Exploring the Potential of a Serious Game Framework in Developing Systems-Thinking Skills.

Effective decision-making within veterinary practice demands a comprehensive understanding of interconnected animal, public, and environmental health systems. To foster systems thinking, participatory modeling and serious games are gaining prominence. Serious games combine play, instruction, and problem-based learning to facilitate skill acquisition.

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury.

Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9Q152H variation.

New Opioid Use after Invasive Mechanical Ventilation and Hospital Discharge.

Patients who receive invasive mechanical ventilation (IMV) are usually exposed to opioids as part of their sedation regimen. The rates of posthospital prescribing of opioids are unknown. To determine the frequency of persistent posthospital opioid use among patients who received IMV.

Trends in opioid use before critical illness among elderly patients in Ontario.

Purpose: To assess temporal trends in pre-existing opioid exposure prior to hospitalization among elderly intensive care unit (ICU) patients and its association with adverse outcomes.

Materials And Methods: We performed a population-based retrospective cohort study using health administrative data from the province of Ontario, Canada. We included all older adult (> 65 years) admissions to an ICU between April 2002 and March 2015.

Opioid Use After ICU Admission Among Elderly Chronic Opioid Users in Ontario: A Population-Based Cohort Study.

Objectives: Critical illness is often associated with painful procedures and prolonged opioid infusions, raising the concern that chronic opioid users may be exposed to escalating doses that are continued after hospital discharge. We sought to assess patterns of opioid use after intensive care among elderly patients identified as chronic opioid users prior to hospitalization.

Design: Population-based cohort study.

Osteopontin as a novel substrate for the proprotein convertase 5/6 (PCSK5) in bone.

Seven proprotein convertases cleave the basic amino acid consensus sequence K/R-X-K/R↓ (where n=0, 2, 4 or 6 variable amino acids) to activate precursor proteins. Despite similarities in substrate specificity, basic amino acid-specific proprotein convertases have a distinct tissue distribution allowing for enzymatic actions on tissue-resident substrates. Proprotein convertase 5/6 (PC5/6) has two splice variants - soluble PC5/6A and membrane-bound PC5/6B - and is expressed during mouse development in many tissues including bone and tooth, but little is known about the substrates for PC5/6 therein.

Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism.

Accumulating evidence implicates endoplasmic reticulum (ER) stress as a mediator of impaired lipid metabolism, thereby contributing to fatty liver disease and atherosclerosis. Previous studies demonstrated that ER stress can activate the sterol regulatory element-binding protein-2 (SREBP2), an ER-localized transcription factor that directly up-regulates sterol regulatory genes, including PCSK9 Given that PCSK9 contributes to atherosclerosis by targeting low density lipoprotein (LDL) receptor (LDLR) degradation, this study investigates a novel mechanism by which ER stress plays a role in lipid metabolism by examining its ability to modulate PCSK9 expression. Herein, we demonstrate the existence of two independent effects of ER stress on PCSK9 expression and secretion.

PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice.

Proprotein convertase subtilisin kexin type 9 (PCSK9), the last member of the family of Proprotein Convertases related to Subtilisin and Kexin, regulates LDL-cholesterol by promoting the endosomal/lysosomal degradation of the LDL receptor (LDLR). Herein, we show that the LDLR cell surface levels dramatically increase in the liver and pancreatic islets of PCSK9 KO male but not female mice. In contrast, in KO female mice, the LDLR is more abundant at the cell surface enterocytes, as is the VLDL receptor (VLDLR) at the cell surface of adipocytes.

The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions.

The secretory proprotein convertase (PC) family comprises nine members: PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9. The first seven PCs cleave their substrates at single or paired basic residues, and SKI-1/S1P cleaves its substrates at non-basic residues in the Golgi. PCSK9 cleaves itself once, and the secreted inactive protease escorts specific receptors for lysosomal degradation.

Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies.

The discovery of PCSK9 in 2003 and its identification as the third protagonist responsible for ADH opened many new avenues of research in the cardiovascular field. Liver PCSK9 binds the LDLR and promotes its degradation in the endosomal/lysosomal pathway. A higher activity of PCSK9 leads to lower liver LDLR levels, resulting in a reduction in LDL-uptake from circulation, and thus in hypercholesterolemia and associated atherosclerosis.

Association between generalized anxiety disorder and asthma morbidity.

Background: Generalized anxiety disorder (GAD) is common among people with asthma, but its association with asthma morbidity remains unexplored. This study examined cross-sectional associations between GAD and asthma control, quality of life, and self-efficacy.

Methods: Seven hundred ninety-four adults with confirmed asthma were recruited from the outpatient clinic of a university hospital.

Characterization of ostrich (Struthio camelus) beta-microseminoprotein (MSP): identification of homologous sequences in EST databases and analysis of their evolution during speciation.

Beta-microseminoprotein, alternatively called prostatic secretory protein of 94 amino acids, is a hydrophilic, unglycosylated, small protein rich in conserved half-cystine residues. Originally found in human seminal plasma and prostatic fluids, its presence was later shown in numerous secretions and its homologs were described in many vertebrate species. These studies showed that this protein had rapidly evolved, but they failed to unambiguously identify its biological role.

Proprotein convertase PC1/3-related peptides are potent slow tight-binding inhibitors of murine PC1/3 and Hfurin.

The proprotein convertase PC1/3 belongs to the subtilisin/kexin-like endoprotease family and is synthesized as a preproenzyme. To investigate the function of its propeptide, murine proPC1/3 and preproPC1/3 were isolated from the inclusion bodies of recombinant preproPC1/3 baculovirus-infected insect cells, rendered soluble with 6 M guanidine HCl and 20 mM dithiothreitol, and purified by gel filtration and metal-binding affinity chromatography. Two NH2-terminal fragments containing the complete propeptide 1-84 region were obtained after CNBr cleavage, purified, and chemically characterized.

In vitro cleavage of internally quenched fluorogenic human proparathyroid hormone and proparathyroid-related peptide substrates by furin. Generation of a potent inhibitor.

The cleavage of parathyroid hormone (PTH) from its precursor proparathyroid hormone (pro-PTH) is accomplished efficiently by the proprotein convertase furin (Hendy, G. N., Bennett, H.

Influence of genetic variability in the nondeletion LDL-receptor allele on phenotypic variation in French-Canadian familial hypercholesterolemia heterozygotes sharing a 'null' LDL-receptor gene defect.

We investigated the associations between low density lipoprotein (LDL)-receptor gene haplotypes and lipid and lipoprotein levels in French-Canadian individuals with familial hypercholesterolemia (FH). The 112 unrelated patients studied shared the same > 10 Kb deletion in the 5' region of the LDL-receptor gene, leading to a null allele. Support for the hypothesis that the deletion is carried on only one LDL-receptor restriction fragment length polymorphism (RFLP) haplotype in this sample has previously been demonstrated [1].

Fluorescent peptidyl substrates as an aid in studying the substrate specificity of human prohormone convertase PC1 and human furin and designing a potent irreversible inhibitor.

The substrate specificities of two human prohormone convertases, furin and PC1, were examined with a series of 7-amino-4-methylcoumarinamide (MCA) containing peptidyl substrates. Using acetyl-Arg-Ser-Lys-Arg-MCA as model, P4 Arg substitution by Lys or Orn resulted for furin in a 538- and a 280-fold lower kcat/Km value, but only in a 14- and 18-fold decrease for PC1. Substitution of P3 Ser by either Pro, Glu, or Lys does not modify significantly the kcat/Km value for PC1, whereas furin activity is seriously impaired by the Glu substitution.