Repair and regeneration: ferroptosis in the process of remodeling and fibrosis in impaired organs.

As common clinical-pathological processes, wound healing and tissue remodelling following injury or stimulation are essential topics in medical research. Promoting the effective healing of prolonged wounds, improving tissue repair and regeneration, and preventing fibrosis are important and challenging issues in clinical practice. Ferroptosis, which is characterized by iron overload and lipid peroxidation, is a nontraditional form of regulated cell death. Emerging evidence indicates that dysregulated metabolic pathways and impaired iron homeostasis play important roles in various healing and regeneration processes via ferroptosis. Thus, we review the intrinsic mechanisms of tissue repair and remodeling via ferroptosis in different organs and systems under various conditions, including the inflammatory response in skin wounds, remodeling of joints and cartilage, and fibrosis in multiple organs. Additionally, we summarize the common underlying mechanisms, key molecules, and targeted drugs for ferroptosis in repair and regeneration. Finally, we discuss the potential of therapeutic agents, small molecules, and novel materials emerging for targeting ferroptosis to promote wound healing and tissue repair and attenuate fibrosis.

Influence of sex and functional status on the value of serum steroid profiling in discriminating adrenocortical carcinoma from adrenocortical adenoma.

Background: It is challenging for clinicians to distinguish adrenocortical carcinoma (ACC) from benign adrenocortical adenomas (ACA) in their early stages. This study explored the value of serum steroid profiling as a complementary biomarker for malignancy diagnosis of ACC other than diameter and explored the influence of sex and functional status. Methods: In this retrospective study, a matched cohort of patients diagnosed with either ACC or ACA based on histopathology was meticulously paired in a 1:1 ratio according to sex, age, and functional status. Eight serum steroids including 11-deoxycortisol, 11-deoxycorticosterone, progesterone, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, and estradiol, were quantified by liquid chromatography tandem mass spectrometry. We conducted a comparative analysis of the clinical characteristics and serum steroid profiles of patients with ACC and ACA, with further subgroup analysis. Results: The study included 31 patients with ACC and 31 matched patients with ACA. Patients with ACC exhibited significantly larger tumor diameters, lower body mass index (BMI), and higher levels of 11-deoxycortisol, progesterone, and androstenedione than those with ACA. 11-deoxycortisol was the only valuable index for discriminating ACC from ACA, regardless of functional status and sex. Progesterone, DHEA, and DHEAS levels were higher in the functional ACC group than in the non-functional ACC group. Female ACC patients, especially in postmenopausal female exhibited higher levels of androstenedione than male patients. The area under the curve of tumor diameter, 11-deoxycortisol, and BMI was 0.947 (95% CI 0.889-1.000), with a sensitivity of 96.8% and specificity of 90.3%. Conclusion: Serum steroid profiling serves as a helpful discriminative marker for ACC and ACA, with 11-deoxycortisol being the most valuable marker. For other steroid hormones, consideration of sex differences and functional status is crucial.

Correction: Selective fluorescence detection of acetylsalicylic acid, succinic acid and ascorbic acid based on a responsive lanthanide metal fluorescent coordination polymer.

Correction for 'Selective fluorescence detection of acetylsalicylic acid, succinic acid and ascorbic acid based on a responsive lanthanide metal fluorescent coordination polymer' by Guo-Ying Chen et al., Anal. Methods, 2024, 16, 4981-4994, https://doi.org/10.1039/d4ay00696h.

Liver transplantation following two conversions in a patient with huge hepatocellular carcinoma and portal vein invasion: A case report.

BACKGROUND: Surgical resection and liver transplantation (LT) are the most effective curative options for hepatocellular carcinoma (HCC). However, few patients with huge HCC (> 10 cm in diameter), especially those with portal vein tumor thrombus (PVTT), can receive these treatments. Selective internal radiation therapy (SIRT) can be used as a conversion therapy for them because it has the dual benefit of shrinking tumors and increasing residual hepatic volume. However, in patients with huge HCC, high lung absorbed dose often prevents them from receiving SIRT. CASE SUMMARY: A 35-year-old man was admitted because of emaciation and pain in the hepatic region for about 1 month. The computed tomography scan showed a 20.2 cm × 19.8 cm tumor located in the right lobe-left medial lobes with right portal vein and right hepatic vein invasion. After the pathological type of HCC was confirmed by biopsy, two conversions were presented. The first one was drug-eluting bead transarterial chemoembolization plus hepatic arterial infusion chemotherapy and lenvatinib and sintilimab, converted to SIRT, and the second one was sequential SIRT with continued systemic treatment. The tumor size significantly decreased from 20.2 cm × 19.8 cm to 16.2 cm × 13.8 cm, then sequentially to 7.8 cm × 6.8 cm. In the meantime, the ratio of spared volume to total liver volume increased gradually from 34.4% to 55.7%, then to 62.9%. Furthermore, there was visualization of the portal vein, indicating regression of the tumor thrombus. Finally, owing to the new tumor in the left lateral lobe, the patient underwent LT instead of resection without major complications. CONCLUSION: Patients with inoperable huge HCC with PVTT could be converted to SIRT first and accept surgery sequentially.

Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment.

BACKGROUND: Pancreatic cancer is one of the most lethal malignancies, characterized by poor prognosis and low survival rates. Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy, often failing to capture the complexity of the disease. The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment. This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer. AIM: To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules. METHODS: This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2, PLAU, and CCNA2. The results were validated in an independent dataset. This study also examined the correlations between the model risk score and various clinical features, components of the immune microenvironment, chemotherapeutic drug sensitivity, and metabolism-related pathways. Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines. RESULTS: The prognostic model demonstrated significant predictive value, with the risk score showing a strong correlation with clinical features: It was significantly associated with tumor grade (G) (b P < 0.01), moderately associated with tumor stage (T) (a P < 0.05), and significantly correlated with residual tumor (R) status (b P < 0.01). There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs. Furthermore, the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer. CONCLUSION: The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

High-temperature emulsification coupled with low-temperature gelation for fabrication of agarose microsphere implants with well-controlled size for skin tissue enhancement.

Soft tissue deficiencies profoundly impact the daily lives, and mental well-being of patients. Microspheres facilitate collagen synthesis by establishing a conducive environment for fibroblast growth. Existing synthetic polymer microspheres are typically prepared through emulsification and cross-linking at normal temperatures. However, residues of cross-linking agents can adversely affect biocompatibility, thereby limiting their biomedical applications. Agarose has garnered significant attention owing to its biodegradability and excellent biocompatibility. We have for the first time developed high-temperature emulsification coupled with low-temperature gelation for fabrication of agarose microsphere implants with well-controlled size for skin tissue enhancement. The agarose microspheres exhibited favorable sphericity and dispersion, possessing a uniform particle size with an average diameter of 37.24 µm. Furthermore, the microspheres demonstrated commendable injectability and biodegradability. Additionally, the implants displayed remarkable biocompatibility, effectively promoting the proliferation of human foreskin fibroblast-1 (HFF-1) cells. The microspheres exhibited no systemic toxicity and induced no hemolytic or thermogenic reactions. In photoaged mice skin models, the agarose microspheres augmented dermal density, and enhanced skin elasticity. The microspheres showed the capacity to stimulate the regeneration of collagen fibers. The agarose microspheres offer a novel avenue for soft tissue filling and hold significance in the field of tissue engineering and skin regeneration.

Circulating extracellular vesicles as novel biomarkers for pulmonary arterial hypertension in patients with systemic lupus erythematosus.

Introduction: Pulmonary arterial hypertension (PAH) is a serious complication of systemic lupus erythematosus (SLE) with increased mortality. A prothrombotic state may contribute to pathogenesis of SLE-PAH. Extracellular vesicles (EVs) are known to be associated with thrombosis. Here, we investigated circulating EVs and their associations with SLE-PAH. Methods: Eighteen SLE-PAH patients, 36 SLE-non-PAH patients, and 36 healthy controls (HCs) were enrolled. Flow cytometry was used to analyze circulating EVs from leukocytes (LEVs), red blood cells (REVs), platelets (PEVs), endothelial cells (EEVs), and Annexin V+ EVs with membrane phosphatidylserine (PS) exposure. Results: Plasma levels of all EV subgroups were elevated in SLE patients with or without PAH compared to HCs. Furthermore, plasma Annexin V+ EVs, LEVs, PEVs, REVs, EEVs, and Annexin V+ REVs were significantly elevated in SLE-PAH patients compared to SLE-non-PAH patients. Additionally, PAH patients with moderate/high SLE showed a significant increase in LEVs, PEVs, REVs, Annexin V+ EVs, and Annexin V+ REVs compared to SLE-non-PAH patients. However, PAH patients with inactive/mild SLE only exhibited elevations in Annexin V+ EVs, REVs, and Annexin V+ REVs. In the SLE-PAH patients, EEVs were positively correlated with pulmonary arterial systolic pressure, while PEVs and EEVs were positively correlated with right ventricular diameter. Moreover, the receiver operating characteristic curve indicated that Annexin V+ EVs, LEVs, PEVs, REVs, EEVs and Annexin V+ REVs could predict the presence of PAH in SLE patients. Importantly, multivariate logistic regression analysis showed that circulating levels of LEVs or REVs, anti-nRNP antibody, and serositis were independent risk factors for PAH in SLE patients. Discussion: Findings reveal that specific subgroups of circulating EVs contribute to the hypercoagulation state and the severity of SLE-PAH. Higher plasma levels of LEVs or REVs may serve as biomarkers for SLE-PAH.

Urban-Rural Differences in the Association of eHealth Literacy With Medication Adherence Among Older People With Frailty and Prefrailty: Cross-Sectional Study.

Background: With advances in science and technology and improvements in health literacy, more studies have focused on frailty prevention by promoting medication adherence, emphasizing the role of eHealth literacy. However, the association between eHealth literacy and medication adherence in frail older adults has not been well studied, and it is unknown whether urban-rural differences exist in this relationship. Objective: This study aims to examine the relationship between eHealth literacy and medication adherence in older people with different frailty statuses, emphasizing variations between rural and urban areas. Methods: Between November and December 2020, a total of 4218 urban and rural community members (aged ≥60 years) in China were recruited as participants using a multistage random sampling method. A face-to-face structured questionnaire survey was conducted to collect information on demographic characteristics, eHealth literacy (consisting of application, evaluation, and decision dimensions), and medication adherence. eHealth literacy was assessed using the Chinese version of the eHealth Literacy Scale developed by Norman and Skinner, and medication adherence was measured using the 4-item Morisky scale. We used a general descriptive analysis and stratified logistic regression models to examine how eHealth literacy is linked to medication adherence and urban-rural differences. Results: There were 4218 respondents, of which 2316 (54.9%) lived in urban areas and 1902 (45.1%) in rural areas, respectively. After adjusting for potential confounders, among participants with prefrailty, eHealth literacy was associated with medication adherence in urban areas in terms of less application (adjusted odds ratio [AOR] 1.16, 95% CI 0.82-1.63), less evaluation (AOR 1.29, 95% CI 0.92-1.81), and less decision ability (AOR 1.20, 95% CI 0.86-1.68); eHealth literacy was linked with medication adherence in the rural areas in terms of less application (AOR 1.10, 95% CI 0.56-2.13), less evaluation (AOR 1.05, 95% CI 0.61-1.79), and less decision ability (AOR 1.10, 95% CI 0.64-1.90). Among frail participants, less eHealth literacy (AOR 0.85, 95% CI 0.48-1.51), along with its dimensions, including less application (AOR 0.85, 95% CI 0.47-1.54), evaluation (AOR 0.89, 95% CI 0.50-1.57), and decision ability (AOR 0.99, 95% CI 0.55-1.76), were associated with medication adherence in urban areas; less eHealth literacy (AOR 0.89, 95% CI 0.48-1.65), along with its dimensions, including less application (AOR 1.23, 95% CI 0.62-2.44), evaluation (AOR 0.98, 95% CI 0.53-1.82), and decision ability (AOR 0.90, 95% CI 0.49-1.67), were associated with medication adherence in rural areas. Conclusions: The results of this study suggest that there is an association between eHealth literacy and medication adherence among older people with frailty and prefrailty. To promote medication adherence, eHealth literacy can be helpful in tailoring interventions.

Linear and non-linear associations of depressive symptoms with oral health knowledge, attitudes, and practices among rural older adults in China: a cross-sectional study.

BACKGROUND: Depression affects the oral health of older adults; however, little is known about its impact on oral health among rural older adults in developing countries, which warrants further research. Taking China as an example, there is a large population base of rural older adults suffering from depression, and many rural older people also have long-term oral health problems, which have seriously affected their quality of life in later life. Therefore, this study aimed to explore linear and non-linear associations of depressive symptoms with oral health knowledge, attitudes, and practices among rural older adults in China. METHODS: From November 2020 to December 2020, 1,902 rural community-dwelling older people aged 60 years and older were investigated, via a cross-sectional survey. The general information, depressive status, oral health knowledge, attitudes, and practices of the participants were obtained through face-to-face structured questionnaires. Among them, the Zung Depression Self-Rating Scale was used to investigate the depressive symptoms of the participants in this survey. The generalized linear model and classification and regression tree model were used, separately. RESULTS: Based on linear analysis results, we found that minimal to mild depressive symptoms [regression coefficient (ß) = -0.345; 95% confidence interval (CI): -0.582 to -0.109, P = 0.004] and depressive symptoms (ß = -1.064; 95% CI: -1.982 to -0.146, P = 0.023) were significantly correlated with oral health knowledge. A negative correlation was observed between minimal to mild depressive symptoms (ß = -0.385; 95% CI: -0.600 to -0.170, P < 0.001) and oral health attitudes. In addition, while both minimal to mild depressive symptoms (ß = 0.018; 95% CI: -0.312 to 0.347, P = 0.916) and depressive symptoms (ß = 0.604; 95% CI: -0.675 to 1.883, P = 0.355) were associated with oral health practices. Furthermore, the non-linear analysis showed a combined effect of depressive symptoms on oral health attitudes, indicating that older people of a younger age, not living alone, and not suffering from depressive symptoms are more likely to report better oral health attitudes. CONCLUSION: Both the linear and non-linear analyses in our study showed that depressive symptoms are significantly correlated with the poor oral health attitudes of older adults in rural communities. Furthermore, depressive symptoms were associated with oral health knowledge in the linear analysis. However, no statistically significant difference was found between depressive symptoms and oral health practices in either analysis. This research deepens our knowledge and understanding of relevant evidence in the mental and oral health of people in later life. In addition, analyzing the factors that affect the oral health of older people from the perspective of their depressive status provides new thinking directions and scientific references for improving the oral health of older adults in practical life.

GFI-YOLOv8: Sika Deer Posture Recognition Target Detection Method Based on YOLOv8.

As the sika deer breeding industry flourishes on a large scale, accurately assessing the health of these animals is of paramount importance. Implementing posture recognition through target detection serves as a vital method for monitoring the well-being of sika deer. This approach allows for a more nuanced understanding of their physical condition, ensuring the industry can maintain high standards of animal welfare and productivity. In order to achieve remote monitoring of sika deer without interfering with the natural behavior of the animals, and to enhance animal welfare, this paper proposes a sika deer individual posture recognition detection algorithm GFI-YOLOv8 based on YOLOv8. Firstly, this paper proposes to add the iAFF iterative attention feature fusion module to the C2f of the backbone network module, replace the original SPPF module with AIFI module, and use the attention mechanism to adjust the feature channel adaptively. This aims to enhance granularity, improve the model's recognition, and enhance understanding of sika deer behavior in complex scenes. Secondly, a novel convolutional neural network module is introduced to improve the efficiency and accuracy of feature extraction, while preserving the model's depth and diversity. In addition, a new attention mechanism module is proposed to expand the receptive field and simplify the model. Furthermore, a new pyramid network and an optimized detection head module are presented to improve the recognition and interpretation of sika deer postures in intricate environments. The experimental results demonstrate that the model achieves 91.6% accuracy in recognizing the posture of sika deer, with a 6% improvement in accuracy and a 4.6% increase in mAP50 compared to YOLOv8n. Compared to other models in the YOLO series, such as YOLOv5n, YOLOv7-tiny, YOLOv8n, YOLOv8s, YOLOv9, and YOLOv10, this model exhibits higher accuracy, and improved mAP50 and mAP50-95 values. The overall performance is commendable, meeting the requirements for accurate and rapid identification of the posture of sika deer. This model proves beneficial for the precise and real-time monitoring of sika deer posture in complex breeding environments and under all-weather conditions.

An integrated machine learning model enhances delayed graft function prediction in pediatric renal transplantation from deceased donors.

BACKGROUND: Kidney transplantation is the optimal renal replacement therapy for children with end-stage renal disease; however, delayed graft function (DGF), a common post-operative complication, may negatively impact the long-term outcomes of both the graft and the pediatric recipient. However, there is limited research on DGF in pediatric kidney transplant recipients. This study aims to develop a predictive model for the risk of DGF occurrence after pediatric kidney transplantation by integrating donor and recipient characteristics and utilizing machine learning algorithms, ultimately providing guidance for clinical decision-making. METHODS: This single-center retrospective cohort study includes all recipients under 18 years of age who underwent single-donor kidney transplantation at our hospital between 2016 and 2023, along with their corresponding donors. Demographic, clinical, and laboratory examination data were collected from both donors and recipients. Univariate logistic regression models and differential analysis were employed to identify features associated with DGF. Subsequently, a risk score for predicting DGF occurrence (DGF-RS) was constructed based on machine learning combinations. Model performance was evaluated using the receiver operating characteristic curves, decision curve analysis (DCA), and other methods. RESULTS: The study included a total of 140 pediatric kidney transplant recipients, among whom 37 (26.4%) developed DGF. Univariate analysis revealed that high-density lipoprotein cholesterol (HDLC), donor after circulatory death (DCD), warm ischemia time (WIT), cold ischemia time (CIT), gender match, and donor creatinine were significantly associated with DGF (P < 0.05). Based on these six features, the random forest model (mtry = 5, 75%p) exhibited the best predictive performance among 97 machine learning models, with the area under the curve values reaching 0.983, 1, and 0.905 for the entire cohort, training set, and validation set, respectively. This model significantly outperformed single indicators. The DCA curve confirmed the clinical utility of this model. CONCLUSIONS: In this study, we developed a machine learning-based predictive model for DGF following pediatric kidney transplantation, termed DGF-RS, which integrates both donor and recipient characteristics. The model demonstrated excellent predictive accuracy and provides essential guidance for clinical decision-making. These findings contribute to our understanding of the pathogenesis of DGF.

High-strength fibrous sensors with an enhanced aggregate state for biomechanical monitoring of the Achilles tendon.

Continuous monitoring of biomechanical signals generated from the injured Achilles tendon is essential for the deep understanding of the recovery or rehabilitation process, thus decreasing the risk of secondary injuries. With tissue-like components and adjustable properties, hydrogel-based biomechanical sensors are considered promising materials for human motion detection. However, existing hydrogels are characterized by inferior mechanical properties with strength and modulus typically lower than 1 MPa, as well as poor stability under physiological conditions, which hampers their applications in implantable devices. Moreover, acquiring the stress signal from collected electrical signals remains challenging. Herein, based on the regulation of polymer aggregation, a high-strength fibrous sensor composed of polyvinyl alcohol (PVA) and reduced graphene oxide (rGO) for in vivo monitoring is prepared through a two-step procedure, including freeze-thaw and freeze-soak. Benefiting from the synergy of crystallization, Hofmeister effect and nanocomposite, the hydrogel fibers feature high tensile strength (8.34 ± 0.66 MPa) and elastic modulus (1.15 ± 0.10 MPa). Meanwhile, the removal of salt ions during fabrication improves the water content (69.18 ± 1.47%) and anti-swelling performance of such fibers and minimizes side effects after implantation. It is demonstrated that the fibrous sensor could record the relative resistance changes upon stretching with ideal sensitivity (GF = 1.57) and convert them into bearing stress through formula derivation and calculations. In vitro and in vivo assays further confirm its feasibility for real-time monitoring of joint motion, providing important references for medical diagnosis and treatment.

Occurrence and risk assessment of p-phenylenediamines and their quinones in aquatic environment: From city wastewater to deep sea.

p-Phenylenediamines (PPDs) and PPD-derived quinones (PPD-Qs) have been considered emerging pollutants recently. Their available data on sediment and sewage sludge are limited, especially the ecological risks. Here, typical PPDs and PPD-Qs were measured in the sludge of wastewater treatment plants and surface sediment of a developed river basin (including reservoirs, estuaries, and rivers) and deep-sea troughs. The total concentrations of PPDs (∑PPD) were highest in sludge (range: 9.06-248 ng g-1), followed by surface sediment of the Dongjiang River basin, China (3.33-85.3 ng g-1), and lowest in sediment of the Okinawa Trough (0.01-7.46 ng g-1). The median value of ∑PPD in surface sediment of rivers (9.54 ng g-1) was higher than those in reservoirs (4.28 ng g-1) and estuaries (5.26 ng g-1). N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) was the major congener in all samples, accounting for over 60 % of ∑PPD. For quinones, 6PPD-Q and IPPD-Q were frequently detected in sludge, only trace 6PPD-Q was detected in the sediment of estuaries (nd-0.62 ng g-1) and rivers (nd-5.24 ng g-1), and both of them were absent from the sediment of the Okinawa Trough. The occurrence of PPDs in the trough may be the in-situ release of microplastics, and due to the low-light and weak alkaline conditions of deep-sea water, quinones may hardly photodegrade from PPDs. The PPD concentrations in sludge were positively correlated with local GDP, and the annual PPD emission from sludge will exceed 1370 kg in China. The results of ecological risk assessments indicated low risks for PPDs in sludge-amended soil, median risks for several PPDs in river sediment, but median to high risks for 6PPD-Q contamination sludge-amended soil. For the first time, we explored the potential environmental risk of PPDs and related quinones in sludge used as a soil conditioner.

Silicone Wristbands as a Personal Passive Sampler to Evaluate Indoor Exposure to Volatile and Non-volatile PFASs.

Exposure to per- and polyfluoroalkyl substances (PFASs) primarily occurs via consumption of contaminated drinking water and food; however, individuals can also be exposed dermally and via inhalation indoors. This study developed an analytical method for measuring volatile PFASs in silicone wristbands and used them to assess personal exposure in a Midwestern community (n = 87). Paired samples of blood and wristbands were analyzed for PFASs using LC-MS/MS and GC-HRMS to monitor both non-volatile and volatile PFASs. The most frequently detected PFASs in wristbands were: 6:2 diPAP, 6:2 FTOH, MeFOSE and EtFOSE. Females had a 4-fold higher exposure to 6:2 diPAP compared to males and age-dependent differences in exposure to 6:2 FTOH, MeFOSE and EtFOSE were observed. Exposure to MeFOSE and EtFOSE differed based on the average time spent in the home. Frequently detected PFASs in blood were: PFOA, PFOS, PFHxS, PFHpS, and N-MeFOSAA. A strong correlation was found between MeFOSE in the wristbands and N-MeFOSAA in serum (rs = 0.90, p-value <0.001), suggesting exposure to this PFAS was primarily via inhalation and dermal exposure. These results demonstrate that wristbands can provide individual level data on exposure to some polyfluoroalkyl precursors present indoors that reflect serum levels of their suspected biotransformation products.

Association between idiopathic normal pressure hydrocephalus and Alzheimer's disease: a bidirectional Mendelian randomization study.

Observational studies have suggested a bidirectional relationship between idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD). However, the causal association between these two neurodegenerative disorders remains unclear. This study aimed to explore the causal relationship between iNPH and AD using a two-sample bidirectional Mendelian randomization (MR) method. Large-scale genome-wide association studies of iNPH (Ncase = 767, Ncontrol = 375,610) and AD (Ncase/proxy = 111,326, Ncontrol = 677,663) in European individuals were used to screen genetic instruments for MR analysis. Inverse variance-weighted (IVW) method was used as the main analysis, other MR methods and a series of sensitivity analyses were performed to ensure the reliability. In the forward MR analysis, genetic predisposition to iNPH had no effects on the risk of AD development. Likewise, in the reverse MR analysis, AD did not demonstrate a significant causal effect on iNPH. Sensitivity analyses bolstered the reliability of the MR results. Our MR study indicated no genetic evidence supporting a suggestive association between AD and iNPH in either direction, and provided evidence on the dichotomy between true iNPH and neurodegenerative NPH.

Interaction and band structure-determined inhibition of negative Cr (VI) and positive Fe (III) for antibiotic photodegradation by nitrogen-doped dissolved black carbon.

The influences of the positive Fe3+ and the negative Cr2O72- on the tetracycline (TC) photodegradation by N-doped dissolved black carbon (NDBC) have been investigated in this work. A series of samples (NDBC300, NDBC400 and NDBC500) have been extracted from the corresponding biochar. NDBC400 has the best photodegradation performance (79%) for TC under visible light irradiation. Adding Cr2O72- and Fe3+ can reduces TC photodegradation efficiency into 37% and 53%, respectively. This maybe from that Cr2O72- has stronger interaction with NDBC400 than Fe3+ since it can quench more fluorescence intensity of NDBC400 than Fe3+. Furthermore, Cr2O72- can reduce the steady-state concentration of 3NDBC400*, 1O2 and •OH, whereas Fe3+can just reduce the steady-state concentration of 3NDBC400* and increase the concentration of •OH. This may explain why Cr2O72- has stronger inhibit performance of TC photodegradation by NDBC400 than Fe3+. The band structures of NDBC400, NDBC400-Fe3+ and NDBC400-Cr2O72- are constructed. And the VB of NDBC400-Fe3+ has a stronger ability to produce •OH than NDBC400. In summary, coupling interaction and band structure characterization of NDBC400, NDBC400-Fe3+ and NDBC400-Cr2O72- can explain well why Cr2O72 has stronger inhibition effect than Fe3+ and Fe3+ can increase the concentration of •OH. This work provides a deep insight for the photochemical behavior of dissolved black carbon and the transformation behavior of the co-existed metal ions and antibiotics.

Identification and functional validation of P450 genes associated with pyrethroid resistance in the malaria vector Anopheles sinensis (Diptera Culicidae).

Cytochrome P450 monooxygenases (P450s), a multifunctional protein superfamily, are one of three major classes of detoxification enzymes. However, the diversity and functions of P450 genes from pyrethroid-resistant populations of Anopheles sinensis have not been fully explored. In this study, P450 genes associated with pyrethroid resistance were systematically screened using RNA-seq in three field pyrethroid-resistant populations (AH-FR, CQ-FR, YN-FR) and one laboratory resistant strain (WX-LR) at developmental stages, tissues, and post blood-meal in comparison to the laboratory susceptible strain (WX-LS) in An. sinensis. Importantly, the expression of significantly upregulated P450s was verified using RT-qPCR, and the function of selected P450s in pyrethroid detoxification was determined with RNA interference using four laboratory pyrethroid-resistant strains (WX-LR, AH-LR, CQ-LR, YN-LR). Sixteen P450 genes were significantly upregulated in at least one field-resistant population, and 44 were significantly upregulated in different developmental stages, tissues or post blood-meal. A total of 19 P450s were selected to verify their association with pyrethroid resistance, and four of them (AsCYP6P3v1, AsCYP6P3v2, AsCYP9J10, and AsCYP9K1) demonstrated significant upregulation in laboratory pyrethroid-resistant strains using RT-qPCR. Knockdown of these four genes all significantly reduced pyrethroid resistance and increased the mortality by 57.19% (AsCYP6P3v1 and AsCYP6P3v2 knockdown group), 38.39% (AsCYP9K1 knockdown group) and 48.87% (AsCYP9J10 knockdown group) in An. sinensis by RNAi, which determined the pyrethroid detoxification function of these four genes. This study revealed the diversity of P450 genes and provided functional evidence for four P450s in pyrethroid detoxification in An. sinensis for the first time, which increases our understanding of the pyrethroid resistance mechanism, and is of potential value for pyrethroid resistance detection and surveillance.

Gaudichaudione H ameliorates liver fibrosis and inflammation by targeting NRF2 signaling pathway.

Gaudichaudione H (GH) is a natural small molecular compound isolated from Garcinia oligantha Merr. (Clusiaceae). Being an uncommon rare caged polyprenylated xanthone, the potential pharmacological functions of GH remain to be fully elucidated currently. In this study, we primarily focused on identifying potential bioavailable targets and elucidating related therapeutic actions. Herein, the network pharmacology analysis, metabolomics analysis and genome-wide mRNA transcription assay were performed firstly to predict the major pharmacological action and potential targets of GH. To confirm the hypothesis, gene knockout model was created using CRISPR/Cas9 method. The pharmacological action of GH was evaluated in vitro and in vivo. Firstly, our results of network pharmacology analysis and omics assay indicated that GH significantly activated NRF2 signaling pathway, and the function could be associated with liver disease treatment. Then, the pharmacological action of GH was evaluated in vitro and in vivo. The treatment with GH significantly increased the protein levels of NRF2 and promoted the transcription of NRF2 downstream genes. Further analysis suggested that GH regulated NRF2 through an autophagy-mediated non-canonical mechanism. Additionally, the administration of GH effectively protected the liver from carbon tetrachloride (CCl4)-induced liver fibrosis and inflammation, which depended on the activation of NRF2 in hepatic stellate cells and inflammatory cells respectively. Collectively, our findings underscore the potential therapeutic effect of GH on alleviating hepatic fibrosis and inflammation through the augmentation of NRF2 signaling pathway, providing a promising avenue for the treatment of liver fibrosis and inflammation in clinical settings.

Posttransplant complications: molecular mechanisms and therapeutic interventions.

Posttransplantation complications pose a major challenge to the long-term survival and quality of life of organ transplant recipients. These complications encompass immune-mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation. Here, we provide a comprehensive overview of the clinical features, risk factors, and molecular mechanisms of major posttransplantation complications. We systematically summarize the current understanding of the immunological basis of allograft rejection and graft-versus-host disease, the metabolic dysregulation associated with immunosuppressive agents, and the role of oncogenic viruses in posttransplantation malignancies. Furthermore, we discuss potential prevention and intervention strategies based on these mechanistic insights, highlighting the importance of optimizing immunosuppressive regimens, enhancing infection prophylaxis, and implementing targeted therapies. We also emphasize the need for future research to develop individualized complication control strategies under the guidance of precision medicine, ultimately improving the prognosis and quality of life of transplant recipients.

Anterior decompression and posterior total laminectomy with fusion for ossification of the cervical posterior longitudinal ligament.

Aims: Surgical approaches to cervical ossification of the posterior longitudinal ligament (OPLL) remain controversial. The purpose of the present study was to analyze and compare the long-term neurological recovery following anterior decompression with fusion (ADF) and posterior laminectomy and fusion with bone graft and internal fixation (PLF) based on > ten-year follow-up outcomes in a single centre. Methods: Included in this retrospective cohort study were 48 patients (12 females; mean age 55.79 years (SD 8.94)) who were diagnosed with cervical OPLL, received treatment in our centre, and were followed up for 10.22 to 15.25 years. Of them, 24 patients (six females; mean age 52.88 years (SD 8.79)) received ADF, and the other 24 patients (five females; mean age 56.25 years (SD 9.44)) received PLF. Clinical data including age, sex, and the OPLL canal-occupying ratio were analyzed and compared. The primary outcome was Japanese Orthopaedic Association (JOA) score, and the secondary outcome was visual analogue scale neck pain. Results: Compared with the baseline, neurological function improved significantly after surgery in all patients of both groups (p < 0.001). The JOA recovery rate in the ADF group was significantly higher than that in the PLF group (p < 0.001). There was no significant difference in postoperative cervical pain between the two groups (p = 0.387). The operating time was longer and intraoperative blood loss was greater in the PLF group than the ADF group. More complications were observed in the ADF group than in the PLF group, although the difference was not statistically significant. Conclusion: Long-term neurological function improved significantly after surgery in both groups, with the improvement more pronounced in the ADF group. There was no significant difference in postoperative neck pain between the two groups. The operating time was shorter and intraoperative blood loss was lower in the ADF group; however, the incidence of perioperative complications was higher.