175 research outputs found
Use of Physiologically Based Biokinetic (PBBK) Modeling to Study Estragole Bioactivation and Detoxification in Humans as Compared with Male Rats
The extent of bioactivation of the herbal constituent estragole to its ultimate carcinogenic metabolite 1′-sulfooxyestragole depends on the relative levels of bioactivation and detoxification pathways. The present study investigated the kinetics of the metabolic reactions of both estragole and its proximate carcinogenic metabolite 1′-hydroxyestragole in humans in incubations with relevant tissue fractions. Based on the kinetic data obtained a physiologically based biokinetic (PBBK) model for estragole in human was defined to predict the relative extent of bioactivation and detoxification at different dose levels of estragole. The outcomes of the model were subsequently compared with those previously predicted by a PBBK model for estragole in male rat to evaluate the occurrence of species differences in metabolic activation. The results obtained reveal that formation of 1′-oxoestragole, which represents a minor metabolic route for 1′-hydroxyestragole in rat, is the main detoxification pathway of 1′-hydroxyestragole in humans. Due to a high level of this 1′-hydroxyestragole oxidation pathway in human liver, the predicted species differences in formation of 1′-sulfooxyestragole remain relatively low, with the predicted formation of 1′-sulfooxyestragole being twofold higher in human compared with male rat, even though the formation of its precursor 1′-hydroxyestragole was predicted to be fourfold higher in human. Overall, it is concluded that in spite of significant differences in the relative extent of different metabolic pathways between human and male rat there is a minor influence of species differences on the ultimate overall bioactivation of estragole to 1′-sulfooxyestragol
Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice
An imbalance between inhibitory and excitatory neurotransmission has been
proposed to contribute to altered brain function in individuals with Down
syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory
neurotransmitter in the central nervous system and accordingly treatment with
GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a
genetic model for DS. However, GABA-A antagonists are also convulsant which
preclude their use for therapeutic intervention in DS individuals. Here, we have
evaluated safer strategies to release GABAergic inhibition using a
GABA-A-benzodiazepine receptor inverse agonist selective for the α5-subtype
(α5IA). We demonstrate that α5IA restores learning and memory functions of
Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks.
Furthermore, we show that following behavioural stimulation, α5IA enhances
learning-evoked immediate early gene products in specific brain regions involved
in cognition. Importantly, acute and chronic treatments with α5IA do not induce
any convulsant or anxiogenic effects that are associated with GABA-A antagonists
or non-selective inverse agonists of the GABA-A-benzodiazepine receptors.
Finally, chronic treatment with α5IA did not induce histological alterations in
the brain, liver and kidney of mice. Our results suggest that non-convulsant
α5-selective GABA-A inverse agonists could improve learning and memory deficits
in DS individuals
A GPU-accelerated immersive audio-visual framework for interaction with molecular dynamics using consumer depth sensors
© the Partner Organisations 2014. With advances in computational power, the rapidly growing role of computational/simulation methodologies in the physical sciences, and the development of new human-computer interaction technologies, the field of interactive molecular dynamics seems destined to expand. In this paper, we describe and benchmark the software algorithms and hardware setup for carrying out interactive molecular dynamics utilizing an array of consumer depth sensors. The system works by interpreting the human form as an energy landscape, and superimposing this landscape on a molecular dynamics simulation to chaperone the motion of the simulated atoms, affecting both graphics and sonified simulation data. GPU acceleration has been key to achieving our target of 60 frames per second (FPS), giving an extremely fluid interactive experience. GPU acceleration has also allowed us to scale the system for use in immersive 360° spaces with an array of up to ten depth sensors, allowing several users to simultaneously chaperone the dynamics. The flexibility of our platform for carrying out molecular dynamics simulations has been considerably enhanced by wrappers that facilitate fast communication with a portable selection of GPU-accelerated molecular force evaluation routines. In this paper, we describe a 360°atmospheric molecular dynamics simulation we have run in a chemistry/physics education context. We also describe initial tests in which users have been able to chaperone the dynamics of 10-alanine peptide embedded in an explicit water solvent. Using this system, both expert and novice users have been able to accelerate peptide rare event dynamics by 3-4 orders of magnitude. This journal i
In Silico Reconstitution of Actin-Based Symmetry Breaking and Motility
Computational modeling and experimentation in a model system for actin-based force generation explain how actin networks initiate and maintain directional movement
Microtubules as Platforms for Assaying Actin Polymerization In Vivo
The actin cytoskeleton is continuously remodeled through cycles of actin filament assembly and disassembly. Filaments are born through nucleation and shaped into supramolecular structures with various essential functions. These range from contractile and protrusive assemblies in muscle and non-muscle cells to actin filament comets propelling vesicles or pathogens through the cytosol. Although nucleation has been extensively studied using purified proteins in vitro, dissection of the process in cells is complicated by the abundance and molecular complexity of actin filament arrays. We here describe the ectopic nucleation of actin filaments on the surface of microtubules, free of endogenous actin and interfering membrane or lipid. All major mechanisms of actin filament nucleation were recapitulated, including filament assembly induced by Arp2/3 complex, formin and Spir. This novel approach allows systematic dissection of actin nucleation in the cytosol of live cells, its genetic re-engineering as well as screening for new modifiers of the process
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