Objective:To discuss the suitable concentration of D-galactose(D-gal)and modeling period,and establish its induced aging-related cognitive dysfunction model in the mice,and perform a comprehensive evaluation.Methods:Fifty C57BL/6J mice were randomly divided into control group and 100,200,400,and 800 mg·kg-1 D-gal groups,with 10 mice in each group.The mice in various D-gal groups were subcutaneously injected with the corresponding concentration of D-gal once daily;the mice in control group were injected with an equal volume of normal saline.The body mass and water consumption of the mice in various groups were monitored;forelimb grip strength test and experiment on the ability of pole climbing sports were used to evaluate the motor coordination ability of the mice in various groups;novel object recognition test,Y maze test,and Morris water maze test were used to evaluate the cognitive function of the mice in various groups;HE staining and Nissl staining were used to observe the pathomorphology of brain tissue of the mice in various groups;immunohistochemistry method was used to detect the expression of β-galactosidase(β-gal)protein in brain tissue of the mice in various groups;real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the mRNA expression levels of interleukin(IL)-1β,tumor necrosis factor-α(TNF-α),IL-18,and IL-4 in hippocampus tissue of the mice in various groups;Western blotting method was used to detect the expression levels of β-gal,p53,and p16 proteins in hippocampus tissue of the mice in various groups.Results:The body mass growth trends of the mice in control group and various D-gal groups were consistent and there was no statistically significant difference(P>0.05),and there was no statistically significant difference in water consumption(P>0.05).After 8 weeks of subcutaneous injection of D-gal,compared with control group,the forelimb grip strength values of the mice in 200 and 400 mg·kg?1 D-gal groups were significantly decreased(P<0.05 or P<0.01);the pole-climbing time of the mice in 200 mg·kg?1 D-gal group was significantly prolonged(P<0.05);the recognition indexes of the mice in 200 and 400 mg·kg?1 D-gal groups were significantly decreased(P<0.01);the spontaneous alternation rate of the mice in 100,200,400,and 800 mg·kg?1 D-gal group was significantly decreased(P<0.05 or P<0.01),the escape latency was significantly increased(P<0.05).Spatial probe test showed that compared with control group,the escape latency of the mice in 200 mg·kg?1 D-gal group was significantly increased(P<0.05).The HE staining and Nissl staining results showed that compared with control group,the hippocampus neurons of the mice in 200 mg·kg-1 D-gal group were arranged disorderly,with obvious nuclear pyknosis,nuclear condensation,and abnormal morphology and structure,and the number of Nissl staining positive cells was significantly decreased.The immunohistochemistry results showed that compared with control group,the β-gal expressions in CA1 region,CA3 region,and cortex region of hippocampus tissue of the mice in 200 mg·kg?1 D-gal group were strongly positive.The RT-qPCR results showed that compared with control group,the expression levels of IL-1β,IL-18,and TNF-α mRNA in hippocampus tissue of the mice in 200 mg·kg?1 D-gal group were significantly increased(P<0.05 or P<0.01),and the expression level of IL-4 mRNA was significantly decreased(P<0.01).The Western blotting results showed that compared with control group,the expression levels of β-gal,p53,and p16 proteins in hippocampus tissue of the mice in 200 mg·kg?1 D-gal group were significantly increased(P<0.05 or P<0.01).Conclusion:The aging-related cognitive dysfunction model in the mice can be established by subcutaneous injection of 200 mg·kg?1 D-gal daily for 8 weeks.

Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

Objective To investigate the pathogenesis of high-altitude cerebral edema(HACE)and develop new therapeutic strategies.Methods Male Sprague-Dawley(SD)rats of 6 weeks old were selected and placed in a hypobaric chamber.The rats were exposed to the high-altitude environment of 7000 m above sea level for 3 days for HACE modeling.Whether the HACE model was successfully established in the rats was evaluated by measuring brain water content,the degree of disruption to the blood-brain barrier(BBB),and brain tissue Nissl staining.The experimental animals were divided into four groups,with 28 rats in each group.The blank control group was exposed to a normobaric and normoxic environment simulating the conditions at 500 m above sea level for 3 d.The other groups,including a model group(the HACE group),a bumetanide group(the positive control group),and a XH-6003 treatment group,were placed at an altitude of 7 000 m above sea level and were injected with normal saline,bumetanide,and XH-6003,a new type of Na-K-2C1 cotransporter 1(NKCC1)inhibitor,via the tail vein,respectively,twice daily for 3 d.The experimental animals were taken out of the hypobaric chamber for testing after 3 d.The primary outcome measures included brain water content,BBB permeability,changes in brain tissue morphology,and the expression levels of aquaporin-4(AQP4)and NKCC1.The secondary outcome measures included behavioral changes,apoptosis,and oxidative stress markers.Results The HACE rat model was successfully established.The model group exhibited increased brain water content(P＜0.0001),BBB disruption(P＜0.0001),impairment in learning skills and memory(P＜0.001),and anxiety/depression-like behaviors(P＜0.01).qPCR results showed significantly increased expression of NKCC1 and AQP4 in the brain tissue of the model group(P＜0.01).Pathology examination revealed neuronal and glial cell damage in the hippocampus of the model group(P＜0.01).Treatment with XH-6003,the NKCC1 inhibitor,reversed brain water content,BBB disruption,and neuronal and glial cell damage to a certain degree(P＜0.05),decreased the expression of NKCC1 and AQP4 in the brain tissue(P＜0.01),and inhibited apoptosis-related proteins.Among the oxidative stress indices,only glutathione(GSH)showed improvement(P＜0.001).Rats treated with XH-6003 showed functional improvement only in the time spent exploring novel objects,while other behavioral outcomes remained unchanged.Conclusion HACE is associated with the activation of the NKCC1/AQP4 pathway.Inhibition of this pathway alleviates brain edema,BBB disruption,and neuronal and glial cell damage.These findings suggest that XH-6003 holds potential as a therapeutic strategy for HACE at the cellular and molecular levels,but its effects in improving HACE-related behavioral disorders warrant further investigation.

Objective:To deeply understand the psychological experiences and needs of ward nurses caring for elderly patients with postoperative delirium, providing insights for improving their care capabilities.Methods:A descriptive qualitative study was conducted using purposive sampling to select nurses from the surgical wards of the Second Affiliated Hospital of Zhejiang University School of Medicine who had cared for elderly patients with postoperative delirium between January and March 2024. Semi-structured interviews were conducted, and traditional content analysis was used to extract themes.Results:Sixteen surgical ward nurses, aged 26-48 years old and all female, were interviewed. Four themes and nine sub-themes were identified: internal stress in caring for elderly patients with postoperative delirium (concerns about failing to recognize changes in condition, leading to delayed treatment; physical and psychological stress overwhelming nursing work); external challenges in caring for elderly patients with postoperative delirium (uncontrollable patient behavior; lack of close collaboration between medical staff; lack of awareness among patient families about postoperative delirium); lack of knowledge about postoperative delirium (difficulty in identifying subtypes of postoperative delirium; lack of knowledge about postoperative delirium management); and a desire for systematic professional support (urgent need for operational guidelines on postoperative delirium management in elderly patients; expectation for the establishment of a multidisciplinary team for postoperative delirium management in elderly patients).Conclusions:Nursing managers should pay attention to the physical and mental health of ward nurses, provide multifaceted support, strengthen their knowledge about postoperative delirium in elderly patients, optimize postoperative delirium management, and improve their care capabilities.

Objective:To deeply understand the psychological experiences and needs of ward nurses caring for elderly patients with postoperative delirium, providing insights for improving their care capabilities.Methods:A descriptive qualitative study was conducted using purposive sampling to select nurses from the surgical wards of the Second Affiliated Hospital of Zhejiang University School of Medicine who had cared for elderly patients with postoperative delirium between January and March 2024. Semi-structured interviews were conducted, and traditional content analysis was used to extract themes.Results:Sixteen surgical ward nurses, aged 26-48 years old and all female, were interviewed. Four themes and nine sub-themes were identified: internal stress in caring for elderly patients with postoperative delirium (concerns about failing to recognize changes in condition, leading to delayed treatment; physical and psychological stress overwhelming nursing work); external challenges in caring for elderly patients with postoperative delirium (uncontrollable patient behavior; lack of close collaboration between medical staff; lack of awareness among patient families about postoperative delirium); lack of knowledge about postoperative delirium (difficulty in identifying subtypes of postoperative delirium; lack of knowledge about postoperative delirium management); and a desire for systematic professional support (urgent need for operational guidelines on postoperative delirium management in elderly patients; expectation for the establishment of a multidisciplinary team for postoperative delirium management in elderly patients).Conclusions:Nursing managers should pay attention to the physical and mental health of ward nurses, provide multifaceted support, strengthen their knowledge about postoperative delirium in elderly patients, optimize postoperative delirium management, and improve their care capabilities.

Objective To analyze the fairness of human resource allocation in professional public health agency (PHA) in Guangdong Province in 2022. Methods Health technical staff, other technical staff, and management staff from PHAs in Guangdong Province, such as disease prevention and control centers, specialized disease prevention and treatment institutions, maternal and child health institutions, health education centers, emergency centers/stations, blood collection and supply institutions, health supervision agencies, and family planning service centers under health departments, were selected as the study subjects. Data on human resource allocation in PHAs were collected, and the Lorenz curve, Gini coefficient, and Theil index were used to analyze the fairness of personnel allocation based on three dimensions: year-end resident population, geographical area, and regional gross domestic product. Results The number of PHA personnel per 10 000 population in four regions of the Pearl River Delta, eastern, western and mountain area in Guangdong Province was (7.49±3.74), (4.74±0.87), (8.73±1.67) and (10.33±1.80), respectively. There was no correlation between the per capita regional gross dumestic product of each prefecture level city and the number of PHA personnel (Spearman′s rank correlation coefficient=0.43, P>0.05). PHA resource allocation based on year-end resident population was more equitable than allocations based on geographical area or regional gross dumestic product, as indicated by the Lorenz curve being closest to the 45° standard line and the lowest Gini coefficient. The fairness of personnel allocation from high to low was ranked as follows: practicing (assistant) physicians, health technicians, registered nurses, managers personnel, and other technical personnel, with Theil indices of 0.035 0, 0.036 4, 0.044 6, 0.048 4, and 0.053 5, respectively. The differences in configuration fairness were derived from within group differences, with contribution rates of 76.0%, 73.9%, 71.8%, 82.9%, and 92.2%. The Lorenz curve, Gini coefficient, and Theil index were consistent in the distribution of permanent residents at the end of the year. Conclusion The fairness of professional human resource allocation in Guangdong Province based on the distribution of permanent residents at the end of the year is better than that based on geographical area and regional gross domestic product. The fairness of the allocation of practicing (assistant) physicians is better than that of other professional categories. Regional differences are the main reason for the relatively unfair allocation of PHA human resources in Guangdong Province.

Objective To analyze the current situation of human resources in county-level specialized disease prevention and control institutions in Guangdong Province in 2022 and propose countermeasures.Methods Analyze the human resources situation of specialized disease prevention and control personnel in counties in Guangdong Province based on their basic informa-tion such as staffing,age,professional title,and income level.Results The education level of county-level specialized disease prevention and control personnel in Guangdong Province is mainly undergraduate(42.60％),the technical title is mainly inter-mediate or below(84.08％),and the age is mainly over 45 years old(39.58％);Comparative analysis was conducted on the education and professional titles of specialized disease prevention and control personnel in counties in the Pearl River Delta,east-ern Guangdong,western Guangdong,and northern Guangdong regions,and the differences were statistically significant(x2=733.751,P＜0.001;x2=142.048,P＜0.001).Conclusion The human resources for specialized disease prevention and control in counties in Guangdong Province are facing problems such as talent shortage,aging of personnel,low academic qualifi-cations and titles,and insufficient financial investment.It is recommended to formulate a scientific and reasonable talent develop-ment plan,attach importance to and strengthen the construction of specialized disease prevention and control talent teams.

AIM:To compare the differences of ocular biometric parameters of age-related cataract between Tibetan and Han ethnic groups, and to analyze the distribution characteristics of ocular biometric parameters in Tibetan cataract patients.METHODS:Retrospective cohort study. A total of 661 patients(1 030 eyes)with age-related cataract confirmed in the hospital between January 2019 and December 2020 were enrolled. The parameters of axial length, anterior chamber depth, keratometry, corneal astigmatism and astigmatic axis were measured by IOL Master 500 in 483 cases(739 eyes)of Tibetan age-related cataract patients and 178 cases(291 eyes)of Han patients.RESULTS:The axial length, anterior chamber depth and corneal astigmatism of the Tibetan patients with age-related cataract were 23.33(22.81, 23.86)mm, 3.04(2.79, 3.30)mm and 0.73(0.47, 1.07)D. The mean keratometry was 43.89±1.35 D. The results indicated that Tibetan cataract patients had shorter axial lengths and smaller keratometry compared to Han patients(all P<0.05). Age in Tibetan patients was negatively correlated with axial length and anterior chamber depth, and positively correlated with keratometry(all P<0.05). Tibetan male patients had longer axial lengths, deeper anterior chambers, and flatter corneas compared to female patients(all P<0.05).CONCLUSION:There were differences in ocular biometric parameters between age-related cataract patients of Tibetan and Han ethnicities. The distribution of ocular biometric parameters in Tibetan cataract patients varied across different age groups and gender groups.

BACKGROUND:Myelodysplastic syndrome has worse hazards of acute myeloid leukemia transformation,and some studies have revealed that immune infiltration plays a vital part in the two.Nevertheless,more studies are required to confirm the relationship between immune infiltration and related differentially expressed gene regulation. OBJECTIVE:To screen the differentially expressed genes with prognostic significance between myelodysplastic syndrome and acute myeloid leukemia by bioinformatics analysis and explore the possible roles and mechanisms among these differentially expressed genes and immune infiltration mechanisms in the occurrence and progression of diseases. METHODS:The differentially expressed genes were screened for bioinformatics analysis using the GEO datasets,and analyzed by DO,GO,KEGG and GSEA.The TCGA prognostic database was used to plot the K-M curves of differentially expressed genes and receiver operating characteristic curve analysis was applied to evaluate the clinical diagnostic performance.Finally,CIBERSORT analysis was used to intuitively demonstrate the correlation between critical prognostic genes and the distribution of immuno-infiltrated cells.RT-qPCR was employed to detect peripheral blood samples from healthy controls,myelodysplastic syndrome and acute myeloid leukemia patients so as to verify the crucial genes preliminarily. RESULTS AND CONCLUSION:(1)A total of 150 differentially expressed genes were obtained between myelodysplastic syndrome and acute myeloid leukemia,among which 16 genes were up-regulated and 134 were down-regulated.(2)The results of DO,GO,KEGG and GSEA analysis suggested that differentially expressed genes might promote the development of myelodysplastic syndrome to acute myeloid leukemia by regulating the immune response.CIBERSORT revealed the differences in immune infiltration between myelodysplastic syndrome and acute myeloid leukemia.The distribution of CD4+ T cells,monocytes,neutrophils and M1 macrophages decreased in acute myeloid leukemia patients.In contrast,the distribution of inflammatory suppressor cells M2 macrophages increased,suggesting that it may be related to the immunosuppression of acute myeloid leukemia.(3)K-M curve and receiver operating characteristic curve analysis of 150 differentially expressed genes screened out four genes relevant to immunity and prognosis with good diagnostic performance:MANSC1,FLT3,BMX and CXCR2.(4)The results of RT-qPCR exhibited that MANSC1,BMX and CXCR2 were low expressed,while FLT3 was highly expressed in acute myeloid leukemia patients.These findings verify that the differential expression of MANSC1,FLT3,BMX and CXCR2 in patients with myelodysplastic syndrome and acute myeloid leukemia is not only significantly correlated with the prognosis of patients but may also affect the occurrence and development of myelodysplastic syndrome and acute myeloid leukemia by regulating the immune infiltration of patients.They can be used as potential biomarkers and therapeutic targets of the transformation from myelodysplastic syndrome to acute myeloid leukemia,providing a new direction for clinical diagnosis and treatment of the transformation of myelodysplastic syndrome.

Epimedin B(EB)is one of the main flavonoid ingredients present in Epimedium brevicornum Maxim.,a traditional herb widely used in China.Our previous study showed that EB was a stronger inducer of melanogenesis and an activator of tyrosinase(TYR).However,the role of EB in melanogenesis and the mechanism underlying the regulation remain unclear.Herein,as an extension to our previous investi-gation,we provide comprehensive evidence of EB-induced pigmentation in vivo and in vitro and eluci-date the melanogenesis mechanism by assessing its effects on the TYR family of proteins(TYRs)in terms of expression,activity,and stability.The results showed that EB increased TYRs expression through microphthalmia-associated transcription factor-mediated p-Akt(referred to as protein kinase B(PKB))/glycogen synthase kinase 3β(GSK3β)/β-catenin,p-p70 S6 kinase cascades,and protein 38(p38)/mitogen-activated protein(MAP)kinase(MAPK)and extracellular regulated protein kinases(ERK)/MAPK pathways,after which EB increased the number of melanosomes and promoted their maturation for melanogenesis in melanoma cells and human primary melanocytes/skin tissues.Furthermore,EB exerted repigmentation by stimulating TYR activity in hydroquinone-and N-phenylthiourea-induced TYR inhibitive models,including melanoma cells,zebrafish,and mice.Finally,EB ameliorated monobenzone-induced depigmentation in vitro and in vivo through the enhancement of TYRs stability by inhibiting TYR misfolding,TYR-related protein 1 formation,and retention in the endoplasmic reticulum and then by downregulating the ubiquitination and proteolysis processes.These data conclude that EB can target TYRs and alter their expression,activity,and stability,thus stimulating their pigmentation function,which might provide a novel rational strategy for hypopigmentation treatment in the pharmaceutical and cosmetic industries.