Ginsenoside Rg1 ameliorates stress-exacerbated Parkinson's disease in mice by eliminating RTP801 and α-synuclein autophagic degradation obstacle.

Emerging evidence shows that psychological stress promotes the progression of Parkinson's disease (PD) and the onset of dyskinesia in non-PD individuals, highlighting a potential avenue for therapeutic intervention. We previously reported that chronic restraint-induced psychological stress precipitated the onset of parkinsonism in 10-month-old transgenic mice expressing mutant human α-synuclein (αSyn) (hαSyn A53T). We refer to these as chronic stress-genetic susceptibility (CSGS) PD model mice. In this study we investigated whether ginsenoside Rg1, a principal compound in ginseng notable for soothing the mind, could alleviate PD deterioration induced by psychological stress. Ten-month-old transgenic hαSyn A53T mice were subjected to 4 weeks' restraint stress to simulate chronic stress conditions that worsen PD, meanwhile the mice were treated with Rg1 (40 mg· kg-1 ·d-1, i.g.), and followed by functional magnetic resonance imaging (fMRI) and a variety of neurobehavioral tests. We showed that treatment with Rg1 significantly alleviated both motor and non-motor symptoms associated with PD. Functional MRI revealed that Rg1 treatment enhanced connectivity between brain regions implicated in PD, and in vivo multi-channel electrophysiological assay showed improvements in dyskinesia-related electrical activity. In addition, Rg1 treatment significantly attenuated the degeneration of dopaminergic neurons and reduced the pathological aggregation of αSyn in the striatum and SNc. We revealed that Rg1 treatment selectively reduced the level of the stress-sensitive protein RTP801 in SNc under chronic stress conditions, without impacting the acute stress response. HPLC-MS/MS analysis coupled with site-directed mutation showed that Rg1 promoted the ubiquitination and subsequent degradation of RTP801 at residues K188 and K218, a process mediated by the Parkin RING2 domain. Utilizing αSyn A53T+; RTP801-/- mice, we confirmed the critical role of RTP801 in stress-aggravated PD and its necessity for Rg1's protective effects. Moreover, Rg1 alleviated obstacles in αSyn autophagic degradation by ameliorating the RTP801-TXNIP-mediated deficiency of ATP13A2. Collectively, our results suggest that ginsenoside Rg1 holds promise as a therapeutic choice for treating PD-sensitive individuals who especially experience high levels of stress and self-imposed expectations.

A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke.

Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-hypoxia inducible factor 1α (HIF-1α) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke.

A novel small-molecular CCR5 antagonist promotes neural repair after stroke.

Chemokine receptor 5 (CCR5) is one of the main co-receptors of HIV-1, and has been found to be a potential therapeutic target for stroke. Maraviroc is a classic CCR5 antagonist, which is undergoing clinical trials against stroke. As maraviroc shows poor blood-brain barrier (BBB) permeability, it is of interest to find novel CCR5 antagonists suitable for neurological medication. In this study we characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 was discovered in screening millions compounds in the Chemdiv library based on the molecular docking diagram of CCR5 and maraviroc. We found that A14 dose-dependently inhibited the CCR5 activity with an IC50 value of 4.29 µM. Pharmacodynamic studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and vivo. In a SH-SY5Y cell line overexpressing CCR5, A14 (0.1, 1 µM) significantly alleviated OGD/R-induced cell injury. We found that the expression of CCR5 and its ligand CKLF1 was significantly upregulated during both acute and recovery period in focal cortical stroke mice; oral administration of A14 (20 mg·kg-1·d-1, for 1 week) produced sustained protective effect against motor impairment. A14 treatment had earlier onset time, lower onset dosage and much better BBB permeability compared to maraviroc. MRI analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of treatment. We further revealed that A14 treatment blocked the protein-protein interaction between CCR5 and CKLF1, increasing the activity of CREB signaling pathway in neurons, thereby improving axonal sprouting and synaptic density after stroke. In addition, A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune cells. These results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke. A14 blocked the protein-protein interaction between CKLF1 and CCR5 after stroke by binding with CCR5 stably, improved the infarct area and promoted motor recovery through reversing the CREB/pCREB signaling which was inhibited by activated CCR5 Gαi pathway, and benefited to the dendritic spines and axons sprouting.

The Role of AMPARs Composition and Trafficking in Synaptic Plasticity and Diseases.

AMPA receptors are tetrameric ionic glutamate receptors, which mediate 90% fast excitatory synaptic transmission induced by excitatory glutamate in the mammalian central nervous system through the activation or inactivation of ion channels. The alternation of synaptic AMPA receptor number and subtype is thought to be one of the primary mechanisms that involve in synaptic plasticity regulation and affect the functions in learning, memory, and cognition. The increasing of surface AMPARs enhances synaptic strength during long-term potentiation, whereas the decreasing of AMPARs weakens synaptic strength during the long-term depression. It is closely related to the AMPA receptor as well as its subunits assembly, trafficking, and degradation. The dysfunction of any step in these precise regulatory processes is likely to induce the disorder of synaptic transmission and loss of neurons, or even cause neuropsychiatric diseases ultimately. Therefore, it is useful to understand how AMPARs regulate synaptic plasticity and its role in related neuropsychiatric diseases via comprehending architecture and trafficking of the receptors. Here, we reviewed the progress in structure, expression, trafficking, and relationship with synaptic plasticity of AMPA receptor, especially in anxiety, depression, neurodegenerative disorders, and cerebral ischemia.

Weak value amplification for angular velocity measurements.

The weak-value-amplification technique has shown great importance in the measurement of tiny physical effects. Here we introduce a polarization-dependent angular velocity measurement system consisting of two Glan prisms and a true zero-order half-wave plate, where a non-Fourier-limited Gaussian pulse acts as the meter. The angular velocities measurements results agree well with theoretical predictions, and its uncertainties are bounded by the Cramér-Rao bound. We also investigate uncertainties of angular velocities for different numbers of detected photons and the smallest reliable postselection probability, which can reach ${3.42*10^{- 6}}$.

Experimental Demonstration of Higher Precision Weak-Value-Based Metrology Using Power Recycling.

The weak-value-based metrology is very promising and has attracted a lot of attention in recent years because of its remarkable ability in signal amplification. However, it is suggested that the upper limit of the precision of this metrology cannot exceed that of classical metrology because of the low sample size caused by the probe loss during postselection. Nevertheless, a recent proposal shows that this probe loss can be reduced by the power-recycling technique, and thus enhance the precision of weak-value-based metrology. Here we experimentally realize the power-recycled interferometric weak-value-based beam-deflection measurement and obtain the amplitude of the detected signal and white noise by discrete Fourier transform. Our results show that the detected signal can be strengthened by power recycling, and the power-recycled weak-value-based signal-to-noise ratio can surpass the upper limit of the classical scheme, corresponding to the shot-noise limit. This work sheds light on higher precision metrology and explores the real advantage of the weak-value-based metrology over classical metrology.

Entanglement and Einstein-Podolsky-Rosen steering between a nanomechanical resonator and a cavity coupled with two quantum dots.

We propose a scheme for generation of the stationary continuous-variable entanglement and Einstein-Podolsky-Rosen (EPR) steering between an optical cavity mode and a nanomechanical resonator (NMR) mode. The cavity and the NMR are commonly coupled with two separated quantum dots (QDs), where the two QDs are driven simultaneously by a strong laser field. By adjusting the frequency of the strong laser field, the two QDs are nearly trapped on different dressed states, which is helpful to generate the entanglement between the cavity mode and the NMR mode. Due to the combined resonant interaction of the two QDs with the NMR-cavity subsystem, the photon and the phonon created and (or) annihilated are correlated. In this regime, the optimal entanglement of the two modes is obtained and the purity of the state of the NMR-cavity subsystem is near to 1. Furthermore, the coupling strength between the cavity and two QDs is different from the dot-NMR coupling strength, which leads to the different mean occupation numbers of the cavity and the NMR. In this case, one-way EPR steering is observed. In addition, through analyzing the purity, we find the conditions of the existence for the different types of EPR steering.

Comparison of ecosystem health in different geomorphic regions of Chishui River Basin, Southwest China.

Ecosystem health of the Chishui River Basin (CRB, a crucial ecological barrier in the upper reaches of the Yangtze River) is vital for the ecological security and sustainability of the Yangtze River Basin. We used RUSLE model, SWAT model, Fragstats and geographic detectors to construct a theoretical framework of ecosystem health assessment for CRB, and examined the spatiotemporal variations and driving factors of ecosystem health in CRB under ecological restoration from 2010 to 2020. The results showed that ecosystem service in the CRB decreased and then increased during 2010-2020 and the overall trend was downward. The overall ecosystem service function was higher in the Danxia (non-karst) area than that in the karst area. The ecosystem health was generally subhealthy, with the Danxia area being mostly extremely healthy and healthy, whereas the karst area mostly subhealthy and unhealthy. There were differences in the dominant drivers of ecosystem health between karst and Danxia areas. Vegetation, precipitation, and bedrock bareness rate were the dominant drivers in the karst area, while vegetation, land use, and precipitation were the dominant factors in Danxia area. After interaction detection, the explanatory power of impact factors increased, and the dominant interaction factor combinations in different geomorphological type regions had shown great differences. Among them, precipitation∩normalized difference vegetation index (NDVI), precipitation∩digital elevation model (DEM) and precipitation ∩ bedrock bareness rate were the dominant interaction factor combinations in the karst area, and NDVI∩precipitation, NDVI∩land use and NDVI∩DEM were the dominant interaction factor combinations in Danxia area. These results would provide scientific support for health maintenance and conservation of CRB ecosystem.

The versatile role of TREM2 in regulating of microglia fate in the ischemic stroke.

Microglia are the earliest activated and the longest lasting immune cells after stroke, and they participate in almost all the pathological reactions after stroke. However, their regulatory mechanism has not been fully elucidated. Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor that is mainly expressed in microglia of the central nervous system. The receptor plays an important role in regulating microglia energy metabolism and phenotypic transformation. At present, TREM2 has been developed as a potential target for AD, coronary atherosclerosis and other diseases. However, TREM2 does not provide a systematic summary of the functional transformation and intrinsic molecular mechanisms of microglia after stroke. In this paper, we have summarized the functional changes of TREM2 in microglia after stroke in recent years, and found that TREM2 has important effects on energy metabolism, phagocytosis and anti-inflammatory function of microglia after stroke, suggesting that TREM2 is a potential therapeutic target for the treatment of stroke.

Processing Chinese hand-radicals activates the medial frontal gyrus: A functional MRI investigation.

Embodied semantics theory asserts that the meaning of action-related words is neurally represented through networks that overlap with or are identical to networks involved in sory-motor processing. While some studies supporting this theory have focused on Chinese characters, less attention has been paid to their semantic radicals. Indeed, there is still disagreement about whether these radicals are processed independently. The present study investigated whether radicals are processed separately and, if so, whether this processing occurs in sensory-motor gions. Materials consisted of 72 high-frequency Chinese characters, with 18 in each of four ries: hand-action verbs with and without hand-radicals, and verbs not related to hand actions, with and without hand-radicals. Twenty-eight participants underwent functional MRI scans while reading the characters. Compared to characters without hand-radicals, reading characters with hand-radicals activated the right medial frontal gyrus. Verbs involving hand-action activated the left inferior parietal lobule, possibly reflecting integration of information in the radical with the semantic meaning of the verb. The findings may be consistent with embodied semantics theory and suggest that neural representation of radicals is indispensable in processing Chinese characters.