Morphine Induced Neuroprotection in Ischemic Stroke by Activating Autophagy Via mTOR-Independent Activation of the JNK1/2 Pathway.

Morphine (Mor) has exhibited efficacy in safeguarding neurons against ischemic injuries by simulating ischemic/hypoxic preconditioning (I/HPC). Concurrently, autophagy plays a pivotal role in neuronal survival during IPC against ischemic stroke. However, the involvement of autophagy in Mor-induced neuroprotection and the potential mechanisms remain elusive. Our experiments further confirmed the effect of Mor in cellular and animal models of ischemic stroke and explored its potential mechanism. The findings revealed that Mor enhanced cell viability in a dose-dependent manner by augmenting autophagy levels and autophagic flux in neurons subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Pretreatment of Mor improved neurological outcome and reduced infarct size in mice with middle cerebral artery occlusion/reperfusion (MCAO/R) at 1, 7 and 14 days. Moreover, the use of autophagy inhibitors nullified the protective effects of Mor, leading to reactive oxygen species (ROS) accumulation, increased loss of mitochondrial membrane potential (MMP) and neuronal apoptosis in OGD/R neurons. Results further demonstrated that Mor-induced autophagy activation was regulated by mTOR-independent activation of the c-Jun NH2- terminal kinase (JNK)1/2 Pathway, both in vitro and in vivo. Overall, these findings suggested Mor-induced neuroprotection by activating autophagy, which were regulated by JNK1/2 pathway in ischemic stroke.

Astrocytes Excessively Engulf Synapses in a Mouse Model of Alzheimer's Disease.

Synapse loss is one of the most critical features in Alzheimer's disease (AD) and correlates with cognitive decline. Astrocytes mediate synapse elimination through multiple EGF-like domains 10 (MEGF10) pathways in the developing and adult brain to build the precise neural connectivity. However, whether and how astrocytes mediate synapse loss in AD remains unknown. We here find that the phagocytic receptor MEGF10 of astrocytes is significantly increased in vivo and in vitro, which results in excessive engulfment of synapses by astrocytes in APP/PS1 mice. We also observe that the astrocytic lysosomal-associated membrane protein 1 (LAMP1) is significantly elevated, colocalized with the engulfed synaptic puncta in APP/PS1 mice, and astrocytic lysosomes contain more engulfed synaptic puncta in APP/PS1 mice relative to wild type mice. Together, our data provide evidence that astrocytes excessively engulf synapses in APP/PS1 mice, which is mediated by increased MEGF10 and activated lysosomes. The approach targeting synapse engulfment pathway in astrocytes would be a potent therapy for AD.

An integrated microfluidic chip for nucleic acid extraction and continued cdPCR detection of pathogens.

This paper introduces an enclosed microfluidic chip that integrates sample preparation and the chamber-based digital polymerase chain reaction (cdPCR). The sample preparation of the chip includes nucleic acid extraction and purification based on magnetic beads, which adsorb nucleic acids by moving around the reaction chambers to complete the reactions including lysis, washing, and elution. The cdPCR area of the chip consists of tens of thousands of regularly arranged microchambers. After the sample preparation processes are completed, the purified nucleic acid can be directly introduced into the microchambers for amplification and detection on the chip. The nucleic acid extraction performance and digital quantification performance of the system were examined using synthetic SARS-CoV-2 plasmid templates at concentrations ranging from 101-105 copies per µL. Further on, a simulated clinical sample was used to test the system, and the integrated chip was able to accurately detect SARS-CoV-2 virus particle samples doped with interference (saliva) with a detection limit of 10 copies per µL. This integrated system could provide a promising tool for point-of-care testing of pathogenic infections.

Sarcopenia is an independent risk factor for depression in patients with advanced lung cancer.

BACKGROUND: Depression is the most prevalent psychological issue among cancer patients and can seriously affect patients' life and disease prognosis and even lead to suicide. Sarcopenia is a manifestation of cancer cachexia, a chronic progressive process. It is accompanied by a sustained decrease in skeletal muscle mass, muscle strength, and physical function and likewise has various negative effects on the patient. This study aimed to evaluate sarcopenia and other factors that may affect depression in patients with lung cancer and to further analyze and discuss. METHODS: A total of 104 eligible patients were enrolled in this cross-sectional study, using the Hamilton Depression Scale to assess depression, obtaining the psoas muscle index (PMI) by computed tomography (CT), and performing the diagnosis of sarcopenia. Clinical and personal characteristics were collected by electronic medical records. RESULTS: We evaluated a total of 104 hospitalized cancer patients in this analysis, with mean age = 57.8 ± 11.0 years, and 65.38% (68) were female. We found that up to 31.7% (33) of the participants had depression and 61.5% (64) of the participants had sarcopenia, and no statistical differences were found among depressed and non-depressed patients in relation to age, smoking, gender, performance status, and pathology. Patients with sarcopenia have more than four times the risk of suffering from depression than patients without sarcopenia (OR = 4.133, 95%CI = 1.390-12.287; p = 0.011). Similarly, the possibility of depression in patients with PD (progressive disease) as efficacy evaluation increased by 13.482 times (95%CI = 2.121-85.679, p = 0.006). CONCLUSION: In individuals with terminal lung cancer, depression and sarcopenia are prevalent. A strong association between the two is now thought to exist. Sarcopenia and efficacy evaluation are independent risk factors for depression. The correlation between sarcopenia and depression underscores the need for early intervention by our clinicians.

Newly Designed Quinazolinone Derivatives as Novel Tyrosinase Inhibitor: Synthesis, Inhibitory Activity, and Mechanism.

We synthesized a series of quinazolinone derivates as tyrosinase inhibitors and evaluated their inhibition constants. We synthesized 2-(2,6-dimethylhepta-1,5-dien-1-yl)quinazolin-4(3H)-one (Q1) from the natural citral. The concentration, which led to 50% activity loss of Q1, was 103 ± 2 µM (IC50 = 103 ± 2 µM). Furthermore, we considered Q1 to be a mixed-type and reversible tyrosinase inhibitor, and determined the KI and KIS inhibition constants to be 117.07 µM and 423.63 µM, respectively. Our fluorescence experiment revealed that Q1 could interact with the substrates of tyrosine and L-DOPA in addition to tyrosinase. Molecular docking studies showed that the binding of Q1 to tyrosinase was driven by hydrogen bonding and hydrophobicity. Briefly, the current study confirmed a new tyrosinase inhibitor, which is expected to be developed into a novel pigmentation drug.

Methods to match high-intensity interval exercise intensity in hypoxia and normoxia - A pilot study.

The aim of this study was to compare high-intensity interval exercise (HIIE) sessions prescribed on the basis of a maximal value (peak power output, PPO) and a submaximal value (lactate threshold, LT) derived from graded exercise tests (GXTs) in normoxia and hypoxia. METHODS: A total of ten males (aged 18-37) volunteered to participate in this study. The experimental protocol consisted of a familiarization procedure, two GXTs under normoxia (FiO2 = 0.209) and two GXTs under normobaric hypoxia (FiO2 = 0.140), and three HIIE sessions performed in a random order. The HIIE sessions included one at hypoxia (HY) and two at normoxia (one matched for the absolute intensity in hypoxia, designated as NA, and one matched for the relative intensity in hypoxia, designated as NR). RESULTS: The data demonstrated that there was significant lower peak oxygen uptake (V̇O2peak), peak heart rate (HRpeak), PPO, and LT derived from GXTs in hypoxia, with higher respiratory exchange ratio (RER), when compared to those from GXTs performed in normoxia (p < 0.001). Among the three HIIE sessions, the NA session resulted in lower percentage of HRpeak (85.0 ± 7.5% vs 94.4 ± 5.0%; p = 0.002) and V̇O2peak (74.1 ± 9.1% vs 88.7 ± 7.7%; p = 0.005), when compared to the NR session. HIIE sessions in HY and NR resulted in similar percentage of HRpeak and V̇O2peak, as well as similar rating of perceived exertion and RER. The blood lactate level increased immediately after all the three HIIE sessions (p < 0.001), while higher blood lactate concentrations were observed immediately after the HY (p = 0.0003) and NR (p = 0.014) sessions when compared with NA. CONCLUSION: Combining of PPO and LT derived from GXTs can be used to prescribe exercise intensity of HIIE in hypoxia.

Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer's disease.

BACKGROUND: Tau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment. METHODS: The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1ß and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1ß and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA. RESULTS: We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition. CONCLUSION: In combination with the previously reported therapeutic effects of rutin on Aß pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aß.

Dexmedetomidine attenuates myocardial ischemia-reperfusion injury in vitro by inhibiting NLRP3 Inflammasome activation.

BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is the most common cause of death worldwide. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the inflammatory response to MIRI. Dexmedetomidine (DEX), a specific agonist of α2-adrenergic receptor, is commonly used for sedation and analgesia in anesthesia and critically ill patients. Several studies have shown that dexmedetomidine has a strong anti-inflammatory effect in many diseases. Here, we investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro. METHODS: We established an MIRI model in cardiomyocytes (CMs) alone and in coculture with cardiac fibroblasts (CFs) by hypoxia/reoxygenation (H/R) in vitro. The cells were treated with dexmedetomidine with or without MCC950 (a potent selective NLRP3 inhibitor). The beating rate and cell viability of cardiomyocytes, NLRP3 localization, the expression of inflammatory cytokines and NLRP3 inflammasome-related proteins, and the expression of apoptosis-related proteins, including Bcl2 and BAX, were determined. RESULTS: Dexmedetomidine treatment increased the beating rates and viability of cardiomyocytes cocultured with cardiac fibroblasts. The expression of the NLRP3 protein was significantly upregulated in cardiac fibroblasts but not in cardiomyocytes after H/R and was significantly attenuated by dexmedetomidine treatment. Expression of the inflammatory cytokines IL-1ß, IL-18 and TNF-α was significantly increased in cardiac fibroblasts after H/R and was attenuated by dexmedetomidine treatment. NLRP3 inflammasome activation induced the increased expression of cleaved caspase1, mature IL-1ß and IL-18, while dexmedetomidine suppressed H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. In addition, dexmedetomidine reduced the expression of Bcl2 and BAX in cocultured cardiomyocytes by suppressing H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. CONCLUSION: Dexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.

Superparamagnetic iron oxide nanoparticles conjugated with Aß oligomer-specific scFv antibody and class A scavenger receptor activator show therapeutic potentials for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. No disease-modifying strategy to prevent or delay AD progression currently exists. Aß oligomers (AßOs), rather than monomers or fibrils, are considered as the primary neurotoxic species. Therapeutic approaches that direct against AßOs and promote Aß clearance may have great value for AD treatment. RESULTS: We here reported a multifunctional superparamagnetic iron oxide nanoparticle conjugated with Aß oligomer-specific scFv antibody W20 and class A scavenger receptor activator XD4 (W20/XD4-SPIONs). Besides the diagnostic value, W20/XD4-SPIONs retained the anti-Aß properties of W20 and XD4 by inhibiting Aß aggregation, attenuating AßO-induced cytotoxicity and increasing microglial phagocytosis of Aß. When applied to APP/PS1 mice, W20/XD4-SPIONs significantly rescued cognitive deficits and alleviated neuropathology of AD mice. CONCLUSION: These results suggest that W20/XD4-SPIONs show therapeutic benefits for AD. In combination with the early diagnostic property, W20/XD4-SPIONs present as a promising agent for early-stage AD diagnosis and intervention.

The Toxicity and Polymorphism of ß-Amyloid Oligomers.

It is widely accepted that ß-amyloid oligomers (Aßos) play a key role in the progression of Alzheimer's disease (AD) by inducing neuron damage and cognitive impairment, but Aßos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aßos. We here review the mechanisms by which Aßos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aß*56 and spherical oligomers, and suggest that Aßos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aßos in AD human brain and examine the relationship between different Aßos and cognitive impairment.

Naturally occurring autoantibodies against α-synuclein rescues memory and motor deficits and attenuates α-synuclein pathology in mouse model of Parkinson's disease.

It has been suggested that aggregation of α-synuclein (α-syn) into oligomers leads to neurodegeneration in Parkinson's disease (PD), but intravenous immunoglobulin (IVIG) which contains antibodies against α-syn monomers and oligomers fails to treat PD mouse model. The reason may be because IVIG contains much low level of antibodies against α-syn, and of which only a small part can penetrate the blood-brain barrier, resulting in an extremely low level of effective antibodies in the brain, and limiting the beneficial effect of IVIG on PD mice. Here, we first isolated naturally occurring autoantibodies against α-syn (NAbs-α-syn) from IVIG. Our further investigation results showed that NAbs-α-syn inhibited α-syn aggregation and attenuated α-syn-induced cytotoxicity in vitro. Compared with vehicles, NAbs-α-syn significantly attenuated the memory and motor deficits by reducing the levels of soluble α-syn, total human α-syn and α-syn oligomers, decreasing the intracellular p-α-synser129 deposits and axonal pathology, inhibiting the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines, increasing the levels of PSD95, synaptophysin and TH in the brain of A53T transgenic mice. These findings suggest that NAbs-α-syn overcomes the deficiency of IVIG and exhibits a promising therapeutic potential for the treatment of PD.

A New Primer to Amplify pmoA Gene From NC10 Bacteria in the Sediments of Dongchang Lake and Dongping Lake.

Nitrite-dependent anaerobic methane oxidation (n-damo) is catalyzed by the NC10 phylum bacterium "Candidatus Methylomirabilis oxyfera" (M. oxyfera). Generally, the pmoA gene is applied as a functional marker to test and identify NC10-like bacteria. However, it is difficult to detect the NC10 bacteria from sediments of freshwater lake (Dongchang Lake and Dongping Lake) with the previous pmoA gene primer sets. In this work, a new primer cmo208 was designed and used to amplify pmoA gene of NC10-like bacteria. A newly nested PCR approach was performed using the new primer cmo208 and the previous primers cmo182, cmo682, and cmo568 to detect the NC10 bacteria. The obtained pmoA gene sequences exhibited 85-92% nucleotide identity and 95-97% amino acid sequence identity to pmoA gene of M. oxyfera. The obtained diversity of pmoA gene sequences coincided well with the diversity of 16S rRNA sequences. These results indicated that the newly designed pmoA primer cmo208 could give one more option to detect NC10 bacteria from different environmental samples.

A rare case of successful treatment of peritoneal dialysis patient with Serratia marcescens peritonitis without catheter removal: case report and literature review.

Serratia marcescens, as a Gram-negative opportunistic pathogen, is a rare cause of peritonitis and has worse clinical outcomes than Gram-positive peritonitis. In this case report, we describe a case of Serratia marcescens associated peritonitis that was successfully cured without catheter removal. A 40-year-old male patient with peritoneal dialysis who worked in the catering industry was admitted to the hospital for 16 hours after the discovery of cloudy peritoneal dialysate and abdominal pain. Ceftazidime and cefazolin sodium were immediately given intravenously as an empirical antibiotic regimen. After detecting Serratia marcescens in the peritoneal diasate culture, the treatment was switched to ceftazidime and levofloxacin. The routine examination of peritoneal dialysate showed a significant decrease in white blood cells, the peritoneal dialysate became clear, and the peritoneal dialysis catheter was retained. The patient was treated for 2 weeks and treated with oral antibiotics for 1 week. It is necessary to further strengthen the hygiene of work environment to prevent Serratia marcescens infection in peritoneal dialysis patients. We recommend that patients with Serratia marcescens associated peritonitis should be treated with a combination of antibiotics as early as possible empirically, and at the same time, the peritoneal dialysis fluid culture should be improved, and the antibiotic regimen should be timely adjusted according to the drug sensitivity results. For patients with clinical symptoms for more than 3 days, considering the strong virulence of Serratia marcescens, whether to use meropenem directly or not can provide a reference for clinical decision-making. Further clinical studies are needed to achieve more precise anti-infective treatment.

An ultrasensitive electrochemical aptasensor based on zeolitic imidazolate framework-67 loading gold nanoparticles and horseradish peroxidase for detection of aflatoxin B1.

Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins and poses a high risk to human health. Highly sensitive and rapid detection is one of the most effective preventive measures to avoid potential hazards. Herein, an electrochemical aptasensor based on DNA nanotetrahedron and zeolitic imidazolate framework-67 loading gold nanoparticles, horseradish peroxidase, and aptamers was designed for the ultrasensitive detection of AFB1. The high specific surface area and large pore volume of zeolitic imidazolate framework-67 can increase the loading capacity and further improve the detection sensitivity of electrochemical aptasensors. DNA nanotetrahedron can enhance the capture ability of AFB1 with steady immobilization. The developed aptasensor showed good analytical performance for AFB1 detection, with a detection limit of 3.9 pg mL-1 and a wide linear range of 0.01-100 ng mL-1. The aptasensor detected AFB1 in corn samples with recovery rates ranging from 94.19%-105.77% and has potential for use in food safety monitoring.

Morphine Preconditioning Alleviates Ischemia/Reperfusion-induced Caspase-8-dependent Neuronal Apoptosis through cPKCγ-NF-κB-cFLIPL Pathway.

BACKGROUND: Perioperative cerebral ischemia/reperfusion injury is a major contributor to postoperative death and cognitive dysfunction in patients. It was reported that morphine preconditioning (MP) can mimic ischemia/hypoxia preconditioning to protect against ischemia/reperfusion injury. However, the mechanism of MP on the ischemia/reperfusion-induced neuronal apoptosis has not been fully clarified. METHODS: The middle cerebral artery occlusion/reperfusion (MCAO/R) model of mice and the oxygen-glucose deprivation/reoxygenation (OGD/R) model in primary cortical neurons were used to mimic ischemic stroke. In vivo, the infarct size was measured by using TTC staining; NDSS, Longa score system, and beam balance test were performed to evaluate the neurological deficits of mice; the expression of the protein was detected by using a western blot. In vitro, the viability of neurons was determined by using CCK-8 assay; the expression of protein and mRNA were assessed by using western blot, RT-qPCR, and immunofluorescent staining; the level of apoptosis was detected by using TUNEL staining. RESULTS: MP can improve the neurological functions of mice following MCAO/R (P<0.001, n=10 per group). MP can decrease the infarct size (P<0.001, n=10 per group) and the level of cleaved-caspase-3 of mice following MCAO/R (P<0.01 or 0.001, n=6 per group). MP can increase the levels of cPKCγ membrane translocation, p-p65, and cFLIPL, and decrease the levels of cleaved-caspase-8, 3 in neurons after OGD/R or MCAO/R 1 d (P<0.05, 0.01 or 0.001, n=6 per group). In addition, MP could alleviate OGD/R-induced cell apoptosis (P<0.001, n=6 per group). CONCLUSION: MP alleviates ischemia/reperfusion-induced Caspase 8-dependent neuronal apoptosis through the cPKCγ-NF-κB-cFLIPL pathway.

Mouse serum albumin induces neuronal apoptosis and tauopathies.

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

Density affects plant size in the Gobi Desert.

Plant size is a crucial functional trait with substantial implications in agronomy and forestry. Understanding the factors influencing plant size is essential for ecosystem management and restoration efforts. Various environmental factors and plant density play significant roles in plant size. However, how plant size responds to mean annual precipitation (MAP), mean annual temperature (MAT), and density in the arid areas remains incomplete. To address this knowledge gap, we conducted comprehensive vegetation surveys in the Gobi Desert in northwestern China with a MAP below 250 mm. We also collected climate data to disentangle the respective influences of climate and density on the community-weighted plant height, crown length, and crown width. Our observations revealed that the community-weighted mean plant height, crown length, and width demonstrated a positive association with MAT but negative relationships with both MAP and density. These patterns can be attributed to the predominance of shrubs over herbs in arid regions, as shrubs tend to be larger in size. The proportion of shrubs increases with MAT, while it decreases with MAP and density, resulting in higher plant height and larger crown dimensions. Although both MAP and MAT affect plant size in the Gobi Desert, our findings highlight the stronger role of plant density in regulating plant size, indicating that the surrounding plant community and competition among individuals are crucial drivers of plant size patterns. Our findings provide valuable guidance for nature-based solutions for vegetation restoration and ecosystem management, highlighting the importance of considering plant density as a key factor when designing and implementing restoration strategies in arid areas.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1ß, which is subsequently secreted into the extracellular space. This secreted IL-1ß then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

Measurement of local government green governance efficiency based on total waste emissions and PM2.5 concentration: Evidence from China.

The problem of environmental pollution is becoming more and more prominent. Making ecological governance take an effective and sustainable development path has become a complex problem for countries to think about. The proposal of green governance provides new ideas for governments to manage enterprises and local environmental governance. The DEA method is commonly used to measure the effectiveness of environmental governance, but the traditional DEA method ignores environmental factors and management factors, and the measurement error is significant. Therefore, this paper introduces the total waste discharge and PM2.5 average concentration and other unexpected outputs, using the three-stage DEA model and three-stage DEA Malmquist index model, creatively constructing the green governance measurement index system, which measures and evaluates the green governance efficiency of 30 provinces in China from 2004 to 2019 from static and dynamic perspectives. The research results show that the efficiency value obtained by the three-stage DEA model is higher than the first stage, which confirms that the external environmental factors have a specific impact on the GGE. At the same time, the comprehensive technical efficiency value presents a "U"-shaped trend with time. From the perspective of sub-regions, there is heterogeneity in the efficiency values between regions, showing a decreasing trend of "east, west, and middle." From the efficiency decomposition results, the main reason for the negative growth rate of GGE is the low efficiency of technological progress, which provides targeted suggestions for governance in various regions of China. This study will help provinces prepare to strengthen investment in technological innovation, maximize the benefits of input and output, and promote green and sustainable development.