Quantitative Modeling of GRK-Mediated β2AR Regulation

We developed a unified model of the GRK-mediated β2 adrenergic receptor (β2AR) regulation that simultaneously accounts for six different biochemical measurements of the system obtained over a wide range of agonist concentrations. Using a single deterministic model we accounted for (1) GRK phosphorylation in response to various full and partial agonists; (2) dephosphorylation of the GRK site on the β2AR; (3) β2AR internalization; (4) recycling of the β2AR post isoproterenol treatment; (5) β2AR desensitization; and (6) β2AR resensitization. Simulations of our model show that plasma membrane dephosphorylation and recycling of the phosphorylated receptor are necessary to adequately account for the measured dephosphorylation kinetics. We further used the model to predict the consequences of (1) modifying rates such as GRK phosphorylation of the receptor, arrestin binding and dissociation from the receptor, and receptor dephosphorylation that should reflect effects of knockdowns and overexpressions of these components; and (2) varying concentration and frequency of agonist stimulation “seen” by the β2AR to better mimic hormonal, neurophysiological and pharmacological stimulations of the β2AR. Exploring the consequences of rapid pulsatile agonist stimulation, we found that although resensitization was rapid, the β2AR system retained the memory of the previous stimuli and desensitized faster and much more strongly in response to subsequent stimuli. The latent memory that we predict is due to slower membrane dephosphorylation, which allows for progressive accumulation of phosphorylated receptor on the surface. This primes the receptor for faster arrestin binding on subsequent agonist activation leading to a greater extent of desensitization. In summary, the model is unique in accounting for the behavior of the β2AR system across multiple types of biochemical measurements using a single set of experimentally constrained parameters. It also provides insight into how the signaling machinery can retain memory of prior stimulation long after near complete resensitization has been achieved

Effects of the neurogranin variant rs12807809 on thalamocortical morphology in schizophrenia

10.1371/journal.pone.0085603PLoS ONE812-POLN

Asynchronous Development of Cerebellar, Cerebello-Cortical, and Cortico-Cortical Functional Networks in Infancy, Childhood, and Adulthood

10.1093/cercor/bhw298Cerebal CortexGUSTO (Growing up towards Healthy Outcomes

Statistical maps of thalamic shape differences between schizophrenia T-allele homozygotes and control T-allele homozygotes (top panel); schizophrenia T-allele homozygotes and control C-allele carriers (middle panel).

<p>T-values are shown only in the regions with significant group differences after the correction of multiple comparisons. Keys: S – superior; I – inferior; A – anterior; P – posterior; L – left; R – right.</p

Enabling future nanomanufacturing through block copolymer self-assembly: A review

Self-assembly approaches, e.g. colloidal, emulsion and polymer phase separation, provide scientists withan exotic yet direct platform to access technologically desired nanostructures at competitive costs. Inparticular, soft nanomaterial systems such as block copolymer (BCP) materials present a powerful meansto tailor templates and spatially controlled systems that are amenable to large scale manufacturing practices.BCP nanoarchitectures in bulk, solution and thin film form can act as structural motifs to templateforeign materials and pave the way towards important applications across industry and society. Whileextensive literature and research efforts exist on electronic device uses using BCPs, we look at nascentapplications outside the integrated circuit realm. Recent reports are discussed including for example;light-harvesting (energy – section 2), metasurfaces (photonics – section 3), nanofiltration membranes(environmental – section 4) and antibacterial activity (biological – section 5). We endeavour to illustratethe window of opportunity presented through BCP self-assembly for nanomanufacturing. We believe thehighlights discussed will aid in directing new research initiatives and facilitate the large-scale integrationof BCP materials with broad societal impact