CsWRKY11 cooperates with CsNPR1 to regulate SA-triggered leaf de-greening and reactive oxygen species burst in cucumber.

Salicylic acid (SA) is a multi-functional phytohormone, regulating diverse processes of plant growth and development, especially triggering plant immune responses and initiating leaf senescence. However, the early SA signaling events remain elusive in most plant species apart from Arabidopsis, and even less is known about the multi-facet mechanism underlying SA-regulated processes. Here, we report the identification of a novel regulatory module in cucumber, CsNPR1-CsWRKY11, which mediates the regulation of SA-promoted leaf senescence and ROS burst. Our analyses demonstrate that under SA treatment, CsNPR1 recruits CsWRKY11 to bind to the promoter of CsWRKY11 to activate its expression, thus amplifying the primary SA signal. Then, CsWRKY11 cooperates with CsNPR1 to directly regulate the expression of both chlorophyll degradation and ROS biosynthesis related genes, thereby inducing leaf de-greening and ROS burst. Our study provides a solid line of evidence that CsNPR1 and CsWRKY11 constitute a key module in SA signaling pathway in cucumber, and gains an insight into the interconnected regulation of SA-triggered processes.

Identifying specific TLS-associated genes as potential biomarkers for predicting prognosis and evaluating the efficacy of immunotherapy in soft tissue sarcoma.

Background: The tertiary lymphatic structure (TLS) is an important component of the tumor immune microenvironment and has important significance in patient prognosis and response to immune therapy. However, the underlying mechanism of TLS in soft tissue sarcoma remains unclear. Methods: A total of 256 RNAseq and 7 single-cell sequencing samples were collected from TCGA-SARC and GSE212527 cohorts. Based on published TLS-related gene sets, four TLS scores were established by GSVA algorithm. The immune cell infiltration was calculated via TIMER2.0 and "MCPcounter" algorithms. In addition, the univariate, LASSO, and multivariate-Cox analyses were used to select TLS-related and prognosis-significant hub genes. Single-cell sequencing dataset, clinical immunohistochemical, and cell experiments were utilized to validate the hub genes. Results: In this study, four TLS-related scores were identified, and the total-gene TLS score more accurately reflected the infiltration level of TLS in STS. We further established two hub genes (DUSP9 and TNFSF14) prognosis markers and risk scores associated with soft tissue sarcoma prognosis and immune therapy response. Flow cytometry analysis showed that the amount of CD3, CD8, CD19, and CD11c positive immune cell infiltration in the tumor tissue dedifferentiated liposarcoma patients was significantly higher than that of liposarcoma patients. Cytological experiments showed that soft tissue sarcoma cell lines overexpressing TNFSF14 could inhibit the proliferation and migration of sarcoma cells. Conclusion: This study systematically explored the TLS and related genes from the perspectives of bioinformatics, clinical features and cytology experiments. The total-gene TLS score, risk score and TNFSF14 hub gene may be useful biomarkers for predicting the prognosis and immunotherapy efficacy of soft tissue sarcoma.

Nature-Inspired Micro/Nano-Structured Antibacterial Surfaces.

The problem of bacterial resistance has become more and more common with improvements in health care. Worryingly, the misuse of antibiotics leads to an increase in bacterial multidrug resistance and the development of new antibiotics has virtually stalled. These challenges have prompted the need to combat bacterial infections with the use of radically different approaches. Taking lessons from the exciting properties of micro-/nano-natural-patterned surfaces, which can destroy cellular integrity, the construction of artificial surfaces to mimic natural functions provides new opportunities for the innovation and development of biomedicine. Due to the diversity of natural surfaces, functional surfaces inspired by natural surfaces have a wide range of applications in healthcare. Nature-inspired surface structures have emerged as an effective and durable strategy to prevent bacterial infection, opening a new way to alleviate the problem of bacterial drug resistance. The present situation of bactericidal and antifouling surfaces with natural and biomimetic micro-/nano-structures is briefly reviewed. In addition, these innovative nature-inspired methods are used to manufacture a variety of artificial surfaces to achieve extraordinary antibacterial properties. In particular, the physical antibacterial effect of nature-inspired surfaces and the functional mechanisms of chemical groups, small molecules, and ions are discussed, as well as the wide current and future applications of artificial biomimetic micro-/nano-surfaces. Current challenges and future development directions are also discussed at the end. In the future, controlling the use of micro-/nano-structures and their subsequent functions will lead to biomimetic surfaces offering great potential applications in biomedicine.

Comparative transcriptome analysis between two different cadmium-accumulating genotypes of soybean (Glycine max) in response to cadmium stress.

BACKGROUND: Cadmium (Cd) is extremely toxic and non-essential for plants. Different soybean varieties differ greatly in their Cd accumulation ability, but little is known about the underlying molecular mechanisms. RESULTS: Here, we performed transcriptomic analysis using Illumina pair-end sequencing on root tissues from two soybean varieties (su8, high-Cd-accumulating (HAS) and su7, low Cd-accumulating (LAS)) grown with 0 or 50 µM CdSO4. A total of 18.76 million clean reads from the soybean root samples were obtained after quality assessment and data filtering. After Cd treatment, 739 differentially expressed genes (DEGs; 265 up and 474 down) were found in HAS; however, only 259 DEGs (88 up and 171 down) were found in LAS, and 64 genes were same between the two varieties. Pathway enrichment analysis suggested that after cadmium treatment, the DEGs between LAS and HAS were mainly enriched in glutathione metabolism and plant-pathogen interaction pathways. KEGG analysis showed that phenylalanine metabolism responding to cadmium stress in LAS, while ABC transporters responding to cadmium stress in HAS. Besides we found more differential expressed heavy metal transporters such as ABC transporters and zinc transporters in HAS than LAS, and there were more transcription factors differently expressed in HAS than LAS after cadmium treatment in two soybean varieties, eg. bHLH transcription factor, WRKY transcription factor and ZIP transcription factor. CONCLUSIONS: Findings from this study will shed new insights on the underlying molecular mechanisms behind the Cd accumulation in soybean.

Predicting TCR sequences for unseen antigen epitopes using structural and sequence features.

T-cell receptor (TCR) recognition of antigens is fundamental to the adaptive immune response. With the expansion of experimental techniques, a substantial database of matched TCR-antigen pairs has emerged, presenting opportunities for computational prediction models. However, accurately forecasting the binding affinities of unseen antigen-TCR pairs remains a major challenge. Here, we present convolutional-self-attention TCR (CATCR), a novel framework tailored to enhance the prediction of epitope and TCR interactions. Our approach utilizes convolutional neural networks to extract peptide features from residue contact matrices, as generated by OpenFold, and a transformer to encode segment-based coded sequences. We introduce CATCR-D, a discriminator that can assess binding by analyzing the structural and sequence features of epitopes and CDR3-ß regions. Additionally, the framework comprises CATCR-G, a generative module designed for CDR3-ß sequences, which applies the pretrained encoder to deduce epitope characteristics and a transformer decoder for predicting matching CDR3-ß sequences. CATCR-D achieved an AUROC of 0.89 on previously unseen epitope-TCR pairs and outperformed four benchmark models by a margin of 17.4%. CATCR-G has demonstrated high precision, recall and F1 scores, surpassing 95% in bidirectional encoder representations from transformers score assessments. Our results indicate that CATCR is an effective tool for predicting unseen epitope-TCR interactions. Incorporating structural insights enhances our understanding of the general rules governing TCR-epitope recognition significantly. The ability to predict TCRs for novel epitopes using structural and sequence information is promising, and broadening the repository of experimental TCR-epitope data could further improve the precision of epitope-TCR binding predictions.

VR23 and Bisdemethoxycurcumin Enhanced Nanofiber Niche with Durable Bidirectional Functions for Promoting Wound Repair and Inhibiting Scar Formation.

Chronic wounds pose a significant clinical challenge worldwide, which is characterized by impaired tissue regeneration and excessive scar formation due to over-repair. Most studies have focused on developing wound repair materials that either facilitate the healing process or control hyperplastic scars caused by over-repair, respectively. However, there are limited reports on wound materials that can both promote wound healing and prevent scar hyperplasia at the same time. In this study, VR23-loaded dendritic mesoporous bioglass nanoparticles (dMBG) are synthesized and electrospun in poly(ester-curcumin-urethane)urea (PECUU) random composite nanofibers (PCVM) through the synergistic effects of physical adsorption, hydrogen bond, and electrospinning. The physicochemical characterization reveals that PCVM presented matched mechanical properties, suitable porosity, and wettability, and enabled sustained and temporal release of VR23 and BDC with the degradation of PCVM. In vitro experiments demonstrated that PCVM can modulate the functions and polarization of macrophages under an inflammatory environment, and possess effective anti-scarring potential and reliable cytocompatibility. Animal studies further confirmed that PCVM can efficiently promote re-epithelialization and angiogenesis and reduce excessive inflammation, thereby remarkably accelerating wound healing while preventing potential scarring. These findings suggest that the prepared PCVM holds promise as a bidirectional regulatory dressing for effectively promoting scar-free healing of chronic wounds.

Induction of Salmonella Enteritidis into a Viable but Nonculturable State by Cinnamaldehyde and Its Resuscitation.

Trans-cinnamaldehyde (TC), a typical plant-derived compound, has been widely used in the control of foodborne pathogen contamination. Nevertheless, the risk associated with the occurrence of viable but nonculturable (VBNC) bacteria induced by TC remains unclear. The results of this study showed that Salmonella Enteritidis (S. Enteritidis) entered the VBNC state after being induced by TC at a minimum inhibitory concentration of 312.5 µg/mL and survived for at least 22 days under TC treatment. Enhanced resistance was found against heat treatment (75°C, 30 s), antibiotics (i.e., ampicillin, ceftriaxone sodium, chloramphenicol), and hydrogen peroxide (3%) in VBNC S. Enteritidis. A synergistic effect against VBNC S. Enteritidis occurred when TC was combined with acid treatment, including lactic acid and acetic acid (pH = 3.5). VBNC and resuscitated S. Enteritidis by sodium pyruvate treatment (100 mM) were found to retain the infectious ability to Caco-2 cells. Relative expression levels of the stress-related genes relA, spoT, ppx, lon, katG, sodA, dnaK, and grpE were upregulated in VBNC S. Enteritidis. Accumulation of reactive oxygen species (ROS) and protein aggregates was observed in VBNC cells. Besides, the resuscitation of VBNC cells was accompanied with clearance of ROS and protein aggregates. In summary, this study presents a comprehensive characterization of stress tolerance and resuscitation of VBNC S. Enteritidis induced by cinnamaldehyde, and the results provide useful information for the development of effective control strategy against VBNC pathogenic bacteria in food production.

A multiview deep learning-based prediction pipeline augmented with confident learning can improve performance in determining knee arthroplasty candidates.

PURPOSE: Preoperative prudent patient selection plays a crucial role in knee osteoarthritis management but faces challenges in appropriate referrals such as total knee arthroplasty (TKA), unicompartmental knee arthroplasty (UKA) and nonoperative intervention. Deep learning (DL) techniques can build prediction models for treatment decision-making. The aim is to develop and evaluate a knee arthroplasty prediction pipeline using three-view X-rays to determine the suitable candidates for TKA, UKA or are not arthroplasty candidates. METHODS: A study was conducted using three-view (anterior-posterior, lateral and patellar) X-rays and surgical data of patients undergoing TKA, UKA or nonarthroplasty interventions from sites A and B. Data from site A were used to derive and validate models. Data from site B were used as external test set. A DL pipeline combining YOLOv3 and ResNet-18 with confident learning (CL) was developed. Multiview Convolutional Neural Network, EfficientNet-b4, ResNet-101 and the proposed model without CL were also trained and tested. The models were evaluated using metrics such as area under the receiver operating characteristic curve (AUC), accuracy, precision, specificity, sensitivity and F1 score. RESULTS: The data set comprised a total of 1779 knees. Of which 1645 knees were from site A as a derivation set and an internal validation cohort. The external validation cohort consisted of 134 knees. The internal validation cohort demonstrated superior performance for the proposed model augmented with CL, achieving an AUC of 0.94 and an accuracy of 85.9%. External validation further confirmed the model's generalisation, with an AUC of 0.93 and an accuracy of 82.1%. Comparative analysis with other neural network models showed the proposed model's superiority. CONCLUSIONS: The proposed DL pipeline, integrating YOLOv3, ResNet-18 and CL, provides accurate predictions for knee arthroplasty candidates based on three-view X-rays. This prediction model could be useful in performing decision making for the type of arthroplasty procedure in an automated fashion. LEVEL OF EVIDENCE: Level III, diagnostic study.

A core competency evaluation index system for the graded use of clinical nurse specialists: A Delphi study.

AIMS AND OBJECTIVES: To describe a grading system that can be used to evaluate core competency of clinical nurse specialists (CNSs) at different levels. BACKGROUND: Evaluate core competence of CNSs at different levels reflects the quality of nursing and the development of the nursing profession. DESIGN: This research employed the Delphi method. METHODS: The STROBE checklist for observational cross-sectional studies was followed to report this research study. This study consisted of two main phases: a literature review and semistructured interviews. Individual semistructured interviews were conducted with 11 healthcare experts and two patients. Two rounds of questionnaire surveys were administered to 21 nursing experts using the Delphi method. The CNSs were classified as primary, intermediate or advanced based on their years of work, professional titles and educational qualifications. RESULTS: The graded competency evaluation system consisted of five first-level indicators (clinical practice, consulting guidance and teaching, scientific research innovation, management and discipline development, and ethical decision-making), 15 second level indicators, and 40 third-level indicators. The authority coefficients (Cr) of the experts were .865 and .901. The Kendall's concordance coefficients of the three-level indicators were .417, .289 and .316 for primary CNSs; .384, .294 and .337 for intermediate CNSs; and .489, .289 and .239 for advanced CNSs. CONCLUSION: The graded use evaluation system in clinical practice initially involves a comprehensive evaluation of the core abilities of CNSs. This is a tool for cultivating and grading the abilities of specialised nurses that can promote a practical upwards spiral. RELEVANCE TO CLINICAL PRACTICE: The evaluation system can promote the scientific management and continuous improvement of CNSs in clinical nursing and can serve as a practical and objective reference for the effective management and development of CNSs. PATIENT OR PUBLIC CONTRIBUTION: Patients participated in the data collection process, during which they shared their health-seeking experience with our research team.

Stress responses and Physiological Changes of Salmonella enterica Serovar Enteritidis on Short-Term and Long-Term Benzalkonium Bromide Adaptation.

Salmonella enterica is a common foodborne pathogen that poses significant safety risks across the world. And benzalkonium bromide (BK) is widely used as a disinfectant to sterilize the food processing equipment. It has been reported that sub-lethal concentration of disinfectants induced not only the homologous resistance but also cross-resistances. This work analyzed the induced resistances of Salmonella Enteritidis by short-term adaptation (STA) and long-term adaptation (LTA) to BK. We have demonstrated that inefficient sterilization exposes Salmonella Enteritidis to sub-lethal concentrations of BK, and adapts bacteria to a higher minimum inhibitory concentration and minimum bactericidal concentration. In addition, STA, but not LTA, to BK induced heterogeneous resistance to sodium hypochlorite, and cross-resistance to freezing, desiccation, and heating, which may be caused by the membrane composition change of Salmonella Enteritidis. This work could be useful to the optimization of cleaning protocol.

Intracardiac leakage of cement during artificial femoral head replacement: a case report and review.

Bone cement leakage from the femoral medullary cavity is a rare complication following hip replacement. Currently, there are no reports of bone cement leakage into the heart. Here, we report an 81-year-old female patient with right femoral neck fracture. A thorough preoperative examination showed that bone cement had leaked into the heart during right femoral head replacement, leading to the death of the patient that night. Postoperative cardiac ultrasound showed that bone cement entered the vascular system through the femoral medullary cavity and subsequently entered the heart. Extreme deterioration in the patient's condition resulted in death that night. Unfortunately, the patient's family abandoned the idea of surgical removal of foreign bodies, leading to inevitable death. This case emphasizes the risk of clinical manifestations of cardiac embolism of bone cement after artificial femoral head replacement, suggesting that the risk of such embolism might be underestimated. We propose routine real-time C-arm X-ray guidance and injection of an appropriate amount of bone cement to prevent serious cardiopulmonary failure.

Fraction dose escalation of hypofractionated radiotherapy with concurrent chemotherapy and subsequent consolidation immunotherapy in locally advanced non-small cell lung cancer: a phase 1 study.

PURPOSE: This phase 1 trial aimed to determine the maximum tolerated fraction dose (MTFD) of hypofractionated radiotherapy (hypo-RT) combined with concurrent chemotherapy and subsequent consolidation immune checkpoint inhibitors (cICI) for patients with locally advanced non-small cell lung cancer (LA-NSCLC). PATIENTS AND METHODS: Split-course hypo-RT and hypo-boost combined with concurrent chemotherapy were administered at three dose levels (DLs), using a stepwise dose-escalation protocol. The sophisticated esophagus-sparing technique was implemented to restrict the dose to the esophagus. Patients who did not experience disease progression or unresolved G2+ toxicities after radiotherapy received cICI. Each DL aimed to treat 6 patients. The MTFD was defined as the highest DL at which <=2 patients of the 6 who were treated experienced treatment-related G3+ toxicity and <=1 patient experienced G4+ toxicity within 12 months post-radiotherapy. RESULTS: Eighteen patients were enrolled with 6 patients in each DL. All patients completed hypo-RT and concurrent chemotherapy, and 16 (88.9%) received at least one infusion of cICI, with a median of 10 infusions. Within the 12-month assessment period, one patient in DL1 experienced G3 pneumonitis, and one patient in DL3 developed G3 tracheobronchitis. The MTFD was not reached. The objective response rate (ORR) was 100%. With a median follow-up of 20.9 months, the 1-year overall survival and progression-free survival rate were 94.4% and 83.3%, respectively. CONCLUSIONS: Utilizing the split-course hypo-RT and hypo-boost approach, a fraction dose of 5Gy to a total dose of 60Gy, combined with concurrent chemotherapy and subsequent cICI, was well-tolerated, and yielded promising ORR and survival outcomes.

From stem cells to pancreatic ß-cells: strategies, applications, and potential treatments for diabetes.

Loss and functional failure of pancreatic ß-cells results in disruption of glucose homeostasis and progression of diabetes. Although whole pancreas or pancreatic islet transplantation serves as a promising approach for ß-cell replenishment and diabetes therapy, the severe scarcity of donor islets makes it unattainable for most diabetic patients. Stem cells, particularly induced pluripotent stem cells (iPSCs), are promising for the treatment of diabetes owing to their self-renewal capacity and ability to differentiate into functional ß-cells. In this review, we first introduce the development of functional ß-cells and their heterogeneity and then turn to highlight recent advances in the generation of ß-cells from stem cells and their potential applications in disease modeling, drug discovery and clinical therapy. Finally, we have discussed the current challenges in developing stem cell-based therapeutic strategies for improving the treatment of diabetes. Although some significant technical hurdles remain, stem cells offer great hope for patients with diabetes and will certainly transform future clinical practice.

Moral Dilemmas Regarding Physical Restraints in Intensive Care Units: Understanding Autonomy, Beneficence, Non-Maleficence and Justice in the Use of Physical Restraints.

In intensive care units, patients are often restrained to ensure their safety, with physical restraints being the most commonly used method. However, physical restraints compromises the patient's freedom, health and comfort, and nurses often face moral dilemmas when deciding whether to use physical restraints. This article examines physical restraints through the four universal principles of autonomy, beneficence, non-maleficence and justice. Through these principles, the authors will critically explore whether the physical restraints of patients by nurses is ethical in practice and what moral issues exist. This paper also explores conflicts and moral dilemmas for nurses in this context. Finally, suggestions are made on changes to education and clinical practice.

A dual-mode fluorometric/colorimetric sensor for sulfadimethoxine detection based on Prussian blue nanoparticles and carbon dots.

A dual-mode (colorimetric/fluorescence) nanoenzyme-linked immunosorbent assay (NLISA) was developed based on Au-Cu nanocubes generating Prussian blue nanoparticles (PBNPs). It is expected that this method can be used to detect the residues of sulfonamides in the field, and solve the problem of long analysis time and high cost of the traditional method. Sulfadimethoxine (SDM) was selected as the proof-of-concept target analyte. The Au-Cu nanocubes were linked to the aptamer by amide interaction, and the Au-Cu nanocubes, SDM and antibody were immobilized on a 96-well plate using the sandwich method. The assay generates PBNPs by oxidising the Cu shells on the Au-Cu nanocubes in the presence of hydrochloric acid, Fe3+ and K3[Fe (CN)6]. In this process, the copper shell undergoes oxidation to Cu2+ and subsequently Cu2 + further quenches the fluorescence of the carbon point. PBNPs exhibit peroxidase-like activity, oxidising 3,3',5,5'-tetramethylbenzidine (TMB) to OX-TMB in the presence of H2O2, which alters the colorimetric signal. The dual-mode signals are directly proportional to the sulfadimethoxine concentration within the range 10- 3~10- 7 mg/mL. The limit of detection (LOD) of the assay is 0.023 ng/mL and 0.071 ng/mL for the fluorescent signal and the colorimetric signal, respectively. Moreover, the assay was successfully applied to determine sulfadimethoxine in silver carp, shrimp, and lamb samples with satisfactory results.

[Alcohol Abstinence and Accelerated Biological Aging Among Middle-Aged and Older Adults: Evidence From the UK Biobank]. / ä¸­è€å¹´ç¾¤ä½“é ’ç²¾æˆ’æ–­ä¸Žç”Ÿç‰©è¡°è€åŠ é€Ÿçš„å ³ç³»ï¼šåŸºäºŽè‹±å›½ç”Ÿç‰©é“¶è¡Œæ•°æ®åº“çš„ç ”ç©¶.

Objective: To investigate the longitudinal association between alcohol abstinence and accelerated biological aging among middle-aged and older adults and to explore the potential effect modifiers influencing the association. Methods: Utilizing the clinico-biochemical and anthropometric data from the baseline and first repeat survey of the UK Biobank (UKB), we employed the Klemera and Doubal method (KDM) to construct the biological age (BA) and calculate BA acceleration. Change analysis based on multivariate linear regression models was employed to explore the association between changes in alcohol abstinence and changes in BA acceleration. Age, sex, smoking status, tea and coffee consumption, and body mass index were considered as the stratification factors for conducting stratified analysis. Results: A total of 5 412 participants were included. Short-term alcohol abstinence (ß=1.00, 95% confidence interval [CI]: 0.15-1.86) was found to accelerate biological aging when compared to consistent never drinking, while long-term abstinence (ß=-0.20, 95% CI: -1.12-0.71) did not result in a significant acceleration of biological aging. Body mass index may be a potential effect modifier. Conclusion: Short-term alcohol abstinence was associated with accelerated biological aging, but the effect gradually diminishes over extended periods of abstinence.

Identification of an immune-related gene signature for predicting prognosis and immunotherapy efficacy in liver cancer via cell-cell communication.

BACKGROUND: Liver cancer is one of the deadliest malignant tumors worldwide. Immunotherapy has provided hope to patients with advanced liver cancer, but only a small fraction of patients benefit from this treatment due to individual differences. Identifying immune-related gene signatures in liver cancer patients not only aids physicians in cancer diagnosis but also offers personalized treatment strategies, thereby improving patient survival rates. Although several methods have been developed to predict the prognosis and immunotherapeutic efficacy in patients with liver cancer, the impact of cell-cell interactions in the tumor microenvironment has not been adequately considered. AIM: To identify immune-related gene signals for predicting liver cancer prognosis and immunotherapy efficacy. METHODS: Cell grouping and cell-cell communication analysis were performed on single-cell RNA-sequencing data to identify highly active cell groups in immune-related pathways. Highly active immune cells were identified by intersecting the highly active cell groups with B cells and T cells. The significantly differentially expressed genes between highly active immune cells and other cells were subsequently selected as features, and a least absolute shrinkage and selection operator (LASSO) regression model was constructed to screen for diagnostic-related features. Fourteen genes that were selected more than 5 times in 10 LASSO regression experiments were included in a multivariable Cox regression model. Finally, 3 genes (stathmin 1, cofilin 1, and C-C chemokine ligand 5) significantly associated with survival were identified and used to construct an immune-related gene signature. RESULTS: The immune-related gene signature composed of stathmin 1, cofilin 1, and C-C chemokine ligand 5 was identified through cell-cell communication. The effectiveness of the identified gene signature was validated based on experimental results of predictive immunotherapy response, tumor mutation burden analysis, immune cell infiltration analysis, survival analysis, and expression analysis. CONCLUSION: The findings suggest that the identified gene signature may contribute to a deeper understanding of the activity patterns of immune cells in the liver tumor microenvironment, providing insights for personalized treatment strategies.

Glutathione peroxidase 4 restrains temporomandibular joint osteoarthritis progression by inhibiting ferroptosis.

There are few effective therapeutic strategies for temporomandibular joint osteoarthritis (TMJOA) due to the unclear pathology and mechanisms. We aimed to confirm the roles of GPX4 and ferroptosis in TMJOA progression. ELISA assay was hired to evaluate concentrations of ferroptosis-related markers. The qRT-PCR assay was hired to assess gene mRNA level. Western blot assay and immunohistochemistry were hired to verify the protein level. CCK-8 assay was hired to detect cell viability. Human fibroblast-like synoviocytes (FLSs) were cultured to confirm the effects of GPX4 and indicated inhibitors, and further verified the effects of GPX4 and ferroptosis inhibitors in TMJOA model rats. Markers of ferroptosis including 8-hidroxy-2-deoxyguanosine (8-OHdG) and iron were notably increased in TMJOA tissues and primary OA-FLSs. However, the activity of the antioxidant system including the glutathione peroxidase activity, glutathione (GSH) contents, and glutathione/oxidized glutathione (GSH/GSSG) ratio was notably inhibited in TMJOA tissues, and the primary OA-FLSs. Furthermore, the glutathione peroxidase 4 (GPX4) expression was down-regulated in TMJOA tissues and primary OA-FLSs. Animal and cell experiments have shown that ferroptosis inhibitors notably inhibited ferroptosis and promoted HLS survival as well as up-regulated GPX4 expression. Also, GPX4 knockdown promoted ferroptosis and GPX4 overexpression inhibited ferroptosis. GPX4 also positively regulated cell survival which was the opposite with ferroptosis. In conclusion, GPX4 and ferroptosis regulated the progression of TMJOA. Targeting ferroptosis might be an effective therapeutic strategy for TMJOA patients in the clinic.

Gbdmr: identifying differentially methylated CpG regions in the human genome via generalized beta regressions.

BACKGROUND: DNA methylation is a biochemical process in which a methyl group is added to the cytosine-phosphate-guanine (CpG) site on DNA molecules without altering the DNA sequence. Multiple CpG sites in a certain genome region can be differentially methylated across phenotypes. Identifying these differentially methylated CpG regions (DMRs) associated with the phenotypes contributes to disease prediction and precision medicine development. RESULTS: We propose a novel DMR detection algorithm, gbdmr. In contrast to existing methods under a linear regression framework, gbdmr assumes that DNA methylation levels follow a generalized beta distribution. We compare gbdmr to alternative approaches via simulations and real data analyses, including dmrff, a new DMR detection approach that shows promising performance among competitors, and the traditional EWAS that focuses on single CpG sites. Our simulations demonstrate that gbdmr is superior to the other two when the correlation between neighboring CpG sites is strong, while dmrff shows a higher power when the correlation is weak. We provide an explanation of these phenomena from a theoretical perspective. We further applied the three methods to multiple real DNA methylation datasets. One is from a birth cohort study undertaken on the Isle of Wight, United Kingdom, and the other two are from the Gene Expression Omnibus database repository. Overall, gbdmr identifies more DMR CpGs linked to phenotypes than dmrff, and the simulated results support the findings. CONCLUSIONS: Gbdmr is an innovative method for detecting DMRs based on generalized beta regression. It demonstrated notable advantages over dmrff and traditional EWAS, particularly when adjacent CpGs exhibited moderate to strong correlations. Our real data analyses and simulated findings highlight the reliability of gbdmr as a robust DMR detection tool. The gbdmr approach is accessible and implemented by R on GitHub: https://github.com/chengzhouwu/gbdmr .

Sleep disorders and cancer incidence: examining duration and severity of diagnosis among veterans.

Introduction: Sleep disruption affects biological processes that facilitate carcinogenesis. This retrospective cohort study used de-identified data from the Veterans Administration (VA) electronic medical record system to test the hypothesis that patients with diagnosed sleep disorders had an increased risk of prostate, breast, colorectal, or other cancers (1999-2010, N=663,869). This study builds upon existing evidence by examining whether patients with more severe or longer-duration diagnoses were at a greater risk of these cancers relative to those with a less severe or shorter duration sleep disorder. Methods: Incident cancer cases were identified in the VA Tumor Registry and sleep disorders were defined by International Classification of Sleep Disorder codes. Analyses were performed using extended Cox regression with sleep disorder diagnosis as a time-varying covariate. Results: Sleep disorders were present among 56,055 eligible patients (8% of the study population); sleep apnea (46%) and insomnia (40%) were the most common diagnoses. There were 18,181 cancer diagnoses (41% prostate, 12% colorectal, 1% female breast, 46% other). The hazard ratio (HR) for a cancer diagnosis was 1.45 (95% confidence interval [CI]: 1.37, 1.54) among those with any sleep disorder, after adjustment for age, sex, state of residence, and marital status. Risks increased with increasing sleep disorder duration (short [<1-2 years] HR: 1.04 [CI: 1.03-1.06], medium [>2-5 years] 1.23 [1.16-1.32]; long [>5-12 years] 1.52 [1.34-1.73]). Risks also increased with increasing sleep disorder severity using cumulative sleep disorder treatments as a surrogate exposure; African Americans with more severe disorders had greater risks relative to those with fewer treatments and other race groups. Results among patients with only sleep apnea, insomnia, or another sleep disorder were similar to those for all sleep disorders combined. Discussion: The findings are consistent with other studies indicating that sleep disruption is a cancer risk factor. Optimal sleep and appropriate sleep disorder management are modifiable risk factors that may facilitate cancer prevention.