The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Objective:To understand the epidemiological characteristics and trends of injury in older adults in Jiangsu Province from 2006 to 2022 and provide a scientific basis for developing prevention and control measures.Methods:The data on injury cases aged 60 and older were collected from 12 sentinel hospitals in Jiangsu Province during 2006-2022. The study analyzed the proportion of injury cases among the elderly in the overall population and calculated the annual percent change and average annual percent change (AAPC). A pairwise comparison between groups was performed, and the differences were judged according to the adjusted standardized residuals.Results:From 2006 to 2022, there were 218 426 injury cases among individuals aged 60 and older in Jiangsu Province, which accounted for an increasing proportion of injury cases within the entire population (AAPC=3.17%, P<0.001). The first five causes of elderly injury were falls (42.06%), road traffic injuries (20.20%), animal injuries (11.45%), knife/sharp injuries (9.43%), and blunt injuries (8.13%). From 2006 to 2022, the proportion of falls, animal injuries, and knife/sharp injuries among the elderly aged ≥60 showed an increasing trend, while the proportion of road traffic injuries and blunt injuries decreased (all P<0.001). The incidence of injury was highest in October, with a daily incidence peak between 8:00 and 10:00. Leisure activities (40.34%) were the major activity leading to injury. The injury occurred mainly at home (53.74%), and the injury intention was mainly unintentional (97.41%), all of which showed an increasing trend ( P<0.001). The injuries were mainly bruises (36.00%), and the most common injured positions of the body were low limbs (27.55%), all of which showed a decreasing trend ( P<0.001). About 69.80% of cases were slight, and 79.38% were discharged after treatment, which showed an increasing trend ( P<0.001). Conclusions:The injury data for individuals aged 60 and older in Jiangsu Province exhibited varying trends from 2006 to 2022. There was a noticeable increase in the proportion of elderly injury cases within the overall injury population, as well as an upward trend in falls, animal injuries, and knife/sharp injuries as leading causes of injury. It is imperative to actively develop prevention measures based on the epidemiological characteristics and evolving trends of elderly injuries in Jiangsu Province.

Objective To detect the expression levels of tumor necrosis factor alpha induced protein 3(TN-FAIP3)and LINC00887 in clear cell renal cell carcinoma(ccRCC)tissue,and to study their relationship with clinical pathological parameters and prognosis.Methods A total of 101 ccRCC patients admitted to the hospi-tal from January 2013 to October 2018 were selected.The expression levels of TNFAIP3 and LINC00887 were detected in ccRCC cancer tissue and paired adjacent tissues,respectively.The relationship between TNFAIP3 and LINC00887 expression and clinical pathological parameters and prognosis of ccRCC patients was analyzed,and the influencing factors of poor prognosis in ccRCC patients were also analyzed.Spearman correlation coef-ficient was used to analyze the correlation between TNFAIP3 and LINC00887 expression.Results The posi-tive rate of TNFAIP3 expression in ccRCC(37.62％)was significantly lower than that in adjacent tissues(52.48％),and the difference was statistically significant(X2=4.500,P=0.034).The expression level of LINC00887 in ccRCC(1.38±0.61)was significantly higher than that in adjacent tissues(1.03±0.43),and the difference was statistically significant(t=5.396,P＜0.001).The positive rates of TNFAIP3 protein in pa-tients with maximum tumor diameter ≥4.5 cm and TNM stage Ⅲ-Ⅳ were lower than those in patients with maximum tumor diameter＜4.5 cm and TNM stage Ⅰ-Ⅱ,and the differences were statistically significant(P＜0.05).The positive rates of LINC00887 in patients with maximum tumor diameter ≥ 4.5 cm,pathologi-cal grading Ⅲ-Ⅳ,and TNM stage Ⅲ-Ⅳ were higher than those in patients with maximum tumor diameter＜4.5 cm,pathological grading Ⅰ-Ⅱ,and TNM stage Ⅰ-Ⅱ,and the differences were statistically signifi-cant(P＜0.05).Compared with the TNFAIP3 high expression group,the TNFAIP3 low expression group had a poorer prognosis,and the difference was statistically significant(x2=5.118,P=0.024).Compared with the LINC00887 low expression group of,the LINC00887 high expression group had a poorer prognosis,and the difference was statistically significant(x2=4.638,P=0.031).Low expression of TNFAIP3,high expres-sion of LINC00887,pathological grade Ⅲ-Ⅳ,and TNM stage Ⅲ-Ⅳ were risk factors for poor prognosis in ccRCC patients(P＜0.05).Spearman rank correlation analysis showed that there was a negative correlation between TNFAIP3 and LINC00887 expression in ccRCC tissue(r=-0.638,P=0.012).Conclusion TN-FAIP3 expression is down-regulated and L1NC00887 expression is up-regulated in ccRCC tissue,and there is a negative correlation.They may jointly regulate the occurrence and development of ccRCC,and have the poten-tial to become tumor markers for evaluating the prognosis of ccRCC patients.

Objective:To investigate the effect of the possibility of sleep-disordered breathing (SDB) as assessed by the four-variable score on the platelet function and the risk of stroke recurrence in patients with acute ischemic stroke.Methods:Patients with acute ischemic stroke admitted to the Department of Neurology, Weihai Municipal Hospital from January 2020 to January 2021 were enrolled prospectively. Main inclusion criteria: admission within 24 h of onset; National Institutes of Health Stroke Scale score ≤3; Receiving aspirin + clopidogrel dual antiplatelet therapy. All patients were divided into a high possibility group and a low possibility group of SDB according to the four-variable score. 7±2 d after dual antiplatelet therapy, PL-12 multi-parameter platelet function analyzer was used to detect the maximum aggregation rate (MAR). The patients were followed up for 6 months after discharge and the recurrence of ischemic stroke was observed. The mediating effect model was established with the high possibility of SDB as the independent variable, MAR as the intermediary variable and stroke recurrence as the dependent variable. Firstly, MAR as the dependent variable and high probability of SDB as the independent variable were analyzed by linear regression; then, a binary logistic regression analysis was performed with ischemic stroke recurrence as the dependent variable and the high probability of SDB and MAR as independent variables. Results:A total of 213 patients were enrolled in the study. The average age of the patients was 62.70 ± 10.04 years old. There were 146 male (68.5%) and 121 patients (56.8%) were in the high possibility group (56.8%). During the follow-up period, 24 patients (11.3%) had stroke recurrence. Univariate analysis showed that arachidonic acid (AA) induced MAR (MAR-AA) and adenosine diphosphate (ADP) induced the MAR (MAR-ADP) in the high possibility group of SDB were significantly higher than those in the low possibility group (all P<0.05); MAR-AA and MAR-ADP in the recurrent group were significantly higher than those in the non-recurrent group (all P<0.05), and the proportion of high possibility of SDB in the recurrent group was significantly higher ( P=0.008). Binary logistic regression analysis showed that homocysteine (odds ratio 1.132, 95% confidence interval 1.048-1.223; P=0.002) and having high possibility of SDB (odds ratio 6.351, 95% confidence interval 1.134-35.566; P=0.035) were the independent risk factors for stroke recurrence in patients treated with dual antiplatelet therapy. Intermediary effect analysis showed that MAR had a significant intermediary effect on the risk of stroke recurrence in patients with high probability of SDB. Conclusion:The MAR and stroke recurrence rates in the high possibility group of SDB were significantly higher than those in the low possibility group, and its stroke risk was probably mediated by platelet hyperreactivity.

Thrombotic thrombocytopenic purpura (TTP) is a rare hematological disease with typical clinical manifestations of thrombocytopenic purpura, microangiopathic hemolytic anemia, neurological symptoms, fever and kidney damage. Two patients with TTP-associated cerebral infarction complicated with microhemorrhage and their shared specific imaging findings manifestations were reported. The magnetic resonance imaging of the 2 patients showed multiple cerebral infarctions at different stages. Susceptibility-weighted imaging showed cerebral microbleeds in the infarcted area. This special imaging feature can provide important clues for early identification and diagnosis of TTP nervous system injury.

Bacteriophages bind to the bacteria receptor through the receptor binding proteins (RBPs), a process that requires the involvement of complex atomic structures and conformational changes. In response to bacteriophage infection, bacteria have developed a variety of resistance mechanisms, while bacteriophages have also evolved multiple antagonistic mechanisms to escape host resistance. The exploration of the "adsorption-anti adsorption-escape process" between bacteriophages and bacteria helps us better understand the co-evolution process of bacteriophages and bacteria, which is important for the development of phage therapeutic technologies and phage-based biotechnologies. This review summarizes the bacteriophage adsorption related proteins, how bacteriophages escape host resistance based on the RBP alternations, and the recent progress of RBP-related biotechnologies.
Bacteria ; Bacteriophage Receptors ; Bacteriophages/genetics* ; Carrier Proteins ; Protein Binding

Objective:To investigate the correlation between heart rate variability (HRV) and cerebral small vessel disease (CSVD) in patients with obstructive sleep apnea (OSA).Methods:Patients with OSA received polysomnography and brain MRI examination in Weihai Municipal Hospital from July 2019 to July 2020 were consecutively collected for cross-sectional analysis. The 5 min HRV before sleep (awake state) was analyzed. The patients were divided into CSVD group and non-CSVD group according to the overall burden of CSVD. The demographic data, clinical data, polysomnography parameters and HRV time domain and frequency domain parameters were compared between the two groups. Multivariate logistic regression analysis was used to determine the correlation between the HRV parameters and CSVD in patients with OSA. Results:A total of 100 patients with OSA were enrolled, including 79 males (79.0%), aged 52.36±8.66 years, apnea hypopnea index (AHI) 38.70±24.65/h. There were 46 patients (46.0%) in the CSVD group and 54 (54.0%) in the non-CSVD group. Univariate analysis showed that there were significant differences in age, AHI, oxygen desaturation index (ODI), percentage of blood oxygen saturation <90% in total sleep time (T90), square root of the mean of the sum of the squares of the difference between adjacent RR intervals (RMSSD), power in high frequency range (HF), power in low frequency range (LF) to HF ratio (LF/HF) between the CSVD group and the non-CSVD group (all P<0.05). Multivariate logistic regression analysis showed that after adjusting for age, body mass index, systolic blood pressure, AHI, ODI, and T90, RMSSD (odds ratio 0.625, 95% confidence interval 0.389-0.981; P=0.041) and LF/HF ratio (odds ratio 1.429, 95% confidence interval 1.011-2.020; P=0.043) were the independent influencing factors of CSVD in patients with OSA. Conclusion:Increased LF/HF and decreased RMSSD in OSA patients with CSVD suggest that the increased sympathetic excitability and decreased vagus function, which may be one of the pathophysiological mechanisms of occurring CSVD in patients with OSA.

Objective:To investigate the correlation between heart rate variability (HRV) and cognitive impairment in patients with obstructive sleep apnea (OSA).Methods:Patients received polysomnography in Weihai Municipal Hospital from June 2019 to November 2020 were enrolled as the subjects of cross-sectional analysis. According to the Montreal Cognitive Assessment score, the patients with OSA were divided into a cognitive impairment group and a non-cognitive impairment group. Multivariate logistic regression analysis was used to determine whether HRV parameters were the independent influencing factors of cognitive impairment in patients with OSA. Multiple linear regression analysis was used to determine the independent correlation between HRV parameters and overall cognition as well as each cognitive domain in patients with OSA. Results:A total of 115 patients with OSA were included, including 80 males (69.6%), aged 58.25±9.88 years. Among them, there were 61 in the cognitive impairment group (53.0%) and 54 in the non-cognitive impairment group (47.0%). The standard deviation of the R-R interval in normal sinus beats (SDNN), the square root of the mean of the sum of the squares of the difference between adjacent NN intervals (RMSSD), the percentage of the number of pairs of adjacent R-R intervals differing by more than 50 ms (pNN50) and the power in high-frequency range (HF; 0.15-0.40 Hz) in the cognitive impairment group were significantly lower than those in non-cognitive impairment group (all P<0.05). Multivariate logistic regression analysis showed that SDNN (odds ratio [ OR] 0.551, 95% confidence interval [ CI] 0.380-0.798; P=0.002), RMSSD ( OR 0.516, 95% CI 0.342-0.779; P=0.002), pNN50 ( OR 0.900, 95% CI 0.834-0.971; P=0.006), LF ( OR 0.821, 95% CI 0.687-0.982; P=0.030) and HF ( OR 0.687, 95% CI 0.525-0.899; P=0.006) were the independent protective factors of cognitive impairment in patients with OSA. Multiple linear regression analysis showed that SDNN ( β=0.208, P=0.023), RMSSD ( β=0.228, P=0.011), pNN50 ( β=0.186, P=0.040), HF ( β=0.235, P=0.010) is independently correlated with overall cognitive function in patients with OSA. Conclusion:The decline of HRV parameters SDNN, RMSSD, pNN50 and HF is independently correlated with cognitive impairment in patients with OSA, suggesting that the decline of vagus nerve function may be involved in the mechanism of cognitive impairment in patients with OSA.