Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Objective:To investigate the differences in acute intestinal injury and regulatory mechanisms in mice following carbon ion FLASH radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT).Methods:Healthy C57BL/6J mice were randomly divided into three groups: control group, FLASH-RT group (100 Gy/s), and CONV-RT group (0.1 Gy/s), with 9 mice in each group. All mice received carbon ion whole abdominal radiotherapy. DNA double-strand breaks (DSB) and cell proliferation were evaluated by measuring the expression of phosphorylated histone H2AX (γ-H2AX) and nuclear-associated antigen 67 (Ki67) using immunohistochemistry; apoptosis was analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL); transcriptome sequencing was used to analyze the differences in molecular pathways between FLASH-RT and CONV-RT.Results:Compared with the CONV-RT group, the FLASH-RT group showed significantly reduced intestinal γ-H2AX signal at 3 h after radiotherapy ( t=3.80, P<0.01), significantly increased expression of Ki67 at the base of intestinal crypts at 6 h after radiotherapy ( t=4.30, P<0.001), and a significantly decreased number of TUNEL-positive cells at 12 h after radiotherapy ( t=3.08, P<0.01). Transcriptome sequencing analysis showed that FLASH-RT specifically activated the insulin-like growth factor (IGF) pathway, avoiding the excessive activation of CONV-RT-induced nuclear factor-κB and B cell receptor inflammatory pathways as well as the inhibition of energy metabolism. Conclusions:Compared with CONV-RT, carbon ion FLASH-RT can reduce DSB damage, preserve the proliferative activity of intestinal stem cells, activate the IGF pathway, and regulate inflammatory, immune, and metabolic pathways, thereby significantly alleviating acute intestinal epithelial injury. Specifically, the regulation of repair pathways mediated by reduced DSB and the inhibition of inflammatory pathways are potential protective mechanisms for normal tissues.

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

OBJECTIVE To preliminarily assess the horizontal sound localization and its influencing factors in patients with unilateral sudden sensorineural hearing loss during the acute phase.METHODS The azimuth discrimination test and azimuth identification test were completed,with the speech sound(65 dB SPL)as the stimulus.The minimum audible angle(MAA)and root-mean-square error(RMSE)were obtained,and the RMSE of the affected side and the healthy side were calculated respectively.According to the WHO(2021)hearing loss classification criteria,the data were analyzed based on the pure-tone average(PTA)of the affected ear.And the best resident hearing at each frequency of the affected ear was recorded.RESULTS The performance of the unilateral sudden sensorineural hearing loss patients in the sound localization varied greatly.Some performed close to the normal level,while others completely lost the ability to localize sound.The RMSE of the moderate hearing loss group(≥35 dB HL)was significantly higher than that of the normal hearing group(P<0.01),the MAA of the moderate to severe hearing loss group(≥50 dB HL)showed statistically significant differencescompared with normal hearing group(P<0.001).The RMSE of the affected side of patients in the severe and above hearing loss group was significantly larger than that of the healthy side.Regression analysis showed that the best resident hearing at each frequency of the affected ear was the most significant factor affecting MAA(R2=0.572,P<0.001)and RMSE(R2=0.768,P<0.001).CONCLUSION The horizontal sound localization of unilateral sudden sensorineural hearing loss patients in the acute phase varies greatly.When the PTA of the affected side reaches moderate hearing loss,the localization ability is significantly lower than that of normal-hearing individuals.The best resident hearing at each frequency of the affected ear is the key factor affecting the localization ability.

Objective To explore the effect of Shengqing Yisui Kaiqiao acupuncture combined with Buyang Huanwu Tang on movement disorder and homocysteine(Hcy)in patients with ischemic stroke(IS).Methods A total of 160 patients with IS who visited Tai'an Traditional Chinese Medicine Hospital from January 2022 to August 2024 were selected and divided into combined group(54 cases),acupuncture group(53 cases),and traditional Chinese medicine group(53 cases)according to the random number table method.The Fugl-Meyer assessment(FMA)scale,modified Barthel index(MBI),manual muscle test(MMT),Hcy and blood lipid indicators of three groups of patients before and after treatment were compared.Results After the treatment,the FMA,MBI and MMT scores of patients in combined group were significantly higher than those in acupuncture group and traditional Chinese medicine group(P＜0.05),and the levels of Hcy,total cholesterol,triglycerides and low density lipoprotein-cholesterol were significantly lower than those in acupuncture group and traditional Chinese medicine group(P＜0.05).The effective rate of treatment in combined group was significantly higher than that in acupuncture group and traditional Chinese medicine group(P＜0.05).Conclusion The Shengqing Yisui Kaiqiao acupuncture combined with Buyang Huanwu Tang in treatment of IS can significantly improve the limb motor function of patients and reduce the levels of Hcy and blood lipid.

With the full implementation of the Diagnosis Related Groups(DRG)payment model,its institutional advantages in optimizing resource allocation and controlling medical costs through fixed disease payment standards have gradually emerged.However,it has also triggered structural value conflicts in the doctor-patient relationship.Based on the four principles of medical ethics,this paper constructed an analytical framework for the value conflicts in doctor-patient relationships under the DRG payment model.Starting from the manifestations of value conflicts,the inducements creating them were analyzed in depth.On these foundations,multi-dimensional optimization paths were proposed,including repairing respect-related conflicts through information transparency and decision-making co-governance;constructing a refined cost management system and embedding an ethical review mechanism to resolve non-harm conflicts;implementing a phased payment mechanism for innovative technologies and an ethical review exemption mechanism to alleviate benefit conflicts;as well as designing dynamic payment rules,unifying payment standards for insurance participation types,and strengthening dynamic monitoring to address justice conflicts.Under this framework,this paper aimed to promote the gradual transformation of DRG from a cost-control tool to a governance tool.While ensuring the security of the fund,it was necessary to maintain the bottom line of quality,stimulate technological innovation,and return to the patient-centered concept,thereby promoting the doctor-patient relationship to shift from a zero-sum game to a symbiotic and win-win situation.

Purpose To investigate the cortical thickness features in Parkinson's disease(PD)patients at various stages and their association with dopamine transporter(DAT)levels in the putamen.Materials and Methods We retrospectively enrolled 30 PD patients and 15 healthy subject who underwent 11C-CFT PET and T1 MRI scans at the Department of Nuclear Medicine/PET Center of Huashan Hospital from August 2016 to October 2020.DAT average radioactivity in the anterior and posterior putamen was analysis using SPM12 software,with the occipital lobe as the reference region.Cortical segmentation and reconstruction were performed on T1 images using Freesurfer v7.2.The differences in cortical thinning between the groups were compared using a general linear model.Additionally,the relationship between cortical thickness in various brain regions and DAT uptake in the putamen were assessed.Results Compared to healthy subjects,significant cortical thinning was observed in the left inferior parietal lobule and the right and left inferior middle frontal gyrus of PD patients(all P<0.05).There was a significant positive correlation between the cortical thickness of the left inferior parietal lobule and right inferior middle frontal gyrus and DAT uptake in the corresponding anterior/posterior parts of the putamen(r=0.30-0.47,all P<0.05).Furthermore,the DAT uptake in the right precentral gyrus was positively correlated with the ipsilateral posterior putamen,exhibiting a stronger correlation than on the contralateral side(r=0.32,P=0.029).Conclusion The results show that the thickness of the thinning cortex area in the PD patients correlates significantly positively with DAT levels in the putamen,highlighting the importance of the basal ganglia cortical circuit and providing a basis for further research into the neural mechanisms of PD.

Objective:To investigate the differences in acute intestinal injury and regulatory mechanisms in mice following carbon ion FLASH radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT).Methods:Healthy C57BL/6J mice were randomly divided into three groups: control group, FLASH-RT group (100 Gy/s), and CONV-RT group (0.1 Gy/s), with 9 mice in each group. All mice received carbon ion whole abdominal radiotherapy. DNA double-strand breaks (DSB) and cell proliferation were evaluated by measuring the expression of phosphorylated histone H2AX (γ-H2AX) and nuclear-associated antigen 67 (Ki67) using immunohistochemistry; apoptosis was analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL); transcriptome sequencing was used to analyze the differences in molecular pathways between FLASH-RT and CONV-RT.Results:Compared with the CONV-RT group, the FLASH-RT group showed significantly reduced intestinal γ-H2AX signal at 3 h after radiotherapy ( t=3.80, P<0.01), significantly increased expression of Ki67 at the base of intestinal crypts at 6 h after radiotherapy ( t=4.30, P<0.001), and a significantly decreased number of TUNEL-positive cells at 12 h after radiotherapy ( t=3.08, P<0.01). Transcriptome sequencing analysis showed that FLASH-RT specifically activated the insulin-like growth factor (IGF) pathway, avoiding the excessive activation of CONV-RT-induced nuclear factor-κB and B cell receptor inflammatory pathways as well as the inhibition of energy metabolism. Conclusions:Compared with CONV-RT, carbon ion FLASH-RT can reduce DSB damage, preserve the proliferative activity of intestinal stem cells, activate the IGF pathway, and regulate inflammatory, immune, and metabolic pathways, thereby significantly alleviating acute intestinal epithelial injury. Specifically, the regulation of repair pathways mediated by reduced DSB and the inhibition of inflammatory pathways are potential protective mechanisms for normal tissues.

Objective To investigate the changes in total hospitalization costs and their structure associated with or-thopedic spinal consumables before and after the implementation of volume-based centralized procurement under the DRG payment system.Methods Data were collected from a tertiary Class A hospital for cases related to spinal fu-sion surgery between June 2022 and May 2024.Grey relational analysis,structural change analysis,interrupted time series analysis,and other statistical methods were employed to analyze the differences in total hospitalization costs and cost structures before and after the implementation of volume-based centralized procurement.Results In the month of volume-based centralized procurement implementation,total hospitalization costs and material costs de-creased by 9 520.82 yuan and 9 878.83 yuan,respectively,with statistically significant differences(P＜0.05).From a long-term trend perspective,after volume-based centralized procurement,there was a growing trend in total hos-pitalization costs,material costs,surgical fees,and drug costs,all with statistically significant differences(P＜0.05).In the month of volume-based centralized procurement"implementation,the proportion of material costs in-stantly decreased by 10.8％,while the proportion of surgical fees increased by 4.8％,both with statistically signifi-cant differences(P＜0.001).From a long-term trend perspective,after volume-based centralized procurement,the proportions of material costs and surgical fees remained stable over the long term,without statistically significant dif-ferences(P＞0.05).Conclusion Volume-based centralized procurement"of medical consumables under the DRG pay-ment system has played a certain role in reducing medical expenses and adjusting the cost structure.However,there are still deficiencies in accompanying policies such as the formulation of DRG payment standards and adjust-ments to medical service prices.