miR-1293 suppresses osteosarcoma progression by modulating drug sensitivity in response to cisplatin treatment.

Chemotherapy is considered the primary treatment for osteosarcoma. however, its effectiveness is limited due to drug resistance and toxicity. Thus, identifying novel therapeutic targets to enhance the efficacy of chemotherapy is urgently needed. Here, we identified a novel cisplatin-sensitivity enhancing mechanism via up-regulation of the tumour suppressor gene, miR-1293. Meanwhile, higher levels of miR-1293 observed in prechemotherapy patients were associated with a more favorable prognosis. The mechanism underlying cisplatin upregulated miR-1293 expression involves hypomethylation of the miR-1293 promoter, which blocks the binding of the transcription repressor TFAP2A to the promoter. Furthermore, miR-1293 inhibits osteosarcoma progression by targeting TIMP1 to inactivate the Notch1/Hes1 and TGFBR1/Smad2/3 pathways, thereby promoting tumour cell death. The findings presented herein unveil a novel mechanism for enhancing cisplatin sensitivity and proposed a potential therapeutic strategy for osteosarcoma through pre-chemotherapy supplementation of miR-1293.

Development of the core competency-based entrustable professional activities for Master of Nursing Specialist (MNS) graduates in China.

BACKGROUND: Advanced nursing practice and education with a Master's degree as the necessary preparation, is viewed as a major strategy to cultivate senior nursing talents. Competencies are central to advanced nursing practice and education, but how can competencies be measured? Entrustable professional activities (EPAs) have been used widely in medicine as a practical approach for bridging the gaps between competency and clinical practice. Considering the paucity of research in EPAs for nursing graduates in China, it is needed to develop EPAs specifically for Chinese Master of Nursing Specialist (MNS) graduates to improve patient safety and quality patient care. OBJECTIVES: To develop and evaluate a core competency-based EPAs framework for Chinese MNS graduates. METHODS: A four-stage approach was adopted for the EPAs development, including: (1) forming a research team, (2) drafting an initial EPAs framework, (3) reviewing EPAs framework, and (4) conducting EPAs consensus assessment. RESULTS: A framework containing twelve EPAs was developed, including: 1) perform health assessments, 2) identify and prioritize nursing diagnoses, 3) formulate and implement care plan, 4) perform basic and specialized care operations, 5) recognize and manage medication needs of patients, 6) assess and manage patients with mental health problems, 7) recognize and assist in rescuing critically ill patients, 8) perform transition and handover, 9) participate in multidisciplinary team collaborative care, 10) provide health education and nursing consultation, 11) formulate and implement discharge plans, and 12) instruct nursing students in a clinical setting. The I-CVI score for the two rounds of Delphi ranged from 0.92 ∼ 1.00 and 0.96 ∼ 1.00, respectively. The mean of Equal's score for the three domains ranged from 4.20 ∼ 4.47, 4.25 ∼ 4.51, and 4.23 ∼ 4.37, respectively. CONCLUSION: The developed EPAs framework in this study is a reliable tool to assess the core competencies of Chinese MNS graduates in clinical practice and assist with their curricula design.

Exploring the sources of cervical cancer screening self-efficacy among rural females: A qualitative study.

AIM: Evidence showed self-efficacy was relevant to rural females' cervical cancer screening behaviour. However, little is known about sources of self-efficacy in cervical cancer screening among rural females. This study aimed to explore sources of self-efficacy in cervical cancer screening among rural females. DESIGN: A qualitative descriptive study was conducted. Both users and providers of cervical cancer screening services in rural areas of China were recruited through maximum variation sampling. METHODS: Individual semi-structured interviews through telephone calls were conducted. Data were analysed via six main stages of the framework method, with the social cognitive theory as a reference. RESULTS: Four main sources were identified, including personal screening experience, hearing about other women's screening experiences, professional health education and consultation, and emotional status. Personal screening experience included enactive mastery of completing the screening behaviour and cognitive mastery of internalisation of the screening. Only the experience of completing cervical cancer screening behaviour was not strong enough to improve self-efficacy. Cognitive mastery showed more critical influence. CONCLUSION: These four sources of rural females' cervical cancer screening self-efficacy matched with the major sources of self-efficacy of the social cognitive theory. Cognition was critical to influencing the screening self-efficacy. Intervention strategies aimed at enhancing rural females' cervical cancer screening self-efficacy can be developed from these four major sources. PUBLIC CONTRIBUTION: A registered nurse with rich experience in cervical cancer-related research and qualitative study was the interviewer of this study. Rural females and cervical cancer screening services providers (healthcare professionals and village staff) were recruited as interviewees. The interview guides were developed by the research team and evaluated by an expert panel including two nurse leaders of gynaecological cancer, one doctor specialised in cervical cancer, and one medical director in a local rural hospital.

3D-Printed Bioactive Scaffold Loaded with GW9508 Promotes Critical-Size Bone Defect Repair by Regulating Intracellular Metabolism.

The process of bone regeneration is complicated, and it is still a major clinical challenge to regenerate critical-size bone defects caused by severe trauma, infection, and tumor resection. Intracellular metabolism has been found to play an important role in the cell fate decision of skeletal progenitor cells. GW9508, a potent agonist of the free fatty acid receptors GPR40 and GPR120, appears to have a dual effect of inhibiting osteoclastogenesis and promoting osteogenesis by regulating intracellular metabolism. Hence, in this study, GW9508 was loaded on a scaffold based on biomimetic construction principles to facilitate the bone regeneration process. Through 3D printing and ion crosslinking, hybrid inorganic-organic implantation scaffolds were obtained after integrating 3D-printed ß-TCP/CaSiO3 scaffolds with a Col/Alg/HA hydrogel. The 3D-printed ß-TCP/CaSiO3 scaffolds had an interconnected porous structure that simulated the porous structure and mineral microenvironment of bone, and the hydrogel network shared similar physicochemical properties with the extracellular matrix. The final osteogenic complex was obtained after GW9508 was loaded into the hybrid inorganic-organic scaffold. To investigate the biological effects of the obtained osteogenic complex, in vitro studies and a rat cranial critical-size bone defect model were utilized. Metabolomics analysis was conducted to explore the preliminary mechanism. The results showed that 50 µM GW9508 facilitated osteogenic differentiation by upregulating osteogenic genes, including Alp, Runx2, Osterix, and Spp1 in vitro. The GW9508-loaded osteogenic complex enhanced osteogenic protein secretion and facilitated new bone formation in vivo. Finally, the results from metabolomics analysis suggested that GW9508 promoted stem cell differentiation and bone formation through multiple intracellular metabolism pathways, including purine and pyrimidine metabolism, amino acid metabolism, glutathione metabolism, and taurine and hypotaurine metabolism. This study provides a new approach to address the challenge of critical-size bone defects.

University-based behavioral interventions to promote safer sex practices: A systematic review and meta-analysis.

OBJECTIVE: This study aims to critically review the characteristics and effectiveness of university-based intervention to promote safer sex practice. PARTICIPANTS AND METHODS: The published studies were selected from 5 databases with the publication year restricted between 1974 and 2018. The data were then pooled using a random-effect meta-analysis. RESULTS: A total of 41 studies with 10,144 participants were included from 5,253 potentially relevant citations. Compared with minimal intervention, those people who participated in the intervention reported a statistically significant increase in the frequency of condom use (SMD 0.61; 95%CI 0.46-0.77, I2 = 9%). There was an insignificant change after the intervention (SMD 0.34; 95%CI -0.04-0.72, I2 = 72%) in communication with sexual partners and the heterogeneity existed in diversity of sessions of the intervention. CONCLUSION: Behavioral interventions can significantly increase in the frequency of condom use but not in communication with sexual partners. A standardized measurement is a necessary consideration for future studies.

Psychological distress as a mediator between workplace violence and turnover intention with caring for patients with COVID-19.

The Coronavirus Disease 2019 (COVID-19) outbreak exacerbated workplace violence and turnover intention among nurses, particularly affecting greater levels of psychological distress. This study aimed to examine psychological distress as a mediator of the relationship between workplace violence and turnover intention among clinical nurses, and to investigate whether caring for patients with COVID-19 moderates this relationship through the lens of the affective events theory. We conducted an online survey of 325 Korean registered nurses (mean age = 30.75; female = 92.6%) who work in clinical settings between August and October 2021 using the convenience sampling method. Psychological distress was measured using the 21-item Depression Anxiety Stress Scale and workplace violence using one dichotomous item adopted from the Workplace violence questionnaire. We measured turnover intention using the six-item Anticipated Turnover Scale. Caring for patients with COVID-19 was determined using one dichotomous item. The research hypotheses assume that the relationship between workplace violence and turnover intention could be mediated by psychological distress and moderated by caring for patients with COVID-19 among Korean nurses. We performed a moderated mediation analysis with workplace violence as the independent variable, turnover intention as the dependent variable, psychological distress as a potential mediator, and caring for patients with COVID-19 as a potential moderator. The analysis revealed that nurses' psychological distress among 308 nurses had a statistically significant mediating effect on the relationship between workplace violence and turnover intention. Furthermore, caring for patients with COVID-19 had a significant further moderating effect on this relationship. These findings highlight the need for psychological support services for clinical nurses at institutional and organizational levels amidst the ongoing COVID-19 pandemic. It is hoped that these findings can contribute to the development of tailored interventions for nurses caring for patients with COVID-19 to attenuate their psychological distress in a timely and effective manner.

Export of polybasic motif-containing secretory proteins BMP8A and SFRP1 from the endoplasmic reticulum is regulated by surfeit locus protein 4.

In the conventional secretory pathway, cargo receptors play important roles in exporting newly synthesized secretory proteins from the endoplasmic reticulum (ER). We previously showed that a cargo receptor, surfeit locus protein 4 (SURF4), promotes ER export of a soluble signaling molecule, sonic hedgehog, via recognizing the polybasic residues within its Cardin-Weintraub motif. In addition to sonic hedgehog, we found 30 more secretory proteins containing the polybasic motif (K/R)(K/R)(K/R)XX(K/R)(K/R), but whether SURF4 plays a general role in mediating ER export of these secretory proteins is unclear. Here, we analyzed the trafficking of four of these secretory proteins: desert hedgehog, Indian hedgehog, bone morphogenetic protein 8A (BMP8A), and secreted frizzled-related protein 1 (SFRP1). We found that the polybasic motifs contained in these cargo proteins are important for their ER export. Further analyses indicated that the polybasic motifs of BMP8A and SFRP1 interact with the triacidic motif on the predicted first luminal domain of SURF4. These interactions with SURF4 are essential and sufficient for the ER-to-Golgi trafficking of BMP8A and SFRP1. Moreover, we demonstrated that SURF4 localizes at a subpopulation of ER exit sites to regulate the ER export of its clients. Taken together, these results suggest that SURF4 is recruited to specific ER exit sites and plays a general role in capturing polybasic motif-containing secretory cargo proteins through electrostatic interactions.

Simultaneous detection of antibody responses to multiple SARS-CoV-2 antigens by a Western blot serological assay.

The nucleic acid test is still the standard assessment for the diagnosis of coronavirus disease 2019 (COVID-19), which is caused by human infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to supporting the confirmation of disease cases, serological assays are used for the analysis of antibody status and epidemiological surveys. In this study, a single Western blot strip (WBS) coated with multiple Escherichia coli (E. coli)-expressed SARS-CoV-2 antigens was developed for comprehensive studies of antibody profiles in COVID-19 patient sera. The levels of specific antibodies directed to SARS-CoV-2 spike (S), S2, and nucleocapsid (N) proteins were gradually increased with the same tendency as the disease progressed after hospitalization. The signal readouts of S, S2, and N revealed by the multi-antigen-coated WBS (mWBS)-based serological assay (mWBS assay) also demonstrated a positive correlation with the SARS-CoV-2 neutralizing potency of the sera measured by the plaque reduction neutralization test (PRNT) assays. Surprisingly, the detection signals against the unstructured receptor-binding domain (RBD) purified from E. coli inclusion bodies were not observed, although the COVID-19 patient sera exhibited strong neutralizing potency in the PRNT assays, suggesting that the RBD-specific antibodies in patient sera mostly recognize the conformational epitopes. Furthermore, the mWBS assay identified a unique and major antigenic epitope at the residues 1148, 1149, 1152, 1155, and 1156 located within the 1127-1167 fragment of the S2 subunit, which was specifically recognized by the COVID-19 patient serum. The mWBS assay can be finished within 14-16 min by using the automatic platform of Western blotting by thin-film direct coating with suction (TDCS WB). Collectively, the mWBS assay can be applied for the analysis of antibody responses, prediction of the protective antibody status, and identification of the specific epitope. KEY POINTS: • A Western blot strip (WBS) coated with multiple SARS-CoV-2 antigens was developed for the serological assay. • The multi-antigen-coated WBS (mWBS) can be utilized for the simultaneous detection of antibody responses to multiple SARS-CoV-2 antigens. • The mWBS-based serological assay (mWBS assay) identified a unique epitope recognized by the COVID-19 patient serum.

Cocktail of isobavachalcone and curcumin enhance eradication of Staphylococcus aureus biofilm from orthopedic implants by gentamicin and alleviate inflammatory osteolysis.

Orthopedic device-related infection (ODRI) caused by Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA) biofilm may lead to persist infection and severe inflammatory osteolysis. Previous studies have demonstrated that both isobavachalcone and curcumin possess antimicrobial activity, recent studies also reveal their antiosteoporosis, anti-inflammation, and immunoregulatory effect. Thus, this study aims to investigate whether the combination of isobavachalcone and curcumin can enhance the anti-S. aureus biofilm activity of gentamicin and alleviate inflammatory osteolysis in vivo. EUCAST and a standardized MBEC assay were used to verify the synergy between isobavachalcone and curcumin with gentamicin against planktonic S. aureus and its biofilm in vitro, then the antimicrobial and immunoregulatory effect of cocktail therapy was demonstrated in a femoral ODRI mouse model in vivo by µCT analysis, histopathology, quantification of bacteria in bone and myeloid-derived suppressor cell (MDSC) in bone marrow. We tested on standard MSSA ATCC25923 and MRSA USA300, 5 clinical isolated MSSA, and 2 clinical isolated MRSA strains and found that gentamicin with curcumin (62.5-250 µg/ml) and gentamicin with isobavachalcone (1.56 µg/ml) are synergistic against planktonic MSSA, while gentamicin (128 µg/ml) with curcumin (31.25-62.5, 250-500 µg/ml) and gentamicin (64-128 µg/ml) with isobavachalcone (1.56-12.5 µg/ml) exhibit synergistic effect against MSSA biofilm. Results of further study revealed that cocktail of 128 µg/ml gentamicin together with 125 µg/ml curcumin +6.25 µg/ml isobavachalcone showed promising biofilm eradication effect with synergy against USA300 biofilm in vitro. Daily intraperitoneal administration of 20 mg/kg/day isobavachalcone, 20 mg/kg/day curcumin, and 20 mg/kg/day gentamicin, can reduce inflammatory osteolysis and maintain microarchitecture of trabecular bone during orthopedic device-related MRSA infection in mice. Cocktail therapy also enhanced reduction of MDSC M1 polarization in peri-implant tissue, suppression of MDSC amplification in bone marrow, and Eradication of USA300 biofilm in vivo. Together, these results suggest that the combination of isobavachalcone and curcumin as adjuvants administrated together with gentamicin significantly enhances its antimicrobial effect against S. aureus biofilm, and can also modify topical inflammation in ODRI and protect bone microstructure in vivo, which may serve as a potential treatment strategy, especially for S. aureus induced ODRI.

Long noncoding RNA XIST: Mechanisms for X chromosome inactivation, roles in sex-biased diseases, and therapeutic opportunities.

Sexual dimorphism has been reported in various human diseases including autoimmune diseases, neurological diseases, pulmonary arterial hypertension, and some types of cancers, although the underlying mechanisms remain poorly understood. The long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in X chromosome inactivation (XCI) in female placental mammals, a process that ensures the balanced expression dosage of X-linked genes between sexes. XIST is abnormally expressed in many sex-biased diseases. In addition, escape from XIST-mediated XCI and skewed XCI also contribute to sex-biased diseases. Therefore, its expression or modification can be regarded as a biomarker for the diagnosis and prognosis of many sex-biased diseases. Genetic manipulation of XIST expression can inhibit the progression of some of these diseases in animal models, and therefore XIST has been proposed as a potential therapeutic target. In this manuscript, we summarize the current knowledge about the mechanisms for XIST-mediated XCI and the roles of XIST in sex-biased diseases, and discuss potential therapeutic strategies targeting XIST.

Elimination of Senescent Cells by Senolytics Facilitates Bony Endplate Microvessel Formation and Mitigates Disc Degeneration in Aged Mice.

Senolytics are a class of drugs that selectively eliminate senescent cells and ameliorate senescence-associated disease. Studies have demonstrated the accumulation of senescent disc cells and the production of senescence-associated secretory phenotype decrease the number of functional cells in degenerative tissue. It has been determined that clearance of senescent cell by senolytics rejuvenates various cell types in several human organs, including the largest avascular structure, intervertebral disc (IVD). The microvasculature in the marrow space of bony endplate (BEP) are the structural foundation of nutrient exchange in the IVD, but to date, the anti-senescence effects of senolytics on senescent vascular endothelial cells in the endplate subchondral vasculature remains unclear. In this study, the relationships between endothelial cellular senescence in the marrow space of the BEP and IVD degeneration were investigated using the aged mice model. Immunofluorescence staining was used to evaluate the protein expression of P16, P21, and EMCN in vascular endothelial cells. Senescence-associated ß-galactosidase staining was used to investigate the senescence of vascular endothelial cells. Meanwhile, the effects of senolytics on cellular senescence of human umbilical vein endothelial cells were investigated using a cell culture model. Preliminary results showed that senolytics alleviate endothelial cellular senescence in the marrow space of BEP as evidenced by reduced senescence-associated secretory phenotype. In the aged mice model, we found decreased height of IVD accompanied by vertebral bone mass loss and obvious changes to the endplate subchondral vasculature, which may lead to the decrease in nutrition transport into IVD. These findings may provide evidence that senolytics can eliminate the senescent cells and facilitate microvascular formation in the marrow space of the BEP. Targeting senescent cellular clearance mechanism to increase nutrient supply to the avascular disc suggests a potential treatment value of senolytics for IVD degenerative diseases.

Impact of physical activity intensity on longitudinal trajectories of cognitive function and depressive symptoms in middle-aged and older Chinese adults: Eight-year prospective study.

BACKGROUND: Little is known about how longitudinal trajectories of cognitive function and depressive symptoms are impacted by varying levels of physical activity (PA) intensity. METHOD: The data were from the China Health and Retirement Longitudinal Study, a nationally representative household study of the Chinese population aged 45 years and older. The sample included 5025 middle-aged and older adults (mean age = 57) who self-reported their cognitive function, depressive symptoms, and PA intensity (vigorous PA, moderate PA, and light PA) every two years from 2011 to 2018. RESULT: On average, every 2 years, cognitive function decreased by 0.17 points (95 % CI: [-0.22, -0.12], P < 0.05), while depressive symptoms increased by 0.23 points (95 % CI: [0.19,0.27], P < 0.001). Middle-aged and older adults who reported a minimum of 6 days/week frequency of moderate PA (ß = 0.14, 95 % CI:[0.01,0.27]) had lower reduction of cognitive function compared to people with none moderate PA but not vigorous PA (ß = 0.04, 95 % CI:[-0.11,0.19]) and light PA (ß = 0.06, 95 % CI:[-0.09,0.22]). The increase in depressive symptoms was significantly slower among middle-aged and older adults with a minimum of 6 days/week light PA (ß = -0.02, 95 % CI:[-0.03,-0.002]). CONCLUSION: A minimum of 6 days of moderate PA a week was associated with a slower reduction in cognitive function and a minimum of 6 days of light PA a week was linked to a delayed increase in depressive symptoms. In middle-aged and older adults, a tailored PA intensity may be more beneficial in achieving the maximum improvement in cognitive function and mental health.

A SURF4-to-proteoglycan relay mechanism that mediates the sorting and secretion of a tagged variant of sonic hedgehog.

SignificanceSonic Hedgehog (Shh) is a key signaling molecule that plays important roles in embryonic patterning, cell differentiation, and organ development. Although fundamentally important, the molecular mechanisms that regulate secretion of newly synthesized Shh are still unclear. Our study reveals a role for the cargo receptor, SURF4, in facilitating export of Shh from the endoplasmic reticulum (ER) via a ER export signal. In addition, our study provides evidence suggesting that proteoglycans promote the dissociation of SURF4 from Shh at the Golgi, suggesting a SURF4-to-proteoglycan relay mechanism. These analyses provide insight into an important question in cell biology: how do cargo receptors capture their clients in one compartment, then disengage at their destination?

Subjective socioeconomic status: An indicator of intimate partner violence in middle-aged adults in Hong Kong.

Intimate partner violence (IPV) has recently been recognised as a global public health issue that can cause various kinds of long-lasting physical, sexual and psychological health problems. Limited studies are available concerning the relationship between objective and subjective socioeconomic status (SES) and IPV, and the impact of experiencing IPV on health consequences. This is a cross-sectional study aiming to examine the association between objective and subjective SES as risk factors of IPV, and further investigate how they affect health status in adults who experienced IPV. A total of 400 participants were recruited from June to September 2016 among 18 districts in Hong Kong. Results from multiple linear regression showed that having a higher education (adjusted B [aB] = 0.22, 95% CI = 0.01, 0.45), having lower levels of subjective SES (aB = -0.08, 95% CI = -0.15, -0.01), experiencing childhood stress (aB = 0.58, 95% CI = 0.27, 0.89) and being married (aB = 0.60, 95% CI = 0.01, 1.19) were significantly associated with IPV. While employment and household income were not associated with IPV. Participants with higher levels of subjective SES were more likely to report somatic symptom (aB = -0.44, 95% CI = -0.87, -0.02), anxiety (aB = -0.38, 95% CI = -0.72, -0.04) and depressive symptom (aB = -0.52, 95% CI = -0.94, -0.10). Low subjective SES, instead of low objective SES, was found associated with IPV in Chinese adults. A priority for future studies is the confirmation and expansion of subjective SES and its function in clinical measures. Programmes instilling hope and optimism will be helpful to enhance subjective SES and boost physical and mental well-being in IPV survivors.

Effects of Social Networking Service (SNS) Addiction on Mental Health Status in Chinese University Students: Structural Equation Modeling Approach Using a Cross-sectional Online Survey.

BACKGROUND: Although social networking services (SNSs) have become popular among young people, problematic SNS use has also increased. However, little is known about SNS addiction and its association with SNS use patterns and mental health status. OBJECTIVE: This study aims to test the mediating role of SNS addiction between SNS use patterns and mental health status among Chinese university students in Hong Kong (HK). METHODS: An online cross-sectional survey was conducted using a convenience sampling method. In total, 533 university students (323 [66.9%] female, mean age [SD]=20.87 [2.68] years) were recruited from February to March 2019. Multiple linear regression was used to assess the association between SNS use and SNS addiction. Structural equation modeling (SEM) was performed to examine the pathways and associations among SNS use, SNS addiction, psychosocial status, and mental health status (including anxiety and depressive symptoms). RESULTS: A longer time spent on SNSs per day (>3 h), a longer time spent on each SNS access (≥31 min), a higher frequency of SNS access (≤every 30 min), a longer duration of SNS use before sleeping (≥61 min), and a shorter duration from waking to first SNS use (≤5 min) were significantly associated with a higher level of SNS addiction (adjusted beta [aß]=6.03, 95% CI 4.66-7.40; aß=4.99, 95% CI 3.14-6.83; aß=5.89, 95% CI 4.14-7.64; aß=5.92, 95% CI 4.19-7.65; and aß=3.27, 95% CI 1.73-4.82, respectively). SEM showed a significant mediating effect of SNS addiction in the relationship between SNS use and psychosocial status, and mental health status, including an indirect effect (ß=0.63, 95% CI 0.37-0.93) and the total effect (ß=0.44, 95% CI 0.19-0.72), while the direct effect was insignificant (ß=-0.19, 95% CI -0.49 to 0.08). CONCLUSIONS: SNS use patterns were associated with SNS addiction, and SNS addiction mediated the associations between SNS use, psychosocial status, and mental health status of Chinese university students in HK. The findings suggest that screening for and addressing excessive SNS use are needed to prevent SNS addiction and mental distress among young people.

The Role of Long Non-coding RNAs in Human Imprinting Disorders: Prospective Therapeutic Targets.

Genomic imprinting is a term used for an intergenerational epigenetic inheritance and involves a subset of genes expressed in a parent-of-origin-dependent way. Imprinted genes are expressed preferentially from either the paternally or maternally inherited allele. Long non-coding RNAs play essential roles in regulating this allele-specific expression. In several well-studied imprinting clusters, long non-coding RNAs have been found to be essential in regulating temporal- and spatial-specific establishment and maintenance of imprinting patterns. Furthermore, recent insights into the epigenetic pathological mechanisms underlying human genomic imprinting disorders suggest that allele-specific expressed imprinted long non-coding RNAs serve as an upstream regulator of the expression of other protein-coding or non-coding imprinted genes in the same cluster. Aberrantly expressed long non-coding RNAs result in bi-allelic expression or silencing of neighboring imprinted genes. Here, we review the emerging roles of long non-coding RNAs in regulating the expression of imprinted genes, especially in human imprinting disorders, and discuss three strategies targeting the central long non-coding RNA UBE3A-ATS for the purpose of developing therapies for the imprinting disorders Prader-Willi syndrome and Angelman syndrome. In summary, a better understanding of long non-coding RNA-related mechanisms is key to the development of potential therapeutic targets for human imprinting disorders.

Identification of aberrantly methylated differentially expressed genes targeted by differentially expressed miRNA in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary bone tumors diagnosed in children and adolescents. Recent studies have shown a prognostic role of DNA methylation in various cancers, including OS. The aim of this study was to identify the aberrantly methylated genes that are prognostically relevant in OS. METHODS: The differentially expressed mRNAs, miRNAs and methylated genes (DEGs, DEMs and DMGs respectively) were screened from various GEO databases, and the potential target genes of the DEMs were predicted by the RNA22 program. The protein-protein interaction (PPI) networks were constructed using the STRING database and visualized by Cytoscape software. The functional enrichment and survival analyses of the screened genes was performed using the R software. RESULTS: Forty-seven downregulated hypermethylated genes and three upregulated hypomethylated genes were identified that were enriched in cell activation, migration and proliferation functions, and were involved in cancer-related pathways like JAK-STAT and PI3K-AKT. Eight downregulated hypermethylated tumor suppressor genes (TSGs) were identified among the screened genes based on the TSGene database. These hub genes are likely involved in OS genesis, progression and metastasis, and are potential prognostic biomarkers and therapeutic targets. CONCLUSIONS: TSGs including PYCARD, STAT5A, CXCL12 and CXCL14 were aberrantly methylated in OS, and are potential prognostic biomarkers and therapeutic targets. Our findings provide new insights into the role of methylation in OS progression.

Anti-TNF-α therapy alters the gut microbiota in proteoglycan-induced ankylosing spondylitis in mice.

Ankylosing spondylitis is a chronic, progressive disease, and its treatment is relevant to the gut microbiota. Anti-tumor necrosis factor-alpha (anti-TNF-α) therapy alters the gut microbiota in many diseases, including inflammatory bowel disease. However, little is known about the effect of TNF-α blocker treatment on the gut microbiota in ankylosing spondylitis. Herein, the effect of a TNF-α blocker on the gut microbiota in proteoglycan-induced arthritis was investigated. Proteoglycan-induced mice were treated with an rhTNFR:Fc solution of etanercept (5 µg/g) for 4 weeks. rhTNFR:Fc treatment attenuated the arthritis incidence and severity of arthritis in the proteoglycan-induced mice and decreased inflammation in the ankle joints and ameliorated ileal tissue destruction. Moreover, high gut permeability occurred, and zonula occludens-1 and occludin protein levels were reduced in proteoglycan-induced mice. These levels were significantly restored by the administration of rhTNFR:Fc. The serum TNF-α and IL-17 levels were also decreased. In addition, flora analysis via 16S rDNA high-throughput sequencing revealed that rhTNFR:Fc treatment restored the gut microbiota composition to a composition similar to that in control mice. In conclusion, anti-TNF-α therapy attenuated proteoglycan-induced arthritis progression and modulated the gut microbiota and intestinal barrier function. These results provide new insights for anti-TNF-α therapy strategies via regulating the gut microbiota in ankylosing spondylitis.

Rifaximin Alters Intestinal Microbiota and Prevents Progression of Ankylosing Spondylitis in Mice.

Recently, accumulating evidence has suggested that gut microbiota may be involved in the occurrence and development of ankylosing spondylitis (AS). It has been suggested that rifaximin have the ability to modulate the gut bacterial communities, prevent inflammatory response, and modulate gut barrier function. The goal of this work is to evaluate the protective effects of rifaximin in fighting AS and to elucidate the potential underlying mechanism. Rifaximin were administered to the proteoglycan (PG)-induced AS mice for 4 consecutive weeks. The disease severity was measured with the clinical and histological of arthritis and spondylitis. Intestinal histopathological, pro-inflammatory cytokine levels and the intestinal mucosal barrier were evaluated. Then, western blot was performed to explore the toll-like receptor 4 (TLR-4) signal transducer and NF-κB expression. Stool samples were collected to analyze the differences in the gut microbiota via next-generation sequencing of 16S rDNA. We found that rifaximin significantly reduced the severity of AS and resulted in down-regulation of inflammatory factors, such as TNF-α, IL-6, IL-17A, and IL-23. Meanwhile, rifaximin prevented ileum histological alterations, restored intestinal barrier function and inhibited TLR-4/NF-κB signaling pathway activation. Rifaximin also changed the gut microbiota composition with increased Bacteroidetes/Firmicutes phylum ratio, as well as selectively promoting some probiotic populations, including Lactobacillales. Our results suggest that rifaximin suppressed progression of AS and regulated gut microbiota in AS mice. Rifaximin might be useful as a novel treatment for AS.