1.Analysis of Blood-absorbed Components and Their Metabolic Differences of Xiebaisan in Normal and Chronic Bronchitis Mice Based on UPLC-Q-Exactive Orbitrap MS
Peng PENG ; Jiaxin LI ; Xinyue YANG ; Fangle LIU ; Chenchen ZHU ; Chaozhan LIN ; Yufeng YAO
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(1):219-227
ObjectiveThis study aims to systematically analyze the blood-absorbed components and metabolic profiles of Xiebaisan(XBS) in normal and chronic bronchitis (CB) mice using ultra performance liquid chromatography-quadrupole-electrostatic field orbitrap high resolution mass spectrometry(UPLC-Q-Exactive Orbitrap MS), while comparing differences between the two states. MethodsThirty female BABL/c mice were randomly divided into the normal group, the normal drug administration group, the CB group, the CB drug administration group and the dexamethasone group, with 6 mice in each group. The CB mouse model was established by inducing with ovalbumin (OVA). The mice in the normal drug administration group and the CB drug administration group started to be gavaged with XBS(13.2 g·kg-1) from the 21st day, and the dexamethasone group mice were simultaneously gavaged with dexamethasone (0.5 mg·kg-1) until the end of the 35th day of the experiment. Subsequently, serum samples were collected and evaluated for their efficacy, based on the pharmacological evaluation indicators, to determine the efficacy of XBS in treating CB. Then the UPLC-Q-Exactive Orbitrap MS was employed to identify and analyze the chemical constituents, blood-absorbed components, and metabolites of XBS. Chemometric analysis was conducted to reveal metabolic profile differences under "dual states". Concurrently, Real-time PCR technology was utilized to detect the expression levels of key liver metabolic enzymes CYP2E1, CYP3A1, UGT1A1, and UGT1A6. ResultsA total of 28 prototype components and 158 metabolites (including 48 phase Ⅰ metabolites and 110 phase Ⅱ metabolites) of XBS were unambiguously identified in the serum of normal mice. Additionally, a comprehensive characterization was performed on a total of 32 prototype components and 178 metabolites (including 50 phase Ⅰ metabolites and 128 phase Ⅱ metabolites) of XBS in the serum of CB mice. Among them, 27 prototype components were detected in both states, including 12 flavonoids, 2 alkaloids, 3 triterpenes, 4 organic acids, 3 amides, 1 stilbene and 2 other compounds. The chemometrics analysis revealed no significant difference in the prototype components and metabolites of XBS between normal and CB mice; however, there was a significant increase in the in-vivo exposure of XBS in CB mice. Compared to normal mice, the levels of phase Ⅰ metabolites such as oxidation, reduction and methylation of blood components of XBS as well as phase Ⅱ metabolites of glucuronidation showed significant changes in CB mice. Real-time PCR further confirmed that these alterations were attributed to the upregulation of CYP2E1 (P<0.05), CYP3A1 (P>0.05), UGT1A1 (P<0.01) and UGT1A6 (P<0.01) enzymes expression in the liver of CB mice. ConclusionThis study elucidated the disparities in the levels of the blood-absorbed components and metabolic profiles of XBS in normal and CB mice, especially in oxidation, reduction, methylation in phase Ⅰ metabolism and glucoaldehyde acidification in phase Ⅱ metabolism. And there are related to the differences in the expression levels of phase Ⅰ and phase Ⅱ metabolic enzymes CYP2E1, CYP3A1, UGT1A1 and UGT1A6 in the liver.
2.Constructing an actor-network theory for integrating sports activity into rehabilitation based on Rehabilitation in Health Service System
Yaning CHENG ; Di CHEN ; Chenchen TANG ; Yifan TIAN ; Lixu LIU ; Yingxin ZHANG ; Yizheng WANG ; Yaling HUANG
Chinese Journal of Rehabilitation Theory and Practice 2026;32(5):508-521
ObjectiveTo construct an actor-network for integrating physical activity into rehabilitation services based on the World Health Organization Rehabilitation in Health Service System framework and actor-network theory (ANT). MethodsContent analysis was employed using the six building blocks of health service systems as the theoretical framework. Actors related to rehabilitation services were extracted and categorized into a rehabilitation actor pool, while a physical activity actor pool was formed based on four major physical activity scenarios. Actors from both pools were integrated, deduplicated and classified to form a final list of integrated actors. Using ANT, the construction process of the actor network integrating physical activity into rehabilitation was analyzed through the four stages of translation: problematization, interessment, enrollment and mobilization. ResultsA dynamic integration network was constructed, comprising human actors (patients, rehabilitation professionals, researchers, sports coaches, government departments, medical institutions, community organizations and industry media, etc.) and non-human actors (assistive devices, sports infrastructure, smart equipment, information systems, online exercise guidance systems, laws and regulations, strategic documents, and exercise prescriptions, etc.). The study identified maximizing rehabilitation outcomes as the mandatory passage point and elaborated on the critical role of government departments as focal actors in coordinating various stakeholders. ConclusionThe integration of physical activity into rehabilitation services is a dynamic network constructed by diverse actors through a process of translation. ANT provides an operational theoretical framework for cross-departmental governance of rehabilitation policies in China, promotes the spatial expansion of the rehabilitation field, and drives its transformation toward a networked and ecological system. The government needs to play a leading role in facilitating role reconstruction and synergy among heterogeneous actors in both the sports and rehabilitation sectors through mechanism design, to create a bidirectional empowerment mechanism that fosters mutual progress and ensures the sustainable development of integrated services.
3.Clinical and radiological features of multiple system atrophy
Journal of Apoplexy and Nervous Diseases 2025;42(4):300-305
Objective To investigate the clinical and radiological features of patients with different phenotypes of multiple system atrophy (MSA). Methods A total of 400 patients with MSA who attended the outpatient service or were hospitalized in Department of Neurology,Chinese PLA General Hospital,were enrolled,among whom there were 294 patients with MSA-cerebellar type (MSA-C) and 106 patients with MSA-Parkinsonian type (MSA-P). The t-test and the chi-square test were used to analyze the clinical manifestations,radiological features,and blood biochemical indicators of the two groups. Results As for clinical manifestations,there were significant differences in cerebellar symptoms,constipation,and Babinski sign between MSA-C patients and MSA-P patients (P<0.05). As for radiological features,positron emission tomography/computed tomography (PET/CT) showed that MSA-P patients had a typical reduction in DAT uptake in the putamen and the caudate nucleus,while magnetic resonance imaging showed that compared with the MSA-C group,the MSA-P group had a significantly higher proportion of patients with putamen fissure sign or white matter demyelination; for MSA-C patients,PET/CT showed cerebellar hypometabolism,and magnetic resonance imaging showed the cross sign and high signal intensity in the pontine arm,as well as a significantly higher proportion of patients cerebellar and pontine atrophy than MSA-P patients (P<0.05). As for laboratory markers,MSA-P patients had a significantly lower level of uric acid than MSA-C patients (P=0.029). Conclusion Patients with different subtypes of MSA have specific clinical features,radiological features,and uric acid level,which has a certain significance in the accurate diagnosis of MSA.
4.A deep learning model for the diagnosis of first-episode schizophrenia and grading of EEG abnormalities using EEG signals
Lili SHUI ; Chenchen LIU ; Yumin LI
Sichuan Mental Health 2025;38(4):308-314
BackgroundSchizophrenia is a highly heterogeneous disease with different clinical subtypes. Artificial intelligence technology represented by deep learning models has provided considerable benefits for the electroencephalogram (EEG)-based schizophrenia diagnosis, treatment and research, however, to date little research has been conducted regarding any of these benefits among Chinese schizophrenic patients. ObjectiveTo investigate the application of deep learning techniques utilizing EEG parameters for the diagnosis of first-episode schizophrenia and grading of EEG abnormalities in patients, with the aim of contributing to improved clinical diagnosis and treatment strategies for the disorder. MethodsFrom January 2020 to January 2023, a total of 130 patients with first-episode schizophrenia who met the diagnostic criteria of International Classification of Diseases, tenth edition (ICD-10), and attended at the Third People's Hospital of Fuyang, along with 150 health checkup examinees, were enrolled. All of them underwent EEG examination. An optimized long short-term memory (LSTM) deep learning model was developed utilizing EEG signals. Ten-fold cross-validation method was employed to evaluate the model's performance. The dataset was then split into two components: a training set (90%) for LSTM model development and a test set (10%) for validation. The accuracy, recall rate, precision, F1-score, schizophrenia diagnosis and EEG abnormality grading were used as evaluation indicators, and the results of the proposed model were compared to the assessments made by experienced psychiatrists. ResultsFor schizophrenia diagnosis, the modeling group achieved the following performance metrics: precision (94.40±3.03)%, recall rate (94.30±3.23)%, accuracy (94.60±2.22)%, and F1-score (94.20±2.20)%. In the validation group, the corresponding metrics were precision (90.90±2.85)%, recall rate (92.20±1.14)%, accuracy (92.20±1.69)%, and F1-score (91.50±1.78)%. Statistical analysis revealed no significant differences between the LSTM diagnostic model and the experienced psychiatrists in terms of precision, recall rate, accuracy, and F1-score for schizophrenia diagnosis (χ2=1.500, 0.750, 2.722, 1.056, P>0.05). The modeling group demonstrated an accuracy rate of (91.71±1.73)% in grading EEG abnormalities. For Grade 1 abnormalities, the modeling group reported a precision of (96.40±2.39)%, a recall rate of (94.77±1.40)%, and an F1-score of (95.55±1.14)%. In the case of Grade 2 abnormalities, the precision was (85.89±2.04)%, the recall rate was (88.10±6.18)%, and the F1-score was (87.06±3.12)%. For the more severe Grade 3 abnormalities, the modeling group's precision was (79.61±7.33)%, the recall rate was (81.79±9.87)%, and the F1-score was (80.41±6.79)%. Additionally, the validation group exhibited an accuracy rate of (85.61±6.16)%. The precision, recall rate, and F1-score for Grade 1 abnormalities were (91.43±6.25)%, (92.64±9.65)% and (91.56±4.83)%, respectively. For Grade 2 abnormalities, these metrics were (71.17±19.02)%, (77.64±17.24)% and (71.88±11.33)%. In the case of Grade 3 abnormalities, the precision was (90.00±21.08)%, the recall rate was (80.00±25.82)%, and the F1-score was (81.67±19.95)%. There was no significant difference in the accuracy, recall, accuracy and F1 value between LSTM model and senior doctors in evaluating the abnormal degree of EEG in schizophrenia (χ2=0.098, 0.036, 0.020, 0.336, P>0.05). The LSTM model takes less time to diagnose schizophrenia and EEG abnormalities than senior doctors, and the differences were statistically significant (t=57.147, 43.104, P<0.01). ConclusionThe study utilizes an EEG-based LSTM deep learning model for diagnosing first-episode schizophrenia and grading EEG abnormalities, and the model not only matches the performance of experienced psychiatrists but also significantly reduces the time required for diagnosis.
5.NEFA induces HIF-2α expression in dairy cow primary hepatocytes
Zifeng YANG ; Fanrong KONG ; Yan SUN ; Menglin LIU ; Jinxia LI ; Chenchen ZHAO ; Lin LEI ; Xinwei LI
Chinese Journal of Veterinary Science 2025;45(4):745-751
Ketosis is an energy metabolism disorder occurring frequently in periparturient dairy cows,primarily attributed to elevated non-esterified fatty acid(NEFA)levels resulting from nega-tive energy balance(NEB).Excessive NEFA will be incompletely oxidated into large amounts of ketone bodies or be re-esterified and deposit in the liver as a consequence of hepatic limited oxida-tive capacity,ultimately leading to ketosis and fatty liver.Hypoxic microenvironments are com-monly found during the progression of various liver diseases.Hypoxia inducible factor-2 alpha(HIF-2 alpha)has been identified as a crucial regulator of lipid metabolism.However,it is still un-clear the association between HIF-2α and disrupted lipid metabolism in the livers of in ketotic cows.This study aims to investigate the effect of high concentrations of NEFA on HIF-2α expres-sion and cellular oxygen homeostasis through bovine liver tissue and primary hepatocytes.In vivo,hepatic triglyceride(TAG)content was assessed to determine the extent of hepatic lipid accumula-tion,and HIF-2α protein and mRNA levels were analyzed by immunohistochemistry staining,Western blot and qRT-PCR assay in liver tissue samples from dairy cows;in vitro,bovine primary hepatocytes were treated with different concentrations of NEFA.Oil Red O staining and TAG con-tent assay were performed to determine hepatocellular steatosis extent,and immunofluorescence staining.Western blot,and qRT-PCR were performed to analyze HIF-2α expression,in addition,lu-minescent oxygen sensor[Ru(dpp)3]Cl2 was added to indicate intracellular oxygen levels.These results showed a significant increase in TAG content and elevated HIF-2α expression in the liver tissue of ketotic cows,and high concentrations of NEFA induced lipid accumulation,upregulation of HIF-2α expression,and intracellular hypoxia in bovine primary hepatocytes.These findings sug-gested that HIF-2α was significantly"activated"in the liver of ketotic cows and high concentration of NEFA-induced bovine primary hepatocytes,and that high concentrations of NEFA induced in-tracellular hypoxia in vitro.This study provides a potential molecular target for further investiga-tion of the mechanism underlying hepatic lipid metabolism disorders in ketotic cows.
6.To explore the curative effect of tangerine peel compound on chicken Eimeria tenella disease
Junze CHENG ; Chenchen WANG ; Qi ZHANG ; Huixin LIU ; Qiyuan ZHAO ; Ting ZHANG ; Zong-gu XIE ; Hongbin SI
Chinese Journal of Veterinary Science 2025;45(10):2264-2272,2281
The study explored the therapeutic effect and mechanism of the compound composed of tangerine peel,plum,agrimony and hawthorn on Eimeria tenella in chicks.In the experiment,144 chicks were divided into six groups:the blank group,the model group,the diclazuril group,and the high-dose,medium-dose and low-dose traditional Chinese medicine compound groups.The 14-day-old chickens were infected,the body weight and mortality were recorded,and the samples were dis-sected at 21 days of age.The anticoccidial effect of Chenpi compound at different doses was evalua-ted by calculating anticoccidial index,feed conversion rate and detecting serum cytokine levels and related mRNA expression levels.The results showed that the anticoccidial index of the middle dose group was 172.86,and the anticoccidial index of the low dose group was 158.98.In the middle and low dose groups,the levels of IL-1β,IL-6 and MDA in serum decreased significantly,while the levels of IL-4,IL10,T-AOC,SOD,CAT and GSH-Px increased significantly,and the mRNA ex-pression levels of related inflammation and antioxidant pathways changed.Further studies found that the medium-dose compound can regulate the ChTLR15/ChMyD88/ChNF-κB/ChNLRP3/Caspase-1 inflammatory signaling pathway,activate the Nrf2/Keap1/HO-1 antioxidant signaling pathway,and enhance the body's anti-inflammatory and antioxidant capacity;at the same time,it can increase the expression of intestinal tight junction ZO-1 and Occludin,repair the damaged in-testinal barrier,and play an anticoccidial role.The results showed that the middle dose of tangerine peel compound had a good effect in the treatment of coccidiosis,and its mechanism involved the regulation of anti-inflammatory and antioxidant pathways.
7.Blood flow restriction training intervention in the elderly with sarcopenic obesity
Chenchen LIU ; Ruize LIU ; Mengmeng BAO ; Li FANG ; Liquan CAO ; Jiangbo WU
Chinese Journal of Tissue Engineering Research 2025;29(32):6963-6970
BACKGROUND:Sarcopenic obesity is a syndrome characterized by the loss of muscle mass and an increase in body fat,which increases the risk of metabolic diseases and physical disabilities in the elderly.Blood flow restriction training involves applying pressure to a body part during exercise to reduce blood flow,achieving the effects of high-intensity training with low-intensity exercise,making it suitable for the elderly and those with limited mobility.OBJECTIVE:To review and discuss the biological mechanisms,effectiveness,and limitations of blood flow restriction training in addressing sarcopenic obesity in the elderly,and to provide exercise prescription recommendations based on current evidence.METHODS:Literature published up to September 2024 was retrieved from major databases.English and Chinese search terms included"blood flow restriction training,KAATSU,elderly,sarcopenia,sarcopenic obesity,muscle,fat."A total of 66 articles were selected,organized,and analyzed.RESULTS AND CONCLUSION:This study explored the biological mechanisms of blood flow restriction training,including creating an ischemic-hypoxic environment,accumulating metabolites,activating potential signaling pathways,and promoting satellite cell proliferation.The effectiveness of blood flow restriction training in improving muscle strength,mass,and reducing body fat was evaluated,and its potential advantages and risks in the elderly population were discussed.It is recommended that elderly patients with sarcopenic obesity undergo blood flow restriction training combined with 20%-40%1 RM resistance training for three to four times per week.Starting from the first week,there are three sets of training with 30,15,and 15 repetitions respectively.From the second week,there are four sets with 30,15,15,and 15 repetitions respectively.The rest interval between each set is 30-60 seconds.The cuffwidth is 3-5 cm.The pressure of each set increases incrementally by 40%,60%,and 80%of the arterial occlusion pressure.The airbag pressure ranges from 80 to 240 mmHg.Future research is needed to further verify the long-term effects of blood flow restriction training,optimize the training protocol,and explore its application possibilities in different disease contexts.
8.A multicenter, randomized, double-blind clinical trial on the efficacy and safety of Gongxuening Capsule in reducing postoperative bleeding after induced abortion
Lirong TENG ; Chunying LI ; Ping PENG ; Shuping ZHAO ; Xiangying GU ; Xiaoxia ZHENG ; Jing JIANG ; Yali NI ; Min WANG ; Banglan WANG ; Chenchen REN ; Li SHAN ; Qing LIN ; Xinyan LIU
Chinese Journal of Reproduction and Contraception 2025;45(1):39-44
Objective:To assess the efficacy and safety of Gongxuening Capsules in reducing post-abortion bleeding following artificial abortion.Methods:A multicenter, randomized, double-blind study was conducted. From May 31, 2022 to March 31, 2023, 484 women who underwent vacuum aspiration abortion for early intrauterine pregnancy were enrolled in 11 centers and randomly assigned to control group and the study group at a 1∶1 ratio using a center-block randomization method. Control group were administered a placebo of Gongxuening Capsules for 9 d, while the study group received the actual Gongxuening Capsules for the same duration. The outcomes measured included vaginal bleeding volume, duration of vaginal bleeding, endometrial thickness, time to menstrual recovery, and complications.Results:1) A total of 484 subjects were enrolled, and 472 completed the study. Totally 450 subjects were included in the efficacy analysis set, with 224 in control group and 226 in the study group; 468 subjects were included in the safety analysis set, with 236 in control group and 232 in the study group. The baseline characteristics of the two groups were comparable (all P>0.05). 2) The vaginal bleeding volume was lower in the study group [(13.30±12.14) mL] than in control group [(19.00±17.67) mL, P<0.001]. The proportion of subjects in the study group with bleeding days less than 4 d [29.65% (67/226)] was higher than that in control group [19.20% (43/224), P=0.010]. 3) No significant differences were observed between the two groups in terms of time to menstrual recovery and endometrial thickness (all P>0.05). 4) In the study group, 3 subjects experienced non-therapeutic-related complications, while 11 subjects in control group. The incidence of complications was lower in the study group [1.29% (3/232)] than in control group [4.66% (11/236), P=0.033]. Conclusion:The administration of Gongxuening Capsules to women following artificial abortion significantly reduced vaginal bleeding volume and was associated with good safety, with the treatment being well-tolerated by the subjects.
9.Analysis of factors associated with intradialytic hypotension in patients undergoing hemodialysis
Chenchen YANG ; Shihua SHEN ; Weile WANG ; Jingjing LIU ; Yiya WANG ; Wei ZHU ; Jing YANG
Chinese Journal of Primary Medicine and Pharmacy 2025;32(6):859-864
Objective:To analyze the risk factors associated with intradialytic hypotension (IDH) in patients undergoing maintenance hemodialysis (MHD).Methods:This study used a cross-sectional design and included 150 adult patients who underwent MHD at The Third Affiliated Hospital of Anhui Medical University from January 2023 to March 2024. Relevant clinical data were collected to analyze the occurrence of IDH in patients undergoing MHD over 3 months, and the associated risk factors.Results:Among the 150 patients undergoing MHD, there were 67 in the IDH group and 83 in the non-IDH group. The IDH group had a higher fibrinogen/albumin ratio (FAR) [89.41 (73.30, 114.50) vs. 76.56 (65.80, 89.60), χ2 = -3.55, P < 0.001], an older age [(68.46 ± 14.10) years vs. (61.30 ± 12.23) years, t = -3.33, P = 0.001], a longer dialysis duration [(4 (3.5, 4.0) hours vs. (4 (4.0, 4.0) hours), U = -2.11, P = 0.044], a greater ultrafiltration volume [(2.20 ± 0.74) L vs. (1.92 ± 0.82) L, t = -2.16, P = 0.032], a higher ultrafiltration rate [(8.90 ± 2.64) mL·h?1·kg?1 vs. (7.75 ± 2.91) mL·h?1·kg?1, t = -2.51, P = 0.013], and a higher ultrafiltration volume/dry body mass ratio [(33.75 ± 9.76) mL/kg vs. (30.21 ± 11.39) mL/kg, t = -2.11, P = 0.046] compared with the non-IDH group. In the IDH group, the proportion of patients with primary chronic glomerulonephritis was lower (19.4% vs. 37.3%, χ2 = 5.76, P = 0.016), fibrinogen levels were higher [(3.63 (3.15, 4.50) μg/L vs. (3.34 (2.90, 3.74) μg/L, U = -2.61, P = 0.009], albumin levels were lower [(41.26 ± 4.03) g/L vs. (43.42 ± 4.29) g/L, t = 3.15, P = 0.002], high-density lipoprotein cholesterol (HDL-C) levels were lower [0.90 (0.77, 1.09) mmol/L vs. 1.05 (0.84, 1.34) mmol/L, U = -2.77, P = 0.006], and C-reactive protein levels were higher [5.92 (2.79, 9.61) mg/L vs. 2.70 (0.99, 6.49) mg/L, U = -2.27, P = 0.023] compared with the non-IDH group. Multivariate logistic regression analysis indicated that higher FAR values ( OR = 1.030, P = 0.025), a history of chronic glomerulonephritis ( OR = 10.408, P = 0.012), older age ( OR = 1.062, P = 0.043), a high ultrafiltration volume/dry body mass ratio ( OR = 1.072, P = 0.037), and low HDL-C levels ( OR = 0.046, P = 0.015) are independent risk factors for IDH. The area under the receiver operating characteristic curve for FAR predicting IDH was 0.699 (95% CI: 0.571-0.827, P = 0.003). The combination of age, chronic glomerulonephritis, ultrafiltration volume/dry body mass ratio, HDL-C levels, and FAR for predicting IDH resulted in a receiver operating characteristic curve area of 0.839 (95% CI: 0.750-0.929, P < 0.001). Conclusions:Among the risk factors for IDH in patients undergoing MHD, FAR is independently associated with an increased risk of IDH and serves as a valuable predictor for its occurrence in these patients.
10.The IL-33/ST2 Axis Protects Retinal Ganglion Cells by Modulating the Astrocyte Response After Optic Nerve Injury.
Zhigang QIAN ; Mengya JIAO ; Na ZHANG ; Xuhuan TANG ; Shiwang LIU ; Feng ZHANG ; Chenchen WANG ; Fang ZHENG
Neuroscience Bulletin 2025;41(1):61-76
IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis. However, their involvement in optic neuropathy due to trauma and glaucoma remains unclear. Here, we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina. Deletion of IL-33 or ST2 exacerbated retinal ganglion cell (RGC) loss, retinal thinning, and nerve fiber degeneration following optic nerve (ON) injury. This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/- mice. In vitro, rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors, thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants. Exogenous IL-33 treatment improved RGC survival in Il33-/- and WT mice after ON injury, but not in ST2-/- mice. Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.
Animals
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Interleukin-33/genetics*
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Interleukin-1 Receptor-Like 1 Protein/genetics*
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Optic Nerve Injuries/pathology*
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Retinal Ganglion Cells/pathology*
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Astrocytes/pathology*
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Mice
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Mice, Knockout
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Mice, Inbred C57BL
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Neuroprotection/physiology*

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