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Recognition of the key text of the Chinese seal can speed up the approval of documents, and improve the office efficiency of enterprises or government administrative departments. Due to image blurring and occlusion, the accuracy of Chinese seal recognition is low. In addition, the real dataset is very limited. In order to solve these problems, we improve the differentiable binarization detection algorithm (DBnet) to construct a model DB-ECA for text region detection, and propose a model named LSTR (Lightweight Seal Text Recognition) for text recognition. The efficient channel attention module is added to the differentiable binarization network to solve the feature pyramid conflict, and the convolutional layer network structure is improved to delay downsampling for reducing semantic feature loss. LSTR uses a lightweight CNN more suitable for small-sample generalization, and dynamically fuses positional and visual information through a self-attention-based inference layer to predict the label distribution of feature sequences in parallel. The inference layer not only solves the weak discriminative power of CNN in the shallow layer, but also facilitates CTC (Connectionist Temporal Classification) to accurately align the feature region with the target character. Experiments on the homemade dataset in this paper, DB-ECA compared with the other five commonly used detection models, the precision, recall, F-measure are the best effect of 90.29, 85.17, 87.65, respectively. LSTR compared with the other five kinds of recognition models in the last three years, to achieve the highest effect of accuracy 91.29%, and has the advantages of a small number of parameters and fast inference. The experimental results fully prove the innovation and effectiveness of our model. [ABSTRACT FROM AUTHOR]

Metalaxyl is an anilide pesticide that is widely used to control plant diseases caused by Peronosporales species. In order to study the toxic effects, zebrafish embryos were exposed to metalaxyl at nominal concentrations of 5, 50 and 500 ng/L for 72 hr, and the cardiac development and functioning of larvae were observed. The results showed that metalaxyl exposure resulted in increased rates of pericardial edema, heart hemorrhage and cardiac malformation. The distance between the sinus venosus and bulbus arteriosus, stroke volume, cardiac output and heart rate were significantly increased in larvae exposed to 50 and 500 ng/L metalaxyl compared to solvent control larvae. Significant upregulation in the transcription of tbx5 , gata4 and myh6 was observed in the 50 and 500 ng/L treatments, and that of nkx2.5 and myl7 was observed in the 5, 50 and 500 ng/L groups. These disturbances may be related to cardiac developmental and functional defects in the larvae. The activity of Na+/K+-ATPase and Ca2+-ATPase was significantly increased in zebrafish embryos exposed to 500 ng/L metalaxyl, and the mRNA levels of genes related to ATPase (atp2a11, atp1b2b, and atp1a3b) (in the 50 and 500 ng/L groups) and calcium channels (cacna1ab) (in the 500 ng/L group) were significantly downregulated; these changes might be associated with heart arrhythmia and functional failure. Unlabelled Image [ABSTRACT FROM AUTHOR]

Our previous study indicated that loureirin A induces hair follicle stem cell (HFSC) differentiation through Wnt/β‑catenin signaling pathway activation. However, if and how microRNAs (miRNAs/miRs) modulate loureirin A‑induced differentiation remains to be elucidated. In the present study, HFSCs were separated from the vibrissae of rats and identified by CD34 and keratin, type 1 cytoskeletal (K)15 expression. Microarray‑based miRNA profiling analysis revealed that miR‑339‑5p was downregulated in loureirin A‑induced HFSC differentiation. miR‑339‑5p overexpression by transfection with miR‑339‑5p mimics markedly inhibited the expression of K10 and involucrin, which are markers of epidermal differentiation, whereas inhibition of miR‑339‑5p by miR‑339‑5p inhibitor transfection promoted the expression of K10 and involucrin. These results suggest that miR‑339‑5p is a negative regulator of HFSC differentiation following induction by loureirin A. These findings were confirmed by a luciferase assay. Homeobox protein DLX‑5 (DLX5) was identified as a direct target of miR‑339‑5p. Furthermore, it was demonstrated that miR‑339‑5p inhibited DLX5. Overexpression of miR‑339‑5p by mimic transfection significantly inhibited protein Wnt‑3a (Wnt3a) expression, while inhibition of miR‑339‑5p by inhibitor transfection significantly increased the expression of Wnt3a. Furthermore, small interfering RNA targeting DLX5 was transfected into HFSCs, and western blot analysis revealed that Wnt3a, involucrin and K10 expression was significantly downregulated. Taken together, these results suggest that miR‑339‑5p negatively regulated loureirin A‑induced HFSC differentiation by targeting DLX5, resulting in Wnt/β‑catenin signaling pathway inhibition. This may provide a possible therapeutic target for skin repair and regeneration. [ABSTRACT FROM AUTHOR]

Procymidone (PCM), a dicarboximide fungicide, is widely used in agriculture to control plant diseases. In the present study, zebrafish embryos were exposed to PCM at 0, 10, 100 and 1000 ng/L for 72 h, the development and cardiac functioning of larvae were observed and determined. The results showed that hatching rate was significantly decreased in the 1000 ng/L treatment, and pericardial edema rate and spine curvature rate were significantly increased in the 100 and 1000 ng/L groups. The PCM-treated larvae exhibited an increased heart rate as well as arrhythmia, and shortened low jaw. The transcription levels of cardiac development-related genes tbx5, nkx2.5, tnnt2, gata4, myh6, myl7, cdh2, ryr2 were altered, which might be responsible for the cardiac developmental and functioning defects in the larvae. The deformation in bone development might be related with the impaired transcription levels of ihh, shh, bmp2b, bmp4, gh, igf1, sox9, gli2 . The activities of Na + /K + -ATPase and Ca 2+ -ATPase were significantly inhibited by 100 ng/L and 1000 ng/L PCM exposure, which might be a cause for the occurrence of pericardial edema and skeletal deformation. The results of this study will be helpful in evaluating the potential threat of PCM to fish population in the aquatic environment. [ABSTRACT FROM AUTHOR]

Bone marrow-derived mesenchymal stem cells (BMSCs) are widely used in regenerative medicine in light of their ability to differentiate along the chondrogenic and osteogenic lineages. As a type of traditional Chinese medicine, quercetin has been preliminarily reported to promote osteogenic differentiation in osteoblasts. In the present study, the effects of quercetin on the proliferation, viability, cellular morphology, osteogenic differentiation and angiogenic factor secretion of rat BMSCs (rBMSCs) were examined by MTT assay, fluorescence activated cell sorter (FACS) analysis, real-time quantitative PCR (RT-PCR) analysis, alkaline phosphatase (ALP) activity and calcium deposition assays, and Enzyme-linked immunosorbent assay (ELISA). Moreover, whether mitogen-activated protein kinase (MAPK) signaling pathways were involved in these processes was also explored. The results showed that quercetin significantly enhanced the cell proliferation, osteogenic differentiation and angiogenic factor secretion of rBMSCs in a dose-dependent manner, with a concentration of 2 μM achieving the greatest stimulatory effect. Moreover, the activation of the extracellular signal-regulated protein kinases (ERK) and p38 pathways was observed in quercetin-treated rBMSCs. Furthermore, these induction effects could be repressed by either the ERK inhibitor PD98059 or the p38 inhibitor SB202190, respectively. These data indicated that quercetin could promote the proliferation, osteogenic differentiation and angiogenic factor secretion of rBMSCs in vitro, partially through the ERK and p38 signaling pathways. [ABSTRACT FROM AUTHOR]

Objectives Icariin, a flavonoid isolated from Epimedium pubescens, has previously been identified to exert beneficial effects on preventing bone loss and promoting bone regeneration. However, molecular mechanisms for its anabolic action have, up to now, remained largely unknown. Materials and methods Effects of icariin on cell proliferation and osteogenic differentiation of rat bone mesenchymal stem cells ( BMSCs) were systematically evaluated. To characterize underlying mechanisms, its effects on mitogen-activated protein kinase ( MAPK) signalling pathways were determined. Results Results showed that icariin might not have enhanced effects on cell proliferation. However, it seemed to significantly enhance osteogenic differentiation of BMSCs, demonstrated by increasing alkaline phosphatase ( ALP) activity and gene expression of collagen type I ( Col I), osteocalcin ( OCN) and osteopotin ( OPN). It was demonstrated that icariin rapidly phosphorylated extracellular signal-regulated kinase ( ERK), p38 kinase and c-Jun N terminal kinase ( JNK). Furthermore, icariin-stimulated osteogenic effects on BMSCs were dramatically attenuated by treatment with either specific ERK inhibitor of PD98059, p38 inhibitor of SB202190 or JNK inhibitor SP600125. Conclusions These results provide a potential mechanism of anabolic activity of icariin on BMSCs involving ERK, p38 and JNK MAPK pathways. [ABSTRACT FROM AUTHOR]

Mechanical stress plays a crucial role in bone formation and absorption. We investigated the osteoblastic differentiation of bone mesenchymal stem cells (BMSCs) affected by intermittent traction stretch at different time points and explored the mechanism of osteoblastic differentiation under this special mechanical stimulation. The BMSCs and C3H10T1/2 cells were subjected to 10% elongation for 1-7 days using a Flexcell Strain Unit, and then the mRNA levels of osteoblastic genes and the expression of core-binding factor a1 (Cbfa1) were examined. Furthermore, we focused specifically on the role of the extracellular signal-regulated kinases 1/2 (ERK1/2) and Cbfa1 in the osteogenesis of BMSCs stimulated by the stretch. The results of these experiments showed that the stretch induces a time-dependent increase in the expression of osteoblastic genes. The synthesis of osteoblastic genes was downregulated after the knockdown of Cbfa1 expression by short-interfering RNA. Furthermore, the stress-induced increase in the expression of Cbfa1 mRNA and osteoblastic genes was inhibited by U0126, an ERK1/2 inhibitor. These results indicate that long periods of intermittent traction stretch promote osteoblastic differentiation of BMSCs through the ERK1/2-activated Cbfa1 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA).Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults.Methods: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education.Results: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up.Conclusion: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty. [ABSTRACT FROM AUTHOR]

The regeneration of bone defects in diabetic patients still faces challenges, as the intrinsic healing process is impaired by hyperglycemia. Inspired by the discovery that the endoplasmic reticulum (ER) is in a state of excessive stress and dysfunction under hyperglycemia, leading to osteogenic disorder, a novel engineered exosome is proposed to modulate ER homeostasis for restoring the function of mesenchymal stem cells (MSCs). The results indicate that the constructed engineered exosomes efficiently regulate ER homeostasis and dramatically facilitate the function of MSCs in the hyperglycemic niche. Additionally, the underlying therapeutic mechanism of exosomes is elucidated. The results reveal that exosomes can directly provide recipient cells with SHP2 for the activation of mitophagy and elimination of mtROS, which is the immediate cause of ER dysfunction. To maximize the therapeutic effect of engineered exosomes, a high‐performance hydrogel with self‐healing, bioadhesive, and exosome‐conjugating properties is applied to encapsulate the engineered exosomes for in vivo application. In vivo, evaluation in diabetic bone defect repair models demonstrates that the engineered exosomes delivering hydrogel system intensively enhance osteogenesis. These findings provide crucial insight into the design and biological mechanism of ER homeostasis‐based tissue‐engineering strategies for diabetic bone regeneration. [ABSTRACT FROM AUTHOR]

Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear. To characterize the role of IL-6 in age-related mitochondrial dysregulation and physical decline, we have developed an inducible human IL-6 (hIL-6) knock-in mouse (TetO-hIL-6mitoQC) that also contains a mitochondrial-quality control reporter. Six weeks of hIL-6 induction resulted in upregulation of proinflammatory markers, cell proliferation and metabolic pathways, and dysregulated energy utilization. Decreased grip strength, increased falls off the treadmill, and increased frailty index were also observed. Further characterization of skeletal muscles postinduction revealed an increase in mitophagy, downregulation of mitochondrial biogenesis genes, and an overall decrease in total mitochondrial numbers. This study highlights the contribution of IL-6 to mitochondrial dysregulation and supports a causal role of hIL-6 in physical decline and frailty. [ABSTRACT FROM AUTHOR]

Background: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk. Results: Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels. Conclusion: In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline. [ABSTRACT FROM AUTHOR]

Losartan is an oral antihypertensive agent that is rapidly metabolized to EXP3174 (angiotensin-subtype-1-receptor blocker) and EXP3179 (peroxisome proliferator-activated receptor gamma [PPARγ] agonist), which was shown in animal studies to reduce inflammation, enhance mitochondrial energetics, and improve muscle repair and physical performance. We conducted an exploratory pilot study evaluating losartan treatment in prefrail older adults (age 70–90 years, N = 25). Participants were randomized to control (placebo) or treatment (daily oral losartan beginning at 25 mg per day and increasing every 8 weeks) for a total of 6 months. Fatigue, hyperkalemia, and hypotension were the most observed side effects of losartan treatment. Participants in the losartan group had an estimated 89% lower odds of frailty (95% confidence interval [CI]: 18% to 99% lower odds, p =.03), with a 0.3-point lower frailty score than the placebo group (95% CI: 0.01–0.5 lower odds, p =.04). Frailty score was also negatively associated with serum losartan and EXP3179 concentrations. For every one standard deviation increase in EXP3179 (ie, 0.0011 ng/μL, based on sample values above detection limit) and EXP3174 (ie, 0.27 ng/μL, based on sample values above detection limit), there was a 0.0035 N (95% CI: 0.0019–0.0051, p <.001) and a 0.0027 N (95% CI: 0.00054–0.0043, p =.007) increase in average knee strength, respectively. [ABSTRACT FROM AUTHOR]

In the article "High-Performance Hydrogel-Encapsulated Engineered Exosomes for Supporting Endoplasmic Reticulum Homeostasis and Boosting Diabetic Bone Regeneration," Yulan Liu, Mingliang Zhou, Xinquan Jiang, and their colleagues propose a new therapeutic platform for diabetic bone regeneration. The platform consists of a high-performance hydrogel and engineered exosomes that help maintain endoplasmic reticulum (ER) homeostasis and accelerate bone regeneration in diabetic conditions. This therapy effectively regulates stress and functional changes caused by hyperglycemia, creating an optimal environment for osteogenesis. The research shows promise for clinical translation. [Extracted from the article]

Schematic representation of constructing CS-Fc@SPCE electrochemical immunosensor for the detection of cTnI. [Display omitted] • A label-free electrochemical immunosensor based on ferrocene derivatives amplified signal for cTnI detection was created. • A novel redox-active hybrid material, CS-Fc, which significantly increases the electron transfer rate. • The immunosensor showed excellent analytical performances in the assay of AMI warning biomarker – cTnI. As a biomarker of acute myocardial infarction (AMI), screening for cardiac troponin I (cTnI) has extremely high clinical sensitivity and specificity, and is extremely important for early intervention and risk assessment of AMI. Therefore, a novel redox-active hybrid material, CS-Fc, was synthesized by the Schiff base reaction of chitosan (CS) and ferrocene-carboxylic acid (Fc(COOH)) to form an amide group bonded together, which was used as a substrate-modified material for screen-printed carbon electrode (SPCE), and then assembled with an antibody (Ab), which was constructed into a label-free electrochemical immunosensor for the highly sensitive and rapid detection of cTnI in this study. The redox activity and biocompatibility of the highly stable and conductive composite CS-Fc significantly increased the effective specific surface area, electron transfer rate, and achieved effective amplification and specific analysis of the response signal. Under the optimized experimental conditions, the immunosensor showed a good linear relationship between its response signal and cTnI concentration in the range of 2.44 × 10−2 ∼ 2.50 × 101 ng mL−1, with a limit of detection (LOD) as low as 3.70 × 10−3 ng mL−1 (3σ, n = 11). Meanwhile, when used for the detection of cTnI in actual serum samples, it showed better reproducibility and stability, and the analytical results were better than those of the ELISA method, which indicated that it has a great potential for the accurate and rapid detection of cTnI in serum samples. In addition, it also provides a reliable means and scientific basis for process screening, early warning and prognostic risk assessment of AMI. [ABSTRACT FROM AUTHOR]

Chronic wounds are a common and debilitating condition associated with aging populations that impact more than 6.5 million patients in the United States. We have previously demonstrated the efficacy of daily topical 1% valsartan in treating wounds in diabetic mouse and pig models. Despite these promising results, there remains a need to develop an extended‐release formulation that would reduce patient burden by decreasing the frequency of daily applications. Here, we used nanotechnology to self‐assemble valsartan amphiphiles into a filamentous structure (val‐filaments) that would serve as a scaffold in wound beds and allow for steady, localised and tunable release of valsartan amphiphiles over 24 days. Two topical treatments of this peptide‐based hydrogel on full‐thickness wounds in Zucker Diabetic Fatty rats resulted in faster rates of wound closure. By day 23, all val‐filament treated wounds were completely closed, as compared to one wound closed in the placebo group. Mechanistically, we observed enrichment of proteins involved in cell adhesion and energetics pathways, downregulation of Tgf‐β signalling pathway mediators (pSmad2, pSmad3 and Smad4) and increased mitochondrial metabolic pathway intermediates. This study demonstrates the successful synthesis of a sustained‐release valsartan filament hydrogel, its impact on mitochondrial energetics and efficacy in treating diabetic wounds. [ABSTRACT FROM AUTHOR]

Background: Invasive malignant pleomorphic adenoma (IMPA) is a highly invasive parotid gland tumor and lacks effective therapy. N6-Methyladenosine (m6A) is the most prevalent post-transcriptional modification of mRNAs in eukaryotes and plays an important role in the pathogenesis of multiple tumors. However, the significance of m6A-modified mRNAs in IMPA has not been elucidated to date. Hence, in this study, we attempted to profile the effect of IMPA in terms of m6A methylation in mRNA. Methods: Methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were utilized to acquire the first transcriptome-wide profiling of the m6A methylome map in IMPA followed by bioinformatics analysis. Results: In this study, we obtained m6A methylation maps of IMPA samples and normal adjacent tissues through MeRIP-seq. In total, 25,490 m6A peaks associated with 13,735 genes were detected in the IMPA group, whereas 33,930 m6A peaks associated with 18,063 genes were detected in the control group. Peaks were primarily enriched within coding regions and near stop codons with AAACC and GGAC motifs. Moreover, functional enrichment analysis demonstrated that m6A-containing genes were significantly enriched in cancer and metabolism relevant pathways. Furthermore, we identified a relationship between the m6A methylome and the RNA transcriptome, indicating a mechanism by which m6A modulates gene expression. Conclusions: Our study is the first to provide comprehensive and transcriptome-wide profiles to determine the potential roles played by m6A methylation in IMPA. These results may open new avenues for in-depth research elucidating the m6A topology of IMPA and the molecular mechanisms governing the formation and progression of IMPA. [ABSTRACT FROM AUTHOR]

Chronic inflammation (CI) in older adults is associated with reduced health span and life span. Interleukin-6 (IL-6) is one CI marker that is strongly associated with adverse health outcomes and mortality in aging. We have previously characterized a mouse model of frailty and chronic inflammatory pathway activation (IL-10tm/tm, IL-10 KO) that demonstrates the upregulation of numerous proinflammatory cytokines, including IL-6. We sought to identify a more specific role for IL-6 within the context of CI and aging and developed a mouse with targeted deletion of both IL-10 and IL-6 (IL-10tm/tm/IL-6tm/tm, DKO). Phenotypic characteristics, cytokine measurements, cardiac myocardial oxygen consumption, physical function, and survival were measured in DKO mice and compared to age- and gender-matched IL-10 KO and wild-type mice. Our findings demonstrate that selective knockdown of IL-6 in a frail mouse with CI resulted in the reversal of some of the CI-associated changes. We observed increased protective mitochondrial-associated lipid metabolites, decreased cardiac oxaloacetic acid, improved myocardial oxidative metabolism, and better short-term functional performance in DKO mice. However, the DKO mice also demonstrated higher mortality. This work shows the pleiotropic effects of IL-6 on aging and frailty. [ABSTRACT FROM AUTHOR]

• Circadian rhythm disruption promoted the development of periodontitis by promoting the proinflammatory response. • Kdm6a deficiency in macrophages alleviated periodontitis. • The aggravation of periodontitis by CRD can be attenuated by Kdm6a deletion in macrophages. Macrophages are highly implicated in the progression of periodontitis, while circadian rhythm disruption (CRD) promotes the inflammatory response of macrophages in many diseases. However, the effects of CRD on periodontitis and the role of macrophages in this process remain unclear. Histone lysine demethylase 6a (Kdm6a), a histone demethylase, has recently been identified as a key regulator of macrophage-induced inflammation. Here, we established an experimental periodontitis model by injecting lipopolysaccharide (LPS) derived from Porphyromonas gingivalis with or without periodontal ligation in mice exposed to an 8-h time shift jet-lag schedule every 3 days. By histomorphometry, tartrate acid phosphatase (TRAP) staining, RT-qPCR, ELISA, immunohistochemistry and immunofluorescence analysis, we found that CRD promoted the inflammatory response, alveolar bone resorption, macrophage infiltration and Kdm6a expression in macrophages. Macrophage-specific Kdm6a knockout mice were further used to elucidate the effects of Kdm6a deficiency on periodontitis. Kdm6a deletion in macrophages rescued periodontal tissue inflammation, osteoclastogenesis, and alveolar bone loss in a mouse model of periodontitis. These findings suggest that CRD may intensify periodontitis by increasing the infiltration and activation of macrophages. Kdm6a promotes the inflammatory response in macrophages, which may participate in aggravated periodontitis via CRD. [ABSTRACT FROM AUTHOR]

Objectives: To screen susceptibility loci for ankylosing spondylitis (AS) using an affected-only linkage analysis based on high-density single nucleotide polymorphisms (SNPs) in a genome-wide manner. Patients and Methods: AS patients from ten families with Cantonese origin of China were enrolled in the study. Blood samples were genotyped using genomic DNA derived from peripheral blood leukocytes by Illumina HumanHap 610-Quad SNP Chip. Genotype data were generated using the Illumina BeadStudio 3.2 software. PLINK package was used to remove non-autosomal SNPs and to further eliminate markers of typing errors. An affected-only linkage analysis was carried out using both non-parametric and parametric linkage analyses, as implemented in MERLIN. Result: Seventy-eight AS patients (48 males and 30 females, mean age: 39±16 years) were enrolled in the study. The mean age of onset was 23±10 years and mean duration of disease was 16.7±12.2 years. Iritis (2/76, 2.86%), dactylitis (5/78, 6.41%), hip joint involvement (9/78, 11.54%), peripheral arthritis (22/78, 28.21%), inflammatory back pain (IBP) (69/78, 88.46%) and HLA-B27 positivity (70/78, 89.74%) were observed in these patients. Using non-parameter linkage analysis, we found one susceptibility locus for AS, IBP and HLA-B27 in 6p21 respectively, spanning about 13.5Mb, 20.9Mb and 21.2Mb, respectively No significant results were found in the other clinical trait groups including dactylitis, hip involved and arthritis. The identical susceptibility locus region spanning above 9.44Mb was detected in AS IBP and HLA-B27 by the parametric linkage analysis. Conclusion: Our genome-wide SNP linkage analysis in ten families with ankylosing spondylitis suggests a susceptibility locus on 6p21 in AS, which is a risk locus for IBP in AS patients. [ABSTRACT FROM AUTHOR]

Aim To investigate whether adalimumab is effective for active ankylosing spondylitis ( AS) patients and whether it has an impact on the formation of fatty deposition lesions ( FDL) and serum Dickkopf homolog 1 ( Dkk-1) level in AS patients. Method This was a randomized, double-blind, placebo-controlled study. Active AS patients received 40 mg adalimumab ( n = 26) or placebo ( n = 20) every other week during an initial 12-week double-blind period, and all switched to adalimumab treatment for another 12 weeks. Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI), Bath Ankylosing Spondylitis Function Index ( BASFI), C-reactive protein ( CRP), Ankylosing Spondylitis Disease Activity Scores ( ASDAS) and serum DKK-1 levels were measured and magnetic resonance imaging ( MRI) of both the lumbar spine and sacroiliac joints were obtained at baseline, week 12 and week 24. Spinal and sacroiliac joint inflammations were evaluated using the Spondyloarthritis Research Consortium of Canada ( SPARCC) MRI index, and FDL were assessed in a dichotomous manner. Results Obvious improvements in clinical assessments ( BASDAI, BASFI, CRP and ASDAS reduced, all P < 0.05), as well as MRI inflammation measurements (both lumbar spine and sacroiliac joints SPARCC scores decreased, all P < 0.05) were shown in active AS patients treated by adalimumab for 12 weeks, but FDL in the lumbar spine seen by MRI increased significantly ( P < 0.05) accompanied by decrease of serum DKK-1 levels ( P < 0.05), while FDL remained stable after the treatment of placebo in AS patients. Conclusion Our study found that adalimumab was highly effective in reducing inflammation in active AS patients, but it was accompanied by the formation of FDL in the lumbar spine and decrease in serum DKK-1 levels. [ABSTRACT FROM AUTHOR]

Background After the onset of rheumatoid arthritis ( RA), fibroblast-like synoviocytes ( RA- FLS) which are specialized types of fibroblasts, become tumor-like, keeping their ability to increase proliferation and invasion. The mechanism of their tumor-like growth is unclear. Fractalkine ( FKN), also called CX3 CL1, plays an important role in the proliferation of cells. FKN may stimulate the proliferation of RA- FLS and the by nuclear factor κ B ( NF-κ B) pathway may be one of the steps in this process. Objective To investigate whether FKN can stimulate cell growth and increase its expression in RA- FLS, and the relationship between the NF-κ B pathway and the function of FKN. Methods FLS were isolated from primary synovial tissue obtained from three patients with RA who had undergone total joint replacement surgery or synovectomy in the Third Hospital Affiliated to Sun Yat-sen University from February 2009 to January 2010. FKN was used in different concentrations to stimulate RA- FLS with or without NF-κ B pathway blocker ( PDTC), and to test the proliferation of FLS after 24 h by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ( MTT) assay. RA- FLS was treated with 100 ng/ mL FKN or 100 μM PDTC for different periods, and messenger RNA ( mRNA) expression of FKN and CX3 CR1 in RA- FLS was detected by reverse transcription - polymerase chain reaction. We then tested the protein expression of NF-κ Bp65 in the cytoplasm and nucleus, respectively by Western blotting after treating the RA- FLS with 100 ng/ mL FKN for different time periods. Results FKN stimulated cell growth in RA- FLS at the concentration of 50 or 100 ng/ mL ( P = 0.005 and P = 0.022, respectively). NF-κ B pathway blocker inhibited FKN, promoting proliferation of RA- FLS. RA- FLS could express FKN and CX3 CR1 mRNA in vitro. FKN up-regulated FKN expression after 18-h treatment ( P = 0.012). PDTC disturbed the expression of FKN mRNA after 16-18 h treatment ( P = 0.001 and P < 0.001, respectively). After stimulation with FKN for 1 h, the expression of NF-κ Bp65 in cytoplasm began to decrease ( P = 0.010), and the expression of NF-κ Bp65 in the nucleus began to increase after 2 h ( P = 0.011). Conclusion These results suggest that FKN stimulates cells growth in RA-FLS and NF-κB pathway blocker inhibits FKN, promoting proliferation of RA-FLS. FKN induced activation of NF-κB activity. FKN up-regulates FKN mRNA expression in RA-FLS via the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Objective. To validate the clinical value of the new Ankylosing Spondylitis Disease Activity Scores (ASDASs) in assessing the disease activity and efficacy of TNF-α inhibitor in AS and uSpA patients in China.Methods. Two hundred and thirty patients were included in our study. They consisted of patients with active AS (n = 87) and uSpA (n = 30) participating in a double-blind placebo-controlled randomized clinical trial of etanercept and patients with active AS (n = 58) and uSpA (n = 55) treated with infliximab. The disease activity and treatment effects were assessed by ASDAS, BASDAI, patient global and the acute inflammation score of lumbar and SI joints by MRI. Discriminatory ability of all the measures was analysed by standardized mean difference and t-score.Results. In both the AS and uSpA groups, ASDAS correlated well with patient global score (AS group: r = 0.65–0.72; uSpA group: r = 0.52–0.62), ESR (AS group: r = 0.57–0.81; uSpA group: r = 0.63–0.85) and CRP (AS group: r = 0.51–0.70; uSpA group: r = 0.61–0.76) both at baseline and in changes from baseline to 6 weeks after TNF-α inhibitor treatment. The ASDAS scores outperformed BASDAI, patient global score, ESR, CRP and the acute inflammation score by MRI in differentiating patients with different levels of disease activity and patients with different levels of change in both AS and uSpA groups. There was little difference in performance between the two versions of the ASDAS.Conclusion. The new ASDAS is a highly effective measure in assessing disease activity and a great discriminatory measurement to assess the efficacy of TNF-α inhibitor in Chinese AS patients and uSpA patients. [ABSTRACT FROM PUBLISHER]

L4936 --> Chronic elevation of inflammatory mediators is common in frail older adults and predicts a host of adverse cardiovascular outcomes, including heart failure and sudden death. To date, few specific molecular mechanisms have been identified that connect chronic inflammation to age‐related cardiomyopathies. Dysregulation in Ca2+and calmodulin‐dependent protein kinase II (CaMKII) signaling has been implicated in promoting inflammatory responses in cardiomyopathies but is understudied in the context of aging. We compared myocardial CaMKII signaling in young (32 weeks) and old (104 weeks) wild type (WT) and interleukin 10 null mice (IL‐10tm/tm), a model of chronic inflammation and frailty. Aged cohorts were treated with 0.6 mg of losartan. Hearts from mouse cohorts were assayed for total and autophosphorylated CaMKII (P‐CaMKII) and the phosphorylation status of phospholamban (PLN) (downstream signaling pathway) using western blot techniques. We observed significant increases in total and activated, autophosphorylated, CaMKII (P‐CaMKII) (2.4 ± 0.38 vs 1.2 ± 0.12 p< 0.02; 9.0 ± 1.9 vs 0.03 ± 0.01 p< 0.002), but decreases in the phosphorylation of PLN (0.6 ±0.3 vs 1.7 ± 0.3 p<0.03) at a validated CaMKII target site (T17) in old compared to young WT hearts. Similarly, we found increased P‐CaMKII (6.9 ± 1.5 vs 0.7 ± 0.4 p< 0.004) and diminished PLN T17 phosphorylation (0.8 ± 0.2 vs 1.5 ± 0.2 p<0.02) in old compared to young IL‐10tm/tm mice. Old IL‐10tm/tm mouse hearts had less total CaMKII compared to old WT mouse hearts (1.1 ± 0.3 vs 2.9 ±0.2 p< 0.002). Four weeks treatment of old WT mice with Losartan was associated with reversal of observed age‐related changes in the CaMKII signaling pathway. We observed decreases in total CaMKII, P‐CaMKII (2.9 ± 0.2 vs.1.5 ± 0.2 p<0.001; 2.2 ± 0.9 vs 0.47 ± 0.1 p <0.03), and an increase in PLN T17 phosphorylation (0.55±0.3 vs 2.23 ± 0.4 p< 0.007). The effects of Losartan on the animals aging with chronic inflammation (old IL‐10tm/tm) was less clear. We observed a losartan associated increase in total CaMKII (1.41 ± 0.02 vs 1.3 ± 0.02 p<0.02) but no impact on P‐CaMKII or PLN T17 phosphorylation. We interpret our findings to suggest that changes in myocardial CaMKII signaling are a feature of aging that is affected by chronic inflammation. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficiency and the predictive factors of clinical response of infliximab in active nonradiographic axial spondyloarthritis patients.Methods: Active nonradiographic patients fulfilling ESSG criteria for SpA but not fulfilling modified New York criteria were included. All patients received infliximab treatment for 24 weeks. The primary endpoint was ASAS20 response at weeks 12 and 24. The abilities of baseline parameters and response at week 2 to predict ASAS20 response at weeks 12 and 24 were assessed using ROC curve and logistic regression analysis, respectively.Results: Of 70 axial SpA patients included, the proportions of patients achieving an ASAS20 response at weeks 2, 6, 12, and 24 were 85.7%, 88.6%, 87.1%, and 84.3%, respectively. Baseline MRI sacroiliitis score (AUC = 0.791; P = 0.005), CRP (AUC = 0.75; P = 0.017), and ASDAS (AUC = 0.778, P = 0.007) significantly predicted ASAS20 response at week 12. However, only ASDAS (AUC = 0.696, P = 0.040) significantly predicted ASAS20 response at week 24. Achievement of ASAS20 response after the first infliximab infusion was a significant predictor of subsequent ASAS20 response at weeks 12 and 24 (wald χ(2) = 6.87, P = 0.009, and wald χ(2) = 5.171, P = 0.023).Conclusions: Infliximab shows efficiency in active nonradiographic axial spondyloarthritis patients. ASDAS score and first-dose response could help predicting clinical efficacy of infliximab therapy in these patients. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs can potentially regulate every aspect of cellular activity. In this study, we investigated whether AS pathogenesis involves microRNAs disorders.Result: The expression of 2 microRNAs, hsa-miR-126-3p and hsa-miR-29a, was significantly lower in active AS group before etanercept therapy than in control group. Marched fold changes of them were 3.76 and 16.22. Moreover, expressions of hsa-miR-126-3p and hsa-miR-29a were dramatically upregulated after 12-weeks etanercept treatment. Fold changes were 2.20 and 3.18. All regulations of microRNAs expression mentioned before were statistically significant (fold change >2 and P < 0.05). The expression disorders of the 2 microRNAs did not statistically significantly correlated with BASDAI, CRP, and ESR.Conclusion: AS pathogenesis involved dysregulation of microRNAs. Hsa-miR-126-3p and hsa-miR-29a will probably become the potential biomarkers and provocative therapeutic targets of AS. [ABSTRACT FROM AUTHOR]