Redox-Sensitive Calcium/Calmodulin-Dependent Protein Kinase IIα in Angiotensin II Intra-Neuronal Signaling and Hypertension

Dysregulation of brain angiotensin II (AngII) signaling results in modulation of neuronal ion channel activity, an increase in neuronal firing, enhanced sympathoexcitation, and subsequently elevated blood pressure. Studies over the past two decades have shown that these AngII responses are mediated, in part, by reactive oxygen species (ROS). However, the redox-sensitive target(s) that are directly acted upon by these ROS to execute the AngII pathophysiological responses in neurons remain unclear. Calcium/calmodulin-dependent protein kinase II (CaMKII) is an AngII-activated intra-neuronal signaling protein, which has been suggested to be redox sensitive as overexpressing the antioxidant enzyme superoxide dismutase attenuates AngII-induced activation of CaMKII. Herein, we hypothesized that the neuronal isoform of CaMKII, CaMKII-alpha (CaMKIIα), is a redox-sensitive target of AngII, and that mutation of potentially redox-sensitive amino acids in CaMKIIα influences AngII-mediated intra-neuronal signaling and hypertension. Adenoviral vectors expressing wild-type mouse CaMKIIα (Ad.wtCaMKIIα) or mutant CaMKIIα (Ad.mutCaMKIIα) with C280A and M281V mutations were generated to overexpress either CaMKIIα isoform in mouse catecholaminergic cultured neurons (CATH.a) or in the brain subfornical organ (SFO) of hypertensive mice. Overexpressing wtCaMKIIα exacerbated AngII pathophysiological responses as observed by a potentiation of AngII-induced inhibition of voltage-gated

The NMDA receptor GluN2C subunit controls cortical excitatoryinhibitory balance, neuronal oscillations and cognitive function

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2Ccontaining NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK- 801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatoryinhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders

Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion.

Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson\u27s disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state, and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits, and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astrocytes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment

Investigation on diffusion kinetics of Ti-X binary systems at 1300–1500 °C

The composition design of titanium alloys and some preparation processes require accurate diffusion kinetic databases. However, the current database of diffusion kinetics at high temperatures is not yet complete. In this work, the diffusion kinetics of five binary systems, Ti–Zr, Ti–Nb, Ti–Mo, Ti–Ta and Ti–W, were systematically investigated at 1300–1500 °C. The interdiffusion coefficients and impurity diffusion coefficients of the Ti-X binary systems were calculated according to the Den-Broeder and Hall methods. The results showed that the Ti–Nb, Ti–Mo, Ti–Ta and Ti–W exhibited strong concentration dependence of the diffusion coefficients at the temperature of 1300–1500 °C compared to the Ti–Zr system, which was considered as the domination of the difference in intrinsic properties between elements. Besides, the activation energies of diffusion were evaluated based on the Arrhenius relationship, where the Ti–Zr system exhibited the lowest activation energy among the five diffusion systems, followed by Ti–Nb, Ti–Mo, Ti–Ta and Ti–W systems. The diffusion kinetic data of titanium-based alloys at high temperatures were obtained in the present work, providing important references for the design, preparation and processing of new titanium alloys

Strength–Ductility Matching Mechanism for Multi-Phase Microstructure Control of High-Ductility Ship Plate Steel

Generally, the development of ship plate steels is mainly concerned with the improvement of strength and toughness, such as F32 and F36. Due to the strength–ductility trade-off, it is difficult to combine excellent ductility with strength improvement, resulting in a poor deformation ability of the traditional ship plate steels during collision. In the present study, a series of high-ductility ship plate steels with property gradients were obtained by multi-phase microstructure control. The strength–ductility matching mechanism was analyzed. Meanwhile, the roles of M/A islands and lamellar pearlites in plastic deformation were also revealed. The results show that the microstructure of “quasi-polygonal ferrite + granular bainite + M/A islands + fewer lamellar pearlites” has the best strength–ductility match. The excellent ductility is mainly dependent on dispersive kernel average misorientation, recrystallized grains without distortion, and soft grains. In addition, the longer branch crack can effectively relieve the stress concentration at the tip of the main crack. Compared with lamellar pearlites, the dispersed M/A island grains have a higher strength contribution and more stable γ-fibers, which is beneficial to delay the appearance of internal micro-voids and micro-cracks. However, the lamellar pearlites can coordinate deformation only when the orientation of thinner lamellae exceeds two