Infantile neuronal ceroid lipofuscinosis (INCL), the most severe form of neuronal ceroid lipofuscinoses, is caused by mutations in the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). Typical symptoms of this disease include progressive psychomotor developmental retardation, visual failure, seizures, and premature death. Here, we investigated seizure activity and relevant pathological changes in PPT1 knock-in mice (PPT1 KI). The behavior studies in this study demonstrated that PPT1 KI mice had no significant seizure activity until 7 months of age, and local field potentials also displayed epileptiform activity at the same age. The expression levels of Iba-1 and CD68 demonstrated, by Western blot analysis, the inflammatory cytokine TNF-α content measured with enzyme-linked immunosorbent assay, and the number of microglia demonstrated by immunohistochemistry (IHC) were significantly increased at age of 7 months, all of which indicate microglia activation at an age of seizure onset. The increased expression of GFAP were seen at an earlier age of 4 months, and such an increase reached its peak at age of 6 months, indicating that astrocyte activation precedes microglia. The purinergic P2X7 receptor (P2X7R) is an ATP-sensitive ionic channel that is highly expressed in microglia and is fundamental to microglial activation, proliferation, cytokines release and epilepsy. We show that the ATP concentration in hippocampal tissue in PPT1 KI mice was increased using an enhanced ATP assay kit and demonstrated that the antagonist of P2X7R, A-438079, significantly reduced seizures in PPT1 KI mice. In contrast to glial cell activation and proliferation, a significant reduction in synaptic proteins GABAAR was seen in PPT1 KI mice. These results indicate that seizure in PPT1 KI mice may be associated with microglial activation involved in ATP-sensitive P2X7R signaling and impaired inhibitory neurotransmission.

Performance, functionality, and cost determine the competitiveness of CNC systems. These factors often conflict with each other. Cloud computing provides an enabling technology to meet the multidimensional challenges, potentially leading to CNC systems with both better performance and functionality, and lower cost. This article presents the architecture of a cloud-computing-based CNC system. This system locates its frontend in a cloud virtual machine and provides the frontend as a service. The frontend in cloud, otherwise known as a cloud-enabled frontend, remotely displays the interactive interface at a client device. The application program for interaction on the client is lightweight compared with the traditional CNC human machine interface and can be easily integrated into mobile devices, such as laptops. The cloud-enabled frontend communicates with an NC device (also known as the backend) on the shop floor via the Internet or an intranet. Only real-time tasks run on the backend, while other tasks (semi-real-time or non-real-time) are executed on the cloud-enabled frontend. Thus, the computing ability and intelligence of CNC systems can be improved by a switch to the cloud architecture. In the proposed solution, users can also launch third-party software (e.g. CAD, CAM, and CAE) on the cloud-enabled frontend, making it more versatile due to a rich application environment.

AimNeural network oscillation at gamma frequency band (γ oscillation, 30–80 Hz) is synchronized synaptic potentials important for higher brain processes and altered in normal aging. Recent studies indicate that activation of dopamine 4 receptor (DR4) enhanced hippocampal γ oscillation of young mice and fully recovered the impaired hippocampal synaptic plasticity of aged mice, we determined whether this receptor is involved in aging-related modulation of hippocampal γ oscillation.MethodsWe recorded γ oscillations in the hippocampal CA3 region from young and aged C57bl6 mice and investigated the effects of dopamine and the selective dopamine receptor (DR) agonists on γ oscillation.ResultsWe first found that γ oscillation power (γ power) was reduced in aged mice compared to young mice, which was restored by exogenous application of dopamine (DA). Second, the selective agonists for different D1- and D2-type dopamine receptors increased γ power in young mice but had little or small effect in aged mice. Third, the D4 receptor (D4R) agonist PD168077 caused a large increase of γ power in aged mice but a small increase in young mice, and its effect is blocked by the highly specific D4R antagonist L-745,870 or largely reduced by a NMDAR antagonist. Fourth, D3R agonist had no effect on γ power of either young or aged mice.ConclusionThis study reveals DR subtype-mediated hippocampal γ oscillations is aging-related and DR4 activation restores the impaired γ oscillations in aged brain, and suggests that D4R is the potential target for the improvement of cognitive deficits related to the aging and aging-related diseases.

No abstract

Infantile neuronal ceroid lipofuscinosis (INCL), the most severe form of neuronal ceroid lipofuscinoses, is caused by mutations in the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). Typical symptoms of this disease include progressive psychomotor developmental retardation, visual failure, seizures, and premature death. Here, we investigated seizure activity and relevant pathological changes in PPT1 knock-in mice (PPT1 KI). The behavior studies in this study demonstrated that PPT1 KI mice had no significant seizure activity until 7 months of age, and local field potentials also displayed epileptiform activity at the same age. The expressional levels of Iba-1 and CD68 demonstrated by Western blot analysis, the inflammatory cytokine TNFα content measured with enzyme-linked immunosorbent assay, and the branch number and length of microglia demonstrated by immunohistochemistry (IHC) were significantly increased at age of 7 months, all of which indicate microglia activation at an age of seizure onset. The increased expressional of GFAP was seen at an earlier age of 4 month and such an increase reached its peak at age of 6 month, indicating that astrocyte activation precedes microglia. The purinergic P2X7 receptor (P2X7R) is a ATP-sensitive ionic channel that is highly expressed in microglia and fundamental to microglial activation, proliferation, cytokines release and epilepsy. We show that the ATP concentration in hippocampal tissue in PPT1 KI mice was increased using an enhanced ATP assay kit and demonstrated that the antagonist of P2X7R, A-438079 significantly reduced seizures in PPT1 KI mice. In contrast to glial cell activation and proliferation, the significant reduction of synaptic proteins GABAAR were seen in PPT1 KI mice. These results indicate that seizure in PPT1 KI mice may be associated with microglial activation involving in ATP-sensitive-P2X7R signaling and damaged inhibitory neurotransmission.