Forme et dynamique sociale de l'entreprise réseau : monographie d'un atelier de dessin technique

Le recours à la stratégie du recentrage sur le cœur de métier (core business) par les entreprises fait apparaître, en discours comme en pratique, trois mouvements qui déstabilisent les ensembles bureaucratiques: la réorganisation de la grande firme en « centres de profits », la multiplication des relations inter-firmes et un changement d’ordre qualitatif dans les termes de l’échange. L’avènement et le maintien de ce que nous convenons d’appeler l’« entreprise réseau » demeurent à ce jour problématique : soit cette forme organisationnelle serait le résultat d’une adaptation unilatérale à son environnement; soit la dynamique sociale serait réglée par la confiance entre les acteurs. Notre démarche inductive et exploratoire d’un cas d’entreprise réseau québécoise veut contribuer au démontage de la notion, puis à la compréhension sociologique du phénomène. Nous constatons que cette forme d’entreprise ne peut être comprise que lorsque nous la mettons en perspective avec l’entreprise bureaucratique.The strategic focus on the core business by bureaucratic firms contributed to the destabilization of this organizational form in three ways: the move to small « profits centers », the multiplication of exchange relations between firms and the changing nature of the relationships between them. The literature that explains the why and how of what we conceptualize as a « network firm » is still problematic. This management literature has two paradigms: either this organizational form is the result of a unilateral adaptation it’s environment ; either the social dynamic between firms is only based on trust. Our inductive research design is based on a single case of a multinational network Quebec firm. It tries to contribute to the analysis of this concept and to its sociological understanding. We conclude that this organizational form cannot be fully understood unless it is putted in perspective with the bureaucratic firm

A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator

Aims A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity. These first-in-human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI-291 in healthy volunteers.Methods In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI-291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle-aged or elderly volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI-291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed.Results LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. C-max, AUC(0-24) and AUC(0-inf) increased in a dose proportional manner. The median half-life was 28.0 hours after multiple dosing. No dose-dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected.Conclusions These first-in-human studies demonstrated that LTI-291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI-291 effects in a GBA1-mutated Parkinson population.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

MalDA, Accelerating Malaria Drug Discovery

© 2021 The Authors The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific laboratories. The aim of MalDA is to improve and accelerate the early antimalarial drug discovery process by identifying new, essential, druggable targets. In addition, it seeks to produce early lead inhibitors that may be advanced into drug candidates suitable for preclinical development and subsequent clinical testing in humans. By sharing resources, including expertise, knowledge, materials, and reagents, the consortium strives to eliminate the structural barriers often encountered in the drug discovery process. Here we discuss the mission of the consortium and its scientific achievements, including the identification of new chemically and biologically validated targets, as well as future scientific directions

The collapsible landscape

© 2013 Laura SkerljThis MFA project draws upon imagery of the natural environment, primarily geological, to construct imaginary landscapes. These landscapes resist the depiction of any actual site, and instead flex between constructed spatial binaries as seen to exist in nature, focusing on the division (and connection) between terrestrial and cosmic space. With a phenomenological underpinning, processes of assemblage pertinent to painting and drawing reinterpret the generic landscape formation to encourage a holistic vision of the environment. In turn, this project questions how constructing a landscape image ‘collapses’ its natural referent. Considering the ‘wilderness’ as a pre- or post-apocalyptic site, landscape without a figurative presence becomes the setting for a re-evaluated sublime experience. Here, potential environmental collapse threatens the terrestrial world (as in Jonathon Bordo’s ‘ecological sublime’), expanding our ‘natural’ position into a cosmic field. From this location, internal and external spaces are seen as interconnected. It is therefore through a geological metaphor or ‘mythologem’ that mountains, crystals and minerals are defined as subjects that create connections between these spatial zones. From this analysis derives a practice that expands and subsides the generic landscape formation through assemblage processes. This is presented in a series of studio investigations (drawing, photographic, sculptural), which pay particular attention to a separation of landscape elements, framing devises and collage techniques. Consequently, these experiments have encouraged a more open and propositional painting practice. In reference to Gilles Deleuze’s interpretation of the Baroque Fold, the work of Per Kirkeby and Laura Owens (among others) reveal a similarly fragmented approach to image making that conjures a flexible pictorial site or threshold. In summary, the construction of a landscape image subjectifies the natural world, transforming the tangible environment into a vision. From studio experiments, theoretical engagement and visual analysis, this project considers mechanisms for collapsing the natural referent of a landscape image. The fundamental technique utilised in this ‘collapse’ is assemblage: a fragmentary and connective visual process that enables the natural world to be envisioned as ‘siteless’

Synthesis and chemistry of alkyl 2, 3-bis(trimethylstannyl)-2-alkenoates and related substances

This thesis describes the synthesis and chemistry of alkyl 2,3-bis(trimethylstannyl)-2-alkenoates ((78) and (83)). It was shown that these compounds could be readily transformed into useful intermediates for the synthesis of functionalized, stereochemically defined tetrasub-stituted alkenes (87) and tricyclic dienes of general structure (322A). The synthesis and chemistry of compounds (277) and (278) is also described. The palladium(O)-catalyzed addition of hexamethylditin to a variety of α,β-acetylenic esters (90), afforded in a stereoselective manner, the corresponding alkyl (Z)-2,3-bis(trimethylstannyl)-2-alkenoates (83). Subsequent thermolysis of these compounds afforded the corresponding alkyl (E)-2 , 3-bis(trimethylstannyl)-2-alkenoates (78). It was found that treatment of alkyl (E)- and (Z)-2,3-bis(tri-methylstannyl)-2-alkenoates with methyllithium at low temperature, followed by reaction of the resultant nucleophilic intermediate with a variety of alkylating agents, afforded the trisubstituted vinylstannanes (80). On the other hand, successive treatment of methyl w-halo-2,3-bis-(trimethylstannyl)-2-alkenoates (202) with methyllithium and HMPA provided a facile route to cyclic β-trimethylstannyl α,β-unsaturated esters (203). Compounds (80) were readily converted into vinyl iodides of general structure (219) in which W is a functionalized group derived from the CO₂R moiety. These latter compounds served as useful intermediates for the synthesis of functionalized, stereochemically defined tetrasubstituted alkenes (87). For example, treatment of compounds (219) with 1.1 or 2.2 equiv of n-butyllithium at -78°C afforded the corresponding vinyllithium species (86) , which could either be alkylated directly or further transposed into the organocopper(I) reagent (263A) and then alkylated, to afford in each case, the tetrasubstituted alkenes (87). The Pd(0)-catalyzed addition of tri-n-butylstannyltrimethylgermane (276) to a variety of α,β-acetylenic esters (90) afforded the corresponding compounds (277) and (278) in a ratio of approximately 3:1, respectively. Treatment of the (E) isomers (277) with n-butyllithium at -98°C, followed by alkylation of the resultant nucleophilic intermediate afforded the corresponding trisubstituted vinylgermanes (293). One of these latter compounds was readily converted into the iodo bromide (308), which is potentially synthetically equivalent to the d,a synthon (310). When the enolate anion of compounds (203) was successively treated with HMPA and compound (308) the esters (311) were obtained. The Pd(0) catalyzed intramolecular coupling of the vinylstannane-vinyl iodide moieties of (311) provided a facile route to the bicyclic triene esters (312). Similarly, alkylation of the enolate anion of compounds (203) with (325) (which was readily obtained from (203), in which n - 1), followed by the Pd(0)-catalyzed coupling of the resulting alkylated material afforded the tricyclic diene esters (322A). [Formula Omitted]Science, Faculty ofChemistry, Department ofGraduat