Ferroptosis in Arthritis: Driver of the Disease or Therapeutic Option?

Ferroptosis is a form of iron-dependent regulated cell death caused by the accumulation of lipid peroxides. In this review, we summarize research on the impact of ferroptosis on disease models and isolated cells in various types of arthritis. While most studies have focused on rheumatoid arthritis (RA) and osteoarthritis (OA), there is limited research on spondylarthritis and crystal arthropathies. The effects of inducing or inhibiting ferroptosis on the disease strongly depend on the studied cell type. In the search for new therapeutic targets, inhibiting ferroptosis in chondrocytes might have promising effects for any type of arthritis. On the other hand, ferroptosis induction may also lead to a desired decrease of synovial fibroblasts in RA. Thus, ferroptosis research must consider the cell-type-specific effects on arthritis. Further investigation is needed to clarify these complexities.

Cell-specific gene networks and drivers in rheumatoid arthritis synovial tissues.

Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease characterized by inflammation and hyperplasia of the synovial tissues. RA pathogenesis involves multiple cell types, genes, transcription factors (TFs) and networks. Yet, little is known about the TFs, and key drivers and networks regulating cell function and disease at the synovial tissue level, which is the site of disease. In the present study, we used available RNA-seq databases generated from synovial tissues and developed a novel approach to elucidate cell type-specific regulatory networks on synovial tissue genes in RA. We leverage established computational methodologies to infer sample-specific gene regulatory networks and applied statistical methods to compare network properties across phenotypic groups (RA versus osteoarthritis). We developed computational approaches to rank TFs based on their contribution to the observed phenotypic differences between RA and controls across different cell types. We identified 18 (fibroblast-like synoviocyte), 16 (T cells), 19 (B cells) and 11 (monocyte) key regulators in RA synovial tissues. Interestingly, fibroblast-like synoviocyte (FLS) and B cells were driven by multiple independent co-regulatory TF clusters that included MITF, HLX, BACH1 (FLS) and KLF13, FOSB, FOSL1 (B cells). However, monocytes were collectively governed by a single cluster of TF drivers, responsible for the main phenotypic differences between RA and controls, which included RFX5, IRF9, CREB5. Among several cell subset and pathway changes, we also detected reduced presence of Natural killer T (NKT) cells and eosinophils in RA synovial tissues. Overall, our novel approach identified new and previously unsuspected Key driver genes (KDG), TF and networks and should help better understanding individual cell regulation and co-regulatory networks in RA pathogenesis, as well as potentially generate new targets for treatment.

Haptic based fundamentals of laparoscopic surgery simulation for training with objective assessments.

Force is crucial for learning psychomotor skills in laparoscopic tissue manipulation. Fundamental laparoscopic surgery (FLS), on the other hand, only measures time and position accuracy. FLS is a commonly used training program for basic laparoscopic training through part tasks. The FLS is employed in most of the laparoscopic training systems, including box trainers and virtual reality (VR) simulators. However, many laparoscopic VR simulators lack force feedback and measure tissue damage solely through visual feedback based on virtual collisions. Few VR simulators that provide force feedback have subjective force metrics. To provide an objective force assessment for haptic skills training in the VR simulators, we extend the FLS part tasks to haptic-based FLS (HFLS), focusing on controlled force exertion. We interface the simulated HFLS part tasks with a customized bi-manual haptic simulator that offers five degrees of freedom (DOF) for force feedback. The proposed tasks are evaluated through face and content validity among laparoscopic surgeons of varying experience levels. The results show that trainees perform better in HFLS tasks. The average Likert score observed for face and content validity is greater than 4.6 ± 0.3 and 4 ± 0.5 for all the part tasks, which indicates the acceptance of the simulator among subjects for its appearance and functionality. Face and content validations show the need to improve haptic realism, which is also observed in existing simulators. To enhance the accuracy of force rendering, we incorporated a laparoscopic tool force model into the simulation. We study the effectiveness of the model through a psychophysical study that measures just noticeable difference (JND) for the laparoscopic gripping task. The study reveals an insignificant decrease in gripping-force JND. A simple linear model could be sufficient for gripper force feedback, and a non-linear LapTool force model does not affect the force perception for the force range of 0.5-2.5 N. Further study is required to understand the usability of the force model in laparoscopic training at a higher force range. Additionally, the construct validity of HFLS will confirm the applicability of the developed simulator to train surgeons with different levels of experience.

Heterologous maternal antibodies derived from infectious bronchitis vaccines prevent the development of lesions associated with false layer syndrome.

Infectious bronchitis virus (IBV) strains of the Delmarva (DMV)/1639 genotype have been causing false layer syndrome (FLS) in the Eastern Canadian layer operations since the end of 2015. FLS is characterized by the development of cystic oviducts in layer pullets infected at an early age. Currently, there are no homologous vaccines for the control of this IBV genotype. Our previous research showed that a heterologous vaccination regimen incorporating Massachusetts (Mass) and Connecticut (Conn) IBV types protects layers against DMV/1639 genotype IBV. The aim of this study was to investigate the role of maternal antibodies conferred by breeders received the same vaccination regimen in the protection against the development of DMV/1639-induced FLS in pullets. Maternal antibody-positive (MA+) and maternal antibody-negative (MA-) female progeny chicks were challenged at 1 day of age and kept under observation for 16 weeks. Oviductal cystic formations were observed in 3 of 14 birds (21.4 %) in the MA- pullets, while the lesions were notably absent in the MA+ pullets. Milder histopathological lesions were observed in the examined tissues of the MA+ pullets. However, the maternal derived immunity failed to demonstrate protection against the damage to the tracheal ciliary activity, viral shedding, and viral tissue distribution. Overall, this study underscores the limitations of maternal derived immunity in preventing certain aspects of viral pathogenesis, emphasizing the need for comprehensive strategies to address different aspects of IBV infection.

A deletion in FLS2 and its expansion after domestication caused global dissemination of melon cultivars defective in flagellin recognition.

FLAGELLIN SENSING 2 (FLS2) encodes a pattern recognition receptor that perceives bacterial flagellin. While putative FLS2 orthologs are broadly conserved in plants, their functional characterization remains limited. Here, we report the identification of orthologs in cucumber (Cucumis sativus) and melon (C. melo), named CsFLS2 and CmFLS2, respectively. Homology searching identified CsFLS2, and virus-induced gene silencing (VIGS) demonstrated that CsFLS2 is required for flg22-triggered ROS generation. Interestingly, genome re-sequencing of melon cv. Lennon and subsequent genomic PCR revealed that Lennon has two CmFLS2 haplotypes, haplotype I encoding full-length CmFLS2 and haplotype II encoding a truncated form. We show that VIGS-mediated knockdown of CmFLS2 haplotype I resulted in a significant reduction in both flg22-triggered ROS generation and immunity to a bacterial pathogen in melon cv. Lennon. Remarkably, genomic PCR of CmFLS2 revealed that 68% of tested commercial melon cultivars possess only CmFLS2 haplotype II: these cultivars thus lack functional CmFLS2. To explore evolutionary aspects of CmFLS2 haplotype II occurrence, we genotyped the CmFLS2 locus in 142 melon accessions by genomic PCR and analyzed 437 released sequences. The results suggest that CmFLS2 haplotype II is derived from C. melo subsp. melo. Furthermore, we suggest that the proportion of CmFLS2 haplotype II increased among the improved melo group compared with the primitive melo group. Collectively, these findings suggest that the deleted FLS2 locus generated in the primitive melo subspecies expanded after domestication, resulting in the spread of commercial melon cultivars defective in flagellin recognition, which is critical for bacterial immunity.

Perspectives on Fracture Liaison Service in Austria: clinical and economic considerations.

Osteoporosis is a widespread disease and affects over 500,000 people in Austria. Fragility fractures are associated with it and represent not only an individual problem for the patients, but also an enormous burden for the healthcare system. While trauma surgery care is well provided in Vienna, there is an enormous treatment gap in secondary prevention after osteoporotic fracture. Systematic approaches such as the Fracture Liaison Service (FLS) aim to identify patients with osteoporosis after fracture, to clarify diagnostically, to initiate specific therapy, and to check therapy adherence. The aim of this article is to describe the practical implementation and operational flow of an already established FLS in Vienna. This includes the identification of potential FLS inpatients, the diagnostic workup, and recommendations for an IT solution for baseline assessment and follow-up of FLS patients. We summarize the concept, benefits, and limitations of FLS and provide prospective as well as clinical and economic considerations for a city-wide FLS, managed from a central location. Future concepts of FLS should include artificial intelligence for vertebral fracture detection and simple IT tools for the implementation of FLS in the outpatient sector.

Cognitive Decline: Current Intervention Strategies and Integrative Therapeutic Approaches for Alzheimer's Disease.

Alzheimer's disease (AD) represents a pressing global health challenge, with an anticipated surge in diagnoses over the next two decades. This progressive neurodegenerative disorder unfolds gradually, with observable symptoms emerging after two decades of imperceptible brain changes. While traditional therapeutic approaches, such as medication and cognitive therapy, remain standard in AD management, their limitations prompt exploration into novel integrative therapeutic approaches. Recent advancements in AD research focus on entraining gamma waves through innovative methods, such as light flickering and electromagnetic fields (EMF) stimulation. Flickering light stimulation (FLS) at 40 Hz has demonstrated significant reductions in AD pathologies in both mice and humans, providing improved cognitive functioning. Additionally, recent experiments have demonstrated that APOE mutations in mouse models substantially reduce tau pathologies, with microglial modulation playing a crucial role. EMFs have also been demonstrated to modulate microglia. The exploration of EMFs as a therapeutic approach is gaining significance, as many recent studies have showcased their potential to influence microglial responses. Th article concludes by speculating on the future directions of AD research, emphasizing the importance of ongoing efforts in understanding the complexities of AD pathogenesis through a holistic approach and developing interventions that hold promise for improved patient outcomes.

Targeting TNF-α-induced expression of TTR and RAGE in rheumatoid arthritis: Apigenin's mediated therapeutic approach.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease induced by TNF-α, which increases fibroblast-like synoviocytes inflammation, resulting in cartilage destruction. The current work sought to comprehend the pathophysiological importance of TNF-α stimulation on differential protein expression and their regulation by apigenin using in-vitro and in-vivo models of RA. METHODS: The human RA synovial fibroblast cells were stimulated with or without TNF-α (10 ng/ml) and treated with 40 µM apigenin. In-silico, in-vitro and in-vivo studies were performed to confirm the pathophysiological significance of apigenin on pro-inflammatory cytokines and on differential expression of TTR and RAGE proteins. RESULTS: TNF-α induced inflammatory response in synoviocytes revealed higher levels of IL-6, IL-1ß, and TNF-α cytokines and upregulated differential expression of TTR and RAGE. In-silico results demonstrated that apigenin has a binding affinity towards TNF-α, indicating its potential effect in the inflammatory process. Both in-vitro and in-vivo results obtained by Western Blot analysis suggested that apigenin reduced the level of p65 (p = 0.005), TTR (p = 0.002), and RAGE (p = 0.020). CONCLUSION: The findings of this study suggested that TNF-α promotes the differential expression of pro-inflammatory cytokines, TTR, and RAGE via NF-kB pathways activation. Anti-inflammatory effect of apigenin impedes TNF-α mediated dysregulation or expression associated with RA pathogenesis.

IMPACT OF VIDEOSURGERY TRAINING IN GENERAL SURGERY RESIDENTS WITH LOW FIDELITY SIMULATOR ADAPTED FROM THE FUNDAMENTS OF LAPAROSCOPIC SURGERY (FLS) / IMPACTO DO TREINAMENTO EM VIDEOCIRURGIA DE MÉDICOS RESIDENTES DE CIRURGIA GERAL EM SIMULADOR DE BAIXA FIDELIDADE ADAPTADO DO PROGRAMA DE FUNDAMENTS OF LAPAROSCOPIC SURGERY (FLS)

Introduction: Teaching in surgery must follow the evolution of medical techniques, procedures and technology. Since the 90s videosurgery has been developing and nowadays is the gold standard for many procedures in general surgery. As there are different characteristics from conventional surgery, residents need to practice in order to adapt to simulators. The world medical literature has established many training programs among them the Fundaments of laparoscopic Surgery (FLS). Evaluation of surgical technical abilities is a major tool for the residency programs. Objectives: To assess the effect of training acquiring skills of residents at first and second postgraduated level year (PGY1 and PGY2) before and after practice using low fidelity simulator based on tasks from FLS. Methods: A prospective study was conducted to determinate skills acquisition of residents at first and second postgraduated level year l (PGY1 and PGY2) before and after standardized practice using low fidelity simulator. Conclusions: There was a significant improve of the technical abilities reaching levels of improvement. Resident's performance was evident in the sample groups. First year residents (PGY1) achieved knowledge retention after training similar to the performance of second in the initial assessment, suggesting that the sequenced training carried out is equivalent to one year of practice in the general surgery residency program

Introdução: O ensino em cirurgia deve acompanhar a evolução das técnicas, procedimentos e tecnologia. Desde a década de 90 a videocirurgia vem se desenvolvendo e hoje é a primeira escolha para muitos procedimentos em cirugia geral. Com características diferentes da cirurgia convencional, os residentes treinaram em simuladores para adaptação. A literatura médica mundial já apresenta programas consagrados para treinamento entre eles os Fundamentos da Cirurgia Laparoscópica (FLS). A avaliação das habilidades técnicas cirúrgicas é uma ferramenta importante em programas de residência médica. Objetivo: Avaliar o impacto do treinamento através de aquisição de habilidades dos médicos residentes em cirurgia geral antes e após treinamento teórico-prático em videocirurgia utilizando um simulador de baixa fidelidade baseado em exercícios do FLS. Método: Estudar de modo prospectivo a aquisição de habilidades de médicos residentes em cirurgia geral de primeiro e segundo ano (R1 e R2), antes e após realização de treinamento teórico-prático pré-definido. Conclusão: Houve melhora significativa com o treinamento atingindo níveis de conhecimento e aprimoramento semelhantes aos trabalhos da literatura mundial. A melhoria no desempenho dos residentes foi evidente em ambos os grupos da amostra. Aqueles do primeiro ano atingiram a concentração de conhecimento após o treinamento semelhante ao desempenho dos residentes de segundo ano na avaliação inicial, destacando que o treinamento sequenciado realizado equivale a um ano de prática no programa de residência geral de cirurgia

A novel lectin receptor kinase gene, AtG-LecRK-I.2, enhances bacterial pathogen resistance through regulation of stomatal immunity in Arabidopsis.

The S-locus lectin receptor kinases (G-LecRKs) have been suggested as receptors for microbe/damage-associated molecular patterns (MAMPs/DAMPs) and to be involved in the pathogen defense responses, but the functions of most G-LecRKs in biotic stress response have not been characterized. Here, we identified a member of this family, G-LecRK-I.2, that positively regulates flg22- and Pseudomonas syringae pv. tomato (Pst) DC3000-induced stomatal closure. G-LecRK-I.2 was rapidly phosphorylated under flg22 treatment and could interact with the FLS2/BAK1 complex. Two T-DNA insertion lines, glecrk-i.2-1 and glecrk-i.2-2, had lower levels of reactive oxygen species (ROS) and nitric oxide (NO) production in guard cells, as compared with the wild-type Col-0, under Pst DC3000 infection. Also, the immunity marker genes CBP60g and PR1 were induced at lower levels under Pst DC3000 hrcC- infection in glecrk-i.2-1 and glecrk-i.2-2. The GUS reporter system also revealed that G-LecRK-I.2 was expressed only in guard cells. We also found that G-LecRK-I.2 could interact H+-ATPase AHA1 to regulate H+-ATPase activity in the guard cells. Taken together, our results show that G-LecRK-I.2 plays an important role in regulating stomatal closure under flg22 and Pst DC3000 treatments and in ROS and NO signaling specifically in guard cells.

Evaluating Motor Dysfunction and Oxidative Stress Induced by Trichloroethylene in Wistar Rats.

Trichloroethylene, a chlorinated solvent widely used as a degreasing agent, is a common environmental contaminant. Emerging evidence suggests that chronic exposure to trichloroethylene (TCE) contributes to the development of Parkinson's disease (PD). TCE induced LRRK2 kinase activity in the rat brain and produced a significant dopaminergic lesion in the nigrostriatal tract with elevated oxidative stress. Here we have utilized TCE-induced PD model for the assessment of test drug. Oral gavage administration of TCE at a dose of 1000 mg/kg/day for 6 weeks was utilized to induced PD. Muscle grip strength was estimated by rotarod and grid performance test. Motor activity by actophotometer and locomotor stability were assessed by forelimb locomotor scale (FLS) and forelimb step alternation test (FSAT). However, the postural stability was assessed by postural stability test (PST). Biochemical estimation consists of determination of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), GSH level (reduced glutathione), and nitrite concentration.

Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. METHODS: First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot. RESULTS: The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1ß, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS. CONCLUSION: These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA.

Learning Curves of OBGYN Residents Preparing for the FLS Manual Skills Exam.

OBJECTIVE: To describe obstetrics and gynecology (OBGYN) resident practice patterns and learning curves as they prepare for the Fundamentals for Laparoscopic Surgery (FLS) manual skills exam and to assess the importance of meeting proficiency, based on published standards, for passing the FLS manual skills exam. METHODS: This is a prospective observational study of OBGYN resident physicians from July 2018 to January 2022. Residents recorded details about their FLS practice sessions and proficiency metrics for each task repetition. Manual skills exam scores were then compared to task practice variables. Learning curves were developed from resident practice patterns. RESULTS: Fifty OBGYN residents participated in the study. The median number of repetitions per FLS manual skills task ranged from 3.5 (interquartile range [IQR] 2-7) (Task 3) to 7.5 (IQR 3-14) (Task 1). The average number of hours spent practicing was 5.4 hours (SD 3.4 hours), with a median of 3.7 sessions with faculty and/or fellow guidance and 1 self-practice session. All residents passed the FLS manual skills exam. Only for Task 2 (95% confidence interval [CI] 0.24, 5.21) and for the total number of repetitions for all tasks (95% confidence interval [CI] 0.22, 3.74) was a greater number of practice repetitions associated with higher FLS manual skills exam scores. Notably, postgraduate year, number and type of practice sessions, and the number of hours were not associated with higher scores. For all tasks, learning curves showed the greatest rate of improvement in the first 10 to 15 repetitions before diminishing returns. CONCLUSION: Greater number of practice hours and sessions were not associated with better manual exam scores in a cohort of OBGYN residents with a high proportion of supervised practice sessions. Achieving more advanced proficiency at certain FLS tasks may allow for better performance on the exam.

Notch ligands are biomarkers of anti-TNF response in RA patients.

Notch and its ligands play a critical role in rheumatoid arthritis (RA) pathogenesis. Hence, studies were conducted to delineate the functional significance of the Notch pathway in RA synovial tissue (ST) cells and the influence of RA therapies on their expression. Morphological studies reveal that JAG1, DLL4, and Notch1 are highly enriched in RA ST lining and sublining CD68+CD14+ MΦs. JAG1 and DLL4 transcription is jointly upregulated in RA MΦs reprogrammed by TLR4/5 ligation and TNF, whereas Syntenin-1 exposure expands JAG1, DLL4, and Notch1 expression levels in these cells. Single-cell RNA-seq data exhibit that JAG1 and Notch3 are overexpressed on all fibroblast-like synoviocyte (FLS) subpopulations, in parallel, JAG2, DLL1, and Notch1 expression levels are modest on RA FLS and are predominately potentiated by TLR4 ligation. Intriguingly, JAG1, DLL1/4, and Notch1/3 are presented on RA endothelial cells, and their expression is mutually reconfigured by TLR4/5 ligation in the endothelium. Synovial JAG1/JAG2/DLL1 or Notch1/3 transcriptomes were unchanged in patients who received disease-modifying anti-rheumatic drugs (DMARDs) or IL-6R Ab therapy regardless of disease activity score. Uniquely, RA MΦs and endothelial cells rewired by IL-6 displayed DLL4 transcriptional upregulation, and IL-6R antibody treatment disrupted RA ST DLL4 transcription in good responders compared to non-responders or moderate responders. Nevertheless, the JAG1/JAG2/DLL1/DLL4 transcriptome was diminished in anti-TNF good responders with myeloid pathotype and was unaltered in the fibroid pathotype except for DLL4. Taken together, our findings suggest that RA myeloid Notch ligands can serve as markers for anti-TNF responsiveness and trans-activate Notch receptors expressed on RA FLS and/or endothelial cells.

APOD acts on fibroblast-like synoviocyte and chondrocyte to alleviate the process of osteoarthritis in vitro.

The pathogenesis of osteoarthritis (OA) is still unclear, leading to the lack of targeted treatment. We aimed to probe into the effect of apolipoprotein D (APOD), the key gene from our previous study through bioinformatics analysis, on fibroblast-like synoviocyte (FLS) and chondrocytes in vitro to confirm its potential roles on the delay of OA progression. Primary FLS and chondrocytes were extracted from synovium and cartilage of OA patients and stimulated with interleukin 1ß (IL-1ß) in vitro. After APOD intervention, viability and proliferation of FLS and chondrocytes were detected. Subsequently, the inflammatory factors of the two cells were detected by quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and western blot, and the apoptosis and autophagy-related substances were determined at the same time. Finally, the oxidation level in FLS and chondrocytes were detected. APOD reversed the change of gene expression stimulated by IL-1ß in FLS and chondrocytes. APOD alleviated the proliferation of FLS while promoted proliferation of chondrocytes, and reduced the expression of inflammatory factors. Moreover, APOD promoted apoptosis of FLS and autography of chondrocytes, while reduced apoptosis of chondrocytes. Finally, decrease level of reactive oxygen species (ROS) in both cells were observed after APOD intervention, as well as the increased expression of antioxidant-related genes. APOD had effects on the proliferation of FLS and chondrocytes through apoptosis and autography as well as the reduction of oxidative stress, delaying the progress of OA.

PTEN-mediated FOXO signaling affects autophagy, migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease. Among them, abnormal proliferation, migration and vascularization of fibroblast-like synoviocytes (FLS) are the main pathological basis of persistent synovitis and bone destruction in RA. In the current study, we attempted to find effective molecular mechanisms for the treatment of RA by investigating RA-FLS. Firstly, the study was conducted to identify the potential target gene PTEN and its related signaling pathway through bioinformatics analysis. Subsequently, the target gene PTEN overexpression was regulated by cell transfection. The expression of FOXO signaling factors and autophagy-related proteins were detected by western blotting assay. Cell proliferation was measured by CCK-8 and EdU assays. Inflammation level was detected by ELISA. Cell migration and invasion were detected using wound healing assay and transwell chamber assay, respectively. Cell apoptosis was detected using flow cytometry. The results showed that overexpression of PTEN activated FOXO1 signaling in RA-FLS, and regulated autophagy, proliferation, invasion, migration, and the levels of pro-inflammatory factors in the disease. In conclusion, PTEN might provide an effective therapeutic strategy for rheumatoid arthritis by mediating the FOXO1 signaling pathway.

Fractional-order finite-time sliding mode control for uncertain teleoperated cyber-physical system with actuator fault.

The stability of the teleoperated cyber-physical system with model uncertainty, external disturbance, and actuator fault is addressed in this study by using a suitable fractional-order sliding mode control (SMC) strategy. First, the sliding surface is designed to ensure the better tracking performance of the system. Second, the suggested control method combines SMC with an adaptive strategy to ensure that the system is stable in finite time. Third, neural network (NN) and fuzzy logic system (FLS) are used to estimate the model uncertainty, time-varying delay, external disturbance and unknown coefficient matrices of sliding mode surface, respectively. Finally, the advantages of the proposed control scheme are confirmed by the simulation example.

Modification of Fundamentals of Laparoscopic Surgery Manual Tasks Simulation Curriculum With the Addition of the Vaginal Cuff Closure Training.

OBJECTIVE: Fundamentals of Laparoscopic Surgery (FLS) is a multiple-choice test and a manual skills exam using simulation that Obstetrics and Gynecology (OBGYN) residents must pass to qualify for board certification. There is insufficient validity evidence supporting the use of FLS as a high-stakes exam. This study examines the correlation between OBGYN residents' performance on the FLS manual tasks and simulated vaginal cuff closure. METHODS: We compared residents' performance on FLS tasks with simulated vaginal cuff suturing on a model. During the first coached simulation session, after completion of training on the standard 5 FLS tasks, residents were coached on vaginal cuff closure using a simulated model placed inside the standard FLS box trainer. At a subsequent session, their performance was scored using the Global Operative Assessment of Laparoscopic Skills Scale (GOALS) and a second task-specific metric, and these scores were compared to their official FLS score. RESULTS: Twenty-nine residents completed the vaginal cuff simulation training between June 2019 and November 2021. Nineteen of the 29 were able to complete the cuff closure with the mean time to completion being 14.5 minutes. We found no correlation between official manual skills FLS scores and vaginal cuff GOALS scores (rho = -0.02, p = 0.90) or cuff closure assessment tool score (rho = -0.015, p = 0.048). There was also no correlation between time to completion for any FLS task and vaginal cuff closure OSAT scores. All residents reported that they found the cuff to be a useful addition to the FLS curriculum. CONCLUSIONS: Our study demonstrated that trainee performance on a simulated vaginal cuff closure model did not correlate with official FLS manual tasks skills. This finding adds to the body of evidence disputing the use of FLS as a high-stakes exam to assess laparoscopic skills in gynecology in the relationship with other variables category.

Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis.

A novel rheumatoid arthritis (RA) synovial fluid protein, Syntenin-1, and its receptor, Syndecan-1 (SDC-1), are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes (FLS). Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9, IL-1ß, IL-6, and CCL2 through SDC-1 ligation and HIF1α, or mTOR activation. Mechanistically, Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling. In Syntenin-1 reprogrammed endothelial cells, the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors, AMPK, PGC-1α, citrate, and inactive oxidative phosphorylation. Conversely, RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity. The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression. We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS, which are also represented in RA explants. Similar to RA explants, morphological and transcriptome studies authenticated the importance of VEGFR1/2, Notch1, RAPTOR, and HIF1α pathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals. Consistently, dysregulation of SDC-1, mTOR, and HIF1α negated Syntenin-1 inflammatory phenotype in RA explants, while inhibition of HIF1α impaired synovial angiogenic imprint amplified by Syntenin-1. In conclusion, since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood, targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.