Circular RNA PDK1 targets miR-4731-5p to enhance TNXB expression in ligamentum flavum hypertrophy.

Hypertrophic ligamentum flavum (LF) is a main factor responsible for lumbar spinal stenosis (LSS); however, the exact mechanisms of the pathogenesis of these processes remain unknown. This study aimed to elucidate whether circular RNAs and microRNAs regulate the pathogenesis of LF and LSS, especially focusing on circPDK1 (hsa_circ_0057105), a circRNA targeting pyruvate dehydrogenase kinase 1 and differentially expressed in LF tissues between lumbar disk herniation and LSS patients. The circPDK1/miR-4731 and miR-4731/TNXB (Tenascin XB) interactions were predicted and validated by luciferase reporter assay. Colony formation, wound-healing, and MTT assays were used for estimating cell proliferation and migration. Protein expression levels were evaluated using Western blotting. TNXB expression was verified using immunohistochemistry (IHC). Overexpressing circPDK1 promoted the proliferation, migration, and expression of fibrosis-related protein (alpha smooth muscle actin (α-SMA), lysyl oxidase like 2 (LOXL2), Collagen I, matrix metalloproteinase-2 (MMP-2) and TNXB) in LF whereas miR-4731-5p showed opposite effects. The expression of TNXB was promoted by circPDK1; contrary results were observed with miR-4731-5p. Co-overexpression of miR-4731-5p partially reversed the proliferative and fibrosis-prompting effects of circPDK1 or TNXB. The circPDK1-miR-4731-TNXB pathway may be proposed as a regulatory axis in LF hypertrophy, which might shed light on in-depth research of LSS, as well as providing a novel therapeutic target for LF hypertrophy-induced LSS.

Explainable Learning-Based Timeout Optimization for Accurate and Efficient Elephant Flow Prediction in SDNs.

Accurately and efficiently predicting elephant flows (elephants) is crucial for optimizing network performance and resource utilization. Current prediction approaches for software-defined networks (SDNs) typically rely on complete traffic and statistics moving from switches to controllers. This leads to an extra control channel bandwidth occupation and network delay. To address this issue, this paper proposes a prediction strategy based on incomplete traffic that is sampled by the timeouts for the installation or reactivation of flow entries. The strategy involves assigning a very short hard timeout (Tinitial) to flow entries and then increasing it at a rate of r until flows are identified as elephants or out of their lifespans. Predicted elephants are switched to an idle timeout of 5 s. Logistic regression is used to model elephants based on a complete dataset. Bayesian optimization is then used to tune the trained model Tinitial and r over the incomplete dataset. The process of feature selection, model learning, and optimization is explained. An extensive evaluation shows that the proposed approach can achieve over 90% generalization accuracy over 7 different datasets, including campus, backbone, and the Internet of Things (IoT). Elephants can be correctly predicted for about half of their lifetime. The proposed approach can significantly reduce the controller-switch interaction in campus and IoT networks, although packet completion approaches may need to be applied in networks with a short mean packet inter-arrival time.

Neuromedin U Induces Activation of Peripheral Group 2 Innate Lymphoid Cells through the ERK Pathway in Allergic Rhinitis Patients.

INTRODUCTION: In allergic diseases, group 2 innate lymphoid cells (ILC2s) play critical roles. Neuromedin U (NMU), a highly conserved multifunctional neuropeptide, is secreted by cholinergic neurons and involved in asthma pathogenesis by amplifying lung inflammation driven by ILC2s. However, the precise effects of NMU on ILC2s in allergic rhinitis (AR) and related diseases remain unclear. METHODS: A total of 15 patients with persistent AR and 8 healthy controls (HCs) were enrolled in the study. Visual analog scale (VAS) scores are used to assess the severity of clinical symptoms in AR patients. The percentages of ILC2s in peripheral blood mononuclear cells (PBMCs) were enumerated using flow cytometry. The soluble or intracellular cytokines (IL-5 and IL-13) in PBMCs or sorted ILC2s were assessed in response to various stimuli with IL-33, NMU, IL-33 combined with extracellular signal-related kinase (ERK) inhibitor or NMU combined with ERK inhibitor in the presence of IL-2. RESULTS: We confirmed the proportion of circulating ILC2s was significantly higher in AR patients than in HCs. ILC2s levels were found to be positively related to VAS scores. We also discovered that the release of IL-5 and IL-13 in AR patients' PBMCs stimulated by NMU (p < 0.0001 and p < 0.0001, respectively) or IL-33 (p = 0.002; p = 0.044, respectively) was significantly higher than in HCs. In AR patients, NMU stimulated PBMCs or ILC2s to generate greater inflammatory factors IL-5 and IL-13 compared to IL-33. Furthermore, we observed that NMU-promoted ILC2s activation and proliferation functions were restricted when the ERK pathway was inhibited. CONCLUSION: NMU effectively activated ILC2s in AR patients to produce Th2-type cytokines, and this activation can be prevented by ERK pathway inhibitors. Our findings shed new light on the neuro-immune mechanism of AR and offer new insights into its prevention and treatment.

Axial superior facet slope may determine anterior or posterior atlantoaxial displacement secondary to os odontoideum and compensatory mechanisms of the atlantooccipital joint and subaxial cervical spine.

OBJECTIVE: To introduce novel parameters in determining directions of os odontoideum (OO) with atlantoaxial displacement (AAD) and compensations of cervical sagittal alignment after displacement. METHODS: Analysis was performed on 96 cases receiving surgeries for upper cervical myelopathy caused by OO with AAD from 2011 to 2021. Twenty-four patients were included in the OO group and divided into the OO-anterior displacement (AD) group and the OO-posterior displacement (PD) group by displacement. Seventy-two patients were included as the control (Ctrl) group and divided into Ctrl-positive (Ctrl-P) group and Ctrl-negative (Ctrl-N) group by axial superior facet slope (ASFS) in a neutral position. ASFS, the sum of C2 slope (C2S) and axial superior facet endplate angle (ASFEA), was measured and calculated by combining cervical supine CT with standing X-ray. Cervical sagittal parameters were measured to analyse the atlantoaxial facet and compensations after AAD. RESULTS: Atlas inferior facet angle (AIFA), ASFS, and ASFEA in Ctrl-P significantly differed from OO-AD.C0-C1, C1-C2, C0-C2, C2-C7, C2-C7 SVA, and C2S in Ctrl-P significant differed from the OO-AD group. C2-C7 SVA and C2S in Ctrl-N significantly were smaller than the OO-PD group. C1-C2 correlated with C0-C1 and C2-C7 negatively in the OO group. Slight kyphosis of C1-C2 in OO-AD was compared with lordosis of C1-C2 in Ctrl-P, inducing increased extension of C0-C1 and C2-C7. Mildly increased lordosis of C1-C2 in OO-PD was compared with C1-C2 in Ctrl-N, triggering augmented flexion of C0-C1 and C2-C7. CONCLUSION: ASFS was vital in determining directions of OO with AAD and explaining compensations. ASFS and ASFEA could provide pre- and intraoperative guidelines. KEY POINTS: • ASFS may determine the directions and compensatory mechanisms of AAD secondary to OO. • ASFS could be achieved by the sum of ASFEA and C2S.

Repair of Oroantral Fistulas Using Free Bone and Mucoperiosteal Flaps After Endoscopic Removal of the Medial Wall of the Maxillary Sinus.

INTRODUCTION: Oroantral fistula (OAF) refers to a pathological connection between the oral cavity and maxillary sinus. It may lead to symptoms that include purulent mucus, nasal congestion, facial swelling, bad breath, and nasal regurgitation of food, all of which negatively impact patients' quality of life. OBJECTIVE: This study presents a novel approach for OAF repair using a 2-layered structure composed of free bone and a mucoperiosteal flap obtained from the medial wall of maxillary sinus. MATERIALS AND METHODS: Ten OAF patients who underwent repair using this method were retrospectively reviewed between August 2015 and June 2022. RESULTS: The extraction of maxillary molars was the most common cause of OAF. The size of the fistulas ranged from 1×2 mm to 5×8 mm. Nine of the 10 patients achieved successful OAF closure following the initial operation using the 2-layer structure composed of free bone and mucoperiosteal flag. One patient was lost to follow-up. The 9 patients were observed for 6 months to 1 year, and they exhibited no obvious complications or recurrence. CONCLUSION: The use of free bone and mucoperiosteal flag from the medial wall of maxillary sinus through an endoscope was effective for OAF repair.

2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The increasing rates of obesity and type 2 diabetes mellitus may lead to increased prevalence of nonalcoholic fatty liver disease (NAFLD). We aimed to determine the current and recent trends on the global and regional prevalence of NAFLD. METHODS: Systematic search from inception to March 26, 2020 was performed without language restrictions. Two authors independently performed screening and data extraction. We performed meta-regression to determine trends in NAFLD prevalence. RESULTS: We identified 17,244 articles from literature search and included 245 eligible studies involving 5,399,254 individuals. The pooled global prevalence of NAFLD was 29.8% (95% confidence interval [CI], 28.6%-31.1%); of these, 82.5% of included articles used ultrasound to diagnose NAFLD, with prevalence of 30.6% (95% CI, 29.2%-32.0%). South America (3 studies, 5716 individuals) and North America (4 studies, 18,236 individuals) had the highest NAFLD prevalence at 35.7% (95% CI, 34.0%-37.5%) and 35.3% (95% CI, 25.4%-45.9%), respectively. From 1991 to 2019, trend analysis showed NAFLD increased from 21.9% to 37.3% (yearly increase of 0.7%, P < .0001), with South America showing the most rapid change of 2.7% per year, followed by Europe at 1.1%. CONCLUSIONS: Despite regional variation, the global prevalence of NAFLD is increasing overall. Policy makers must work toward reversing the current trends by increasing awareness of NAFLD and promoting healthy lifestyle environments.

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

High hepatitis C virus cure rates with approved interferon-free direct-acting antivirals among diverse mainland Chinese patients including genotypes 3a and 3b.

BACKGROUND AND AIM: Globally, China has the highest chronic hepatitis C (CHC) burden, but its real-world direct-acting antiviral (DAA) data are limited. Our aim is to investigate the real-world outcome of China Food and Drug Administration-approved DAA therapies across mainland China including those with genotype (GT) 3. METHODS: The REAL-C is a multinational real-world interferon-free DAA-treated CHC registry of several mainland China and other Asian centers. We evaluated the sustained virological response rate 12 weeks after end of treatment (SVR12), adverse events, and treatment effect on liver function and fibrosis (fibrosis-4 index). RESULTS: We analyzed 859 DAA-treated CHC patients (6/1/2017-5/30/2019) from 12 mainland China centers (three municipalities and nine provinces): median age 52, 49.9% male, 33.1% cirrhosis, 95% treatment naïve, and 2.5% HBsAg+ . The most common GT was GT1b (523, 62.2%), followed by GT2a (156, 18.5%), GT3b (74, 8.8%), GT3a (41, 4.9%), and GT6 (37, 4.4%). SVR12 rates were 98.0% overall (95% confidence interval 96.9-98.8%), 98.1% for GT1b, 96.8% GT2a, 100% GT3a, 97.3% GT3b, and 100% GT6. Baseline cirrhosis and male sex but not prior treatment history, renal dysfunction, age, and GTs were associated with SVR12. For both cirrhotic and non-cirrhotic patients, there were significant improvement in liver function tests, alpha fetoprotein, and fibrosis-4 index with SVR12. Serious adverse events were rare (1.1%) with only nine patients discontinuing therapy prematurely and anemia being the most common adverse event (13.1%, mostly with ribavirin). CONCLUSIONS: In real-world Chinese patients with diverse GTs, Chinese Food and Drug Administration-approved interferon-free DAAs were well tolerated, provided high cure rates (98.0% overall) including GT3a/3b, and led to improvement of liver function.

A novel COL2A1 mutation causing spondyloepiphyseal dysplasia congenita in a Chinese family.

BACKGROUND: Spondyloepiphyseal dysplasia congenita is an autosomal dominant cartilaginous dysplasia characterized by short trunk, abnormal epiphysis, and flattened vertebral body. Skeletal features of SEDC are present at birth and evolve over time. Other features of SEDC include myopia and/or retinal degeneration with retinal detachment and cleft palate. A mutation in the COL2A1 gene located in 12q13.11 is considered as one of the important causes of SEDC. In 2016, Barat-Houari et al. reported a large number of COL2A1 mutations. Among them, a non-synonymous mutation in COL2A1 exon 37, c.2437G>A (p. Gly813Arg), has been reported to cause SEDC in only one patient from France so far. METHODS: We followed up a patient with SEDC phenotype and his family members. The clinical manifestations, physical examination and imaging examination, including X-ray, CT and MRI, were recorded. The whole-exome sequencing was used to detect the patients' genes, and the pathogenic genes were screened out by comparing with many databases. RESULTS: We report a Chinese patient with SEDC phenotype characterized by short trunk, abnormal epiphysis, flattened vertebral body, narrow intervertebral space, dysplasia of the odontoid process, chicken chest, scoliosis, hip and knee dysplasia, and joint hypertrophy. Gene sequencing analysis showed that the patient had a heterozygous mutation (c.2437G>A; p. Gly813Arg) in the COL2A1 gene. No COL2A1 mutation or SEDC phenotype was observed in his family members. This is the first report of SEDC caused by this mutation in an East Asian family. CONCLUSION: This report provides typical clinical, imaging, and genetic evidence for SEDC, confirming that a de novo mutation in the COL2A1 gene, c.2437G>A (p. Gly813Arg), causes SEDC in Chinese population.

Laminoplasty with selective fusion at unstable segment versus laminectomy with fusion for multilevel cervical myelopathy: a case-control study.

BACKGROUND: Segmental cervical instability is a risk factor for the progression of osteophytic bone spurs and development of myelopathy, and is treated as a relative contraindication of cervical laminoplasty. The aim of this study was to compare laminoplasty with selective fixation (LPSF) versus laminectomy with fusion (LCF) in patients with multilevel cervical myelopathy accompanied by segmental instability. METHODS: A case-control study was conducted by reviewing data from 63 patients who underwent LPSF (n = 30) or LCF (n = 33). Cervical alignment, range of motion (ROM), neurologic status and axial symptom severity pre-operation, 3-days after operation, and at the final follow-up (minimum 24 months) were measured and compared between groups. RESULTS: Postoperation, patients in the LPSF group lost 31.1 ± 17.3 % of cervical lordosis and 43.2 ± 10.9 % cervical ROM while patients in the LCF group lost 5.7 ± 8.2 % and 67.9 ± 15.5 %, respectively. Both LPSF and LCF groups significantly improved neurologic status and axial symptom severity at the final follow-up with similar between-group results(P > 0.05). Blood loss, operation time, hospital stay, and medical cost in the LPSF group were significantly less than in the LCF group(P < 0.05). CONCLUSIONS: In 2 years of clinical observation, LPSF was effective in maintaining the stability of the cervical spine with less sacrifice of mobility and surgical trauma for multilevel myelopathy with segmental instability compared to LCF.

Application of a modified biological flocculant in total nitrogen treatment of leather wastewater.

Leather wastewater harms the ecological environment and human health. In this study, a modified bio-flocculant was prepared to facilitate treatment of leather wastewater. A bio-flocculant produced by Bacillus cereus was combined with amphoteric starch and modified using a cerium ammonium nitrate initiator. Single factor optimization and orthogonal optimization were used to determine the optimal preparation conditions as follows: amphoteric starch-to-flocculant ratio = 22:30; reaction temperature = 64 °C; initiator dosage = 2.00%; reaction time = 15 min; stirring speed = 600 rpm; and flocculation system pH = 8.0. At a dosage of 1 g/L added to simulated leather industry wastewater, the flocculation efficiency (98.17%) and the total nitrogen removal efficiency (100.00%) of modified bio-flocculant was superior to that achieved by 1 g/L of unmodified bio-flocculant (72.16% and 50.00%, respectively), amphoteric starch (8.50% and 0.00%) and polyacrylamide (95.55% and 75.00%). Analysis of natural and flocculated precipitates in the wastewater showed that the modified bio-flocculant significantly changed several characteristics of the flocculated particles; in addition, it promoted the removal of nitrogenous substances in the process of denitrification. These changes helped explain the material's flocculating ability. The results confirmed that the modified bio-flocculant was an effective additive for treating leather wastewater.

Real-World Effectiveness From the Asia Pacific Rim Liver Consortium for HBV Risk Score for the Prediction of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Treated With Oral Antiviral Therapy.

BACKGROUND: Patients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort. METHODS: Adult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV (REAL-B) score. RESULTS: A total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001). CONCLUSIONS: The REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy.

[Study on mechanism of salidroside against liver fibrosis by regulating CXCL16].

In order to investigate the effect of salidroside on inhibiting liver fibrosis and its relationship with CXC chemokine ligand 16(CXCL16) in vivo and in vitro, totally 45 C57 BL/6 J male mice were randomly divided into normal group, model group and salidroside group, with 15 mice in each group. The mice in model group and salidroside group were injected intraperitoneally with 15% carbontetrachloride(CCl_4) olive oil solution to establish liver fibrosis model, and the mice in normal group were injected intraperitoneally with the same dose of olive oil. Salidroside group was given with 100 mg·kg~(-1 )salidroside by gavage, while the normal group and model group received the same amount of double distilled water by gavage. All mice were sacrificed after 5 weeks of intragastric administration. The pathological changes of mouse liver were observed by hematoxylin-eosin(HE) staining, and the degree of liver fibrosis was observed by sirius red staining. The protein expressions of collagen Ⅰ(ColⅠ), α-smooth muscle actin(α-SMA), fibronectin(FN), CXCL16, phosphorylated Akt(p-Akt), Akt in liver tissues were detected by Western blot. Hepatic stellate cell line JS 1 was cultured in vitro and divided into control group, model group(100 µg·L~(-1) CXCL16) and salidroside group(100 µg·L~(-1) CXCL16+1×10~(-5) mol·L~(-1) salidroside). Cell migration was detected by cell scratch, the mRNA expressions of ColⅠ and α-SMA were detected by RT-PCR, and the protein expressions of p-Akt and Akt were detected by Western blot. As compared with the normal group, the protein expressions of ColⅠ, α-SMA, FN, CXCL16, and p-Akt in the model group were significantly increased, and salidroside could reduce the expression of these indicators(P<0.05 or P<0.01). In vitro, CXCL16 could promote the migration of JS 1, increase the mRNA expressions of ColⅠ and α-SMA in JS 1, and enhance Akt phosphorylation in JS 1(P<0.05 or P<0.01). As compared with the model group, salidroside could inhibit the migration of JS 1 induced by CXCL16(P<0.05), and reduce the high expression of ColⅠ and α-SMA mRNA and the phosphorylation of Akt in JS 1 induced by CXCL16(P<0.05). In conclusion, salidroside might attenuate CCl_4-induced liver fibrosis in mice by inhibiting the migration, activation and Akt phosphorylation of hepatic stellate cells induced by CXCL16.

Tenofovir Versus Entecavir for Hepatocellular Carcinoma Prevention in an International Consortium of Chronic Hepatitis B.

INTRODUCTION: It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differ in their effectiveness for preventing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS: This retrospective cohort study analyzed an international consortium that encompassed 19 centers from 6 countries or regions composed of previously untreated CHB patients then treated with either ETV or TDF monotherapy. Those who developed HCC before antiviral treatment or within 1 year of therapy were excluded. The association between antiviral regimen and HCC risk was evaluated using competing-risk survival regression. We also applied propensity score matching (PSM) to 1:1 balance the 2 treatment cohorts. A total of 5,537 patients were eligible (n = 4,837 received ETV and n = 700 received TDF) and observed for HCC occurrence until December 23, 2018. Before PSM, the TDF cohort was significantly younger and had generally less advanced diseases. RESULTS: In the unadjusted analysis, TDF was associated with a lower risk of HCC (subdistribution hazard ratio [SHR], 0.45; 95% confidence interval [CI], 0.26-0.79; P = 0.005). The multivariable analysis, however, found that the association between TDF and HCC no longer existed (SHR, 0.81; 95% CI, 0.42-1.56; P = 0.52) after adjustment for age, sex, country, albumin, platelet, α-fetoprotein, cirrhosis, and diabetes mellitus. Furthermore, the PSM analysis (n = 1,040) found no between-cohort differences in HCC incidences (P = 0.51) and no association between regimens (TDF or ETV) and HCC risk in the multivariable-adjusted analysis (adjusted SHR, 0.89; 95% CI, 0.41-1.92; P = 0.77). DISCUSSION: TDF and ETV did not significantly differ in the prevention of HCC in patients with CHB.

Attachment-Oriented Endoscopic Treatment of Inverted Papilloma Involving the Frontal Sinus/Recess.

PURPOSE: Sinonasal inverted papilloma (IP) is a benign but locally aggressive tumor for which an endoscopic or external surgical approach is the treatment of choice. Complete resection of IP involving the frontal sinus/recess forms one of the most challenging procedures in the field of sinonasal surgery. This study aims to present our experience in the management of extensive frontal sinus IP based on the attachment sites of the tumor. METHODS: Thirteen patients with IP involving the frontal sinus/recess between 2010 and 2018 were presented. The data collected include demographic data, tumor attachment sites, tumor extension, tumor staging according to Meng's staging system, surgical approach, recurrence, and follow-up. RESULTS: The patients were successfully treated by endoscopic surgery without any additional external approaches. The attachment sites of the IP were multifocal in some patients. No recurrence was identified after an average follow-up period of 52.88 months. No major intra- or postoperative complications were observed. CONCLUSION: The present study shows that attachment-oriented excision for IP involving the frontal sinus/recess is an acceptable approach. Surgeons should select the surgical approach based on the attachment sites of the tumor rather than the extension of the tumor. Even more importantly, the tumor attachment sites should include the sites of adhesion to the bone wall and the site of origin.

LogEvent2vec: LogEvent-to-Vector Based Anomaly Detection for Large-Scale Logs in Internet of Things.

Log anomaly detection is an efficient method to manage modern large-scale Internet of Things (IoT) systems. More and more works start to apply natural language processing (NLP) methods, and in particular word2vec, in the log feature extraction. Word2vec can extract the relevance between words and vectorize the words. However, the computing cost of training word2vec is high. Anomalies in logs are dependent on not only an individual log message but also on the log message sequence. Therefore, the vector of words from word2vec can not be used directly, which needs to be transformed into the vector of log events and further transformed into the vector of log sequences. To reduce computational cost and avoid multiple transformations, in this paper, we propose an offline feature extraction model, named LogEvent2vec, which takes the log event as input of word2vec to extract the relevance between log events and vectorize log events directly. LogEvent2vec can work with any coordinate transformation methods and anomaly detection models. After getting the log event vector, we transform log event vector to log sequence vector by bary or tf-idf and three kinds of supervised models (Random Forests, Naive Bayes, and Neural Networks) are trained to detect the anomalies. We have conducted extensive experiments on a real public log dataset from BlueGene/L (BGL). The experimental results demonstrate that LogEvent2vec can significantly reduce computational time by 30 times and improve accuracy, comparing with word2vec. LogEvent2vec with bary and Random Forest can achieve the best F1-score and LogEvent2vec with tf-idf and Naive Bayes needs the least computational time.

Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration.

Although mesenchymal stem cells (MSCs) transplantation into the IVD (intervertebral disc) may be beneficial in inhibiting apoptosis of nucleus pulposus cells (NPCs) and alleviating IVD degeneration, the underlying mechanism of this therapeutic process has not been fully explained. The purpose of this study was to explore the protective effect of MSC-derived exosomes (MSC-exosomes) on NPC apoptosis and IVD degeneration and investigate the regulatory effect of miRNAs in MSC-exosomes and associated mechanisms for NPC apoptosis. MSC-exosomes were isolated from MSC medium, and its anti-apoptotic effect was assessed in a cell and rat model. The down-regulated miRNAs in apoptotic NPCs were identified, and their contents in MSC-exosomes were detected. The target genes of eligible miRNAs and possible downstream pathway were investigated. Purified MSC-exosomes were taken up by NPCs and suppressed NPC apoptosis. The levels of miR-21 were down-regulated in apoptotic NPCs while MSC-exosomes were enriched in miR-21. The exosomal miR-21 could be transferred into NPCs and alleviated TNF-α induced NPC apoptosis by targeting phosphatase and tensin homolog (PTEN) through phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Intradiscal injection of MSC-exosomes alleviated the NPC apoptosis and IVD degeneration in the rat model. In conclusion, MSC-derived exosomes prevent NPCs from apoptotic process and alleviate IVD degeneration, at least partly, via miR-21 contained in exosomes. Exosomal miR-21 restrains PTEN and thus activates PI3K/Akt pathway in apoptotic NPCs. Our work confers a promising therapeutic strategy for IVD degeneration.

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway.

BACKGROUND/AIMS: Hypertrophic ligamentum flavum (LF) is a major cause of lumbar spinal stenosis. Our previous work showed that high levels of lysophosphatidic acid (LPA) expression are positively correlated with LF hypertrophy. This study aimed to further unveil how LPA regulates LF hypertrophy Methods: We studied LPAR1 expression in human LF cells using PCR and western blotting. Cell viability cell cycle, apoptosis rate and molecular mechanisms were assayed in LPAR1 knockdown or overexpression LF cells. LF hypertrophy and the molecular mechanism was confirmed in human samples and in in vivo studies. RESULTS: The expression of LPA and its receptor LPAR1 is significantly higher in tissues or cells harvested from hypertrophic LF compared to healthy controls. Moreover, LPA promoted LF cell proliferation by interacting with LPAR1. This conclusion is supported by the fact that depletion or overexpression of LPAR1 changed the effect of LPA on LF cell proliferation. LPA also inhibits apoptosis in LF cells through the receptor LPAR1. Importantly, we demonstrated that the LPA-LPAR1 interaction initiated Akt phosphorylation and determined cell proliferation and apoptosis. Our in vitro findings were supported by our in vivo evidence that lyophilized LPA significantly induced LF hypertrophy via the LPAR1-Akt signaling pathway. More importantly, targeted inhibition of LPAR1 by Ki16425 with a gel sponge implant effectively reduced LPA-associated LF hypertrophy. Taken together, these data indicate that LPA binds to the receptor LPAR1 to induce LF cell proliferation and inhibit apoptosis by activating AKT signaling cascades. Targeting this signaling cascade with Ki16425 is a potential therapeutic strategy for preventing LF hypertrophy. CONCLUSION: LPA-LPAR1-Akt activation is positively correlated with the proliferation and survival of LF cells. LPAR1 could be a target for new drugs and the development of new therapeutic methods for treating LF hypertrophy.

Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein.

OBJECTIVES: Circular RNAs (circRNAs) have been proven to function as competing endogenous RNAs to interact with microRNAs (miRNAs) and influence the expression of miRNA target mRNAs. In this study, we investigated whether circRNAs could act as competing endogenous RNAs to regulate the pathological process of intervertebral disc degeneration (IVDD). METHODS: The role and mechanism of a circRNA, circVMA21, in IVDD were explored in nucleus pulposus (NP) cells and degenerative NP tissues from patients and rat models. The interaction between circVMA21 and miR-200c as well as the target mRNA, X linked inhibitor-of-apoptosis protein (XIAP), was examined. RESULTS: The decreased expression of XIAP in the inflammatory cytokines-treated NP cells and the degenerative NP tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of extracellular matrix. miR-200c regulated NP cell viability and functions through inhibiting XIAP. circVMA21 acted as a sponge of miR-200c and functioned in NP cells through targeting miR-200c and XIAP. Intradiscal injection of circVMA21 alleviated IVDD in the rat model. CONCLUSIONS: CircVMA21 could alleviate inflammatory cytokines-induced NP cell apoptosis and imbalance between anabolism and catabolism of extracellular matrix through miR-200c-XIAP pathway. It provides a potentially effective therapeutic strategy for IVDD.