[Arbutin ameliorates liver fibrosis in mice by inhibiting macrophage recruitment and regulating the Akt/NF-κB and Smad signaling pathways].

OBJECTIVE: To investigate the protective effect of arbutin against CCl4-induced hepatic fibrosis in mice and explore the underlying mechanisms. METHODS: Twenty-four C57BL/6 mice were randomly divided into control group, model group, and low- and high-dose arbutin treatment (25 and 50 mg/kg, respectively) groups. Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4, and arbutin was administered daily via gavage for 6 weeks. After the treatments, serum biochemical parameters of the mice were tested, and liver tissues were taken for HE staining, Sirius Red staining and immunohistochemical staining. RT-qPCR was used to detect the mRNA levels of α-SMA, Pdgfb, Col1α1, Timp-1, Ccl2 and Tnf-a, and Western blotting was performed to detect α-SMA protein expression in the liver tissues. In the cell experiment, the effect of arbutin treatment for 24 h on THP-1 and RAW264.7 cell migration and recruitment was examined using Transwell migration assay and DAPI staining; The changes in protein levels of Akt, p65, Smad3, p-Akt, p-p65, p-Smad3 and α-SMA in arbutintreated LX-2 cells were detected with Western blotting. RESULTS: Arbutin treatment significantly lowered serum alanine aminotransferase and aspartate aminotransferase levels, alleviated liver tissue damage and collagen deposition, and reduced macrophage infiltration and α-SMA protein expression in the liver of the mouse models (P < 0.05 or 0.001). Arbutin treatment also significantly reduced CCl4-induced elevation of a-SMA, Pdgfb, Col1α1, Timp-1, Ccl2 and Tnf-a mRNA levels in mice (P < 0.05). In the cell experiment, arbutin treatment obviously inhibited migration and recruitment of THP-1 and RAW264.7 cells and lowered the phosphorylation levels of Akt, p65 and Smad3 and the protein expression level of α-SMA in LX-2 cells. CONCLUSION: Arbutin ameliorates liver inflammation and fibrosis in mice by inhibiting hepatic stellate cell activation via reducing macrophage recruitment and infiltration and suppressing activation of the Akt/NF-κB and Smad signaling pathways.

[Multicenter evaluation of the diagnostic efficacy of jaundice color card for neonatal hyperbilirubinemia].

Objective: To evaluate the diagnostic efficacy and practicality of the Jaundice color card (JCard) as a screening tool for neonatal jaundice. Methods: Following the standards for reporting of diagnostic accuracy studies (STARD) statement, a multicenter prospective study was conducted in 9 hospitals in China from October 2019 to September 2021. A total of 845 newborns who were admitted to the hospital or outpatient department for liver function testing due to their own diseases. The inclusion criteria were a gestational age of ≥35 weeks, a birth weight of ≥2 000 g, and an age of ≤28 days. The neonate's parents used the JCard to measure jaundice at the neonate's cheek. Within 2 hours of the JCard measurement, transcutaneous bilirubin (TcB) was measured with a JH20-1B device and total serum bilirubin (TSB) was detected. The Pearson's correlation analysis, Bland-Altman plots and the receiver operating characteristic (ROC) curve were used for statistic analysis. Results: Out of the 854 newborns, 445 were male and 409 were female; 46 were born at 35-36 weeks of gestational age and 808 were born at ≥37 weeks of gestational age. Additionally, 432 cases were aged 0-3 days, 236 cases were aged 4-7 days, and 186 cases were aged 8-28 days. The TSB level was (227.4±89.6) µmol/L, with a range of 23.7-717.0 µmol/L. The JCard level was (221.4±77.0) µmol/L and the TcB level was (252.5±76.0) µmol/L. Both the JCard and TcB values showed good correlation (r=0.77 and 0.80, respectively) and agreements (96.0% (820/854) and 95.2% (813/854) of samples fell within the 95% limits of agreement, respectively) with TSB. The JCard value of 12 had a sensitivity of 0.93 and specificity of 0.75 for identifying a TSB ≥205.2 µmol/L, and a sensitivity of 1.00 and specificity of 0.35 for identifying a TSB ≥342.0 µmol/L. The TcB value of 205.2 µmol/L had a sensitivity of 0.97 and specificity of 0.60 for identifying TSB levels of 205.2 µmol/L, and a sensitivity of 1.00 and specificity of 0.26 for identifying TSB levels of 342.0 µmol/L. The areas under the ROC curve (AUC) of JCard for identifying TSB levels of 153.9, 205.2, 256.5, and 342.0 µmol/L were 0.96, 0.92, 0.83, and 0.83, respectively. The AUC of TcB were 0.94, 0.91, 0.86, and 0.87, respectively. There were both no significant differences between the AUC of JCard and TcB in identifying TSB levels of 153.9 and 205.2 µmol/L (both P>0.05). However, the AUC of JCard were both lower than those of TcB in identifying TSB levels of 256.5 and 342.0 µmol/L (both P<0.05). Conclusion: JCard can be used to classify different levels of bilirubin, but its diagnostic efficacy decreases with increasing bilirubin levels. When TSB level are ≤205.2 µmol/L, its diagnostic efficacy is equivalent to that of the JH20-1B. To prevent the misdiagnosis of severe jaundice, it is recommended that parents use a low JCard score, such as 12, to identify severe hyperbilirubinemia (TSB ≥342.0 µmol/L).

Nomogram based on MRI and clinical features to predict progression-free survival in patients with stage IIIC1r cervical squamous cell carcinoma: A two-center study.

PURPOSE: To develop a nomogram based on MRI and clinical features to predict progression-free survival (PFS) of 2018 FIGO stage ⅢC1r cervical squamous cell carcinoma (CSCC). METHODS: 144 consecutive patients with stage ⅢC1r CSCC from two independent institutions were stratified into training cohort (from Institution 1, n=100) and independent validation cohort (from Institution 2, n=44). Univariate and multivariate Cox regression analyses of MRI and clinical features before treatment were performed to determine independent risk factors for PFS in training cohort. Nomogram was developed based on them. Concordance index (C-index), calibration curves, and receiver operating characteristic (ROC) analyses were performed to assess and validate the nomogram. RESULTS: In training cohort, 2009 FIGO stage, maximum length of the primary tumor, short diameter and roundness index of the maximum metastatic lymph node were independent risk factors of PFS in patients with stage IIIC1r CSCC (all P-values < 0.05). Nomogram based on them to predict 1- and 3-year PFS achieved C-indexes of 0.835 (95% confidence interval (CI): 0.809-0.862) and 0.789 (95%CI: 0.683-0.895) in the training and validation cohorts, respectively. Areas under ROC curves for the nomogram to predict 1- and 3-year PFS were 0.891 (95%CI: 0.829-0.954), 0.921 (95%CI: 0.861-0.981) in training cohort, and 0.902 (95%CI: 0.803-0.999), 0.885 (95%CI: 0.778-0.992) in validation cohort, respectively. Calibration curves indicated the nomogram predictions were in good agreement with actual observations. CONCLUSIONS: The nomogram based on MRI and clinical features has high accuracy and stability in predicting PFS of patients with stage IIIC1r CSCC.

Heralded Three-Photon Entanglement from a Single-Photon Source on a Photonic Chip.

In the quest to build general-purpose photonic quantum computers, fusion-based quantum computation has risen to prominence as a promising strategy. This model allows a ballistic construction of large cluster states which are universal for quantum computation, in a scalable and loss-tolerant way without feed forward, by fusing many small n-photon entangled resource states. However, a key obstacle to this architecture lies in efficiently generating the required essential resource states on photonic chips. One such critical seed state that has not yet been achieved is the heralded three-photon Greenberger-Horne-Zeilinger (3-GHZ) state. Here, we address this elementary resource gap, by reporting the first experimental realization of a heralded 3-GHZ state. Our implementation employs a low-loss and fully programmable photonic chip that manipulates six indistinguishable single photons of wavelengths in the telecommunication regime. Conditional on the heralding detection, we obtain the desired 3-GHZ state with a fidelity 0.573±0.024. Our Letter marks an important step for the future fault-tolerant photonic quantum computing, leading to the acceleration of building a large-scale optical quantum computer.

Analysis of the effect of elevated systemic immuno-inflammation index on hepatic steatosis based on the NHANES database.

OBJECTIVE: Based on data from the National Health and Nutrition Examination Survey (NHANES), this study aimed to investigate the effect of high levels of systemic immune inflammation (SII) on hepatic steatosis by conducting a population-based cross-sectional survey of research subjects. SUBJECTS AND METHODS: The population included 5,119 participants from the NHANES 2017-2020 cycle who were selected as the research subjects. We used (neutrophil count × platelet count)/lymphocyte count as the formula for calculating SII. The formula for calculating HSI levels was 8 × the ratio of [alanine aminotransferase (ALT) / aspartate aminotransferase (AST)] + body mass index (BMI) + 2 (with diabetes mellitus) + 2 (for women). HSI=36 was taken as the cut-off value for evaluating hepatic steatosis. Multivariate logistic regression analysis was used to evaluate the relationship between hepatic steatosis and SII in different models. Subgroup analysis was used to explore the relationship between different subgroups of SII and hepatic steatosis. Interaction analyses were used to assess the heterogeneity. RESULTS: Out of a total of 5,119 participants, hepatic steatosis was observed in 2,742 individuals. Multivariate logistic regression showed that the independent risk factor for hepatic steatosis was a high SII level (OR=1.33, 95% CI: 1.11-1.49, p<0.05). After adjusting for differences in BMI and HSI using propensity score matching (PSM), bariatric surgery also reduced SII risk. CONCLUSIONS: There is a correlation between SII and hepatic steatosis, and bariatric surgery can effectively reduce SII risk in the hepatic steatosis population.

Effects of transcranial direct current stimulation combined with tinnitus retraining therapy on sleep disorders in patients with chronic tinnitus.

OBJECTIVE: The aim of this study was to investigate the effects of transcranial direct current stimulation (TDCS) combined with tinnitus retraining therapy (TRT) on clinical efficacy and sleep disorder in patients with chronic tinnitus. PATIENTS AND METHODS: 126 patients with chronic tinnitus treated in our hospital from May 2020 to June 2022 were retrospectively analyzed. These subjects were randomly divided into two groups: the electrical stimulation group and the combined group, in line with the random table method, with 63 patients in each group. Patients in the electrical stimulation group received TDCS treatment, and patients in the combined group were given TDCS combined with TRT. The clinical effects, tinnitus severity [Tinnitus Evaluation Questionnaire (TEQ) score and Tinnitus handicap inventory (THI) score], sleep status [Sleep Status Rating Scale (SRSS) score and Pittsburgh Sleep Quality Index (PSQI) score], psychological status [Hamilton Anxiety Scale (HAMA) score and Self Rating Depression Scale (SDS) score] and the quality of life (Quality of Life Scale) of these subjects in two groups were analyzed. RESULTS: The clinical effect of simple TDCS was 82.53%, which was sharply lower compared to 95.24% in the combined group (p<0.05). After the treatment, TEQ score, THI score, SRSS score, PSQI score, HAMA score, and SDS score were decreased in both groups (p<0.05), and the combined group was much lower than the TDCS group (p<0.01). Compared with the pre-treatment period, the scores of restrictions in daily living, medical resource utilization, somatic symptoms, and emotional disturbance were elevated in both groups after treatment, and the combined group had markedly higher scores than the TDCS group (p<0.05). CONCLUSIONS: TDCS combined with TRT had obvious effects in treating chronic tinnitus, which largely reduced the severity of tinnitus, improved patients' sleep quality and psychological status, and improved the quality of life, indicating a certain worthy of clinical application and promotion.

[Progress on microneedle drug delivery systems for the treatment of corneal diseases].

Corneal diseases are prevalent eye conditions in China, and the lack of effective treatment in the short term can lead to blindness. However, delivering drugs to the cornea safely and effectively poses a significant challenge due to the presence of ocular barriers and clearance mechanisms. Conventional drug delivery methods exhibit low bioavailability, making it difficult to achieve therapeutic effects. Microneedles, with their ability to penetrate ocular surface barriers effectively, offer a low-invasive and highly promising drug delivery technology. This article introduces the main delivery barriers on the ocular surface, classifies microneedles, and highlights the latest developments in the treatment of corneal diseases. Finally, the potential challenges of applying microneedle delivery systems to the ocular surface are analyzed, aiming to provide insights for the clinical application of microneedles in corneal diseases.

Altered brain iron deposition in patients with minimal hepatic encephalopathy: an MRI quantitative susceptibility mapping study.

AIM: To explore the use of quantitative susceptibility mapping (QSM) in assessing changes in brain iron deposits and their association with cognitive function in patients with minimal hepatic encephalopathy (MHE). MATERIALS AND METHODS: The study cohort comprised 27 cases with hepatitis B-associated cirrhosis with MHE (MHE group), 25 with hepatitis B-associated cirrhosis without MHE (NMHE group), and 25 healthy controls (HC group). Iron deposits in the bilateral frontal white matter, caudate nucleus (CN), putamen, globus pallidus, thalamus, red nucleus, substantia nigra (SN), hippocampus, and dentate nucleus were measured by QSM. The associations between iron deposition with the time taken to complete number connection tests A (NCT-A) and the score on digital-symbol test (DST) were analysed. RESULTS: Susceptibility values differed significantly in the bilateral CN, left thalamus, right SN, and left hippocampus in the MHE group compared with the other groups and were positively associated with the times taken to complete the NCT-A in the bilateral CN, left thalamus, and right SN and negatively associated with DST scores in the bilateral CN, left TH, and left HP. CONCLUSION: Reduced cognitive function in MHE patients was significantly associated with abnormally increased iron deposition in certain brain areas. The quantification of brain iron deposition by QSM may thus be an objective and accurate means of evaluating MHE.

Effects of different dietary vitamin D combinations during the grower phase and the feed restriction phase on growth performance and sternal morphology, mineralization, and related genes expression of bone metabolism in Pekin ducks.

Our study aimed to investigate the effects of different dietary vitamin D (VD) combinations during the grower (1-32 d of age) and feed restriction (33-52 d of age) phases on growth performance. We also evaluated sternal morphology, mineralization, and related genes expression of bone metabolism as well as absorption of calcium and phosphorous in duodenal mucosa and kidney in Pekin ducks. During the grower phase, we used 2 VD regimes (Group A: 3,160 IU/kg VD3; Group B: 400 IU/kg VD3 + 69 µg/kg 25-OH-D3). Each dietary treatment had 50 replicate pens of 10 ducks per pen. During the feed restriction phase, 30 replicate pens selected from Group A and Group B, repetitively, were redivided into 5 different dietary VD regimes to form a 2 × 5 experimental design. Each group consisted of 6 replicates, each with 10 ducks. During the feed restriction phase, we evaluated 5 different dietary VD combinations were as follows: T1: 2,000 IU/kg VD3 ; T2: 5,000 IU/kg VD3; T3: 3,620 IU/kg VD3 + 34.5 µg/kg 25-OH-D3; T4: 2,240 IU/kg VD3 + 69 µg/kg 25-OH-D3; T5: 1,800 IU/kg VD3 + 80 µg/kg 25-OH-D3). Results showed that Group B combinations with T5 had a better growth performance and breast meat deposition (P < 0.1). Regardless of 5 dietary VD regimes during the feed restriction phase, Group B significantly increased (P < 0.05) 52 d sternal depth and tended to increase (P < 0.1) 52 d sternal defatted weight, ash content, and phosphate (P) content of ducks. A significant interactive effect (P < 0.05) was observed on the mRNA abundance of DMP1 and Sost1 as well as RANKL/OPG in sternum and of VDR in duodenal mucosa of ducks at 52 d of age between dietary VD combinations during 2 phases. These results indicated that dietary VD regimes during the grower phase could affect the effectiveness of dietary VD regimes during the feed restriction phases; Dietary VD combinations of both phases could affect the genes expression of bone formation and the absorption as well as reabsorption of calcium and phosphorus in duodenum and kidney.

[Correlation analysis of dynamic enhanced energy spectrum CT parameters with Ki-67 high expression in hepatocellular carcinoma].

Objective: To investigate the correlation between dynamic enhanced energy spectral CT parameters and Ki-67 high expression in hepatocellular carcinoma (HCC). Methods: A cross-sectional study. This retrospective case-control study analyzed the clinical data of 101 patients with pathologically confirmed HCC in Xiamen Hospital of Traditional Chinese Medicine and Zhongshan Hospital of Xiamen University from December 2017 to March 2023. These 101 patients included 84 males and 17 females, and the age[M(Q1, Q3)] was 59.0(49.0,66.0)years. These patients were divided into two groups according to the immunohistochemical Ki-67 expression levels in tumor tissues: the high expression group (Ki-67%>20%, n=59) and the low expression group (Ki-67%≤20%, n=42).CT values on 70 keV and 140 keV monochromatic energy images (HU70 keV-a, HU140 keV-a, HU70 keV-p, HU140 keV-p) and water density (Dwater-a, Dwater-p) were measured in arterial phase and portal vein phase, and the difference of HU70 keV, HU140 keV, Dwater values between portal vein and arterial phase (ΔHU70 keV, ΔHU140 keV, ΔDwater), as well as ratio of HU70 keV, HU140 keV, Dwatervalues between portal vein and arterial phase (HU70 keVratio, HU140 keVratio, Dwaterratio) were calculated. Spearman correlation analysis was used to analyze the correlation between the CT spectral parameters and Ki-67%. Multivariate logistic regression model was used to determine the factors associated with high expression of Ki-67. The receiver operating characteristics (ROC) curves were used to indicate the efficacy of dynamic enhanced spectral CT in evaluating Ki-67 high expression in HCC. Results: The high Ki-67 expression group revealed higher alpha fetal protein levels, larger tumor diameter and more irregular tumor shape compared with the low Ki-67 expression group,and the differences were statistically significant (all P<0.05). Spearman correlation analysis showed that the HU140 keV-p, Dwater-p, HU70 keV ratio, HU140 keV ratio, Dwater ratio, ΔHU70 keV, ΔHU140 keV, ΔDwater were positively correlated with Ki-67 positivity rate (r:0.31-0.50, all P<0.05). The spectral CT parameters (HU70 keV-p, HU140 keV-p, Dwater-p, HU70 keV ratio, HU140 keV ratio, Dwater ratio, ΔHU70 keV, ΔHU140 keV, ΔDwater) in high Ki-67 expression group were significantly higher than those in low Ki-67 expression group (all P<0.05). Multivariate logistic regression model shows that Dwater-p(OR=1.16, 95%CI: 1.05-1.29, P=0.005), ΔHU140 keV(OR=1.39, 95%CI: 1.20-1.62, P<0.001) and irregular tumor morphology (OR=5.25, 95%CI: 1.61-17.12, P=0.006) were correlative factors for high Ki-67 expression. The HU140 keV ratio and ΔHU140 keV alone evaluated the highest AUC of high Ki-67 high expression in HCC, which were 0.82 (95%CI: 0.74-0.90), the sensitivity were 61.0%, and the specificity were 88.1% and 85.7%. The combined analysis of Dwater-p, ΔHU140 keV and irregular tumor morphology had an increased AUC of 0.88 (95%CI: 0.81-0.95) in assessment high Ki-67 expression, with the sensitivity of 84.7% and the specificity of 78.6%. Conclusions: Dynamic enhanced spectral CT parameters were positively correlated with the Ki-67 expression in HCC. Spectral CT provides a non-invasive method to evaluate the proliferation status of HCC cells, and the efficiency could be improved by multi-parameter analysis combining spectral CT parameters and morphologic features.

[Analysis of the prognosis and survival of patients with acute-on-chronic liver failure].

Objective: To explore the influencing factors and the impact of artificial liver treatment on the prognosis and survival of patients with acute-on-chronic liver failure (ACLF). Methods: Clinical data from 201 cases with ACLF from January 2016 to December 2019 was retrospectively analyzed. The survival rate was calculated by the Kaplan-Meier method, the log-rank test of univariate analysis, and the multivariate analysis of the stepwise Cox regression forward method. Results: The median survival time of patients was 6 months, and the survival rates at 6, 9, and 12 months were 51.2%, 38.3%, and 29.9%, respectively. In univariate analysis, age, presence or absence of hypertension and upper gastrointestinal bleeding, treatment method, model for end-stage liver disease (MELD) score, and cholinesterase were associated with prognosis (P < 0.05). Multivariate regression analysis results showed that MELD score was the main factor affecting the 1-year prognosis of ACLF patients (P = 0.002). Artificial liver treatment was beneficial for the 1-year prognosis of ACLF patients aged < 50 years or with a MELD score of ≥20 (P < 0.05 ). The relative risk ratio (RR) of mortality was 2.55 times higher in patients with advanced age (≥50 years old) than that of younger patients (P < 0.001). Regression analysis was performed using age as a stratification factor, and upper gastrointestinal bleeding was related to the prognosis of younger patients, while choline esterase was related to the prognosis of advanced age. Regression analysis after stratified MELD score showed that age and hypertension were related to the prognosis of patients with MELD score < 20, and treatment method and age were related to the prognosis of patients with MELD score≥20. Conclusion: Artificial liver treatment is beneficial for the 1-year prognosis of ACLF patients. Age, MELD score, hypertension, and upper gastrointestinal bleeding are independent risk factors affecting the prognosis of ACLF patients.

Clinical effectiveness of semaglutide on weight loss, body composition, and muscle strength in Chinese adults.

OBJECTIVE: The aim of this study was to investigate the clinical effectiveness of semaglutide on weight loss, body composition and muscle strength in the Chinese population with obesity. PATIENTS AND METHODS: Data were retrospectively analyzed for participants prescribed semaglutide in 2021 and 2022 from a Chinese weight management clinic. Changes in weight, body composition, biochemical indicators, calf circumference and handgrip strength were collected. Body fat and skeletal muscle were also measured using the bioelectrical impedance analysis. Paired t-test was used to compare the values after 6 months of treatment with the baseline values. RESULTS: A total of 53 obese patients received 24 weeks of lifestyle intervention plus semaglutide treatment. 10 patients who failed to adhere to the follow-up were excluded, and 43 patients were studied. The average baseline body mass index (BMI) was 33.0 kg/m2, and the average body weight was 90.0 kg. After 6 months of treatment, the patient's weight was significantly reduced by 9.9 ± 3.9 kg (p < 0.001), and the weight loss percentage was 11.2 ± 4.5% (p< 0.001). The proportion of patients with weight loss ≥ 5% and ≥ 10% was 93% and 54%, respectively. Fasting blood glucose, fasting insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index, blood uric acid and blood lipid levels also decreased after treatment. Body composition analysis showed that the loss of skeletal muscle mass was 1.4 ± 1.3 kg (p < 0.001), which was significantly less than the loss of fat mass of 5.6 ± 3.7 kg (p < 0.001). By percentage, the fat mass loss was 15.6 ± 10.1%, and the muscle mass loss was 4.8 ± 4.4% (p < 0.001). The visceral fat area was significantly reduced by 24.4 ± 17.7 cm (p < 0.001). There was no significant change in skeletal muscle index (8.1 ± 1.0 kg/m2 at baseline and 7.9 ± 1.0 kg/m2 at 24 weeks). The calf circumference (42.6 ± 3.6 cm at baseline, 41.2 ± 3.8 cm at 24 weeks) and grip strength (33.3 ± 9.5 kg at baseline, 32.3 ± 9.0 kg at 24 weeks) did not decrease significantly. The main adverse reactions were mild gastrointestinal dysfunction (nausea, diarrhea and vomiting), without ketoacidosis. CONCLUSIONS: In a real-world setting, semaglutide can reduce the weight and fat of obese patients while effectively maintaining muscle mass and muscle strength.

[Hsa_circ_0000392 affects the radiation sensitivity of cervical cancer by targeting the miR-145-5p/CRKL/MAPK pathway].

Objective: To investigate the effect of hsa_circ_0000392 (circ_0000392) on the radiosensitivity of cervical cancer cells and explore its potential mechanism. Methods: Cervical cancer tissues and adjacent normal tissues of 42 patients with cervical cancer who were confirmed pathologically for the first time in Huaihe Hospital of Henan University from 2016 to 2019 were collected. According to the patients' response to radiotherapy, the cancer tissues were divided into radio-sensitive tissues and radio-resistant tissues. The expressions of circ_0000392, miR-145-5p, and CRKL in radiation-sensitive, radiation-resistant cervical cancer tissues and Hela, SiHa cells were detected by reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and western blot. SiRNA circ_0000392, miR-145-5p mimic, miR-145-5p inhibitor, pcDNA 3.1-CRKL and its negative control were transfected into HeLa and Siha cells, respectively. After radiation induction, the survival fraction of cells was detected by clone formation assay, apoptosis was detected by flow cytometry, and the expressions of apoptosis-related proteins Bax and Bcl-2 and ERK pathway protein p-ERK1/2 and ERK1/2 were detected by western blot. The targeting relationship between circ_0000392, miR-145-5p and CRKL was verified by dual luciferase reporter gene assay. The effect of circ_0000392 on radiotherapy sensitivity of cervical cancer in vivo was observed in the tumor formation experiment in nude mice. Results: circ_0000392 and CRKL were upregulated in radiation-resistant tissues and cancer cells of cervical cancer, while miR-145-5p was downregulated. The clone formation numbers of Hela and SiHa cells in si-circ_0000392#1+ 6 Gy group were (78.67±10.97) and (71.00±9.54), respectively, which were lower than those in si-Ctrl+ 6 Gy group [(176.00±22.27) and (158.33±17.56), respectively]. The apoptosis rates were (41.55±3.40)% and (31.41±3.29)%, respectively, which were higher than those in si-Ctrl+ 6 Gy group [(15.91±1.37)% and (13.70±1.89)%, P<0.05]. The protein expression of Bax was higher than that of si-Ctrl+ 6 Gy group, and the protein expressions of Bcl2 was lower than those of si-Ctrl+ 6 Gy group. The clone formation numbers of Hela and SiHa cells in si-circ_0000392#1+ miR-145-5p inhibitor+ 6 Gy group were (171.33±25.01) and (137.00±21.66), higher than those in si-circ_0000392#1+ inhibitor NC+ 6 Gy group [(84.67±17.79) vs (71.00±11.00), P<0.05]. The apoptosis rates were (17.41±2.58) % and (15.96±1.25) %, lower than those of si-circ_0000392 #1+ inhibitor NC+ 6 Gy [(40.29±2.92)% and (30.82±2.34)%, respectively, P<0.05]. The expression of Bax protein was lower than that of si-circ_0000392#1+ inhibitor NC+ 6 Gy group, and the expressions of Bcl2 protein were higher than those of si-circ_0000392#1+ inhibitor NC+ 6 Gy group. Circ_0000392 can target miR-145-5p, and CRKL is the downstream target gene of miR-145-5p. The clone formation numbers of Hela and SiHa cells in miR-145-5p mimic+ 6 Gy group were (74.33±10.02) and (66.00±12.17), respectively, which were lower than those of mimic NC+ 6 Gy group [(197.67±17.21) vs (157.67±11.59), respectively, P<0.05]. The apoptosis rates were (45.58±2.16)% and (32.10±3.55)%, higher than those of mimic NC+ 6 Gy group [(15.85±2.45)% and (13.99±1.69)%, respectively, P<0.05]. The expression of Bax protein was higher than that of the mimic NC+ 6 Gy mimic group, and the expression of Bcl2 protein was lower than that of the mimic NC+ 6 Gy group. The clone formation numbers of Hela and SiHa cells in miR-145-5p mimic+ pcDNA-CRKL+ 6 Gy group were (158.00±15.88) and (122.33±13.65), respectively, which were higher than those of miR-145-5p mimic+ pcDNA+ 6 Gy group [(71.33±8.02) vs (65.67±12.22), P<0.05]. The apoptosis rates were (19.50±3.45)% and (17.04±0.94)%, respectively, which were lower than those of miR-145-5p mimic+ pcDNA+ 6 Gy group [(44.33±2.36)% and (32.05±2.76)%, respectively, P<0.05]. The expression of Bax protein was lower than that of miR-145-5p mimic+ pcDNA group+ 6 Gy group, and the expression of Bcl2 protein was higher than that of miR-145-5p mimic+ pcDNA+ 6 Gy group. Sh-circ_0000392 group had smaller tumor volume and decreased tumor weight (P<0.05). The relative mRNA expression levels of circ_0000392, miR-145-5p and CRKL and the relative protein expression levels of CRKL, Bcl-2 and p-ERK1/2 were decreased, while the relative expression level of Bax protein was increased (P<0.05). Conclusion: Circ_0000392 could enhance the radiosensitivity of cervical cancer cells, and its mechanism may be related to the regulation of CRKL/ERK signaling pathway by targeting miR-145-5p, which provides a new reference for enhancing the radiosensitivity of cervical cancer cells.

Itaconic acid and dimethyl itaconate exert antibacterial activity in carbon-enriched environments through the TCA cycle.

Itaconic acid (IA), a metabolite generated by the tricarboxylic acid (TCA) cycle in eukaryotic immune cells, and its derivative dimethyl itaconate (DI) exert antibacterial functions in intracellular environments. Previous studies suggested that IA and DI only inhibit bacterial growth in carbon-limited environments; however, whether IA and DI maintain antibacterial activity in carbon-enriched environments remains unknown. Here, IA and DI inhibited the bacteria with minimum inhibitory concentrations of 24.02 mM and 39.52 mM, respectively, in a carbon-enriched environment. The reduced bacterial pathogenicity was reflected in cell membrane integrity, motility, biofilm formation, AI-2/luxS, and virulence. Mechanistically, succinate dehydrogenase (SDH) activity and fumaric acid levels decreased in the IA and DI treatments, while isocitrate lyase (ICL) activity was upregulated. Inhibited TCA circulation was also observed through untargeted metabolomics. In addition, energy-related aspartate metabolism and lysine degradation were suppressed. In summary, these results indicated that IA and DI reduced bacterial pathogenicity while exerting antibacterial functions by inhibiting TCA circulation. This study enriches knowledge on the inhibition of bacteria by IA and DI in a carbon-mixed environment, suggesting an alternative method for treating bacterial infections by immune metabolites.

[Short-term prognostic predictive value of the neutrophil/lymphocyte ratio combined with prognostic nutritional index in hepatitis B virus-related acute-on-chronic liver failure].

Objective: To explore the prognostic predictive value of neutrophil/lymphocyte ratio (NLR) combined with prognostic nutritional index (PNI) in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Methods: Clinical data from 149 HBV-ACLF patients admitted to the infectious diseases Department of the General Hospital of Ningxia Medical University were retrospectively analyzed. Demographic data of the enrolled patients and the initial clinical-related data after admission were collected. Patients were divided into survival (93 cases) and death groups (56 cases) according to their prognostic condition 90 days after discharge. Demographic and clinical differences were compared between the two groups data. Receiver operating characteristic (ROC) curves were plotted to determine the optimal cutoff values for NLR and PNI in predicting the 90-day mortality rate of HBV-ACLF patients. The COX regression model was used to conduct univariate and multivariate analyses to investigate the correlation between NLR and PNI and the prognosis of HBV-ACLF patients. Kaplan-Meier survival analysis was used to explore the effects of NLR and PNI on the survival of HBV-ACLF patients. Results: The death group NLR was higher than that of the survival group, while the PNI was lower than that of the survival group, with a statistically significant difference. The area under the receiver operating characteristic curve (0.842, 95% CI: 0.779-0.906) showed patients with adverse prognosis assessed by NLR combined with PNI had a superior prognosis than that of the Model for End-Stage Liver Disease (MELD) and its combined serum sodium (MELD-Na) and Child-Turcotte-Pugh (CTP) scores. COX regression analysis showed that NLR≥3.03 and MELD score were independent risk factors affecting the prognosis of HBV-ACLF patients. PNI > 36.13 was a protective factor for evaluating the prognosis of HBV-ACLF patients. Conclusion: NLR combined with PNI can enhance the prognostic predictive value of HBV-ACLF.

Microstructural and Metabolic Changes in Normal Aging Human Brain Studied with Combined Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging.

PURPOSE: This study aimed to detect age-related brain metabolic and microstructural changes in healthy human brains by the use of whole-brain proton magnetic resonance spectroscopic imaging (1H­MRSI) and quantitative MR imaging (qMRI). METHODS: In this study, 60 healthy participants with evenly distributed ages (between 21 and 69 years) and sex underwent MRI examinations at 3T including whole-brain 1H­MRSI. The concentrations of the metabolites N­acetylaspartate (NAA), choline-containing compounds (Cho), total creatine and phosphocreatine (tCr), glutamine and glutamate (Glx), and myo-inositol (mI), as well as the brain relaxation times T2, T2' and T1 were measured in 12 regions of interest (ROI) in each hemisphere. Correlations between measured parameters and age were estimated with linear regression analysis and Pearson's correlation test. RESULTS: Significant age-related changes of brain regional metabolite concentrations and tissue relaxation times were found: NAA decreased in eight of twelve ROIs, Cho increased in three ROIs, tCr in four ROIs, and mI in three ROIs. Glx displayed a significant decrease in one ROI and an increase in another ROI. T1 increased in four ROIs and T2 in one ROI, while T2' decreased in two ROIs. A negative correlation of tCr concentrations with T2' relaxation time was found in one ROI as well as the positive correlations of age-related T1 relaxation time with concentrations of tCr, mI, Glx and Cho in another ROI. CONCLUSION: Normal aging in human brain is associated with coexistent brain regional metabolic alterations and microstructural changes, which may be related to age-related decline in cognitive, affective and psychomotor domains of life in the older population.

[Comparison of diagnostic performance of Clear Cell Likelihood Score v1.0 and v2.0 for clear renal cell carcinoma].

OBJECTIVE: To compare the performance of Clear Cell Likelihood Score (ccLS) v1.0 and v2.0 in diagnosing clear cell renal cell carcinoma (ccRCC) from small renal masses (SRM). METHODS: We retrospectively analyzed the clinical data and MR images of patients with pathologically confirmed solid SRM from the First Medical Center of the Chinese PLA General Hospital between January 1, 2018, and December 31, 2021, and from Beijing Friendship Hospital of Capital Medical University and Peking University First Hospital between January 1, 2019 and May 17, 2021. Six abdominal radiologists were trained for use of the ccLS algorithm and scored independently using ccLS v1.0 and ccLS v2.0. Random- effects logistic regression modeling was used to generate plot receiver operating characteristic curves (ROC) to evaluate the diagnostic performance of ccLS v1.0 and ccLS v2.0 for ccRCC, and the area under curve (AUC) of these two scoring systems were compared using the DeLong's test. Weighted Kappa test was used to evaluate the interobserver agreement of the ccLS score, and differences in the weighted Kappa coefficients was compared using the Gwet consistency coefficient. RESULTS: In total, 691 patients (491 males, 200 females; mean age, 54 ± 12 years) with 700 renal masses were included in this study. The pooled accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ccLS v1.0 for diagnosing ccRCC were 77.1%, 76.8%, 77.7%, 90.2%, and 55.7%, as compared with 80.9%, 79.3%, 85.1%, 93.4%, 60.6% with ccLS v2.0, respectively. The AUC of ccLS v2.0 was significantly higher than that of ccLS v1.0 for diagnosis of ccRCC (0.897 vs 0.859; P < 0.01). The interobserver agreement did not differ significantly between ccLS v1.0 and ccLS v2.0 (0.56 vs 0.60; P > 0.05). CONCLUSION: ccLS v2.0 has better performance for diagnosing ccRCC than ccLS v1.0 and can be considered for use to assist radiologists with their routine diagnostic tasks.

[Construction and biological characterization of a Proteus mirabilis strain with modABC gene deletion].

OBJECTIVE: To construct a modABC gene knockout strain of Proteus mirabilis and explore the effect of modABC gene deletion on biological characteristics of Proteus mirabilis. METHODS: Fusion PCR was used to obtain the fusion gene of modABC and the kanamycin-resistant gene Kn, which was ligated with the suicide vector pCVD442 and transduced into Proteus mirabilis. The modABC gene knockout strain of Proteus mirabilis was obtained after homologous recombination with the suicide vector. PCR and Sanger sequencing were used to identify genomic deletion of modABC gene in the genetically modified strain. The concentration of molybdate in the wild-type and gene knockout strains was determined using inductively coupled plasma mass spectrometry (ICP-MS), and their survival ability in LB medium was compared under both aerobic and anaerobic conditions. RESULTS: PCR and sanger sequencing confirmed genomic deletion of modABC gene in the obtained Proteus mirabilis strain. The concentration of intracellular molybdenum in the modABC gene knockout strain was 1.22 mg/kg, significantly lower than that in the wild-type strain (1.46 mg/kg, P < 0.001). Under the aerobic condition, the modABC gene knockout strain grown in LB medium showed no significant changes in survival ability compared with the wild-type strain, but its proliferation rate decreased significantly under the anaerobic condition and also when cultured in nitrate-containing LB medium under anaerobic condition. CONCLUSION: Homologous recombination with the suicide vector can be used for modABC gene knockout in Proteus mirabilis. modABC gene participates in molybdate uptake and is associated with anaerobic growth of Proteus mirabilis in the presence of nitrate.

Precision Measurement of Reactor Antineutrino Oscillation at Kilometer-Scale Baselines by Daya Bay.

We present a new determination of the smallest neutrino mixing angle θ_{13} and the mass-squared difference Δm_{32}^{2} using a final sample of 5.55×10^{6} inverse beta-decay (IBD) candidates with the final-state neutron captured on gadolinium. This sample is selected from the complete dataset obtained by the Daya Bay reactor neutrino experiment in 3158 days of operation. Compared to the previous Daya Bay results, selection of IBD candidates has been optimized, energy calibration refined, and treatment of backgrounds further improved. The resulting oscillation parameters are sin^{2}2θ_{13}=0.0851±0.0024, Δm_{32}^{2}=(2.466±0.060)×10^{-3} eV^{2} for the normal mass ordering or Δm_{32}^{2}=-(2.571±0.060)×10^{-3} eV^{2} for the inverted mass ordering.