Whole-Transcriptome Sequencing of Knee Joint Cartilage from Kashin-Beck Disease and Osteoarthritis Patients.

The aim of this study was to provide a comprehensive understanding of similarities and differences in mRNAs, lncRNAs, and circRNAs within cartilage for Kashin-Beck disease (KBD) compared to osteoarthritis (OA). We conducted a comparison of the expression profiles of mRNAs, lncRNAs, and circRNAs via whole-transcriptome sequencing in eight KBD and ten OA individuals. To facilitate functional annotation-enriched analysis for differentially expressed (DE) genes, DE lncRNAs, and DE circRNAs, we employed bioinformatic analysis utilizing Gene Ontology (GO) and KEGG. Additionally, using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), we validated the expression levels of four cartilage-related genes in chondrocytes. We identified a total of 43 DE mRNAs, 1451 DE lncRNAs, and 305 DE circRNAs in KBD cartilage tissue compared to OA (q value < 0.05; |log2FC| > 1). We also performed competing endogenous RNA network analysis, which identified a total of 65 lncRNA-mRNA interactions and 4714 miRNA-circRNA interactions. In particular, we observed that circRNA12218 had binding sites for three miRNAs targeting ACAN, while circRNA12487 had binding sites for seven miRNAs targeting COL2A1. Our results add a novel set of genes and non-coding RNAs that could potentially serve as candidate diagnostic biomarkers or therapeutic targets for KBD patients.

[Expression and Regulatory Mechanism of Autophagy-related Genes in Synovial Tissues of Patients with Rheumatoid Arthritis].

Objective To investigate the expression regulation of autophagy-related genes(ATG)and the mechanism of autophagy in rheumatoid arthritis(RA).Methods The differentially expressed genes(DEG)of RA were identified from GSE55235 and GSE55457,on the basis of which the differentially expressed autophagy-related genes(DE-ATG)were selected from the Human Autophagy Database.STRING 11.0 and GeneMANIA were used to establish protein-protein interaction networks.Further,the transcription factor-gene-miRNA co-expression network was established via NetworkAnalyst and Cytoscape.Finally,receiver operating characteristic(ROC)curve and DrugBank were employed to evaluate the efficacy of the predicted biomarkers and the performance of drugs targeting DE-ATG.GraphPad Prism 8.2.1 and R 4.0.3 were used for statistical analysis and graphics.Results A total of 485 DEG were enriched in signaling pathways such as T cell activation,hormone regulation,osteoclast differentiation,RA,and chemokines.Eleven DE-ATG regulated the expression of RUNX1,TP53,SOX2,and hsa-mir-155-5p in synovial tissues of RA patients and were involved in the response to environmental factors such as 2,3,7,8-tetrachlorodibenzodioxin and silicon dioxide.The ROC curve analysis identified the DE-ATG with good sensitivity and specificity,such as MYC,MAPK8,CDKN1A,and TNFSF10,which can be used to distinguish certain phenotypes and serve as novel biomarkers for RA.Conclusions In RA,down-regulated DE-ATG expression may promote apoptosis and lysis of chondrocytes.The identified novel biomarkers provides new ideas and methods for diagnosing and treating RA.The establishment of transcription factor-miRNA-gene co-expression network provides direct evidence for dissecting synovial inflammation and articular cartilage destruction.

Quantitative decision-making in randomized Phase II studies with a time-to-event endpoint.

One of the most critical decision points in clinical development is Go/No-Go decision-making after a proof-of-concept study. Traditional decision-making relies on a formal hypothesis testing with control of type I and type II error rates, which is limited by assessing the strength of efficacy evidence in a small isolated trial. In this article, we propose a quantitative Bayesian/frequentist decision framework for Go/No-Go criteria and sample size evaluation in Phase II randomized studies with a time-to-event endpoint. By taking the uncertainty of treatment effect into consideration, we propose an integrated quantitative approach for a program when both the Phase II and Phase III trials share a common endpoint while allowing a discount of the observed Phase II data. Our results confirm the argument that an increase in the sample size of a Phase II trial will result in greater increase in the probability of success of a Phase III trial than increasing the Phase III trial sample size by equal amount. We illustrate the steps in quantitative decision-making with a real example of a randomized Phase II study in metastatic pancreatic cancer.

[A four-generation pedigree affected with X-linked adrenal hypoplasia congenita due to a novel missense DAX1 mutation].

OBJECTIVE: To report on the clinical pictures of 7 patients from a pedigree affected with X-linked adrenal hypoplasia congenita (XL-AHC) and hypogonadotropic hypogonadism (HH) and the underlying mutations. METHODS: Seven patients were identified from a four-generation pedigree affected with XL-AHC and HH. Their clinical features, endocrinological changes, treatment and drug response were recorded. The patients were subjected to next-generation sequencing, and the result was verified by Sanger sequencing. PolyPhen-2 was used for predicting the influence of the mutation on protein production. RESULTS: Three deceased patients had manifested adrenal insufficiency (AI) within one year after birth. Two died at 6 and one died at 12. The four survivors presented with salient clinical and endocrinological features of AHC and HH, adrenal and testicular atrophy, and renin-angiotensin compensation. Two adult patients had testicular micro-stone detected by ultrasound.One of them also had remarkable seminiferous tubule degeneration by biopsy. The patients were followed up for 0.5 to 10 years. All required hyper-physiological dose of hydrocortisone to stabilize their clinical condition. In three patients, gonadotropic or androgen replacement induced cardinal masculine development but with unsatisfactory testis growth and sperm production.Genetic analysis revealed a novel missense c.827A>C (p.Q276P) mutation in a hotspot region within a highly conserved domain. PolyPhen-2 predicted the mutation to be highly hazardous. CONCLUSION: The novel p.Q276P mutation of the DAX1 gene probably underlies the XL-AHC and HH in this pedigree with variable clinical presentations in the patients.

Acupuncture for the treatment of obesity in adults: a systematic review and meta-analysis.

OBJECTIVE: Meta-analysis was used to assess the clinical efficacy of acupuncture treatment for simple obesity and to provide evidence-based medical data for treating obesity with acupuncture. METHODS: A comprehensive search of studies on MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Chinese databases (Wan Fang,CNKI and VIP) from 1 January 1915 through 30 November 2015 (MEDLINE search updated through 31 December 2015) was performed. We included only randomised controlled trials (RCTs) that used acupuncture and sham acupuncture to treat simple obesity. The effect of acupuncture on simple obesity was measured using body mass index (BMI), body fat mass (BFM), waist circumference (WC), hip circumference (HC), and body weight (BW). The Jadad scale was used to assess methodological quality. The random effects model was used in the pooled analysis to adjust for the heterogeneity of the included studies, and funnel plots were used to examine publication bias. The differences between treatment groups were reported as mean differences (MD). RESULTS: Eleven RCTs were selected after all relevant literature from the electronic databases had been screened. There were 338 and 305 participants in the acupuncture and sham acupuncture groups, respectively. Auricular and electro acupuncture were both able to reduce BMI in obese patients (MD 0.47 kg/m2, 95% CI 0.35 to 0.58, p<0.001; MD 0.50 kg/m2, 95% CI 0.38 to 0.62, p<0.001). BFM change after acupuncture treatment compared with sham treatment was statistically significant (MD 0.66 kg, 95% CI 0.51 to 0.80, p<0.001). There were also significant differences in WC and HC between the acupuncture and sham acupuncture groups (MDwc2.02 cm, 95% CI 0.21 to 3.83, p=0.03; MDHC2.74 cm, 95% CI 1.21 to 4.27, p=0.0004). BW was not statistically significantly different between the acupuncture and sham acupuncture groups (MD 0.60 kg, 95% CI -0.20 to 1.39, p=0.14). Begg's test and funnel plots showed that the potential publication bias of the included studies was very slight (p>0.05). CONCLUSION: Acupuncture for simple obesity appeared to be an effective treatment, but more studies on the safety of acupuncture used to treat simple obesity are required.

Molecular characterization of Sp110 gene in pigs.

Speckled 110 kDa (Sp110) plays an important role in infectious diseases, as revealed by studies in humans. However, little is known regarding porcine Sp110. To elucidate its potential role in porcine resistance to viral diseases, here, the complete coding sequence of porcine Sp110 gene and its 26 alternatively spliced isoforms were isolated using reverse transcription (RT)-polymerase chain reaction (PCR), and another seven splicing patterns were obtained using a minigene construct. Subcellular distribution of 11 representative isoforms was characterized in PK-15 cells transiently transfected with their respective GFP fusion constructs, and only isoforms (R and V) bearing all functional domains were localized in nucleus, indicating all the other isoforms lose normal functions of Sp110 owing to alternative splicing. Real-time quantitative PCR and competitive RT-PCR showed that both isoforms R and V had similar tissue expression profile, half-life and response to poly(I:C), a synthetic analog of viral double-stranded RNA, while the longer one (isoform R) was transcribed at a higher level. The results indicated that porcine Sp110 has a role in viral infection and that isoform R is the dominant active form. Overall the data provide potential resource for molecular breeding of pig resistant to diseases and contributes to breeding pigs resistant to viral infection.

Inhibition of Notch Signaling Promotes the Adipogenic Differentiation of Mesenchymal Stem Cells Through Autophagy Activation and PTEN-PI3K/AKT/mTOR Pathway.

BACKGROUND: The Notch signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. This study was designed to determine the role of Notch signaling in adipogenic differentiation of human bone marrow derived MSCs (BM-MSCs). METHODS: The Notch signaling was inhibited by the γ-secretase inhibitor N-[N-(3,5-difluor- ophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT). The markers involving adipogenic differentiation of MSCs, the relative pathway PTEN-PI3K/Akt/mTOR and autophagy activation were then analyzed. Furthermore, the autophagy inhibitor chloroquine (CQ) and 3-methyladenine (3-MA) were used to study the role of autophagy in the DAPT-induced the adipogenic differentiation of MSCs. RESULTS: We first confirmed the down -regulation of Notch gene expression during MSCs adipocyte differentiation, and showed that the inhibition of Notch signaling significantly enhanced adipogenic differentiation of MSCs. Furthermore, Notch inhibitor DAPT induced early autophagy by acting on PTEN-PI3K/Akt/mTOR pathway. The autophagy inhibitor CQ and 3-MA dramatically abolished the effects of DAPT-induced autophagy and adipogenic differentiation of MSCs. CONCLUSION: Our results indicate that inhibition of Notch signaling could promote MSCs adipogenesis mediated by autophagy involving PTEN-PI3K/Akt/mTOR pathway. Notch signaling could be a novel target for regulating the adipogenic differentiation of MSCs.

[The effects and mechanism of islet amyloid polypeptide on insulin secretion in INS-1 cells stimulated by glibenclamide].

OBJECTIVE: To observe the effects, and study the mechanism of islet amyloid polypeptide (IAPP) on insulin secretion in INS-1 cells stimulated by glibenclamide. METHODS: Whole cell patch clamp technique was employed to study the influences of short exposure to IAPP on electrophysiological characteristics of ATP-sensitive K+ channel (K(ATP) channel) upon sulfonylurea stimulation. Intracellular free calcium changes in this process was observed by laser scanning confocal microscope. Insulin was measured by enzyme-linked immunoassay. RESULTS: (1) Insulin secretion stimulated by 1 micomol/L glibenclamide was significantly decreased from (11.43 +/- 1.22) microg/L to (9.40 +/- 0.87) microg/L and to (7.11 +/- 1.85) microg/L after 1 micromol/L and 10 micromol/L IAPP incubation, respectively. (2) Glibenclamide-stimulated calcium influx was dose dependently inhibited by IAPP from 1 micromol/L to 10 micromol/L, with the AUC of fluorescence intensity-time reduced from 427.78 +/- 2.32 to 380.59 +/- 1.49, and to 246.53 +/- 8.41, respectively. (3) Compared with that in control cells (14.59 +/- 0.69) mV, the half activation voltage of KA, channel in response to glibenclamide was significantly increased to (28.75 +/- 0.77) mV and to (46.95 +/- 1.81) mV in cells pretreated with 1 micromol/L and 10 micromol/L IAPP, implicating an inhibitory effect of IAPP on activation of K(ATP) channel. CONCLUSION: Short-term exposure to high concentration of IAPP inhibited glibenclamide-induced closure of K(ATP) channels and decreased calcium influx, which may ultimately lead to the reduction of insulin secretion in INS-1 cells

Cloning and identification of splice variants of the porcine PILRA gene.

Paired immunoglobulin-like type 2 receptors (PILRs) are members of the immunoglobulin superfamily and composed of two subtypes, α and ß. PILRα plays an important role in the immune response against invading pathogens, but so far there is no report on porcine PILRα. In order to analyze the potential role of PILRα in porcine disease-resistant breeding, we first cloned the PILRA gene (V1-V3, GenBank accession Nos. KJ143679-81) into pigs, and identified its three splice variants. Each variant conceptually translates into proteins of 271 amino acids (aa), 254aa and 283aa, respectively. Furthermore, quantitative real-time PCR was used to construct expression profiles of each variant in tissues and that induced by Poly(I:C). All three variants had the highest expression levels in the spleen, followed by liver and lung tissues. While levels were low or undetectable in the heart, kidney, stomach, muscle, lymph, large intestine, small intestine and bladder. Poly(I:C) significantly induced the expression of splice variant 1 (V1) of porcine PILRA, but hardly affected the expression of V2 and V3. The results lay a foundation for further study on the role of PILRA in porcine breeding and disease resistance.

The effects of venlafaxine on cortical motor area activity in healthy subjects: a pilot study.

In the study, we used functional magnetic resonance imaging associated with behavioral assessment to observe the effects of venlafaxine on the modulation of human motor cortex activation and to provide preliminary data for further assessing its influence on motor functional reorganization after stroke injury. In a randomized, double-blind, crossover study, 8 right-handed subjects received 75 mg of either venlafaxine or a placebo daily over a period of 7 days separated by 3 washout days. The volunteers were asked to execute motor tasks, which included the dynamometer and finger-tapping test. In addition, laboratory tests and functional magnetic resonance imaging examination, before the start of the experiment and after administration of placebo and venlafaxine, were performed. It was shown that the finger-tapping rate of each hand in the venlafaxine stage was significantly improved compared with that observed in the placebo stage (n = 8, F left hand = 57.69, F right hand = 184.48, P < 0.001). The changes in the recorded grip strengths of both hands were not significant between the stages (n = 8, F = 2.63, P > 0.05). In the venlafaxine stage, the activations of the contralateral primary sensorimotor cortex, contralateral premotor cortex, and contralateral supplementary motor area were enhanced significantly, whereas the activation of the bilateral parietal cortices was decreased when compared with the placebo stage. Meanwhile, the enhancement of contralateral primary sensorimotor cortex activation had a positive correlation with the improvement of the finger-tapping rate. It was concluded that venlafaxine could modulate the cortical excitability and improve finger dexterity and reaction speed, which greatly related to the increase of contralateral motor cortical excitability.

[Brain mappings in non-fluent late Chinese-English bilinguals].

OBJECTIVE: To discuss the distribution characteristics of language areas in Chinese-English non-fluent late bilinguals. METHODS: Six Chinese-English bilinguals with eloquent tumors underwent awake-surgeries. The activated areas of BOLD-fMRI were obtained as the patients performed pure naming, verb generation, and abstract/concrete judgment tasks. Direct cortical stimulation(DCS) as the golden standard of language mapping were performed during awake-surgeries on the exposed cortical areas. BOLD-fMRI results of 3 language tasks were compared with DCS results. The statistical method was McNemer. RESULTS: Sixteen positive sites(22.5%) were comfirmed out of 71 stimulations. There were 3 specific language sites, in which 2 sites were specific English sites and 1 site was specific Chinese site. When activated areas of BOLD-fMRI were compared with the DCS results, verb generation task had the highest concordance rate 40.9% (95%CI:30.2%-52.5%) . There were significant differences between the results of BOLD-fMRI and DCS of all 3 bilingual tasks(P < 0.017). CONCLUSIONS: There are specific language areas in Chinese-English non-fluent late bilinguals. The BOLD-fMRI language mapping could not substitute DCS in the context of mapping language areas in bilinguals.

Enhanced biological S0 accumulation by using signal molecules during simultaneous desulfurization and denitrification.

A high rate of elemental sulfur (S0) accumulation from sulfide-containing wastewater has great significance in terms of resource recovery and pollution control. This experimental study used Thiobacillus denitrificans and denitrifying bacteria incorporated with signal molecules (C6 and OHHL) for simultaneous sulfide (S2-) and nitrate (NO3-) removal in synthetic wastewater. Also, the effects on S0 accumulation due to changes in organic matter composition and bacteria proportion through signal molecules were analyzed. The 99.0% of S2- removal and 99.3% of NO3- was achieved with 66% of S0 accumulation under the active S2- removal group. The S0 accumulation, S2- and NO3- removal mainly occurred in 0-48 h. The S0 accumulation in the active S2- removal group was 2.0-6.3 times higher than the inactive S2- removal groups. In addition, S0/SO42- ratio exhibited that S0 conversion almost linearly increased with reaction time under the active S2- removal group. The proportion of Thiobacillus denitrificans and H+ consumption showed a positive correlation with S0 accumulation. However, a very high or low ratio of H+/S0 is not suitable for S0 accumulation. The signal molecules greatly increased the concentration of protein-I and protein-II, which resulted in the high proportion of Thiobacillus denitrificans. Therefore, high S0 accumulation was achieved as Thiobacillus denitrificans regulated the H+ consumption and electron transfer rate and provided suppressed oxygen environment. This technology is cost-effective and commercially applicable for recovering S0 from wastewater.

Multivariable System Prediction Based on TCN-LSTM Networks with Self-Attention Mechanism and LASSO Variable Selection.

Intelligent prediction of key output variables that are difficult to measure online in complex systems has important research significance. In this paper, by using the least absolute shrinkage and selection operator (LASSO) algorithm to analyze the principal elements of input variables, a temporal convolutional network fused with long short-term memory (TCN-LSTM) network and self-attention mechanism (SAM) is designed to realize dynamic modeling of multivariate feature sequences. For complex processes with multiple input variables, each variable has different effects on the output, so it is necessary to use the LASSO algorithm to perform regression analysis on the input and output data for selecting the principal component variables and reducing the redundancy and computation burden of the network. The TCN network is used to extract the features of the input variables efficiently. The long-term memory performance of time series is enhanced by applying an LSTM network. The multihead SAM is used to optimize the network, and the role of key features is enhanced by assigning weights with probability to further improve the accuracy of sequence prediction. Finally, by comparison with the existing network model, the offline data generated by the high and low converters in the synthetic ammonia industry is used to predict the CO content so as to verify the superiority and applicability of the proposed network model.

Effect of Sleep Quality on Anxiety and Depression Symptoms among College Students in China's Xizang Region: The Mediating Effect of Cognitive Emotion Regulation.

BACKGROUND: While the exact mechanisms are not fully understood, there are significant links between sleep quality, anxiety, depressive symptoms, and cognitive emotion regulation. This research examines how sleep quality affects anxiety and depressive symptoms, as well as the potential of cognitive emotion regulation strategies (CERS) to moderate the impact of sleep quality on these symptoms. METHODS: The Chinese version of the Pittsburgh Sleep Quality Index (CPSQI), the Cognitive Emotion Regulation Questionnaire (CERQ), the Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder Scale-7 (GAD-7) were all completed online by students from two colleges in China's Xizang region. RESULTS: The study included 4325 subjects. The prevalence of poor sleep quality, anxiety symptoms, and depression symptoms was 45.69%, 36.81%, and 51.86%, respectively. We observed significant direct effects on poor sleep and severity of anxiety/depression: c'1 = 0.586 (0. 544-0.628), and c'2 = 0.728 (0.683-0.773). Adaptive CERS only had a mediating effect on the relationship between sleep quality and depression symptoms, with a1b3 = -0.005 (-0.011--0.001). The link between poor sleep quality and the intensity of anxiety and depression was significantly affected by the indirect effects of maladaptive CERS: effect a2b2 = 0.126 (0.106-0.147), and effect a2b4 = 0.145 (0.123-0.167). CONCLUSIONS: Individuals who experience poor sleep quality are more likely to have increased levels of anxiety and depression. However, enhancing sleep quality led to a decrease in anxiety and depression levels. Adaptive CERS did not predict anxiety, but they did predict depression. Multiple maladaptive CERS could increase levels of anxiety and depression. To prevent mental stress, it is crucial to examine sleep problems among college students, understand their cognitive strategies, promote the adoption of adaptive CERS, and reduce the reliance on maladaptive CERS.

Associations of B Vitamin-Related Dietary Pattern during Pregnancy with Birth Outcomes: A Population-Based Study in Northwest China.

This study aimed to derive a maternal dietary pattern to explain the variation in B vitamins during pregnancy and to investigate this pattern in relation to birth outcomes. A total of 7347 women who gave birth to live newborns less than one year were included. Their dietary pattern during pregnancy was derived using the reduced-rank regression method with six B vitamins as response variables. Associations between dietary pattern score and birth weight, gestational age at delivery, birth weight Z score, low birth weight, preterm, and small-for-gestational-age (SGA) were estimated using generalised linear mixed models. We identified a high B-vitamin dietary pattern characterised by high intakes of animal foods, vegetables, fungi and algae, legumes, and low intakes of oils and cereals. Women in the highest quartile of this pattern score had newborns with a 44.5 g (95% CI: 13.8, 75.2 g) higher birth weight, 0.101 (95% CI: 0.029, 0.172) higher birth weight Z score, and 27.2% (OR: 0.728; 95% CI: 0.582, 0.910) lower risk of SGA than those in the lowest quartile. Our study suggested that adherence to the high B-vitamin dietary pattern during pregnancy was associated with a higher birth weight and a lower risk of SGA.

[A study on the neuronal mechanism of retrieval of long-term digital memory in human by functional magnetic resonance imaging].

To investigate the neuronal mechanism of retrieval of long-term digital memory in healthy volunteers, functional magnetic resonance imaging (fMRI) technique was used in the study. Twenty-two right-handed volunteers were subjected to a long-term digital memory test with block-design. The memory task and control task were adopted in the experiment alternatively. The fMRI data were recorded by a Siemens 1.5T MR machine and analyzed by SPM99. The activated brain regions were shown in the Talairach coordinate. The results showed that the Brodmann's area (BA) 9 region in left middle frontal gyrus was the most activated cortex during the long-term digital memory task. The left medial frontal gyrus, left inferior frontal gyrus, right inferior frontal gyrus, cingulate gyrus, left inferior parietal lobule, left superior parietal lobule, right superior parietal lobule, right middle temporal gyrus, left lingual gyrus, left middle occipital gyrus, right middle brain, cerebellum and right caudate nucleus tail were also involved. The activation in cortices showed obvious left predominance. It is suggested that a series of brain regions with left predominance are involved in long-term digital memory. Left lateral frontal cortex would be the most important structure for information extraction, while the other cortices and their connections may be important for processing and long-term storage of digital information.

Speckled 100 kDa gene in pigs: Alternative splicing, subcellular localization, and response to interferon-α stimulation.

Speckled 100 kDa (Sp100) plays an important role in the antiviral immune response, however, little is known about porcine Sp100. In this study, porcine Sp100 was cloned and its response to interferon (IFN) α was identified. We obtained the cDNA (V1) of the gene, SP100, and seven alternative splicing variants (V2-8). Isoform V1 encoded a 386 amino acid protein and contained a homogeneously-staining region (HSR) domain. Isoforms V3, 4, 6 and 7 were deletion/insertion variants and contained HSR domain as V1. The splicing of porcine SP100 was very complicated and many transcripts existed as revealed by cloning and minigene analyses. Using GFP-fusion constructs isoforms V1, 3, 4, 6 and 7 were localized to nucleus and the nuclear localization signal was identified as PSNRKRR at positions 331-337 of V1. Porcine SP100 was unevenly distributed in all tissues studied and differentially expressed between pigs with different disease-resistance/susceptibilities. Porcine SP100 was strongly increased by IFNα due to the existence of an IFN-stimulated response element in the promoter. A single nucleotide - 70A > C polymorphism enhanced promoter activity. The results provided the basis for determining the role of Sp100 in antiviral responses and may assist in breeding pigs with high disease-resistance.

Identification of potential biomarkers for differential diagnosis between rheumatoid arthritis and osteoarthritis via integrative genome­wide gene expression profiling analysis.

The present study aimed to identify potential novel biomarkers in synovial tissue obtained from patients with Rheumatoid Arthritis (RA) and Osteoarthritis (OA) for differential diagnosis. The genome­wide expression profiling datasets of synovial tissues from RA and OA cohorts, including GSE55235, GSE55457 and GSE55584 datasets, were retrieved and used to identify differentially expressed genes (DEGs; P<0.05; false discovery rate <0.05 and Fold Change >2) between RA and OA using R software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs were performed to determine molecular and biochemical pathways associated with the identified DEGs, and a protein­protein interaction (PPI) network of the DEGs was constructed using Cytoscape software. Significant modules in the PPI network and candidate driver genes were screened using the Molecular Complex Detection Algorithm. Potential biomarkers were evaluated by receiver operating characteristic and logistic regression analyses. Large numbers of DEGs were detected, including 273, 205 and 179 DEGs in the GSE55235, GSE55457 and GSE55584 datasets, respectively. Among them, 80 DEGs exhibited identical expression trends in all the three datasets, including 49 upregulated and 31 downregulated genes in patients with RA. DEGs in patients suffering from RA compared with patients suffering from OA were predominantly associated with the primary immunodeficiency pathway, including interleukin 7 receptor (IL7R) and signal transducer activator of transcription 1 (STAT1). The sensitivity of IL7R + STAT1 to differentiate RA from OA was 93.94% with a specificity of 80.77%. The results generated from analyses of the GSE36700 dataset were closely associated with results generated from analyses of GSE55235, GSE55457 and GSE55584 datasets, which further verified the reliability of the aforementioned results. The results of the present study suggested that increased expression of IL7R and STAT1 in synovial tissue as well as in the primary immunodeficiency may be associated with RA occurrence. These identified novel biomarkers may be used to predict disease occurrence and clinically differentiate RA from OA.

Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. OBJECTIVE: Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. METHODS: Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. RESULTS: FVC% p annual change was greater for CINRG DNHS Exon 51 controls (- 6.00) versus patients in studies 201/202, study 204, and study 301 (- 2.19, P < 0.001; - 3.66, P 0.004; and - 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (- 5.67) and All CINRG DNHS (- 5.56) cohorts (P < 0.05, all comparisons). CONCLUSIONS: Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

Blockade of cytosolic phospholipase A2 alpha prevents experimental autoimmune encephalomyelitis and diminishes development of Th1 and Th17 responses.

Cytosolic phospholipase A2 alpha (cPLA2 alpha) is the rate-limiting enzyme for release of arachidonic acid, which is converted primarily to prostaglandins via the cyclooxygenase (COX) 1/2 pathways, and leukotrienes via the 5-lipoxygenase (LO) pathway. We utilized inhibitors of cPLA2 alpha, COX-1/2 and 5-LO to determine the potential roles of these enzymes in development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Blocking cPLA2 alpha prevented EAE development and greatly reduced antigen-induced production of Th1-type cytokines and IL-17. Blocking COX-1/2 delayed onset and reduced severity of EAE, and reduced production of Th1-type cytokines, but not IL-17. Blocking 5-LO delayed onset and reduced cumulative severity of EAE, but did not reduce production of Th1-type cytokines or IL-17. Finally, blockade of cPLA2 alpha from the onset of clinical EAE reduced duration of EAE relapses. Therefore, cPLA2 alpha represents a potential therapeutic target for treatment of MS.