Extraction of methane hydrate from subseafloor reservoir may potentially trigger seabed slides and induce subsidence.To address the problems,it is crucial to properly characterize the phase equilibrium condition of po...Extraction of methane hydrate from subseafloor reservoir may potentially trigger seabed slides and induce subsidence.To address the problems,it is crucial to properly characterize the phase equilibrium condition of pore hydrate and the shear strength of the soil.As one of the key constitutive components,the phase equilibrium condition enforces a constraint over pore gas pressure,temperature and unhydrated water content.Such a constraint,however,has been traditionally ignored in analyzing the mechanical behavior of hydrate-bearing soil.In this paper,a series of stepwise hydrate dissociation tests was performed,and the phase equilibrium condition of pore hydrate was determined,providing an effective way to evaluate the unhydrated water content during hydrate dissociation.Meanwhile,a series of direct shear tests was also conducted to explore the shear strength characteristics of the soil.It is shown that the shear strength of the hydrate-bearing soil can be significantly influenced by pore gas pressure,unhydrated water content,hydrate saturation and several other factors.In particular,the measured shear strength depends upon the initial water content of the sample,pointing to a potential problem that the shear strength could be wrongly determined if not properly interpreted.A shear strength criterion,which enforces the equilibrium condition of pore hydrate,is developed for hydrate-bearing soil,establishing a link between the equilibrium condition and the shear strength.The proposed equation describes well the shear strength characteristics of hydrate-bearing soils,remarkably unifying the effects of pore pressure,temperature,water content and hydrate saturation.展开更多
Grouting is a widely used approach to reinforce broken surrounding rock mass during the construction of underground tunnels in fault fracture zones,and its reinforcement effectiveness is highly affected by geostress.I...Grouting is a widely used approach to reinforce broken surrounding rock mass during the construction of underground tunnels in fault fracture zones,and its reinforcement effectiveness is highly affected by geostress.In this study,a numerical manifold method(NMM)based simulator has been developed to examine the impact of geostress conditions on grouting reinforcement during tunnel excavation.To develop this simulator,a detection technique for identifying slurry migration channels and an improved fluid-solid coupling(FeS)framework,which considers the influence of fracture properties and geostress states,is developed and incorporated into a zero-thickness cohesive element(ZE)based NMM(Co-NMM)for simulating tunnel excavation.Additionally,to simulate coagulation of injected slurry,a bonding repair algorithm is further proposed based on the ZE model.To verify the accuracy of the proposed simulator,a series of simulations about slurry migration in single fractures and fracture networks are numerically reproduced,and the results align well with analytical and laboratory test results.Furthermore,these numerical results show that neglecting the influence of geostress condition can lead to a serious over-estimation of slurry migration range and reinforcement effectiveness.After validations,a series of simulations about tunnel grouting reinforcement and tunnel excavation in fault fracture zones with varying fracture densities under different geostress conditions are conducted.Based on these simula-tions,the influence of geostress conditions and the optimization of grouting schemes are discussed.展开更多
The phase equilibrium and mechanical behaviors of natural gas hydrate-bearing sediment are essential for gas recovery from hydrate reservoirs.In heating closed systems,the temperature-pressure path of hydrate-bearing ...The phase equilibrium and mechanical behaviors of natural gas hydrate-bearing sediment are essential for gas recovery from hydrate reservoirs.In heating closed systems,the temperature-pressure path of hydrate-bearing sediment deviates from that of pure bulk hydrate,reflecting the porous media effect in phase equilibrium.A generalized phase equilibrium equation was established for hydrate-bearing sediments,which indicates that both capillary and osmotic pressures cause the phase equilibrium curve to shift leftward on the temperature-pressure plane.In contrast to bulk hydrate,hydrate-bearing sediment always contains a certain amount of unhydrated water,which keeps phase equilibrium with the hydrate within the hydrate stability field.With changes in temperature and pressure,a portion of pore hydrate and unhydrated water may transform into each other,affecting the shear strength of hydrate-bearing sediment.A shear strength model is proposed to consider not only hydrate saturation but also the change in temperature and pressure of hydrate-bearing sediment.The model is validated by experimental data with various hydrate saturation,temperature and pressure conditions.The deformation induced by partial dissociation was studied through depressurization tests under constant effective stress.The reduction in gas pressure within the hydrate stability field indeed caused sediment deformation.The dissociation-induced deformation can be reasonably estimated as the difference in volume between hydrate-bearing and hydrate-free sediments from the compression curves.展开更多
Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature ...Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer.Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer.Results: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.展开更多
Myopia is a huge health problem due to its high frequency,vision losses and public health cost.According to the World Health Organization,at least 2.2 billion people have vision impairment.Although myopia can be contr...Myopia is a huge health problem due to its high frequency,vision losses and public health cost.According to the World Health Organization,at least 2.2 billion people have vision impairment.Although myopia can be controlled at its early and middle stages,unfortunately,no cure can be achieved so far.Among the methods to control myopia,atropine,a muscarinic receptor antagonist,is the oldest but still the most effective for retardation of myopia progression.Despite such a fact,standard protocols have not been established for clinicians to use atropine for treatment of myopia.In this article,a concise and up to date summary of myopia epidemiology and pathogenesis and summarized therapeutic effects and side effects,possible mechanisms and application methods of atropine were provided in hope for clinical doctors to effectively control this problematic disease.At present,the protocol is recommend:use higher dose(1%)of atropine intermittently to effectively slowdown myopia progression in schoolchildren for 2y,and to significantly reduce side effects of atropine by decrease of atropine frequency for 1y and inhibit myopic rebound by withdrawal of topical atropine gradually for 1y.Application of a lower dose(0.05%)atropine regime should also be considered due to its effectiveness and application at regular basis.展开更多
The single-shot readout data process is essential for the realization of high-fidelity qubits and fault-tolerant quantum algorithms in semiconductor quantum dots. However, the fidelity and visibility of the readout pr...The single-shot readout data process is essential for the realization of high-fidelity qubits and fault-tolerant quantum algorithms in semiconductor quantum dots. However, the fidelity and visibility of the readout process are sensitive to the choice of the thresholds and limited by the experimental hardware. By demonstrating the linear dependence between the measured spin state probabilities and readout visibilities along with dark counts, we describe an alternative threshold-independent method for the single-shot readout of spin qubits in semiconductor quantum dots. We can obtain the extrapolated spin state probabilities of the prepared probabilities of the excited spin state through the threshold-independent method. We then analyze the corresponding errors of the method, finding that errors of the extrapolated probabilities cannot be neglected with no constraints on the readout time and threshold voltage. Therefore, by limiting the readout time and threshold voltage, we ensure the accuracy of the extrapolated probability. We then prove that the efficiency and robustness of this method are 60 times larger than those of the most commonly used method. Moreover, we discuss the influence of the electron temperature on the effective area with a fixed external magnetic field and provide a preliminary demonstration for a single-shot readout of up to 0.7K/1.5T in the future.展开更多
BACKGROUND Benign gallbladder diseases have become a high-prevalence condition not only in China but also worldwide.The main types of benign gallbladder diseases include gallbladder polyps,acute and chronic cholecysti...BACKGROUND Benign gallbladder diseases have become a high-prevalence condition not only in China but also worldwide.The main types of benign gallbladder diseases include gallbladder polyps,acute and chronic cholecystitis,and gallstones,with gallstones being the most common,accounting for over 70%of cases.Although the mortality rate of benign gallbladder diseases is low,they carry obvious potential risks.Studies have shown that an increased incidence of benign gallbladder diseases can increase the risk of cardiovascular diseases and gallbladder cancer,resulting in a substantial disease burden on patients and their families.AIM To assess the medical utility of the Configuration-Procedure-Consequence(CPC)three-dimensional quality evaluation model in modulating the prognosis of laparoscopic cholecystectomy patients.METHODS A total of 98 patients who underwent laparoscopic cholecystectomy in our hospital from February 2020 to January 2022 were selected as the subjects.According to the random number table method,they were divided into a study group and a control group,with 49 patients in each group.The control group received routine perioperative care,while the study group had the addition of the CPC three-dimensional quality evaluation.The postoperative recovery-related indicators(time to first flatus,time to oral intake,time to ambulation,hospital stay),stress indicators(cortisol and adrenaline levels),distinctions in anxiety and RESULTS The time to first flatus,time to oral intake,time to ambulation,and hospital stay of the study group patients were obviously lower than those of the control group patients,with statistical significance(P<0.05).On the 1st day after admission,there were no obvious distinctions in cortisol and adrenaline levels in blood samples,as well as in the Self-Rating Anxiety Scale(SAS)and Self-Rating Depression Scale(SDS)scores between the study group and the control group(P>0.05).However,on the 3rd day after surgery,the cortisol and adrenaline levels,as well as SAS and SDS scores of the study group patients,were obviously lower than those of the control group patients(P<0.05).The study group had 2 cases of incisional infection and 1 case of pulmonary infection,with a total incidence of complications of 6.12%(3/49),which was obviously lower than the 20.41%(10/49)in the control group(P<0.05).CONCLUSION Implementing the CPC three-dimensional quality evaluation model for patients undergoing laparoscopic cholecystectomy can help accelerate their perioperative recovery process,alleviate perioperative stress symptoms,mitigate anxiety,depression,and other adverse emotions,and to some extent,reduce the incidence of perioperative complications.展开更多
Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a ...Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.展开更多
基金This work was supported by the Scientific Instrument Developing Project of the Chinese Academy of Sciences(No.YJKYYQ20190027)Youth Innovation Promotion Association,Chinese Academy of Science(No.2021255)+2 种基金Shandong Energy Research Institute Enterprise Joint Fund(SE1 U202312)"Strategic Priority Research Program"of the Chinese Academy of Sciences(No.XDA02020000)the National Natural Science Foundation of China(No.22273065).
基金This research was funded by the National Science Foundation of China(NSFC)(Grant Nos.51939011 and 42171135)Youth Innovation Promotion Association,Chinese Academy of Sciences(CAS)(Grant No.2020326),which are gratefully acknowledged.
文摘Extraction of methane hydrate from subseafloor reservoir may potentially trigger seabed slides and induce subsidence.To address the problems,it is crucial to properly characterize the phase equilibrium condition of pore hydrate and the shear strength of the soil.As one of the key constitutive components,the phase equilibrium condition enforces a constraint over pore gas pressure,temperature and unhydrated water content.Such a constraint,however,has been traditionally ignored in analyzing the mechanical behavior of hydrate-bearing soil.In this paper,a series of stepwise hydrate dissociation tests was performed,and the phase equilibrium condition of pore hydrate was determined,providing an effective way to evaluate the unhydrated water content during hydrate dissociation.Meanwhile,a series of direct shear tests was also conducted to explore the shear strength characteristics of the soil.It is shown that the shear strength of the hydrate-bearing soil can be significantly influenced by pore gas pressure,unhydrated water content,hydrate saturation and several other factors.In particular,the measured shear strength depends upon the initial water content of the sample,pointing to a potential problem that the shear strength could be wrongly determined if not properly interpreted.A shear strength criterion,which enforces the equilibrium condition of pore hydrate,is developed for hydrate-bearing soil,establishing a link between the equilibrium condition and the shear strength.The proposed equation describes well the shear strength characteristics of hydrate-bearing soils,remarkably unifying the effects of pore pressure,temperature,water content and hydrate saturation.
基金This work was supported by the Guangdong Basic and Applied Basic Research Foundation(Grant No.2021A1515110304)the Na-tional Natural Science Foundation of China(Grant Nos.42077246 and 52278412).
文摘Grouting is a widely used approach to reinforce broken surrounding rock mass during the construction of underground tunnels in fault fracture zones,and its reinforcement effectiveness is highly affected by geostress.In this study,a numerical manifold method(NMM)based simulator has been developed to examine the impact of geostress conditions on grouting reinforcement during tunnel excavation.To develop this simulator,a detection technique for identifying slurry migration channels and an improved fluid-solid coupling(FeS)framework,which considers the influence of fracture properties and geostress states,is developed and incorporated into a zero-thickness cohesive element(ZE)based NMM(Co-NMM)for simulating tunnel excavation.Additionally,to simulate coagulation of injected slurry,a bonding repair algorithm is further proposed based on the ZE model.To verify the accuracy of the proposed simulator,a series of simulations about slurry migration in single fractures and fracture networks are numerically reproduced,and the results align well with analytical and laboratory test results.Furthermore,these numerical results show that neglecting the influence of geostress condition can lead to a serious over-estimation of slurry migration range and reinforcement effectiveness.After validations,a series of simulations about tunnel grouting reinforcement and tunnel excavation in fault fracture zones with varying fracture densities under different geostress conditions are conducted.Based on these simula-tions,the influence of geostress conditions and the optimization of grouting schemes are discussed.
基金supported by the National Natural Science Foundation of China(Grant Nos.42171135 and 12262009)the“CUG Scholar”Scientific Research Funds at China University of Geosciences(Wuhan)(Project No.2022098).
文摘The phase equilibrium and mechanical behaviors of natural gas hydrate-bearing sediment are essential for gas recovery from hydrate reservoirs.In heating closed systems,the temperature-pressure path of hydrate-bearing sediment deviates from that of pure bulk hydrate,reflecting the porous media effect in phase equilibrium.A generalized phase equilibrium equation was established for hydrate-bearing sediments,which indicates that both capillary and osmotic pressures cause the phase equilibrium curve to shift leftward on the temperature-pressure plane.In contrast to bulk hydrate,hydrate-bearing sediment always contains a certain amount of unhydrated water,which keeps phase equilibrium with the hydrate within the hydrate stability field.With changes in temperature and pressure,a portion of pore hydrate and unhydrated water may transform into each other,affecting the shear strength of hydrate-bearing sediment.A shear strength model is proposed to consider not only hydrate saturation but also the change in temperature and pressure of hydrate-bearing sediment.The model is validated by experimental data with various hydrate saturation,temperature and pressure conditions.The deformation induced by partial dissociation was studied through depressurization tests under constant effective stress.The reduction in gas pressure within the hydrate stability field indeed caused sediment deformation.The dissociation-induced deformation can be reasonably estimated as the difference in volume between hydrate-bearing and hydrate-free sediments from the compression curves.
基金supported by the National Natural Science Foundation of China (No. U20A20371)the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (No. D171100006517004)+2 种基金Beijing Municipal Administration of Hospitals’ Youth Program (QML20191103)Clinical Medicine Plus X-Young Scholars Project, Peking Universitythe Fundamental Research Funds for the Central Universities and the Science Foundation of Peking University Cancer Hospital。
文摘Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer.Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer.Results: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.
基金Supported by the Basic Research Fund for Science and Technology Department of Yunnan Province and Kunming Medical University(No.202401AY070001-289).
文摘Myopia is a huge health problem due to its high frequency,vision losses and public health cost.According to the World Health Organization,at least 2.2 billion people have vision impairment.Although myopia can be controlled at its early and middle stages,unfortunately,no cure can be achieved so far.Among the methods to control myopia,atropine,a muscarinic receptor antagonist,is the oldest but still the most effective for retardation of myopia progression.Despite such a fact,standard protocols have not been established for clinicians to use atropine for treatment of myopia.In this article,a concise and up to date summary of myopia epidemiology and pathogenesis and summarized therapeutic effects and side effects,possible mechanisms and application methods of atropine were provided in hope for clinical doctors to effectively control this problematic disease.At present,the protocol is recommend:use higher dose(1%)of atropine intermittently to effectively slowdown myopia progression in schoolchildren for 2y,and to significantly reduce side effects of atropine by decrease of atropine frequency for 1y and inhibit myopic rebound by withdrawal of topical atropine gradually for 1y.Application of a lower dose(0.05%)atropine regime should also be considered due to its effectiveness and application at regular basis.
基金Project supported by the National Natural Science Foundation of China (Grant Nos.12074368,92165207,12034018,and 62004185)the Anhui Province Natural Science Foundation (Grant No.2108085J03)the USTC Tang Scholarship。
文摘The single-shot readout data process is essential for the realization of high-fidelity qubits and fault-tolerant quantum algorithms in semiconductor quantum dots. However, the fidelity and visibility of the readout process are sensitive to the choice of the thresholds and limited by the experimental hardware. By demonstrating the linear dependence between the measured spin state probabilities and readout visibilities along with dark counts, we describe an alternative threshold-independent method for the single-shot readout of spin qubits in semiconductor quantum dots. We can obtain the extrapolated spin state probabilities of the prepared probabilities of the excited spin state through the threshold-independent method. We then analyze the corresponding errors of the method, finding that errors of the extrapolated probabilities cannot be neglected with no constraints on the readout time and threshold voltage. Therefore, by limiting the readout time and threshold voltage, we ensure the accuracy of the extrapolated probability. We then prove that the efficiency and robustness of this method are 60 times larger than those of the most commonly used method. Moreover, we discuss the influence of the electron temperature on the effective area with a fixed external magnetic field and provide a preliminary demonstration for a single-shot readout of up to 0.7K/1.5T in the future.
基金reviewed and approved by the Institutional Review Board of The Second People's Hospital of Lianyungang(Approval No.LW-20220707001).
文摘BACKGROUND Benign gallbladder diseases have become a high-prevalence condition not only in China but also worldwide.The main types of benign gallbladder diseases include gallbladder polyps,acute and chronic cholecystitis,and gallstones,with gallstones being the most common,accounting for over 70%of cases.Although the mortality rate of benign gallbladder diseases is low,they carry obvious potential risks.Studies have shown that an increased incidence of benign gallbladder diseases can increase the risk of cardiovascular diseases and gallbladder cancer,resulting in a substantial disease burden on patients and their families.AIM To assess the medical utility of the Configuration-Procedure-Consequence(CPC)three-dimensional quality evaluation model in modulating the prognosis of laparoscopic cholecystectomy patients.METHODS A total of 98 patients who underwent laparoscopic cholecystectomy in our hospital from February 2020 to January 2022 were selected as the subjects.According to the random number table method,they were divided into a study group and a control group,with 49 patients in each group.The control group received routine perioperative care,while the study group had the addition of the CPC three-dimensional quality evaluation.The postoperative recovery-related indicators(time to first flatus,time to oral intake,time to ambulation,hospital stay),stress indicators(cortisol and adrenaline levels),distinctions in anxiety and RESULTS The time to first flatus,time to oral intake,time to ambulation,and hospital stay of the study group patients were obviously lower than those of the control group patients,with statistical significance(P<0.05).On the 1st day after admission,there were no obvious distinctions in cortisol and adrenaline levels in blood samples,as well as in the Self-Rating Anxiety Scale(SAS)and Self-Rating Depression Scale(SDS)scores between the study group and the control group(P>0.05).However,on the 3rd day after surgery,the cortisol and adrenaline levels,as well as SAS and SDS scores of the study group patients,were obviously lower than those of the control group patients(P<0.05).The study group had 2 cases of incisional infection and 1 case of pulmonary infection,with a total incidence of complications of 6.12%(3/49),which was obviously lower than the 20.41%(10/49)in the control group(P<0.05).CONCLUSION Implementing the CPC three-dimensional quality evaluation model for patients undergoing laparoscopic cholecystectomy can help accelerate their perioperative recovery process,alleviate perioperative stress symptoms,mitigate anxiety,depression,and other adverse emotions,and to some extent,reduce the incidence of perioperative complications.
基金supported by grants from the National Natural Science Foundation of China, Nos. 81930031 (to JNZ), 81720108015 (to JNZ), 81901525 (to SZ), 82101440 (to DDS), 81801234 (to YZ) and 82071389 (to GLY)the Natural Science Foundation of Tianjin, Nos. 20JCQNJC01270 (to JWW), 20JCQNJC00460 (to GLY), 18JCQNJC81000 (to HTR)+4 种基金Scientific Research Project of Tianjin Education Commission (Natural Science), No. 2018KJ052 (to ZWZ)Tianjin Health and Health Committee Science and Technology Project, No. QN20015 (to JWW)the Science & Technology Development Fund of Tianjin Education Commission for Higher Education, No. 2016YD02 (to YW)Tianjin Key Science and Technology Projects of Innovative Drugs and Medical Devices, No. 19ZXYXSY00070 (to YW)the Clinical Research Fundation of Tianjin Medical University, No. 2018kylc002 (to YW)
文摘Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.
