Explore the vast range of titles available.

BackgroundJoints are commonly involved in systemic lupus erythematosus (SLE). Ultrasound (US) has been widely used in rheumatoid arthritis (RA), however rarely applied and studied in SLE.ObjectivesTo investigate the ultrasonic changes of the symptomatic joints and their correlations with clinical manifestations in SLE patients.Methods114 SLE patients who complained of arthralgia or arthritis from May 2014 to Aug 2017 and 15 Rhupus patients due to overlapping with RA were recruited for ultrasound evaluation. Ultrasound scan of the symptomatic joint areas was completed. The correlation between ultrasonographic changes and clinical characteristics was analysed. Besides that, US changes of bilateral wrists and hands of Rhupus patients were compared with those of the SLE patients.ResultsIn a total of 1866 joints scanned, synovial hyperplasia, tenosynovitis, erosion and osteophytes were all observed. Synovial hyperplasia was more often observed in knees in 28.6% patients (12/42), ankles in 25% patients (7/28), wrists in 23.3% patients (23/69) and elbows in 20% patients (5/25). Tenosynovitis and erosion were most commonly found in shoulders in 35% (7/20) and 65% (13/20) patients. Osteophytes were more common in proximal interphalangeal (PIP) joints, elbows and knees. Among 69 patients with 22 joints (bilateral wrists and hands) scanned, synovial hyperplasia was observed in 25 patients (36.2%) and erosion in 22 patients (31.8%). The agreement between synovial hyperplasia and swollen joints in PIP was fair (κ=0.633, p<0.01), however poor in wrists (κ=0.089, p=0.584). 18.4% patients with synovial hyperplasia had no tenderness or swollen clinically, while 15.7% patients with tenderness or swollen had no synovial hyperplasia on ultrasound. No correlation was found between ultrasound changes with SLE disease activity index. Both synovial hyperplasia and erosion were more common in Rhupus patients (73.3% vs. 36.2%, p=0.08; 66.7% vs. 26.0%, p=0.03) with significantly higher GS score (7.4±6.4 vs.1.6±4.1, p=0.04) than SLE alone patients.ConclusionsVariety of changes can be observed by ultrasound at different joints in SLE patients. The ultrasonographic changes and clinical manifestations did not always correspond to each other. Synovial hyperplasia and erosion was more common in Rhupus patients.Disclosure of InterestNone declared

Background:Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, in which the imbalance of CD4+ T cells plays an important role. 25-hydroxycholesterol (25-HC) is an important regulator of the mevalonate pathway in cholesterol metabolism. Previous studies have suggested that 25-HC may inhibit the transformation of CD4+ T cells from interferon-γ (IFN-γ) +CD4+ T cells to IL-10+CD4+ T cells through the interaction with liver X receptor (LXR), therefore decreasing the expression of IL-10.Objectives:This study aims to explore the mechanism by which 25-HC promotes the inflammatory process of RA by regulating the phenotypic transformation of CD4+ T cells through histological and cellular and molecular biology techniques, and propose possible molecular regulatory pathways.Methods:Patients with RA from December 2019 to January 2022, and gender and age-matched osteoarthritis (OA) and healthy controls (HC) were enrolled. Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) were collected and CD4+ T cells were sorted by magnetic beads. The expression levels of different phenotypes of CD4+ T cells and important cytokines were analyzed by flow cytometry; the secretion levels of IL-10 and IFN-γ were detected by ELISA technology. In the intervention experiment, the CD4+ T cells were treated with different concentrations of atorvastatin to inhibit the cholesterol metabolism mevalonate pathway and supplement mevalonate acid, and then CD4+ T cell phenotype and cytokine expression were detected. The synovial tissues were obtained from RA and OA patients receiving joint replacement surgery, and the expressions of 25-hydroxycholesterol hydroxylase (CH25H) and LXR were detected by immunohistochemistry and multiplex immunofluorescence. Real-time PCR and Western Blot were used to detect the expression of inflammasome signaling pathway of CD4+ T cells. CH25H was knocked down suing small interfering RNA (siRNA), and the effects of knockdown of CH25H on inflammasome and the effect on the transformation of CD4+ T cells were detected by the above methods.Results:(1) IL-10+CD4+ T cells in PBMC/SFMC of RA patients were significantly lower than HC/OA, as well as the expression of IL-10. After interfering the mevalonate pathway by atorvastatin, the ratio of IL-10+IFN-γ+CD4+ T cells and IL-10+IFN-γ-CD4+ T cells as well as the expression of IL-10 decreased in a concentration-dependent manner. The down-regulation effect induced by atorvastatin was compensated after the supplementation of mevalonate acid. (2) The expressions of CH25H and LXR in CD4+ T cells of RA synovial tissue increased detected by immunohistochemistry and multiplex immunofluorescence, and the expressions of CH25H, LXR and caspase-1 in CD4+ T cells in synovial fluid were found increased by Western Blot, as compared with that of OA. (3) After the successful knockdown of CH25H confirmed by Real-time PCR and Western Blot, a significant decrease in the proportion of IL-10-IFN-γ+CD4+ T cells, and increase in proportion of IL-10+IFN-γ-CD4+ T cells were found in RA patients, accompanied with increase in IL-10+CD4+ T cells, while the proportion of IFN-γ+CD4+ T cells and expression of IL-10 decreased significantly. After supplementation with 25-HC, the siRNA-CH25H-mediated decrease in IL-10+CD4+ T cells was reversed and IFN-γ+CD4+ T cell formation was reduced. Meanwhile, the expression of NLRP3 and activated caspase-1 (capsase-1 p20) in peripheral blood CD4+ T cells was reduced, and could eliminate after supplementation with 25-HC.Conclusion:In peripheral CD4+ T cells in RA patients, 25-HC may activate the NLRP3 inflammasome through CH25H-LXR pathway, thereby inhibiting the phenotypic transformation of IFN-γ+CD4+ T cells to IL-10+CD4+ T cells, and eventually promoting the inflammatory process in RA. These findings provide new clue for the mechanism of CD4+ T cells in the pathogenesis of RA and suggest that the cholesterol metabolism pathway may become a new target of RA treatment.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Salivary gland ultrasound (SGUS) is a valuable modality for the diagnosis of primary Sjögren’s syndrome (pSS). However, the widespread use of it as standardized diagnostic tools is limited by inter/intra operator variability.Objectives:The aim of this study was to evaluate the utility of deep learning-based SGUS image recognition system in the diagnosis of pSS.Methods:Between June 2022 and Sep 2023, 4017 SGUS images of 678 patients from one center were included in this study. Among them, 259 patients with 1524 images were diagnosed as pSS and 419 patients with 2493 images were non-SS. All the SGUS image data were randomly divided into training dataset (64%), validation dataset (16%) and testing dataset (20%). The SGUS automatic classification model was developed by using a 2D deep residual convolutional network architecture (RESNET-50). The predictive performance was validated by sensitivity, specifcity and area under reciver operating characteristic curve (ROC).Results:When applying deep learning-based SGUS assessment, it show similar performance with operator based SGUS score system.The specifcity is similar (89.3% vs. 90.0%), while a little bit lower sensitivity (55.8% vs. 61.4%). The area under the ROC were comparable between them (0.805 vs 0.890).Figure 1.ROC curves of diagnostic performance of deep learning-based SGUS score for pSSThe area under ROC of deep learning-based SGUS recognition system was 0.805 which was comparable with operator based SGUS score system 0.890.Conclusion:Deep learning-based SGUS image recognition system maybe an objective and promising tool compared to expert-based scoring of SGUS in the diagnosis of pSS. This may support SGUS as an effective and prospective diagnostic tool to supplement current diagnostic methods.REFERENCES:[1] Olivier A, Hoffmann C, Jousse-Joulin S, Mansour A, Bressollette L, Clement B. Machine and Deep Learning Approaches Applied to Classify Gougerot-Sjögren Syndrome and Jointly Segment Salivary Glands. Bioengineering (Basel). 2023 Nov 3;10(11):1283.[2] Vukicevic AM, Radovic M, Zabotti A, Milic V, Hocevar A, Callegher SZ, De Lucia O, De Vita S, Filipovic N. Deep learning segmentation of Primary Sjögren’s syndrome affected salivary glands from ultrasonography images. Comput Biol Med. 2021 Feb;129:104154.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Tofacitinib is the first Janus Kinase (JAK) inhibitor available in China, and it has significantly improved the efficacy of treatment of rheumatoid arthritis (RA). Previous clinical trials found that tofacitinib can affect lipid metabolism in patients.Objectives:Whether lipid and lipoprotein concentrations can recover by themselves and whether lipid-lowering drugs intervention is required, are currently inconclusive, and there is a lack of real-world experience.Methods:Patients from the CENTRA (Collaboratively intENsive Treat-to-target in RA) cohort, a prospective follow-up cohort for RA in the Department of Rheumatology and Clinical Immunology, Peking University First Hospital were enrolled, and those who used lipid-lowering drugs were excluded. Patients were divided into tofacitinib exposure group and non-exposure group according to whether patients were prescribed with or without tofacitinib. Disease activity scores, TG, TCHO, HDL and LDL at baseline and during follow-up were calculated, and the ratios of TCHO/HDL to HDL/LDL was also calculated. Changes in lipid and lipoprotein concentrations after use of tofacitinib during follow-up were analyzed. Age, gender, disease duration, and the Simplified Disease Activity Index (SDAI) at baseline as covariates for propensity score matching was performed on patients with and without tofacitinib, and the lipid and lipoprotein profiles of the two groups were compared.Results:A total of 304 patients were included, with 88 prescribed with tofacitinib and 216 without tofacitinib. (1) In patients with tofacitinib, the median TG and TCHO were 0.95 mmol/L and 4.45 mmol/L, respectively, the mean HDL and LDL were 1.32 mmol/L and 2.63 mmol/L at baseline, and the median TCHO/HDL and HDL/LDL ratios were 3.62 and 2.24, respectively. After 4 weeks of use of tofacitinib, the levels of TCHO, HDL and LDL increased compared with baseline by 16.6%, 12.9% and 14.4%, respectively. At week 12, LDL increased by 12.9% compared with baseline, indicating the returning to baseline levels, while the levels of TCHO and HDL were still significantly elevated. At week 48, TCHO also returned to baseline levels (increased by 2.9%). HDL levels remained elevated during follow-up. There were no significant increases in TG, TCHO/HDL and LDL/HDL ratios throughout the follow-up. In addition, there was no significant difference in lipid and lipoprotein changes between tofacitinib monotherapy (43 patients) and tofacitinib combined with csDMARDs (45 patients) during follow-up. (2) After 1:1 matched by propensity score matching, there were 83 patients prescribed with tofacitinib exposure and 83 without. In the 4 weeks of follow-up, there was no significant difference in the increase of lipid and lipoprotein between the two groups. At week 12, week 24, and week 48, the increase of TCHO in patients with tofacitinib was significantly higher than those without (0.47 vs. -0.1, p<0.001; 0.33 vs.-0.06, p=0.001; 0.22 vs.-0.1, p=0.017). The LDL elevation in patient with tofacitinib was higher than that in patients without at week 12 and continued to week 24 (0.17 vs.-0.07, p=0.002; 0.18 vs.-0.09, p=0.001), but at week 48, there was no significant difference between the two groups compared with baseline. At week 12, patients in the tofacitinib-exposure group had higher HDL elevations (0.22 vs. 0.02, p < 0.001), but there was no significant difference between the two groups form week 24 to week 48. Elevation in TG, THCO/HDL or LDL/HDL was not significantly different between the two groups throughout the follow-up.Conclusion:After 4 weeks of using tofacitinib, TCHO, HDL and LDL levels increased in RA patients. LDL and TCHO returned to the baseline level at the week 12 and week 48, respectively, while HDL continued to increase. There was no significant change in TG, THCO/HDL or LDL/HDL throughout the follow-up. The elevation in lipid and lipoprotein profiles in RA patients prescribed with tofacitinib was significantly higher than those without.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Plant environmental responses involve dynamic changes in growth and signaling, yet little is understood as to how progress through these events is regulated. Here, we explored the phenotypic and transcriptional events involved in the acclimation of the Arabidopsis thaliana seedling root to a rapid change in salinity. Using live-imaging analysis, we show that growth is dynamically regulated with a period of quiescence followed by recovery then homeostasis. Through the use of a new high-resolution spatio-temporal transcriptional map, we identify the key hormone signaling pathways that regulate specific transcriptional programs, predict their spatial domain of action, and link the activity of these pathways to the regulation of specific phases of growth. We use tissue-specific approaches to suppress the abscisic acid (ABA) signaling pathway and demonstrate that ABA likely acts in select tissue layers to regulate spatially localized transcriptional programs and promote growth recovery. Finally, we show that salt also regulates many tissue-specific and time point—specific transcriptional responses that are expected to modify water transport, Casparian strip formation, and protein translation. Together, our data reveal a sophisticated assortment of regulatory programs acting together to coordinate spatially patterned biological changes involved in the immediate and long-term response to a stressful shift in environment.

BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, in which the imbalance of CD4+ T cells plays an important role. 25-hydroxycholesterol (25-HC) is an important regulator of the mevalonate pathway in cholesterol metabolism. Previous studies have suggested that 25-HC may inhibit the transformation of CD4+ T cells from interferon-γ (IFN-γ) +CD4+ T cells to IL-10+CD4+ T cells through the interaction with liver X receptor (LXR), therefore decreasing the expression of IL-10.ObjectivesThis study aims to explore the mechanism by which 25-HC promotes the inflammatory process of RA by regulating the phenotypic transformation of CD4+ T cells through histological and cellular and molecular biology techniques, and propose possible molecular regulatory pathways.MethodsPatients with RA from December 2019 to January 2022, and gender and age-matched osteoarthritis (OA) and healthy controls (HC) were enrolled. Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) were collected and CD4+ T cells were sorted by magnetic beads. The expression levels of different phenotypes of CD4+ T cells and important cytokines were analyzed by flow cytometry; the secretion levels of IL-10 and IFN-γ were detected by ELISA technology. In the intervention experiment, the CD4+ T cells were treated with different concentrations of atorvastatin to inhibit the cholesterol metabolism mevalonate pathway and supplement mevalonate acid, and then CD4+ T cell phenotype and cytokine expression were detected. The synovial tissues were obtained from RA and OA patients receiving joint replacement surgery, and the expressions of 25-hydroxycholesterol hydroxylase (CH25H) and LXR were detected by immunohistochemistry and multiplex immunofluorescence. Real-time PCR and Western Blot were used to detect the expression of inflammasome signaling pathway of CD4+ T cells. CH25H was knocked down suing small interfering RNA (siRNA), and the effects of knockdown of CH25H on inflammasome and the effect on the transformation of CD4+ T cells were detected by the above methods.Results(1) IL-10+CD4+ T cells in PBMC/SFMC of RA patients were significantly lower than HC/OA, as well as the expression of IL-10. After interfering the mevalonate pathway by atorvastatin, the ratio of IL-10+IFN-γ+CD4+ T cells and IL-10+IFN-γ-CD4+ T cells as well as the expression of IL-10 decreased in a concentration-dependent manner. The down-regulation effect induced by atorvastatin was compensated after the supplementation of mevalonate acid. (2) The expressions of CH25H and LXR in CD4+ T cells of RA synovial tissue increased detected by immunohistochemistry and multiplex immunofluorescence, and the expressions of CH25H, LXR and caspase-1 in CD4+ T cells in synovial fluid were found increased by Western Blot, as compared with that of OA. (3) After the successful knockdown of CH25H confirmed by Real-time PCR and Western Blot, a significant decrease in the proportion of IL-10-IFN-γ+CD4+ T cells, and increase in proportion of IL-10+IFN-γ-CD4+ T cells were found in RA patients, accompanied with increase in IL-10+CD4+ T cells, while the proportion of IFN-γ+CD4+ T cells and expression of IL-10 decreased significantly. After supplementation with 25-HC, the siRNA-CH25H-mediated decrease in IL-10+CD4+ T cells was reversed and IFN-γ+CD4+ T cell formation was reduced. Meanwhile, the expression of NLRP3 and activated caspase-1 (capsase-1 p20) in peripheral blood CD4+ T cells was reduced, and could eliminate after supplementation with 25-HC.ConclusionIn peripheral CD4+ T cells in RA patients, 25-HC may activate the NLRP3 inflammasome through CH25H-LXR pathway, thereby inhibiting the phenotypic transformation of IFN-γ+CD4+ T cells to IL-10+CD4+ T cells, and eventually promoting the inflammatory process in RA. These findings provide new clue for the mechanism of CD4+ T cells in the pathogenesis of RA and suggest that the cholesterol metabolism pathway may become a new target of RA treatment.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Tofacitinib is the first Janus Kinase (JAK) inhibitor available in China, and it has significantly improved the efficacy of treatment of rheumatoid arthritis (RA). Previous clinical trials found that tofacitinib can affect lipid metabolism in patients. Whether lipid and lipoprotein concentrations can recover by themselves and whether lipid-lowering drugs intervention is required, are currently inconclusive, and there is a lack of real-world experience. Patients from the CENTRA (Collaboratively intENsive Treat-to-target in RA) cohort, a prospective follow-up cohort for RA in the Department of Rheumatology and Clinical Immunology, Peking University First Hospital were enrolled, and those who used lipid-lowering drugs were excluded. Patients were divided into tofacitinib exposure group and non-exposure group according to whether patients were prescribed with or without tofacitinib. Disease activity scores, TG, TCHO, HDL and LDL at baseline and during follow-up were calculated, and the ratios of TCHO/HDL to HDL/LDL was also calculated. Changes in lipid and lipoprotein concentrations after use of tofacitinib during follow-up were analyzed. Age, gender, disease duration, and the Simplified Disease Activity Index (SDAI) at baseline as covariates for propensity score matching was performed on patients with and without tofacitinib, and the lipid and lipoprotein profiles of the two groups were compared. A total of 304 patients were included, with 88 prescribed with tofacitinib and 216 without tofacitinib. (1) In patients with tofacitinib, the median TG and TCHO were 0.95 mmol/L and 4.45 mmol/L, respectively, the mean HDL and LDL were 1.32 mmol/L and 2.63 mmol/L at baseline, and the median TCHO/HDL and HDL/LDL ratios were 3.62 and 2.24, respectively. After 4 weeks of use of tofacitinib, the levels of TCHO, HDL and LDL increased compared with baseline by 16.6%, 12.9% and 14.4%, respectively. At week 12, LDL increased by 12.9% compared with baseline, indicating the returning to baseline levels, while the levels of TCHO and HDL were still significantly elevated. At week 48, TCHO also returned to baseline levels (increased by 2.9%). HDL levels remained elevated during follow-up. There were no significant increases in TG, TCHO/HDL and LDL/HDL ratios throughout the follow-up. In addition, there was no significant difference in lipid and lipoprotein changes between tofacitinib monotherapy (43 patients) and tofacitinib combined with csDMARDs (45 patients) during follow-up. (2) After 1:1 matched by propensity score matching, there were 83 patients prescribed with tofacitinib exposure and 83 without. In the 4 weeks of follow-up, there was no significant difference in the increase of lipid and lipoprotein between the two groups. At week 12, week 24, and week 48, the increase of TCHO in patients with tofacitinib was significantly higher than those without (0.47 vs. -0.1, p<0.001; 0.33 vs.-0.06, p=0.001; 0.22 vs.-0.1, p=0.017). The LDL elevation in patient with tofacitinib was higher than that in patients without at week 12 and continued to week 24 (0.17 vs.-0.07, p=0.002; 0.18 vs.-0.09, p=0.001), but at week 48, there was no significant difference between the two groups compared with baseline. At week 12, patients in the tofacitinib-exposure group had higher HDL elevations (0.22 vs. 0.02, p < 0.001), but there was no significant difference between the two groups form week 24 to week 48. Elevation in TG, THCO/HDL or LDL/HDL was not significantly different between the two groups throughout the follow-up. After 4 weeks of using tofacitinib, TCHO, HDL and LDL levels increased in RA patients. LDL and TCHO returned to the baseline level at the week 12 and week 48, respectively, while HDL continued to increase. There was no significant change in TG, THCO/HDL or LDL/HDL throughout the follow-up. The elevation in lipid and lipoprotein profiles in RA patients prescribed with tofacitinib was significantly higher than those without. NIL. NIL. None Declared.

In this study, We demonstrated that Bax mitochondrial translocation plays a vital role in the initiation of the mitochondrial signaling pathway upon activation by heat stress. In addition, both p53 mitochondrial translocation and Ca 2+ signal mediated MPTP opening activate Bax mitochondrial translocation. Employing pifithrin-α (a p53 mitochondrial translocation inhibitor) and CsA (a permeability transition pore (MPTP) inhibitor), we found that heat stress induced Bax mitochondrial translocation was significantly inhibited in cells pretreated with both PFT and CsA. Furthermore, we demonstrated that generation of reactive oxygen species (ROS) is a critical mediator in heat stress induced apoptosis and that the antioxidant MnTBAP significantly decreased heat stress induced p53 mitochondrial translocation and Ca 2+ signal mediated MPTP opening, as well as the subsequent Bax mitochondrial translocation and activation of the caspase cascade. Taken together, our results indicate that heat stress induces apoptosis through the mitochondrial pathway with ROS dependent mitochondrial p53 translocation and Ca 2+ dyshomeostasis and the ensuing intro Bax mitochondrial translocation as the upstream events involved in triggering the apoptotic process observed upon cellular exposure to heat stress.

The phase diagram of hydrogen is one of the most important challenges in high-pressure physics and astrophysics. Especially, the melting of dense hydrogen is complicated by dimer dissociation, metallization and nuclear quantum effect of protons, which together lead to a cold melting of dense hydrogen when above 500 GPa. Nonetheless, the variation of the melting curve at higher pressures is virtually uncharted. Here we report that using ab initio molecular dynamics and path integral simulations based on density functional theory, a new atomic phase is discovered, which gives an uplifting melting curve of dense hydrogen when beyond 2 TPa, and results in a reentrant solid-liquid transition before entering the Wigner crystalline phase of protons. The findings greatly extend the phase diagram of dense hydrogen, and put metallic hydrogen into the group of alkali metals, with its melting curve closely resembling those of lithium and sodium.