Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic ...abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin-binding protein cyclase-associated protein 2 (
), the sheddase a disintegrin and metalloproteinase 10 (
), and the synapse-associated protein 97 (
). Our analysis of the SCZ post-mortem brain indicated increased
mRNA in DLPFC and decreased
mRNA in the hippocampus of SCZ patients, compared to non-psychiatric control subjects, while the
transcript was unaffected. Conversely, no differences in
,
, and
protein levels were detected between SCZ and control individuals in both brain regions. To assess whether
and
transcript alterations were selective for SCZ, we also measured their expression in the superior frontal gyrus of patients affected by neurodegenerative disorders, like Parkinson's and Alzheimer's disease. Interestingly, also in Parkinson's disease patients, we found a selective reduction of
mRNA levels relative to controls but unaltered protein levels. Taken together, we reported for the first time altered
expression in the brain of patients with psychiatric and neurological disorders, thus suggesting that aberrant expression of this gene may contribute to synaptic dysfunction in these neuropathologies.
Compartmentalization of cAMP and PKA activity in cardiac muscle cells plays a key role in maintaining basal and enhanced contractility stimulated by sympathetic nerve activity. In cardiomyocytes, ...activation of adrenergic receptor increases cAMP production, which is countered by the hydrolytic activity of selective phosphodiesterases (PDEs). The intracellular regional dynamics of cAMP production and hydrolysis modulate downstream signals resulting in different biological responses. The interplay between beta receptors (βARs) signalling and phosphodiesterase 5 (PDE5) activity remains to be addressed.
Using combined strategies with pharmacological inhibitors and genetic deletion of PDEs and βAR isoforms, we revealed a specific pool of cAMP that is under dual regulation by PDE2 and, indirectly, PDE5 activity. Inhibition of PDE5 with sildenafil produces a cGMP-dependent activation of PDE2 that attenuates cAMP generation induced by βAR agonists, with concomitant modulation of stimulated contraction rate and calcium transients. PDE2 haploinsufficiency abolished the effects of sildenafil. The negative chronotropic effect of PDE5 inhibition through PDE2 activation was also observed in sinoatrial node tissue from adult mice. PDE5 inhibition selectively lowered contraction rate stimulated by β2AR, but not β1AR activation, supporting a compartmentalization of the cGMP-modulated pool of cAMP.
These data identify a new effect of PDE5 inhibitors on the modulation of cardiomyocyte response to adrenergic stimulation via PDE5-PDE2-mediated cross-talk.
We report on the first direct comparisons of microtearing turbulence simulations to experimental measurements in a representative high bootstrap current fraction (f_{BS}) plasma. Previous studies of ...high f_{BS} plasmas carried out in DIII-D with large radius internal transport barriers (ITBs) have found that, while the ion energy transport is accurately reproduced by neoclassical theory, the electron transport remains anomalous and not well described by existing quasilinear transport models. A key feature of these plasmas is the large value of the normalized pressure gradient, which is shown to completely stabilize conventional drift-wave and kinetic ballooning mode instabilities in the ITB, but destabilizes the microtearing mode. Nonlinear gyrokinetic simulations of the ITB region performed with the cgyro code demonstrate that the microtearing modes are robustly unstable and capable of driving electron energy transport levels comparable to experimental levels for input parameters consistent with the experimental measurements. These simulations uniformly predict that the microtearing mode fluctuation and flux spectra extend to significantly shorter wavelengths than the range of linear instability, representing significantly different nonlinear dynamics and saturation mechanisms than conventional drift-wave turbulence, which is also consistent with the fundamental tearing nature of the instability. The predicted transport levels are found to be most sensitive to the magnetic shear, rather than the temperature gradients more typically identified as driving turbulent plasma transport.
The high poloidal-beta (
β
P
) regime was first proposed as a high bootstrap current scenario for a steady-state fusion pilot plant (FPP) in the 1990s (Kikuchi in Nucl Fusion 30:265, 1990). Since ...then, there have been many theoretical, modeling, and experimental research activities on this topic. A joint DIII-D/EAST research team began exploring the high-
β
P
regime in 2013, focusing on addressing the needs of attractive FPP design by taking advantage of the extensive diagnostic set and sophisticated plasma control system on DIII-D and the well-developed integrated modeling capability at General Atomics. The ultimate goal is to demonstrate such a scenario on EAST with truly long pulse and metal wall compatibility. This paper summarizes the highlights of the research results on DIII-D by the joint team in the past decade. Experimental evidence and modeling analysis show the high-
β
P
scenario has great advantages in addressing key needs for an attractive FPP design, such as high-energy confinement quality at low rotation, excellent core-edge integration, high line-averaged density above the Greenwald limit, low disruption risk, and high bootstrap current fraction for steady-state operation. This provides a relatively safe and economical option to base an FPP design on that will lead to commercial fusion energy.
Abstract DIII-D experiments demonstrate that high pressure, broad current profile equilibria can be accessed in the high poloidal beta regime by optimizing the MHD mode control poloidal spectrum. A ...novel, variable spectrum (VS) magnetic feedback scheme implemented using the DIII-D internal non-axisymmetric coils (I-coils) facilitated access to reduced internal inductance ℓ i operation above the no-wall beta limit compared with both no feedback and fixed spectrum feedback. In addition, the VS feedback helped avoid beta collapses caused by marginally unstable resistive wall mode activity. The lower and upper I-coil rows were configured in two independent feedback loops, allowing the feedback field’s poloidal spectrum to vary and track changes in the plasma mode structure as the edge safety factor q 95 varied from 11 to 6 during the discharges. The q 95 dependence of the measured phase difference between the lower and upper I-coil rows during VS feedback is qualitatively compatible with ideal MHD simulations of the least-stable plasma kink mode and with plasma response simulations that included kinetic modifications to ideal MHD. The VS feedback approach is a straightforward way to improve resilience to variations in mode structure that occur as plasma parameters change. The demonstrated expansion of the operating space to lower ℓ i is expected to improve the coupling of the plasma kink mode to external fields and beneficial wall eddy currents, and is compatible with high bootstrap fraction operation.
A path to a new high performance regime has been discovered in tokamaks that could improve the attractiveness of a fusion reactor. Experiments on DIII-D using a quiescent H-mode edge have navigated a ...valley of improved edge peeling-ballooning stability that opens up with strong plasma shaping at high density, leading to a doubling of the edge pressure over the standard H mode with edge localized modes at these parameters. The thermal energy confinement time increases as a result of both the increased pedestal height and improvements in the core transport and reduced low-k turbulence. Calculations of the pedestal height and width as a function of density using constraints imposed by peeling-ballooning and kinetic-ballooning theory are in quantitative agreement with the measurements.
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