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1.
Dr. Christine Brotschi Dr. Martin H. Bolli Dr. John Gatfield Dr. Bibia Heidmann Dr. Francois Jenck Dr. Catherine Roch Dr. Thierry Sifferlen Dr. Alexander Treiber Dr. Jodi T. Williams Dr. Christoph Boss 《ChemMedChem》2020,15(5):430-448
The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 . 相似文献
2.
Riham Gharib Jouda Mediouni Ben Jema Catherine Charcosset Sophie Fourmentin Hlne Greige‐Gerges 《European Journal of Lipid Science and Technology》2020,122(5)
Eucalyptol (Euc) is a natural monoterpene with insecticide effects. Being highly volatile and sensitive to ambient conditions, its encapsulation would enlarge its application. Euc‐loaded conventional liposomes (CL), cyclodextrin/drug inclusion complex, and drug‐in‐cyclodextrin‐in‐liposomes (DCL) are prepared to protect Euc from degradation, reduce its evaporation, and provide its controlled release. The liposomal suspension is freeze‐dried using hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) as cryoprotectant. The liposomes are characterized before and after freeze‐drying. The effect of Euc on the fluidity of liposomal membrane is also examined. A release study of Euc from delivery systems, in powder and reconstituted forms, is performed by multiple head extraction at 60 °C after 6 months of storage at 4 °C. CL and DCL suspensions are homogeneous, show nanometric vesicles size, spherical shape, and negative surface charge before and after freeze‐drying. Moreover, HP‐β‐CD does not affect the fluidity of liposomes. CL formulations present a weak encapsulation for Euc. The loading capacity of eucalyptol in DCL is 38 times higher than that in CL formulation. In addition, freeze‐dried DCL and HP‐β‐CD/Euc inclusion complex show a higher retention of eucalyptol than CL delivery system. Both carrier systems HP‐β‐CD/Euc and Euc‐loaded DCL decrease Euc evaporation and improve its retention. Practical Applications: Eucalyptol is a natural insecticide. It is highly volatile and poorly soluble in water. To enlarge its application, its encapsulation in three delivery systems (conventional liposomes, cyclodextrin/drug inclusion complex, combined system composed of cyclodextrin inclusion complex and liposome) is studied. In this paper it is proved that cyclodextrin/eucalyptol inclusion complex and eucalyptol‐in‐cyclodextrin‐in‐liposome are effective delivery systems for encalyptol encapsulation, retention, and release. 相似文献
3.
Stewart Clegg Catherine P. Killen Christopher Biesenthal Shankar Sankaran 《International Journal of Project Management》2018,36(5):762-772
Project portfolio management (PPM) bridges strategy and project management. Traditional research in PPM has primarily investigated the rational, top-down and structural aspects of strategizing. By doing so, it has failed to focus on the underlying practices that are triggered by the strategy and how these practices frame strategy implementation. Practice-based research provides a methodological lens to explore the reality of strategic enactment through the project portfolio. Practice-based perspectives are under-represented in PPM research; therefore the aim of this paper is to provide an agenda for further practice-based research in PPM. Central to this agenda is a concern with various aspects of practice, including its discursivity, representation, dynamic capabilities, leadership and materiality. 相似文献
4.
Catherine O'Leary Yvonne de Kluizenaar Piet Jacobs Wouter Borsboom Ian Hall Benjamin Jones 《Indoor air》2019,29(3):423-438
There is growing awareness that indoor exposure to particulate matter with diameter ≤ 2.5 μm (PM2.5) is associated with an increased risk of adverse health effects. Cooking is a key indoor source of PM2.5 and an activity conducted daily in most homes. Population scale models can predict occupant exposures to PM2.5, but these predictions are sensitive to the emission rates used. Reported emission rates are highly variable and are typically for the cooking of single ingredients and not full meals. Accordingly, there is a need to assess PM2.5 emissions from the cooking of complete meals. Mean PM2.5 emission rates and source strengths were measured for four complete meals. Temporal PM2.5 concentrations and particle size distributions were recorded using an optical particle counter (OPC), and gravimetric sampling was used to determine calibration factors. Mean emission rates and source strengths varied between 0.54—3.7 mg/min and 15—68 mg, respectively, with 95% confidence. Using a cooker hood (apparent capture efficiency > 90%) and frying in non‐stick pans were found to significantly reduce emissions. OPC calibration factors varied between 1.5 and 5.0 showing that a single value cannot be used for all meals and that gravimetric sampling is necessary when measuring PM2.5 concentrations in kitchens. 相似文献
5.
Domingue Catherine Lemieux Jean-Michel Grenon Martin Molson John Therrien René Lajoie Pierre-Luc Blessent Daniela 《Mine Water and the Environment》2019,38(3):497-506
Mine Water and the Environment - Water inflows through fracture networks are a major economic and safety issue in underground mines. Although pre-grouting of pilot holes during mine development... 相似文献
6.
Daniel J. Owens Julien Messant Sophie Moog Mark Viggars Arnaud Ferry Kamel Mamchaoui Emmanuelle Lacne Norma Romro Astrid Brull Gisle Bonne Gillian Butler-Browne Catherine Coirault 《International journal of molecular sciences》2021,22(1)
Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/β catenin adhesion complexes. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective fusion of activated MuSCs, defective protein synthesis and defective remodeling of the neuromuscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the yes-associated protein (YAP). We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely related but less severe EDMD models. In conclusion, combining studies in vitro, in vivo, and patient samples, we find that LMNA-CMD mutations interfere with mechanosignaling pathways in skeletal muscle, implicating A-type lamins in the regulation of skeletal muscle growth. 相似文献
7.
El Mahdi Halim Hubert Perrot Ozlem Sel Catherine Debiemme-Chouvy Khalid Lafdi Mama El Rhazi 《International Journal of Hydrogen Energy》2021,46(38):19926-19938
The development of highly efficient catalysts using inexpensive and earth-abundant metals is a crucial factor in a large-scale commercialization of direct methanol fuel cells (DMFCs). In this study, we explored a new catalyst based on copper nanodendrites (CuNDs) supported on carbon nanofibers/poly (para-phenylenediamine) (CNF/PpPD) nanocomposite for methanol oxidation reaction (MOR). The catalyst support was prepared on a carbon paste electrode by electropolymerization of para-phenylenediamine monomer on a drop-cast carbon nanofibers network. Afterwards, CuNDs were electrodeposited on the nanocomposite through a potentiostatic method. The morphology and the structure of the prepared nanomaterials were characterized by transmission electron microscope, scanning electron microscope, energy dispersive X-ray, X-ray diffraction, and X-ray photoelectron spectroscope. The results suggested that a three-dimensional nanodendritic structure consisting of Cu2O and Cu(OH)2 formed on the hybrid CNF/PpPD nanocomposite. The catalytic performance of CuNDs supported on CNF, PpPD and CNF/PpPD was evaluated for MOR under alkaline conditions. The CNF/PpPD/CuNDs exhibits a highest activity (50 mA cm?2) and stability toward MOR over 6 h, with respect to CNF/CuNDs (40 mA cm?2) and PpPD/CuNDs (36 mA cm?2). This inexpensive catalyst with high catalytic activity and stability is a promising anode catalyst for alkaline DMFC applications. 相似文献
8.
Xuwei Liu Carine Le Bourvellec Sylvain Guyot Catherine M. G. C. Renard 《Comprehensive Reviews in Food Science and Food Safety》2021,20(5):4841-4880
Flavanols, a subgroup of polyphenols, are secondary metabolites with antioxidant properties naturally produced in various plants (e.g., green tea, cocoa, grapes, and apples); they are a major polyphenol class in human foods and beverages, and have recognized effect on maintaining human health. Therefore, it is necessary to evaluate their changes (i.e., oxidation, polymerization, degradation, and epimerization) during various physical processing (i.e., heating, drying, mechanical shearing, high-pressure, ultrasound, and radiation) to improve the nutritional value of food products. However, the roles of flavanols, in particular for their polymerized forms, are often underestimated, for a large part because of analytical challenges: they are difficult to extract quantitatively, and their quantification demands chemical reactions. This review examines the existing data on the effects of different physical processing techniques on the content of flavanols and highlights the changes in epimerization and degree of polymerization, as well as some of the latest acidolysis methods for proanthocyanidin characterization and quantification. More and more evidence show that physical processing can affect content but also modify the structure of flavanols by promoting a series of internal reactions. The most important reactivity of flavanols in processing includes oxidative coupling and rearrangements, chain cleavage, structural rearrangements (e.g., polymerization, degradation, and epimerization), and addition to other macromolecules, that is, proteins and polysaccharides. Some acidolysis methods for the analysis of polymeric proanthocyanidins have been updated, which has contributed to complete analysis of proanthocyanidin structures in particular regarding their proportion of A-type proanthocyanidins and their degree of polymerization in various plants. However, future research is also needed to better extract and characterize high-polymer proanthocyanidins, whether in their native or modified forms. 相似文献
9.
Yi-Ming Zhao Shikha Ojha Catherine M. Burgess Da-Wen Sun Brijesh K. Tiwari 《International Journal of Food Science & Technology》2021,56(2):721-732
This study aimed to evaluate the influence of plasma treatment time, bacterial exposure time to PAW and bacterial species on the inactivation efficacy of plasma-activated water (PAW), with additional investigation of the inactivation mechanisms of PAW. Six bacterial species, including Listeria innocua, Staphyloccus aureus, Escherichia coli, Pseudomonas fluorescens, Shewanella putrefaciens and Aeromonas hydrophila were selected as the representative bacteria. The initial bacterial concentration was around 7 log CFU ml−1 after mixing with PAW, and the inactivation efficacy was measured after different exposure times during the 4 °C storage. Scanning electron microscopy (SEM) images of the bacteria after PAW treatment were carried out to inspect the cell structure damage, and physicochemical properties of PAW, including pH, conductivity and long-living reactive species of H2O2, , and , were examined. The results showed that the inactivation efficacy of PAW was positively correlated with plasma treatment time and bacterial exposure time, and for the species examined in this study, the Gram-negative species were more sensitive to PAW than the Gram-positive species. Cell structure damage, including shrinkage, distortion, or holes, was observed after PAW treatment. The pH of PAW was acidified to 2.5–2.9, and conductivity was significantly increased to 518.0 μs cm−1. and H2O2 were reduced during the 48 h storage, while an increased concentration was observed for . This study demonstrated that the processing parameters of plasma treatment time, exposure time and characteristics of bacteria can significantly affect the inactivation efficacy of PAW. 相似文献
10.
Catherine S. Birch Graham A. Bonwick 《International Journal of Food Science & Technology》2019,54(5):1467-1485
Consumption of functional foods suggests a strategy to reduce the incidence of chronic health disorders. This message has resonated with consumers and driven market growth. Functional food research has significantly increased over the last decade but few studies have addressed the bioavailability of active ingredients for clinical efficacy. Baked goods such as bread, biscuits and cake are popular categories for innovation due to their widespread consumption. These new developments have often impacted on organoleptic properties of the finished products and thus consumer acceptance. Blending of bioactive ingredients may overcome this deficit. However, an understanding of the role of the microbiome in health has indicated that the efficacy of functional foods is unlikely to be uniform within the population. Further growth in the functional foods market, is likely to require greater evidence of the bioavailability of active ingredients, clinical effect and support for health claims by regulators especially in the EU. 相似文献