of PGE2, which has a bronchoprotective role in asthma. In paper III, we explored the potential of IL-33 to exacerbate allergen-induced asthma responses by exposing OVA-sensitized mice to IL-33 before each antigen challenge. We found that IL-33 acted cooperatively with antigen to aggravate AHR, remodeling and several inflammatory responses, including a substantial potentiation of antigen-specific IgE antibody production, increased mast cell activity, elevated levels of the TH2 cytokines IL-4, IL-5 and IL- 13, and accumulation of inflammatory cells in the airways and lung tissue, including expansion of the ILC2 population in the lungs. In paper IV, we evaluated the effects of vaccination against IL-33 in a mouse model of HDM-induced asthma. The vaccine comprised a recombinant IL-33 protein modified to induce immunological memory response, while reducing its cytokine activity. Vaccination against IL- 33 induced high titers of anti-IL-33 IgG antibodies, and attenuated several HDM-induced responses including AHR, airway eosinophilia, accumulation of inflammatory cells in the airways, and the levels of inflammatory cytokines including IL-25, IL-33 and TSLP. In conclusion, the work presented in this thesis provides further evidence and new insights into the importance of the IL-33/ST2 pathway in the development of asthma. The studies of this thesis identify an important role for this pathway in the regulation of AHR in the peripheral lung compartment, a protective role on AHR mediated by mast cells, and a role in asthma exacerbations associated with the expansion of the ILC2 population. Finally, we demonstrate that targeting the IL-33/ST2 pathway by vaccination against IL-33 has the potential to be an effective therapeutic tool for treating asthma

Oxidant/Antioxidant Imbalance in Alzheimer’s Disease: Therapeutic and Diagnostic Prospects

Alzheimer’s disease (AD) is the most common cause of dementia and a great socioeconomic burden in the aging society. Compelling evidence demonstrates that molecular change characteristics for AD, such as oxidative stress and amyloid β (Aβ) oligomerization, precede by decades the onset of clinical dementia and that the disease represents a biological and clinical continuum of stages, from asymptomatic to severely impaired. Nevertheless, the sequence of the early molecular alterations and the interplay between them are incompletely understood. This review presents current knowledge about the oxidative stress-induced impairments and compromised oxidative stress defense mechanisms in AD brain and the cross-talk between various pathophysiological insults, with the focus on excessive reactive oxygen species (ROS) generation and Aβ overproduction at the early stages of the disease. Prospects for AD therapies targeting oxidant/antioxidant imbalance are being discussed, as well as for the development of novel oxidative stress-related, blood-based biomarkers for early, noninvasive AD diagnostics

Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset.

Familial Alzheimer’s disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO. Pathogenic mutations affect the protease (PSEN/γ-secretase) and the substrate (APP) that generate amyloid β (Aβ) peptides. Altered Aβ metabolism has long been associated with AD pathogenesis, with absolute or relative increases in Aβ42 levels most commonly implicated in the disease development. However, analyses addressing the relationships between these Aβ42 increments and AAO are inconsistent. Here, we investigated this central aspect of AD pathophysiology via comprehensive analysis of 25 FAD-linked Aβ profiles. Hypothesis- and data-driven approaches demonstrate linear correlations between mutation-driven alterations in Aβ profiles and AAO. In addition, our studies show that the Aβ (37 + 38 + 40) / (42 + 43) ratio offers predictive value in the assessment of ‘unclear’ PSEN1 variants. Of note, the analysis of PSEN1 variants presenting additionally with spastic paraparesis, indicates that a different mechanism underlies the aetiology of this distinct clinical phenotype. This study thus delivers valuable assays for fundamental, clinical and genetic research as well as supports therapeutic interventions aimed at shifting Aβ profiles towards shorter Aβ peptides

Scoping review exploring the evidence base on Vitis vinifera toxicity in dogs after ingestion: Clinical effects, treatments and types of V. vinifera

BackgroundTreatment of Vitis vinifera fruit (VVF) ingestion can be challenging due to no clear toxic dose, signalment factors and variable clinical signs. Current treatment guidance is generalised: decontamination, aggressive fluid therapy, monitoring and/or treatment of renal dysfunction. The objective of this study was to conduct a scoping review of scientific evidence regarding the ingestion of VVF in dogs. Three primary areas were reviewed: VVF types ingested, clinical signs reported and treatments given. The inclusion criterion was any paper presenting data on clinical signs or treatments of dogs that had ingested VVF (unprocessed VVF only).MethodsThe following databases were searched: CAB Abstracts, Medline, Embase and Scopus. No limits were placed on language or date. The review followed the Joanna Briggs Institute scoping review methodology.ResultsTwenty-four papers were identified. A wide range of VVF types were ingested, but the toxic dose was difficult to ascertain. The most commonly reported signs were gastrointestinal, renal, neurological and haematological. Treatment commonly consisted of fluid therapy, diuretics and antiemetics.LimitationsThis scoping review neither explored cases of processed VVF ingestion nor did it chart laboratory findings; therefore, potentially clinically significant findings in these areas may have been missed.ConclusionsVVF ingestion typically causes gastrointestinal/renal dysfunction, with no clear toxicity attributable to VVF type. Treatments varied according to the presence/absence of clinical signs, and the prognosis was varied. Further research on current treatment efficacy is warranted, permitting an evidence-based, risk–benefit approach to be adopted by clinicians

Alzheimers disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimers disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling

Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators

γ‐Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN‐2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early‐onset AD. GSECs successively cut APP to generate amyloid‐β (Aβ) peptides of various lengths. AD‐causing mutations destabilize GSEC‐APP/Aβ_{n} interactions and thus enhance the production of longer Aβs, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP/Aβ_{n} during the sequential proteolysis. Our studies reveal that a direct interaction between NCT ectodomain and APP_{C99} influences the stability of GSEC‐Aβn assemblies and thereby modulates Aβ length. The data suggest a potential link between single‐nucleotide variants in NCSTN and AD risk. Furthermore, our work indicates that an extracellular interface between the protease (NCT, PSEN) and the substrate (APP) represents the target for compounds (GSMs) modulating Aβ length. Our findings may guide future rationale‐based drug discovery efforts

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnIL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.Netherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmar

Tau protein liquid–liquid phase separation can initiate tau aggregation

Abstract The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases