Group 3 innate lymphoid cells promotes Th17 cells differentiation in rheumatoid arthritis.

OBJECTIVES: To investigate the correlation between innate lymphoid cell (ILC) subsets with T-helper (Th) cells and to explore the effect of ILCs on T cells in rheumatoid arthritis (RA). METHODS: We analysed the frequencies of ILC subsets in RA patients with varying disease activity and their correlation with Th cell subsets. We further investigated this correlation in various organs of collagen-induced arthritis (CIA) mice. The effects of ILCs on CD4+ T cells were determined by in vitro cell co-culture experiments. RESULTS: ILCs were less frequent in RA patients than in healthy controls, with higher levels of group 3 ILCs (ILC3s) in RA (p<0.05). ILC3s correlated positively with Th1 and Th17 cells in RA peripheral blood (p<0.05). In the peripheral blood, spleen, and lymph nodes of CIA, ILC3s decreased and then increased during arthritis progression. ILC3s correlated positively with Th1 and Th17 cells in the spleen and lymph nodes of CIA (p<0.05). NKp46+ ILC3s in the spleen positively correlated with Th1 and Th17 cells (p<0.05). Under Th17 cell differentiation conditions, co-culturing CIA-derived ILC3s directly with naive CD4+ T cells promoted Th17 differentiation and increased IL-17 secretion. However, co-culturing through a transwell insert impeded Th17 differentiation without affecting IL-17 secretion. CONCLUSIONS: ILC3s positively correlated with Th1 and Th17 cells in RA. In CIA, the frequencies of ILC3s changed with disease development and showed a positive correlation with Th1 and Th17 cells. ILC3s may facilitate the differentiation of Th17 cells through direct cell-cell contact.

3D MR Fingerprinting for Dynamic Contrast-Enhanced Imaging of Whole Mouse Brain.

Quantitative MRI enables direct quantification of contrast agent concentrations in contrast-enhanced scans. However, the lengthy scan times required by conventional methods are inadequate for tracking contrast agent transport dynamically in mouse brain. We developed a 3D MR fingerprinting (MRF) method for simultaneous T1 and T2 mapping across the whole mouse brain with 4.3-min temporal resolution. We designed a 3D MRF sequence with variable acquisition segment lengths and magnetization preparations on a 9.4T preclinical MRI scanner. Model-based reconstruction approaches were employed to improve the accuracy and speed of MRF acquisition. The method's accuracy for T1 and T2 measurements was validated in vitro, while its repeatability of T1 and T2 measurements was evaluated in vivo (n=3). The utility of the 3D MRF sequence for dynamic tracking of intracisternally infused Gd-DTPA in the whole mouse brain was demonstrated (n=5). Phantom studies confirmed accurate T1 and T2 measurements by 3D MRF with an undersampling factor up to 48. Dynamic contrast-enhanced (DCE) MRF scans achieved a spatial resolution of 192 x 192 x 500 um3 and a temporal resolution of 4.3 min, allowing for the analysis and comparison of dynamic changes in concentration and transport kinetics of intracisternally infused Gd-DTPA across brain regions. The sequence also enabled highly repeatable, high-resolution T1 and T2 mapping of the whole mouse brain (192 x 192 x 250 um3) in 30 min. We present the first dynamic and multi-parametric approach for quantitatively tracking contrast agent transport in the mouse brain using 3D MRF.

Clinical features and prognosis of idiopathic inflammatory myopathies with coexistent multiple myositis-specific antibodies.

OBJECTIVES: This study aimed to evaluate the clinical significance of the coexistence of 2 or more myositis-specific antibodies (multiple MSAs) in adult patients with idiopathic inflammatory myopathies (IIM). METHODS: We assessed a cohort of 202 consecutive patients with IIM. Clinical features and survival rates were compared between patients with and without multiple MSAs. RESULTS: Of those 202 patients, 44 (21.8%) were found to have multiple MSAs. 63.6% of the 44 patients tested positive for anti-aminoacyl-tRNA synthetase antibodies (anti-ARS+) and 52.3% positive for anti-melanoma differentiation-associated protein-5 antibody (anti-MDA5+). The presence of multiple MSAs was associated with less rapidly progressive interstitial lung disease (RP-ILD), fever, rash, periungual erythema, more muscle involvement and dysphagia, higher albumin level, and higher positive rate of ANA antibody in anti-MDA5+ population. In anti-ARS+ population with multiple MSAs, there were more V-neck sign, skin ulcers, dysphagia and peripheral edema. No differences in survival rates were observed between patients with or without multiple MSAs in the overall and anti-ARS+ populations. However, the survival rate in anti-MDA5+ population with multiple MSAs was significantly higher than those without multiple MSAs (p = 0.003). Moreover, multiple MSAs remained an independent protective factor against mortality in multivariable Cox regression analysis of anti-MDA5+ population [HR 0.108 (95% CI 0.013, 0.908), p=0.041]. CONCLUSIONS: Multiple MSAs coexist in some IIM patients and their existence indicates mixed features from concomitant MSAs in anti-MDA5+ population and anti-ARS+ population. Identifying multiple MSAs could help to discover a more favourable disease phenotype with decreased mortality in anti-MDA5+ population.

Analysis of the impact of temperature on the spectral shift in ultraviolet hyperspectral imaging spectrometers.

The imaging spectrometer's high performance in practical applications may be compromised by environmental factors, particularly temperature variations, posing a challenge to its stability. Temperature fluctuations can induce spectral shift, directly impacting the accuracy of spectral measurements, subsequently influencing the precision of radiometric measurements. To address this issue, this study investigates a dual-channel UV imaging spectrometer. This instrument boasts a wavelength calibration accuracy of 0.01 nm. This paper conducts an in-depth analysis of the various mechanisms through which temperature changes influence the spectral line offset in the imaging spectrometer, integrating actual orbital temperature data to discuss the instrument's temperature load settings. The impact of temperature on spectral shift is examined using finite element analysis and optical design software. Estimations of spectral shift were made based on temperature variations. Simulation results indicated that the maximum deviation of spectral shift is estimated at 0.018 nm under a temperature condition of 16 ± 1°C. Under a more controlled orbital temperature condition (16 ± 0.3°C), the maximum deviation of spectral shift decreased to 0.01 nm. Experimental data revealed that at 16 ± 1°C, the maximum deviation of spectral shift did not exceed 0.01 nm. This effectively corroborates our theoretical analysis. The relationship between temperature and spectral shift offers a crucial theoretical foundation for calibrating spectral measurements and managing the thermal conditions of the instrument.

Internalisation of neutrophils extracellular traps by macrophages aggravate rheumatoid arthritis via Rab5a.

OBJECTIVES: Although elevated levels of neutrophil extracellular traps (NETs) have been reported in patients with rheumatoid arthritis (RA), the role of NETs in RA and the relationship between NETs and macrophages in the pathogenesis of RA requires further research. Here, we sought to determine the role of NETs in RA pathogenesis and reveal the potential mechanism. METHODS: Neutrophil elastase (NE) and myeloperoxidase (MPO)-DNA were measured in human serum and synovium. NETs inhibitor GSK484 was used to examine whether NETs involved with RA progression. We stimulated macrophages with NETs and detected internalisation-related proteins to investigate whether NETs entry into macrophages and induced inflammatory cytokines secretion through internalisation. To reveal mechanisms mediating NETs-induced inflammation aggravation, we silenced GTPases involved in internalisation and inflammatory pathways in vivo and in vitro and detected downstream inflammatory pathways. RESULTS: Serum and synovium from patients with RA showed a significant increase in NE and MPO, which positively correlated to disease activity. Inhibiting NETs formation alleviated the collagen-induced arthritis severity. In vitro, NETs are internalised by macrophages and located in early endosomes. Rab 5a was identified as the key mediator of the NETs internalisation and inflammatory cytokines secretion. Rab 5a knockout mice exhibited arthritis alleviation. Moreover, we found that NE contained in NETs activated the Rab5a-nuclear factor kappa B (NF-κB) signal pathway and promoted the inflammatory cytokines secretion in macrophages. CONCLUSIONS: This study demonstrated that NETs-induced macrophages inflammation to aggravate RA in Rab 5a dependent manner. Mechanically, Rab5a mediated internalisation of NETs by macrophages and NE contained in NETs promoted macrophages inflammatory cytokines secretion through NF-κB-light-chain-enhancer of activated B cells signal pathway. Therapeutic targeting Rab 5a or NE might extend novel strategies to minimise inflammation in RA.

DKK-1 and Its Influences on Bone Destruction: A Comparative Study in Collagen-Induced Arthritis Mice and Rheumatoid Arthritis Patients.

Dickkopf-1 (DKK-1) has been considered a master regulator of bone remodeling. As precursors of osteoclasts (OCs), myeloid-derived suppressor cells (MDSCs) were previously shown to participate in the process of bone destruction in rheumatoid arthritis (RA). However, the role of DKK-1 and MDSCs in RA is not yet fully understood. We investigated the relevance between the level of DKK-1 and the expression of MDSCs in different tissues and joint destruction in RA patients and collagen-induced arthritis (CIA) mouse models. Furthermore, the CIA mice were administered recombinant DKK-1 protein. The arthritis scores, bone destruction, and the percentage of MDSCs in the peripheral blood and spleen were monitored. In vitro, the differentiation of MDSCs into OCs was intervened with recombinant protein and inhibitor of DKK-1. The number of OCs differentiated and the protein expression of the Wnt/ß-catenin signaling pathway were explored. The level of DKK-1 positively correlates with the frequency of MDSCs and bone erosion in RA patients and CIA mice. Strikingly, recombinant DKK-1 intervention significantly exacerbated arthritis scores and bone destruction, increasing the percentage of MDSCs in the peripheral blood and spleen in CIA mice. In vitro experiments showed that recombinant DKK-1 promoted the differentiation of MDSCs into OCs, reducing the expression of ß-catenin and TCF4 and increasing the expression of CyclinD1. In contrast, the DKK-1 inhibitor had the opposite effect. Our findings highlight that DKK-1 promoted MDSCs expansion in RA and enhanced the differentiation of MDSCs into OCs via targeting the Wnt/ß-catenin pathway, aggravating the bone destruction in RA.

Design of a Focusing Mechanism Actuated by Piezoelectric Ceramics for TMA Telescope.

With the development of space telescopes towards high-resolution and intelligent imaging, the scale and complexity of the focal plane components of large-aperture, off-axis, three-mirror anastigmatic (TMA) optical systems are increasing. Traditional focal plane focusing technology reduces the system reliability and increases the scale and complexity. This paper proposes a three-degrees-of-freedom focusing system based on a folding mirror reflector, with a piezoelectric ceramic actuator as the driver. An environment-resistant flexible support was designed for the piezoelectric ceramic actuator through an integrated optimization analysis. The fundamental frequency of the large-aspect-ratio rectangular folding mirror reflector focusing mechanism was around 121.5 Hz. After testing, it was found to meet the requirements of the space mechanics environment. This system shows promise for application to other optical systems as an open-shelf product in the future.

Fusobacterium nucleatum aggravates rheumatoid arthritis through FadA-containing outer membrane vesicles.

Rheumatoid arthritis (RA) is an autoimmune disorder that has been associated with the gut microbiota. However, whether and how the gut microbiota plays a pathogenic role in RA remains unexplored. Here, we observed that Fusobacterium nucleatum is enriched in RA patients and positively associated with RA severity. F. nucleatum similarly aggravates arthritis in a mouse model of collagen-induced arthritis (CIA). F. nucleatum outer membrane vesicles (OMVs) containing the virulence determinant FadA translocate into the joints, triggering local inflammatory responses. Specifically, FadA acts on synovial macrophages, resulting in the activation of the Rab5a GTPase involved in vesicle trafficking and inflammatory pathways and YB-1, a key regulator of inflammatory mediators. OMVs containing FadA and heightened Rab5a-YB-1 expression were observed in RA patients compared with controls. These findings suggest a causal role of F. nucleatum in aggravating RA and provide promising therapeutic targets for clinically ameliorating RA.

Monitoring and Identification of Road Construction Safety Factors via UAV.

The safety of road construction is one of the most important concerns of construction managers for the following reasons: long-span construction operation, no fixed monitoring cameras, and huge impacts on existing traffic, while the managers still rely on manual inspection and a lack of image records. With the fast development of Unmanned Aerial Vehicle (UAV) and Artificial Intelligence (AI), monitoring safety concerns of road construction sites becomes easily accessible. This research aims to integrate UAVs and AI to establish a UAV-based road construction safety monitoring platform. In this study, road construction safety factors including constructors, construction vehicles, safety signs, and guardrails are defined and monitored to make up for the lack of image data at the road construction site. The main findings of this study include three aspects. First, the flight and photography schemes are proposed based on the UAV platform for information collection for road construction. Second, deep learning algorithms including YOLOv4 and DeepSORT are utilized to automatically detect and track safety factors. Third, a road construction dataset is established with 3594 images. The results show that the UAV-based monitoring platform can help managers with security inspection and recording images.

Natural Killer Cells Infiltration in the Joints Exacerbates Collagen-Induced Arthritis.

Introduction: The role of natural killer (NK) cells in rheumatoid arthritis remains controversial. We aimed to assess the role of NK cells in the pathogenesis of rheumatoid arthritis. Materials and Methods: The percentage of NK cells in the peripheral blood, spleen, lymph nodes and inflamed paws from collagen-induced arthritis mice were examined through the disease progression. Correlation between the proportion of NK cells and subsets with arthritis score, histopathological changes, and bone destruction were evaluated. Adoptive cell transfer was performed to determine the effect of NKp46+NK cells on arthritis development, and the role of receptor NKp46 was explored with NKp46 knockout mice. Results: The percentage of NK cells in peripheral blood decreased at the late stage of the disease and negatively correlated with arthritis score. NK cells increased in the inflamed paws during arthritis development and were positively associated with arthritis score, histopathological change, and bone destruction. Adoptive transfer of NKp46+NK cells before disease onset resulted in increased NK cells infiltration in the joints, higher incidence of arthritis, more severe clinical symptoms, and more pronounced joint inflammation and bone damage. NKp46 deficiency had no significant influence on the incidence and severity of arthritis in collagen-induced arthritis mice. Conclusions: NK cell infiltration in the joints positively correlates with arthritis progression, inflammation, and bone destruction. The pathogenic role of NK cells in rheumatoid arthritis may be independent of the receptor NKp46.

Quantitative assessment of myelin density using [11C]MeDAS PET in patients with multiple sclerosis: a first-in-human study.

PURPOSE: Multiple sclerosis (MS) is a disease characterized by inflammatory demyelinated lesions. New treatment strategies are being developed to stimulate myelin repair. Quantitative myelin imaging could facilitate these developments. This first-in-man study aimed to evaluate [11C]MeDAS as a PET tracer for myelin imaging in humans. METHODS: Six healthy controls and 11 MS patients underwent MRI and dynamic [11C]MeDAS PET scanning with arterial sampling. Lesion detection and classification were performed on MRI. [11C]MeDAS time-activity curves of brain regions and MS lesions were fitted with various compartment models for the identification of the best model to describe [11C]MeDAS kinetics. Several simplified methods were compared to the optimal compartment model. RESULTS: Visual analysis of the fits of [11C]MeDAS time-activity curves showed no preference for irreversible (2T3k) or reversible (2T4k) two-tissue compartment model. Both volume of distribution and binding potential estimates showed a high degree of variability. As this was not the case for 2T3k-derived net influx rate (Ki), the 2T3k model was selected as the model of choice. Simplified methods, such as SUV and MLAIR2 correlated well with 2T3k-derived Ki, but SUV showed subject-dependent bias when compared to 2T3k. Both the 2T3k model and the simplified methods were able to differentiate not only between gray and white matter, but also between lesions with different myelin densities. CONCLUSION: [11C]MeDAS PET can be used for quantification of myelin density in MS patients and is able to distinguish differences in myelin density within MS lesions. The 2T3k model is the optimal compartment model and MLAIR2 is the best simplified method for quantification. TRIAL REGISTRATION: NL7262. Registered 18 September 2018.

A retrospective cohort study in Chinese patients with adult polymyositis and dermatomyositis: risk of comorbidities and subclassification using machine learning.

OBJECTIVES: To identify the risk factors in Chinese patients with adult polymyositis and dermatomyositis for their comorbidities and explore a subclassification system. METHODS: Clinical records of 397 patients with idiopathic inflammatory myopathies were retrospectively reviewed. Logistic regression was used to identify potential risk factors for interstitial lung disease (ILD), other rheumatic diseases, and malignancy after bivariate analysis. Hierarchical clustering and decisional tree were utilised to identify subgroups and explore a subclassification system. RESULTS: A total of 119 polymyositis and 191 dermatomyositis patients were included. Anti-PM/Scl, anti-Ro52, anti-aminoacyl-tRNA synthetase and anti-MDA5 (adjusted odds ratios (AOR)=4.779, 1.917, 5.092 and 7.714 respectively) antibodies were risks (p<0.05), whereas overlapping malignancy was protective (AOR=0.107; p=0.002) for ILD across polymyositis, dermatomyositis and the total group. In subgroup models, Raynaud's phenomenon, arthralgia and semi-quantitative anti-nuclear antibody (AOR=51.233, 4.261, 3.047 respectively) were risks for other overlapping rheumatic diseases (p<0.05). For overlapping malignancy, male and anti-TIF1γ antibodies (AOR=2.533, 16.949) were risks (p<0.05), whereas disease duration and combination of ILD (AOR=0.954, 0.106) were protective in the total group (p<0.05); while anti-NXP2 antibodies were identified as risk factors (AOR=73.152; p=0.038) in polymyositis. Hierarchical clustering suggested a subclassification with 6 subgroups: malignancy overlapping dermatomyositis, classical dermatomyositis, polymyositis with severe muscle involvement, dermatomyositis with ILD, polymyositis with ILD, and overlapping of myositis with other rheumatic diseases. CONCLUSIONS: Accompanying ILD, other rheumatic diseases and malignancy are strongly associated with clinical manifestation and myositis-specific or myositis-associated autoantibodies among Chinese polymyositis and dermatomyositis patients. The subclassification system proposed a more precise phenotype defining toward stratified treatments.

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Oridonin (OD), which is the major active ingredient of the traditional Chinese medicine Rabdosia rubescens, reportedly exerts anti-inflammatory and antioxidative effects. Here, we first find that OD protects against APAP-induced hepatotoxicity. The results of hepatic tissue-associated RNA-seq and metabolomics showed that the protective effects of OD were dependent upon urea cycle regulation. And such regulation of OD is gut microbiota partly dependent, as demonstrated by fecal microbiota transplantation (FMT). Furthermore, using 16S rRNA sequencing, we determined that OD significantly enriched intestinal Bacteroides vulgatus, which activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to regulate redox homeostasis against APAP by urea cycle. In conclusion, our study suggests that the Bacteroides vulgatus-urea cycle-Nrf2 axis may be a potential target for reducing APAP-induced liver injury, which is altered by OD.

Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis.

Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). It is urgent to develop new drugs that can effectively inhibit the abnormal activation of RA-FLS. In our study, the RA-FLS cell line, MH7A, and mice with collagen-induced arthritis (CIA) were used to evaluate the effect of paclitaxel (PTX). Based on the results, PTX inhibited the migration of RA-FLS in a dose-dependent manner and significantly reduced the spontaneous expression of IL-6, IL-8, and RANKL mRNA and TNF-α-induced transcription of the IL-1 ß, IL-8, MMP-8, and MMP-9 genes. However, PTX had no significant effect on apoptosis in RA-FLS. Mechanistic studies revealed that PTX significantly inhibited the TNF-α-induced phosphorylation of ERK1/2 and JNK in the mitogen-activated protein kinase (MAPK) pathway and suppressed the TNF-α-induced activation of AKT, p70S6K, 4EBP1, and HIF-1α in the AKT/mTOR pathway. Moreover, PTX alleviated synovitis and bone destruction in CIA mice. In conclusion, PTX inhibits the migration and inflammatory mediator production of RA-FLS by targeting the MAPK and AKT/mTOR signaling pathways, which provides an experimental basis for the potential application in the treatment of RA.

Resveratrol Relieves Gouty Arthritis by Promoting Mitophagy to Inhibit Activation of NLRP3 Inflammasomes.

BACKGROUND: Gouty arthritis (GA) is a common inflammatory disease with pain caused by the deposition of monosodium urate (MSU) crystals into joints and surrounding tissues. Resveratrol (Res), derived from grapes and peanuts and the traditional Chinese medicine (TCM) Reynoutria japonica for GA, acts against oxidation and inflammation. The present study aimed to investigate the therapeutic effect and mechanism of Res on GA. METHODS: Arthritis rat models, MSU-induced peritonitis mouse models, and inflammatory models of mouse bone marrow-derived macrophage (BMDM) were used in this study. Enzyme-linked immunosorbent assay (ELISA), JC-1, histopathological, immunofluorescence, flow cytometry, Western blot methods were applied to observe the effects of resveratrol on NLRP3 inflammasomes and mitophagy. RESULTS: Res significantly improves the gait score and synovitis of rats with GA and inhibits the peritoneal inflammation induced by MSU. Res inhibits the MSU-induced activation of NLRP3 inflammasomes by reducing the levels of IL-1ß, IL-18, and Caspase-1 and the pyroptosis of macrophages. In addition, Res raises the level of mitochondrial membrane potential, inhibits the expression of P62 and Pink1, enhances the expressions of LC3B-II, Parkin, and TOMM20, and promotes mitophagy, while mitophagy inhibitors reverse the inhibitory effect of Res on the activation of NLRP3 inflammasomes. CONCLUSION: Res significantly improves GA, and the underlying mechanism might be inhibiting the activation of NLRP3 inflammasomes by triggering the Pink1/Parkin pathway to promote mitophagy.

Toward net-zero sustainable aviation fuel with wet waste-derived volatile fatty acids.

With the increasing demand for net-zero sustainable aviation fuels (SAF), new conversion technologies are needed to process waste feedstocks and meet carbon reduction and cost targets. Wet waste is a low-cost, prevalent feedstock with the energy potential to displace over 20% of US jet fuel consumption; however, its complexity and high moisture typically relegates its use to methane production from anaerobic digestion. To overcome this, methanogenesis can be arrested during fermentation to instead produce C2 to C8 volatile fatty acids (VFA) for catalytic upgrading to SAF. Here, we evaluate the catalytic conversion of food waste-derived VFAs to produce n-paraffin SAF for near-term use as a 10 vol% blend for ASTM "Fast Track" qualification and produce a highly branched, isoparaffin VFA-SAF to increase the renewable blend limit. VFA ketonization models assessed the carbon chain length distributions suitable for each VFA-SAF conversion pathway, and food waste-derived VFA ketonization was demonstrated for >100 h of time on stream at approximately theoretical yield. Fuel property blending models and experimental testing determined normal paraffin VFA-SAF meets 10 vol% fuel specifications for "Fast Track." Synergistic blending with isoparaffin VFA-SAF increased the blend limit to 70 vol% by addressing flashpoint and viscosity constraints, with sooting 34% lower than fossil jet. Techno-economic analysis evaluated the major catalytic process cost-drivers, determining the minimum fuel selling price as a function of VFA production costs. Life cycle analysis determined that if food waste is diverted from landfills to avoid methane emissions, VFA-SAF could enable up to 165% reduction in greenhouse gas emissions relative to fossil jet.

Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bone erosion in rheumatoid arthritis.

OBJECTIVES: While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. METHODS: We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. RESULTS: Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. CONCLUSION: Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

[Classification of idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific antibodies].

OBJECTIVE: To investigate the classification of idiopathic inflammatory myopathies (IIM) based on clinical manifestations and myositis- specific antibodies using cluster analysis. METHODS: We retrospectively analyzed the data of patients with IIM admitted in Nanfang Hospital in 2015-2019. The clinical data of the patients including serum creatine kinase (CK), interstitial lung disease (ILD), cancer, and myositis-specific antibodies were collected for two-step cluster analysis to identify the distinct clusters of patients, whose clinical characteristics were subsequently analysed. RESULTS: A total of 71 patients with IIM were included in this study, including 30 (42.3%) with polymyositis (PM), 20 (28.2%) with classic dermatomyositis (DM), 16 (22.5%) with amyopathic dermatomyositis (CADM), and 5 (7.0%) with immune-mediated necrotizing myopathy (IMNM). Two-step cluster analysis identified 3 distinctive subgroups: Cluster 1 of 15 (51.7%) patients characterized by rash, positive anti-MDA5 antibody and hypoproteinemia (P < 0.05) with normal or slightly elevated CK level, mainly corresponding to CADM; Cluster 2 of 4 (57.1%) patients with significantly elevated CK and positive anti-SRP antibody (P < 0.001) corresponding to IMNM; and Cluster 3 of 17 (48.6%) patients consisting primarily of patients with PM, characterized by positivity for anti- aminoacyl transfer RNA synthetases antibodies (P=0.022) corresponding to antisynthetase syndrome (ASS). CONCLUSIONS: Patients with IIM can be divided into 3 subgroups based on their clinical and serological characteristics (especially myositis-specific antibodies), and among them ASS may represent an independent IIM subgroup with unique clinical characteristics.

4-Hydroxy-7-oxo-5-heptenoic acid lactone is a potent inducer of brain cancer cell invasiveness that may contribute to the failure of anti-angiogenic therapies.

Previously, we discovered that free radical-induced oxidative fragmentation of the docosahexaenoate ester of 2-lysophosphatidylcholine produces 4-hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone that, in turn, promotes the migration and invasion of endothelial cells. This suggested that HOHA lactone might similarly promote migration and invasion of glioblastoma multiformae (GBM) brain cancer stem cells (CSCs). A bioinformatics analysis of clinical cancer genomic data revealed that matrix metalloproteinase (MMP)1 and three markers of oxidative stress - superoxide dismutase 2, NADPH oxidase 4, and carbonic anhydrase 9 - are upregulated in human mesenchymal GBM cancer tissue, and that MMP1 is positively correlated to all three of these oxidative stress markers. In addition, elevated levels of MMP1 are indicative of GBM invasion, while low levels of MMP1 indicate survival. We also explored the hypothesis that the transition from the proneural to the more aggressive mesenchymal phenotype, e.g., after treatment with an anti-angiogenic therapy, is promoted by the effects of lipid oxidation products on GBM CSCs. We found that low micromolar concentrations of HOHA lactone increase the cell migration velocity of cultured GBM CSCs, and induce the expression of MMP1 and two protein biomarkers of the proneural to mesenchymal transition (PMT): p65 NF-κß and vimentin. Exposure of cultured GBM CSCs to HOHA lactone causes an increase in phosphorylation of mitogen-activated protein kinases and Akt kinases that are dependent on both protease-activated receptor 1 (PAR1) and MMP1 activity. We conclude that HOHA lactone promotes the PMT in GBM through the activation of PAR1 and MMP1. This contributes to a fatal flaw in antiangiogenic, chemo, and radiation therapies: they promote oxidative stress and the generation of HOHA lactone in the tumor that fosters a change from the proliferative proneural to the migratory mesenchymal GBM CSC phenotype that seeds new tumor growth. Inhibition of PAR1 and HOHA lactone are potential new therapeutic targets for impeding GBM tumor recurrence.