With the extension of the global population's lifespan and the increasingly severe aging problem,cardio-vascular diseases have become the leading cause of death among the elderly population.Most cardiovascular diseases orig-inate from the formation of atherosclerotic plaques.In addition to common risk factors such as dyslipidemia,diabetes,hy-pertension,smoking,and obesity,circadian rhythm disruption is also regarded as an important but often overlooked risk factor for atherosclerosis.The circadian rhythm is involved in regulating key physiological processes such as inflammation and metabolism,which in turn affect the pathological processes of arteriosclerosis and thrombosis.In this process,the key genes that maintain the stability of the circadian rhythm,namely clock gene,play a crucial role.Clock gene have an important role in the pathological mechanism of atherosclerosis,and they may become potential new targets for the preven-tion and treatment of atherosclerosis.This paper reviews the latest research progress on the mechanism of action of clock gene in the occurrence and development of atherosclerosis.These findings may provide new ideas for the diagnosis and treatment of atherosclerosis.

Grounded in organizational change-complex systems theory,it investigates the pathways and mechanisms for deep integration of Artificial Intelligence(AI)into clinical management.Addressing structural challenges in current clinical management systems,it propose a dynamic three-phase model"unfreezing-changing-refreezing"driven by AI technologies.By deconstructing systemic contradictions arising from technological penetration e.g.,multi-agent coordination,ethical risks,and responsibility ambiguity,a layered governance framework and dynamic regulatory mechanisms are established.Through synergistic evolution of technology,organization,and institution,an adaptive transition in clinical management paradigms can be achieved,ultimately fostering an AI-augmented healthcare ecosystem that balances efficiency with safety.

With the extension of the global population's lifespan and the increasingly severe aging problem,cardio-vascular diseases have become the leading cause of death among the elderly population.Most cardiovascular diseases orig-inate from the formation of atherosclerotic plaques.In addition to common risk factors such as dyslipidemia,diabetes,hy-pertension,smoking,and obesity,circadian rhythm disruption is also regarded as an important but often overlooked risk factor for atherosclerosis.The circadian rhythm is involved in regulating key physiological processes such as inflammation and metabolism,which in turn affect the pathological processes of arteriosclerosis and thrombosis.In this process,the key genes that maintain the stability of the circadian rhythm,namely clock gene,play a crucial role.Clock gene have an important role in the pathological mechanism of atherosclerosis,and they may become potential new targets for the preven-tion and treatment of atherosclerosis.This paper reviews the latest research progress on the mechanism of action of clock gene in the occurrence and development of atherosclerosis.These findings may provide new ideas for the diagnosis and treatment of atherosclerosis.

Grounded in organizational change-complex systems theory,it investigates the pathways and mechanisms for deep integration of Artificial Intelligence(AI)into clinical management.Addressing structural challenges in current clinical management systems,it propose a dynamic three-phase model"unfreezing-changing-refreezing"driven by AI technologies.By deconstructing systemic contradictions arising from technological penetration e.g.,multi-agent coordination,ethical risks,and responsibility ambiguity,a layered governance framework and dynamic regulatory mechanisms are established.Through synergistic evolution of technology,organization,and institution,an adaptive transition in clinical management paradigms can be achieved,ultimately fostering an AI-augmented healthcare ecosystem that balances efficiency with safety.

Morita therapy has been bom for more than 100 years.Inpatient Morita therapy is highly oper-able and easy to master.It can improve many refractory neuroses through four-stage treatment.But more neuroses are treated in outpatient clinics,and Morita therapy cannot be used in hospitalized patients.Therefore,the formula-tion of expert opinions on outpatient operations is particularly important.This paper is based on domestic and for-eign references,and after many discussions by domestic Morita therapy experts,and then drew up the first version of the expert opinions on operation of outpatient Morita therapy.Meanwhile the operation rule of Morita therapy in three stages of outpatient treatment was formulated:in the etiological analysis stage,under the theoretical guidance of Morita therapy,analyze the pathogenic factors,to improve treatment compliance and reduce resistance;during the operating stage,guide patients to engage in constructive and meaningful actions,realizing the achievement of letting nature take its course principle;in the cultivating character and enriching life stage,pay attention to positive infor-mation,expanding the scope and content of actions,improving the ability to adapt to complex life,and preventing recurrence caused by insufficient abilities.It will lay a foundation for the promotion of Morita therapy in domestic outpatient clinics,so that more patients with neurosis and other psychological diseases could receive characteristic Morita therapy treatment in outpatient clinics.

Objective:To evaluate the role of aquaporin 4 (AQP4) in dexmedetomidine-induced reduction of blood-brain barrier permeability in mechanically ventilated mice and the relationship with protein kinase C (PKC).Methods:One hundred and fifty clean-grade healthy male C57BL6 mice, weighing 20-25 g, aged 8-12 weeks, were divided into 5 groups ( n=30 each) using a random number table method: control group (group C), mechanical ventilation group (group V), LY317615 group (group L), dexmedetomidine group (group D), and dexmedetomidine+ PMA group (group DP). Group C spontaneously breathed air for 6 h. The animals were mechanically ventilated for 6 h in group V. PKC inhibitor LY3176 15 μg/kg was intraperitoneally injected at 30 min before mechanical ventilation in group L. Dexmedetomidine 50 μg/kg was intraperitoneally injected at 30 min before mechanical ventilation in D and DP groups. PKC activator PMA 15 μg/kg was intraperitoneally injected at 60 min before mechanical ventilation in group DP. Mice were anesthetized at 1 day after mechanical ventilation, then sacrificed and hippocampal tissues were taken for microscopic examination of pathological changes in the hippocampal CA1 and CA3 areas (with a light microscope). Brain tissues were also taken to measure the water content and content of Evans blue (EB) and to detect the expression of PKC and AQP4 (by Western blot). The cognitive function was evaluated using a novel object recognition task at 3 days after mechanical ventilation. Results:Compared with group C, the water content and EB content of brain tissues were significantly increased after mechanical ventilation, the expression of PKC and AQP4 in brain tissues was up-regulated, the percentage of novel object exploration and discrimination index were decreased ( P<0.05), and the histopathological damage in the hippocampal CA1 and CA3 areas was aggravated in group V and group DP. Compared with group V, the water content and EB content of brain tissues were significantly decreased after mechanical ventilation, the expression of PKC and AQP4 in brain tissues was down-regulated, the percentage of novel object exploration and discrimination index were increased ( P<0.05), and the histopathological damage in the hippocampal CA1 and CA3 areas was significantly attenuated in group D and group L. Compared with group D, the water content and EB content of brain tissues were significantly increased after mechanical ventilation, the expression of PKC and AQP4 in brain tissues was up-regulated, the percentage of novel object exploration and discrimination index were decreased ( P<0.05), and the histopathological damage in the hippocampal CA1 and CA3 areas was aggravated in group DP. Conclusions:AQP4 is involved in dexmedetomidine-induced reduction of blood-brain barrier permeability in mechanically ventilated mice, and the mechanism is related to inhibiting activation of PKC.

Objective:This study aimed to evaluate the immunoprotective effect of anti-rabies virus cocktail monoclonal antibody Zamerovimab/Mazorelvimab after rabies exposure.Methods:The dynamic data of rabies virus neutralizing antibody (RVNA) were analyzed in the Zamerovimab/Mazorelvimab Chinese phase Ⅲ study (clinical trial registration number: CTR20201819).Results:The full analysis set showed that RVNA geometric mean titers (GMT) on the 4 th, 8 th, 15 th, 43 rd, and 99 th day in the Zamerovimab/Mazorelvimab group were 4.413 IU/ml, 5.178 IU/ml, 17.062 IU/ml, 14.672 IU/ml, and 2.836 IU/ml, respectively, while those in the human rabies immunoglobulin (HRIG) group were 0.299 IU/ml, 0.451 IU/ml, 11.374 IU/ml, 18.063 IU/ml, and 6.769 IU/ml, respectively. The positive rates of RVNA on the 4 th, 8 th, 15 th, 43 rd, and 99 th day in the Zamerovimab/Mazorelvimab group were 99.9%, 99.6%, 100%, 100%, and 97.4%, respectively, while those in the HRIG group were 23.3%, 34.1%, 97.6%, 99.6%, and 98.4%, respectively. Conclusions:Compared with HRIG, Zamerovimab/Mazorelvimab cocktail monoclonal antibody reached the required protection level of RVNA very soon, thus effectively provided an immediate neutralizing effect of passive immunization therapies against rabies virus.

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis, but the targets and molecular functions of RBM46 remain unknown. Here, we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation. Using a recently reported, high-resolution technique known as LACE-seq and working with low-input cells, we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes. We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions. In Rbm46 knockout mice, the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation, resulting in the failed assembly of axial elements, synapsis disruption, and meiotic arrest. Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.
Animals ; Mice ; 3' Untranslated Regions/genetics* ; Cell Cycle Proteins/metabolism* ; Gametogenesis/genetics* ; Meiosis/genetics* ; Nuclear Proteins/genetics* ; RNA-Binding Proteins/genetics*

ObjectiveTo explore the differences between the ancient decocting methods and modern decocting method of Yihuangtang by taking the dry extract rate， the content of active ingredients and the fingerprint information as indicators， so as to provide reference for the preparation of benchmark samples and the development of compound preparations of this famous classical formula. MethodAccording to the three decocting methods recorded in Paozhi Dafa and Jianming Yigou and Management Specifications of Traditional Chinese Medicine Decoction Chambers in Medical Institutions， the Yihuangtang was decocted respectively. The polysaccharide content in the samples was determined by ultraviolet spectrophotometer （UV） at 488 nm， and the contents of alkaloids （berberine hydrochloride， phellodendrine chloride and magnoflorine） in the samples and their fingerprint profiles were determined by high performance liquid chromatography （HPLC）， and the dry extract rate was combined to compare the differences of the three decocting methods of Yihuangtang. Among them， the fingerprint was gradient eluted with acetonitrile （A） -0.1% phosphoric acid aqueous solution （B） as mobile phase （0-10 min， 5%-8%A； 10-35 min， 8%A； 35-45 min， 8%-12% A； 45-75 min， 12%-17%A； 75-105 min， 17%-35%A； 105-110 min， 35%-100%A； 110-112 min， 100%-5%A； 112-122 min， 5%A）， and the detection wavelength was 230 nm. ResultWhen the decoction was carried out according to the method described in Paozhi Dafa， the content of polysaccharides was higher than that of the modern decocting method and the method described in Jianming Yigou. However， the contents of berberine hydrochloride， phellodendrine chloride and magnoflorine were the highest in the modern decocting method. Meanwhile， the number of peaks in fingerprint of the samples prepared by the three decocting methods was basically the same， and 13 common peaks were matched， and the three common peaks of berberine hydrochloride， phellodendrine chloride and magnoflorine were identified. However， the relative peak areas of the common peaks in the fingerprint of the samples prepared by the three decocting methods varied greatly， suggesting that there were differences in the extracting effects of different decocting methods. In addition， there were also differences in the dry extract rate among the three decocting methods of Yihuangtang， and the highest value was obtained by decocting the samples according to the method recorded in Paozhi Dafa. ConclusionDecocting method can affect the dry extract rate， fingerprint information and active ingredient content of Yihuangtang， among which the modern decocting method is conducive to the extraction of alkaloids and the preparation transformation of this famous classical formula， and it is recommended to determine its preparation process by optimizing the modern decocting method.

Interleukin (IL)-17A, a pro-inflammatory cytokine, is a fundamental function in the onset and advancement of multiple immune diseases. To uncover the primary compounds with IL-17A inhibitory activity, a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions. Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus, Myrothecium gramineum, showed remarkable IL-17A inhibitory activity. Nine new aureane-type sesquiterpene tetraketides, myrogramins A-I ( 1, 4- 11), and two known ones ( 2 and 3) were isolated and identified from the strain. Compounds 1, 3, 4, 10, and 11 exhibited significant IL-17A inhibitory activity. Among them, compound 3, with a high fermentation yield dose-dependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions. Strikingly, compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension. Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity, and hold great promise applications in treating IL-17A-mediated immune diseases.