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Tissue-specific expression of CYP450s can regulate the intracellular concentration of drugs and explain inter-subject variability in drug action. The overall objective of our study was to determine in a large cohort of samples, mRNA levels and CYP450 activity expressed in the human heart. CYP450 mRNA levels were determined by RTPCR in left ventricular samples (n = 68) of explanted hearts from patients with end-stage heart failure. Samples were obtained from ischemic and non-ischemic hearts. In some instances (n = 7), samples were available from both the left and right ventricles. A technique for the preparation of microsomes from human heart tissue was developed and CYP450-dependent activity was determined using verapamil enantiomers as probe-drug substrates. Our results show that CYP2J2 mRNA was the most abundant isoform in all human heart left ventricular samples tested. Other CYP450 mRNAs of importance were CYP4A11, CYP2E1, CYP1A1 and CYP2C8 mRNAs while CYP2B6 and CYP2C9 mRNAs were present at low levels in only some of the hearts analyzed. CYP450 mRNAs did not differ between ischemic and non-ischemic hearts and appeared to be present at similar levels in the left and right ventricles. Incubation of verapamil with heart microsomes led to the formation of nine CYP450-dependent metabolites: a major finding was the observation that stereoselectivity was reversed compared to human liver microsomes, in which the R-enantiomer is metabolized to a greater extent. This study determined cardiac mRNA levels of various CYP450 isozymes involved in drug metabolism and demonstrated the prevalent expression of CYP2J2 mRNA. It revealed that cardiomyocytes can efficiently metabolize drugs and that cardiac CYP450s are highly relevant with regard to clearance of drugs in the heart. Our results support the claim that drug metabolism in the vicinity of a drug effector site can modulate drug effects.

A specific probiotic formulation composed of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+) has been marketed in North America since 1996. The strains and the commercial products have been evaluated for safety, identity, gastrointestinal survival, and stability throughout shelf life. The capacity of both the fermented beverages and the capsules to reduce incidences of antibiotic-associated diarrhea and Clostridium difficile infection (CDI) has been demonstrated in human clinical trials. Individual strains and the finished products have shown antimicrobial activity against C. difficile and toxin A/B neutralization capacity in vitro. The use of this specific probiotic formulation as part of a bundle of preventive measures to control CDI in healthcare settings is discussed.

Dyslipidemia, specifically abnormal levels of low-density lipoprotein cholesterol (LDL-C), is an important risk factor of cardiovascular disease. Evidence showing the promising abilities of probiotics to lower total cholesterol or LDL-C has, however, not yet convinced experts to recommend probiotic bacteria as treatment for blood lipid management. Therefore, there are opportunities for the development of new efficient cholesterol-lowering probiotics. Bile salt hydrolase (BSH) and feruloyl esterase (FAE) are bacterial enzymes proposed to explain the cholesterol-lowering capacity of some bacteria and have both been shown to be responsible for lipid reduction in vivo. Here, in order to select for cholesterol-lowering bacteria, 70 strains related to Lactobacillaceae were screened for BSH and FAE activities. Based on this two-way screening approach, two bacteria were selected and assessed for their capacity to assimilate cholesterol in vitro, another suggested mechanism. Lactobacillus acidophilus CL1285 showed BSH and FAE activity as well as capacity to assimilate cholesterol in vitro. Lactiplantibacillus plantarum CHOL-200 exhibited BSH activity and ability to assimilate cholesterol. These properties observed in vitro make both strains good probiotic candidates for the management of dyslipidemia. Further investigation is needed to assess their ability to reduce blood cholesterol in human trial.

Le principal objectif est l'étude qualitative et quantitative du comportement structural de panneaux non-contreventés soumis à un chargement horizontal représentant les efforts de vent et de séisme. Les objectifs spécifiques du projet sont: (i) de déterminer la capacité structurale des panneaux Murox non-contreventés afin d'évaluer les charges de dimensionnement (état limite ultime); (ii) de déterminer la rigidité latérale des panneaux Murox non-contreventés afin d'en évaluer le comportement en service (état limite de service); (iii) de déterminer le comportement et la capacité maximale des connexions vissées utilisées comme éléments connecteurs entre le revêtement et l'ossature métallique des panneaux Murox; (iv) de calculer la période fondamentale et l'amortissement d'une charpente composée de panneaux Murox dans le but d'en évaluer le comportement dynamique de base; et (v) de réaliser un modèle par éléments finis d'un panneau standard non-contreventé afin de pouvoir démontrer analytiquement la pertinence des hypothèses formulées en laboratoire par la reproduction du comportement expérimental et d'établir les bases d'un dimensionnement. (Abstract shortened by UMI.)

The boom in social entrepreneurship is evidence of the interest in a new development model.

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

Although quantitative isotope data from speleothems has been used to evaluate isotope-enabled model simulations, currently no consensus exists regarding the most appropriate methodology through which to achieve this. A number of modelling groups will be running isotope-enabled palaeoclimate simulations in the framework of the Coupled Model Intercomparison Project Phase 6, so it is timely to evaluate different approaches to using the speleothem data for data–model comparisons. Here, we illustrate this using 456 globally distributed speleothem δ18O records from an updated version of the Speleothem Isotopes Synthesis and Analysis (SISAL) database and palaeoclimate simulations generated using the ECHAM5-wiso isotope-enabled atmospheric circulation model. We show that the SISAL records reproduce the first-order spatial patterns of isotopic variability in the modern day, strongly supporting the application of this dataset for evaluating model-derived isotope variability into the past. However, the discontinuous nature of many speleothem records complicates the process of procuring large numbers of records if data–model comparisons are made using the traditional approach of comparing anomalies between a control period and a given palaeoclimate experiment. To circumvent this issue, we illustrate techniques through which the absolute isotope values during any time period could be used for model evaluation. Specifically, we show that speleothem isotope records allow an assessment of a model's ability to simulate spatial isotopic trends. Our analyses provide a protocol for using speleothem isotope data for model evaluation, including screening the observations to take into account the impact of speleothem mineralogy on δ18O values, the optimum period for the modern observational baseline and the selection of an appropriate time window for creating means of the isotope data for palaeo-time-slices.

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

L’augmentation du nombre de personnes âgées présentant des incapacités et ayant des maladies chroniques entraîne une hausse des besoins en services de santé à domicile. Le nombre d’études et de revues systématiques traitant des approches préventives pour cette clientèle a proliféré, générant un besoin de synthèse des connaissances. Nous avons mené une revue systématique de revues systématiques évaluant l’effet des programmes de visite préventive pour les personnes âgées. Des 5 973 citations identifiées dans plus de 30 bases de données de littérature grise et scientifique, 10 articles répondaient à tous les critères d’inclusion. Les revues systématiques étaient retenues si elles comprenaient des essais randomisés contrôlés comparant des interventions de soins à domicile offerts par un professionnel de la santé et ceux sans professionnels. Les interventions sont souvent des évaluations gériatriques globales et s’accompagnent de visites de suivi. Il ressort que les visites préventives multidimensionnelles à domicile ont le potentiel de diminuer la mortalité, en particulier chez les personnes âgées plus jeunes, et offrent aussi un potentiel d’amélioration de l’autonomie fonctionnelle. Toutefois, ces résultats doivent être interprétés avec prudence vue la diversité des interventions analysées. The rising number of older people living with disabilities and chronic diseases has increased home care needs. Studies and reviews exploring preventive approaches have proliferated, creating a need for a synthesis of evidence. We conducted a systematic review of systematic reviews to evaluate the effectiveness of preventive home visiting approaches for older people. Of the 5,973 citations identified in over 30 scientific and grey literature databases, 10 papers met all inclusion criteria. Systematic reviews were considered if they included controlled trials comparing interventions with and without professional home care. We found that interventions often included comprehensive geriatric assessments and follow-up visits. Results indicate that multidimensional preventive home visiting programs might have the potential to reduce mortality, in particular for younger subjects, and show a potential to improve functional autonomy, but these findings should be interpreted with caution due to the diversity of the interventions analysed.

Anomaly-based intrusion detection systems are essential defenses against cybersecurity threats because they can identify anomalies in current activities. However, these systems have difficulties providing entity processing independence through a programming language. In addition, a degradation of the detection process is caused by the complexity of scheduling the training and detection processes, which are required to keep the anomaly detection system continuously updated. This paper shows how to use the algebraic state-transition diagram (ASTD) language to develop flexible anomaly detection systems. This paper provides a model for detecting point anomalies using the unsupervised non-parametric technique Kernel Density Estimation to estimate the probability density of event occurrence. The proposed model caters for both the training and the detection phase continuously. The ASTD language streamlines the modeling of detection systems thanks to its process algebraic operators that provide a solution to overcome these challenges. By delegating the combination of anomaly-based detection processes to the ASTD language, the effort and complexity are reduced during detection models development. Finally, using a qualitative evaluation, this study demonstrates that the algebraic operators in the ASTD specification language overcome these challenges.