The exponential increase in available neural data has combined with the exponential growth in computing (“Moore's law”) to create new opportunities to understand neural systems at large scale and high detail. The ability to produce large and sophisticated simulations has introduced unique challenges to neuroscientists. Computational models in neuroscience are increasingly broad efforts, often involving the collaboration of experts in different domains. Furthermore, the size and detail of models have grown to levels for which understanding the implications of variability and assumptions is no longer trivial. Here, we introduce the model design platform N2A which aims to facilitate the design and validation of biologically realistic models. N2A uses a hierarchical representation of neural information to enable the integration of models from different users. N2A streamlines computational validation of a model by natively implementing standard tools in sensitivity analysis and uncertainty quantification. The part-relationship representation allows both network-level analysis and dynamical simulations. We will demonstrate how N2A can be used in a range of examples, including a simple Hodgkin-Huxley cable model, basic parameter sensitivity of an 80/20 network, and the expression of the structural plasticity of a growing dendrite and stem cell proliferation and differentiation.
Objective
Platelet activation following stimulation of protease-activated receptor-4 (PAR4) is heightened in platelets from blacks compared to whites. The difference in PAR4 signaling by race is partially explained by a single nucleotide variant in PAR4 encoding for either an alanine (Ala) or threonine (Thr) at amino acid 120 in the second transmembrane domain. The current study sought to determine whether the difference in PAR4 signaling by this PAR4 variant is due to biased Gq signaling and whether the difference in PAR4 activity results in resistance to traditional antiplatelet intervention.
Approach and Results
Membranes expressing human PAR4 120 variants were reconstituted with either Gq or G13 to determine the kinetics of G protein activation. The kinetics of Gq and G13 activation were both increased in membranes expressing PAR4-Thr120 compared to those expressing PAR4-Ala120. Further, inhibiting PAR4-mediated platelet activation by targeting cyclooxygenase (COX) and P2Y12 receptor was less effective in platelets from subjects expressing PAR4-Thr120 compared to PAR4-Ala120. Additionally, ex vivo thrombus formation in whole blood was evaluated at high shear to determine the relationship between PAR4 variant expression, and response to antiplatelet drugs. Ex vivo thrombus formation was enhanced in blood from subjects expressing PAR4-Thr120 in the presence or absence of antiplatelet therapy.
Conclusions
Together this data supports that the signaling difference by the PAR4 120 variant results in the enhancement of both Gq and G13 activation, and an increase in thrombus formation resulting in a potential resistance to traditional antiplatelet therapies targeting COX-1 and the P2Y12 receptor.
Abstract. The Transportation Security Administration has a large workforce of Transportation Security Officers, most of whom perform interrogation of x-ray images at the passenger checkpoint. To date, TSOs on the x-ray have been limited to a 30-min session at a time, however, it is unclear where this limit originated. The current paper outlines methods for empirically determining if that 30-min duty cycle is optimal and if there are differences between individual TSOs. This work can inform scheduling TSOs at the checkpoint and can also inform whether TSOs should continue to be cross-trained (i.e., performing all 6 checkpoint duties) or whether specialization makes more sense.
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