The knockdown of lncRNA DLGAP1-AS2 suppresses osteosarcoma progression by inhibiting aerobic glycolysis via the miR-451a/HK2 axis.

Osteosarcoma (OS) is one of the most aggressive bone tumors worldwide. Emerging documents have shown that long noncoding RNAs (lncRNAs) elicit crucial regulatory functions in the process of tumorigenesis. LncRNA DLGAP1-AS2 is recognized as a regulator in several types of cancers, but its biological functions and molecular mechanisms in OS remain to be elucidated. RT-qPCR and In situ hybridization (ISH) were used to evaluate DLGAP1-AS2 expression in OS samples. Western blotting was used for the measurement of the protein levels of hexokinase 2 (HK2) and epithelial-mesenchymal transition (EMT)-related markers. The proliferation of OS cells was determined using a CCK-8 assay and EdU assay. TUNEL assay and flow cytometry were performed to assess OS cell apoptosis. Glucose metabolism in vitro assays were used. The binding relations among miR-451a, HK2, and DLGAP1-AS2 were validated by luciferase reporter assay. The cellular distribution of DLGAP1-AS2 in OS cells was determined by FISH and subcellular fractionation assays. Mouse xenograft models were established to perform the experiments in vivo. We found that DLGAP1-AS2 expression was upregulated in OS tissues and cells. Downregulation of DLGAP1-AS2 expression suppressed the malignancy of OS cells by restraining cell proliferation, the EMT process, invasiveness, migration, and aerobic glycolysis and accelerating apoptotic behaviors. Of note, silenced DLGAP1-AS2 restrained tumor growth and metastasis in vivo. However, DLGAP1-AS2 overexpression accelerated the progression of OS. We further found that DLGAP1-AS2 upregulation was induced by hypoxia and low glucose. Additionally, DLGAP1-AS2 bound to miR-451a to upregulate HK2 expression. Rescue assays revealed that the DLGAP1-AS2/miR-451a/HK2 axis contributed to OS cell malignancy by promoting aerobic glucose metabolism. Overall, these findings revealed a new regulatory pathway where DLGAP1-AS2 upregulated HK2 expression by sponging miR-451a to accelerate OS development.

Mining the Influencing Factors and Their Asymmetrical Effects of mHealth Sleep App User Satisfaction From Real-world User-Generated Reviews: Content Analysis and Topic Modeling.

BACKGROUND: Sleep disorders are a global challenge, affecting a quarter of the global population. Mobile health (mHealth) sleep apps are a potential solution, but 25% of users stop using them after a single use. User satisfaction had a significant impact on continued use intention. OBJECTIVE: This China-US comparison study aimed to mine the topics discussed in user-generated reviews of mHealth sleep apps, assess the effects of the topics on user satisfaction and dissatisfaction with these apps, and provide suggestions for improving users' intentions to continue using mHealth sleep apps. METHODS: An unsupervised clustering technique was used to identify the topics discussed in user reviews of mHealth sleep apps. On the basis of the two-factor theory, the Tobit model was used to explore the effect of each topic on user satisfaction and dissatisfaction, and differences in the effects were analyzed using the Wald test. RESULTS: A total of 488,071 user reviews of 10 mainstream sleep apps were collected, including 267,589 (54.8%) American user reviews and 220,482 (45.2%) Chinese user reviews. The user satisfaction rates of sleep apps were poor (China: 56.58% vs the United States: 45.87%). We identified 14 topics in the user-generated reviews for each country. In the Chinese data, 13 topics had a significant effect on the positive deviation (PD) and negative deviation (ND) of user satisfaction. The 2 variables (PD and ND) were defined by the difference between the user rating and the overall rating of the app in the app store. Among these topics, the app's sound recording function (ß=1.026; P=.004) had the largest positive effect on the PD of user satisfaction, and the topic with the largest positive effect on the ND of user satisfaction was the sleep improvement effect of the app (ß=1.185; P<.001). In the American data, all 14 topics had a significant effect on the PD and ND of user satisfaction. Among these, the topic with the largest positive effect on the ND of user satisfaction was the app's sleep promotion effect (ß=1.389; P<.001), whereas the app's sleep improvement effect (ß=1.168; P<.001) had the largest positive effect on the PD of user satisfaction. The Wald test showed that there were significant differences in the PD and ND models of user satisfaction in both countries (all P<.05), indicating that the influencing factors of user satisfaction with mHealth sleep apps were asymmetrical. Using the China-US comparison, hygiene factors (ie, stability, compatibility, cost, and sleep monitoring function) and 2 motivation factors (ie, sleep suggestion function and sleep promotion effects) of sleep apps were identified. CONCLUSIONS: By distinguishing between the hygiene and motivation factors, the use of sleep apps in the real world can be effectively promoted.

Diabetic ferroptosis plays an important role in triggering on inflammation in diabetic wound.

Impaired wound healing is a major complication of diabetes and involves sustained inflammation and oxidative stress at the wound site. Here, we investigated the potential involvement of ferroptosis, a newly discovered form of cell death characterized by iron-dependent accumulation of lipid peroxides in the pathogenesis of diabetic wound healing. Fibroblasts and vascular endothelial cells exposed to high glucose concentrations in vitro contained elevated levels of reactive oxygen species (ROS), lipid peroxidation products, and ferroptosis-associated proteins and displayed reduced survival and migration. These effects of high glucose were all significantly reduced by treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Similarly, in a rat model of diabetes, direct application of Fer-1 to the wound site reduced the expression of oxidative stress and inflammation markers and accelerated wound healing via activation of the anti-inflammatory phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Our results implicate ferroptosis in wound healing and identify a potential new therapeutic target for difficult-to-treat diabetic wounds.NEW & NOTEWORTHY Ferroptosis-related characteristic changes were found in diabetic wound models. Inhibition of ferroptosis improved inflammatory infiltration of diabetic wounds. PI3K/AKT signal pathway was rescued by restraining of ferroptosis. Mitigation of ferroptosis in diabetic wound promoted the wound healing.

MiR-487a-3p suppresses the malignant development of pancreatic cancer by targeting SMAD7.

OBJECTIVE: To uncover the role of microRNA-487a-3p (miR-487a-3p) in influencing the malignant development of pancreatic cancer and the involvement of its downstream target SMAD7. METHODS: MiR-487a-3p level in 40 pancreatic cancer and paracancerous tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between miR-487a-3p level and clinical indicators in pancreatic cancer patients was analyzed. Regulatory effects of miR-487a-3p on biological phenotypes of pancreatic cancer cells were assessed. At last, the involvement of miR-487a-3p and its downstream target SMAD7 in pancreatic cancer was determined. RESULTS: MiR-487a-3p was lowly expressed in pancreatic cancer tissues. Pancreatic cancer patients expressing a low level of miR-487a-3p suffered high metastasis rate and poor prognosis. Overexpression of miR-487a-3p markedly attenuated proliferative and migratory capacities in pancreatic cancer cells. SMAD7 was the downstream target of miR-487a-3p, which was highly expressed in pancreatic cancer samples. Overexpression of SMAD7 reversed the regulatory effects of miR-487a-3p on pancreatic cancer cell phenotypes. CONCLUSIONS: MiR-487a-3p is downregulated in pancreatic cancer samples, which is linked to metastasis and prognosis in pancreatic cancer. It inhibits the malignant development of pancreatic cancer by negatively regulating SMAD7.

The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity.

BACKGROUND/AIMS: Alpha-synuclein (α-Syn) is a neuronal protein that is highly implicated in Parkinson's disease (PD), and protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that is associated with neurodegenerative diseases, such as PD. α-Syn can directly upregulate PP2A activity, but the underling mechanism remains unclear. Therefore, we investigated the molecular mechanism of α-Syn regulating PP2A activity. METHODS: α-Syn and its truncations were expressed in E.coli, and purified by affinity chromatography. PP2A Cα and its mutants were expressed in recombinant baculovirus, and purified by affinity chromatography combined with gel filtration chromatography. The interaction between α-Syn and PP2A Cα was detected by GST pull-down assay. PP2A activity was investigated by the colorimetric assay. RESULTS: The hydrophobic non-amyloid component (NAC) domain of α-Syn interacted with PP2A Cα and upregulated its activity. α-Syn aggregates reduced its ability to upregulate PP2A activity, since the hydrophobic domain of α-Syn was blocked during aggregation. Furthermore, in the hydrophobic center of PP2A Cα, the residue of I123 was responsible for PP2A to interact with α-Syn, and its hydrophilic mutation blocked its interaction with α-Syn as well as its activity upregulation by α-Syn. CONCLUSIONS: α-Syn bound to PP2A Cα by the hydrophobic interaction and upregulated its activity. Blocking the hydrophobic domain of α-Syn or hydrophilic mutation on the residue I123 in PP2A Cα all reduced PP2A activity upregulation by α-Syn. Overall, we explored the mechanism of α-Syn regulating PP2A activity, which might offer much insight into the basis underlying PD pathogenesis.

MicroRNA-1270 is associated with poor prognosis and its inhibition yielded anticancer mechanisms in human osteosarcoma.

In this work, we explored the aberrant expression pattern, clinical association, and functional regulations of microRNA-1270 (miR-1270) in osteosarcoma. Among in vitro osteosarcoma cell lines and in situ tissues of osteosarcoma patients, quantitative real time-PCR was used to examine their endogenous miR-1270 expression. Clinical correlation between endogenous miR-1270 expression and clinicopathological features of osteosarcoma patients, as well as cancer patients' overall survival, was statistically examined. MiR-1270 was downregulated in 143B and MG-63 cells by lentiviral transduction. The mechanistic effects of miR-1270 downregulation on osteosarcoma in vitro proliferation and migration, as well as in vivo tumorigenesis, were further examined. MiR-1270 was aberrantly upregulated in both in vitro osteosarcoma cell lines and in situ human tumors. Statistical analysis demonstrated endogenous miR-1270 was associated with poor clinical outcomes and shorter overall survival of osteosarcoma patients. Lentivirus-induced miR-1270 downregulation inhibited cancer in vitro proliferation and migration, as well as in vivo tumorigenesis. Aberrant upregulation miR-1270 may be a prognostic biomarker for osteosarcoma patients with poor clinical outcomes and shorter survival. Inhibition of miR-1270 may also be a potential therapeutic target for anticancer treatment in osteosarcoma. © 2018 IUBMB Life, 70(7):625-632, 2018.

How to best assess abdominal obesity.

PURPOSE OF REVIEW: Abdominal obesity, especially the increase of visceral adipose tissue (VAT), is closely associated with increased mortality related to cardiovascular disease, diabetes, and fatty liver disease. This review provides an overview of the recent advances for abdominal obesity measurement. RECENT FINDINGS: Compared to simple waist circumference, emerging three-dimensional (3D) body-scanning techniques also measure abdominal volume and shape. Abdominal dimension measures have been implemented in bioelectrical impedance analysis to improve accuracy when estimating VAT. Geometrical models have been applied in ultrasound to convert depth measurement into VAT area. Only computed tomography (CT) and MRI can provide direct measures of VAT. Recent advances in imaging allow for evaluating functional aspects of abdominal fat such as brown adipose tissue and fatty acid composition. SUMMARY: Waist circumference is a simple, inexpensive method to measure abdominal obesity. CT and MRI are reference methods for measuring VAT. Further studies are needed to establish the accuracy for dual-energy X-ray absorptiometry in estimating longitudinal changes of VAT. Further studies are needed to establish whether bioelectrical impedance analysis, ultrasound, or 3D body scanning is consistently superior to waist circumference in estimating VAT in different populations.

Diabetes mellitus and the risk of gastrointestinal cancer in women compared with men: a meta-analysis of cohort studies.

BACKGROUND: The increasing epidemic proportions of diabetes mellitus (DM) are a major cause of premature illness and death. However, whether DM confers the same excess risk of gastrointestinal cancer for women as it does for men remains controversial. The purpose of this study was to estimate the relation between DM and gastrointestinal cancer in women compared with men after accounting for other major risk factors based on cohort studies. METHODS: We performed a meta-analysis of cohort studies published through May 2017 from PubMed, Embase, and the Cochrane Library. Studies with cohort designs were stratified by sex and reported the relation between DM and esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), colon cancer (CC), rectal cancer (RC), hepatocellular carcinoma (HCC), or pancreatic cancer (PC) risk. The ratio of relative risk (RRR) between men and women was employed to measure the sex differences in the relation between DM and gastrointestinal cancer with a random effects model with inverse variance weighting. RESULTS: We included 38 cohort studies reporting data on 18,060,698 individuals. The pooled RRR indicated DM women was associated with an increased risk of GC (RRR: 1.14; 95%CI: 1.06-1.22; p < 0.001), while the risk of HCC was lower (RRR: 0.88; 95%CI: 0.79-0.99; p = 0.031) as compared with DM men. Further, there was no evidence of sex differences in the RRR between participants who had DM compared with those without DM for EC (p = 0.068), CRC (p = 0.618), and PC (p = 0.976). In addition, the pooled RRR showed a statistically significant association between DM and the risk of CC in women compared with men (RRR: 0.93; 95%CI: 0.86-1.00; p = 0.050), and there was no evidence of sex differences for RC among participants with DM compared to those without DM (p = 0.648). Finally, the sex differences of the comparison between DM and non-DM for gastrointestinal cancer risk at different sites were variable after stratification for different effect estimates. CONCLUSIONS: The findings of this study suggested female-to-male RRR of DM was increased for GC, while reduced for HCC and CC. However, there were no sex differences for the relation between DM and the risk of EC, CRC, PC, and RC.

Identification of mitochondria-related biomarkers in childhood allergic asthma.

BACKGROUND: The mechanism of mitochondria-related genes (MRGs) in childhood allergic asthma (CAS) was unclear. The aim of this study was to find new biomarkers related to MRGs in CAS. METHODS: This research utilized two CAS-related datasets (GSE40888 and GSE40732) and extracted 40 MRGs from the MitoCarta3.0 Database. Initially, differential expression analysis was performed on CAS and control samples in the GSE40888 dataset to obtain the differentially expressed genes (DEGs). Differentially expressed MRGs (DE-MRGs) were obtained by overlapping the DEGs and MRGs. Protein protein interactions (PPI) network of DE-MRGs was created and the top 10 genes in the degree ranking of Maximal Clique Centrality (MCC) algorithm were defined as feature genes. Hub genes were obtained from the intersection genes from the Least absolute shrinkage and selection operator (LASSO) and EXtreme Gradient Boosting (XGBoost) algorithms. Additionally, the expression validation was conducted, functional enrichment analysis, immune infiltration analysis were finished, and transcription factors (TFs)-miRNA-mRNA regulatory network was constructed. RESULTS: A total of 1505 DEGs were obtained from the GSE40888, and 44 DE-MRGs were obtained. A PPI network based on these 44 DE-MRGs was created and revealed strong interactions between ADCK5 and MFN1, BNIP3 and NBR1. Four hub genes (NDUFAF7, MTIF3, MRPS26, and NDUFAF1) were obtained by taking the intersection of genes from the LASSO and XGBoost algorithms based on 10 signature genes which obtained from PPI. In addition, hub genes-based alignment diagram showed good diagnostic performance. The results of Gene Set Enrichment Analysis (GSEA) suggested that hub genes were closely related to mismatch repair. The B cells naive cells were significantly expressed between CAS and control groups, and MTIF3 was most strongly negatively correlated with B cells naive. In addition, the expression of MTIF3 and MRPS26 may have influenced the inflammatory response in CAS patients by affecting mitochondria-related functions. The quantitative real-time polymerase chain reaction (qRT‒PCR) results showed that four hub genes were all down-regulated in the CAS samples. CONCLUSION: NDUFAF7, MTIF3, MRPS26, and NDUFAF1 were identified as an MRGs-related biomarkers in CAS, which provides some reference for further research on CAS.

Cerebellar gray matter and white matter damage among older adults with prediabetes.

AIMS: To investigate alterations in cerebrum and cerebellum in prediabetes. Cerebellar injury in diabetes is traceable, but it has not been systematically studied, and whether cerebellar injury occurs and the degree of damage in prediabetes are not known. METHODS: The current study investigated cerebral and cerebellar gray matter volume, white matter volume, white matter microstructure and white matter hyperintensity on T1-weighted, T2-weighted fluid-attenuated inversion recovery and diffusion tensor imaging scans in 78 individuals with normal glucose metabolism, 92 with prediabetes, and 108 with type 2 diabetes. RESULTS: Participants with prediabetes showed significant gray matter and white matter atrophy, microstructural damage in the cerebellar and cerebral regions. Additionally, widespread structural alterations were observed in the diabetic stage. The function of the damaged brain area was further decoded in Neurosynth, and the damaged cerebellar area with prediabetic lesions was closely related to motor function, while the area affected by diabetes was related to complex cognitive function in addition to motor function. CONCLUSIONS: Cerebellar injury had already appeared in the prediabetic stage, and cerebellar injury was aggravated in the diabetic stage; therefore, the cerebellum is a key area that is damaged early in the development of diabetes.

Acupuncture improved hepatic steatosis in HFD-induced NAFLD rats by regulating intestinal microbiota.

Background: Intestinal dysbiosis has been increasingly implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Acupuncture has been shown to have beneficial effects on NAFLD, but the mechanism is not yet clear. This study explores the potential beneficial effects of acupuncture on intestinal microbiota in NAFLD. Methods: An NAFLD model in Sprague Dawley rats was established using a high-fat diet (HFD) for 10 weeks. NAFLD rats were randomly divided into control, model, and acupuncture groups. Following acupuncture treatment over 6 weeks, automated biochemical analysis was used to measure serum lipid metabolism parameters, including levels of alanine transferase, aspartate transferase, alkaline phosphatase, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The level of serum inflammatory factors interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α) were measured by enzyme-linked immunosorbent assay. The characteristics of steatosis were evaluated using quantitative computed tomography, hematoxylin and eosin staining, and Oil Red O staining in the liver, while the intestinal microbiota was determined using 16S rRNA gene sequencing. Results: Acupuncture decreased the systemic inflammatory response, ameliorated dyslipidemia, and improved liver function indexes in NAFLD model rats. Tomography and staining indicated that acupuncture reduced steatosis and infiltration of inflammatory cells in the liver. 16S rRNA analysis showed that acupuncture reduced the Firmicutes to Bacteroidetes (F/B) ratio, increased the abundance of microbiota, including Bacteroidales_S24-7_group, Prevotellaceae, Bacteroidaceae, Blautia, norank_f_Bacteroidales_S24-7_group, Bacteroides, and Prevotella_9, and decreased the abundance of Ruminococcaceae_UCG-014. Correlation analysis suggested a close correlation between lipid metabolism, inflammation factors, hepatic steatosis, and the changed intestinal microbiota. Conclusion: Acupuncture can significantly improve lipid metabolism and the systemic inflammatory response in HFD-induced NAFLD rats, potentially by regulating intestinal microbiota composition.

Understanding the research on tracking, diagnosing, and intervening in sleep disorders using mHealth apps: Bibliometric analysis and systematic reviews.

Objectives: In solving the global challenge of sleep disorders, Mobile Health app is one of the important means to monitor, diagnose, and intervene in sleep disorders. This study aims to (1) summarize the status and trends of research in this field; (2) assess the production and usage of sleep mHealth apps; (3) calculate the conversion rate of grants that the proportion of newly developed apps from being funded and developed to published on application stores. Methods: Using bibliometric and content analysis methods, based on "Research Paper-Product Output-Product Application" chain and considering the "Research Grants" of articles, we conducted a systematic review of eight databases, to identify relevant studies over the last decade. Results: Over the past decade, 1399 authors published 313 papers in 182 journals and conferences. The number of publications increased with an average annual growth of 41.6%. The current focus area is research using cognitive behavioral therapy to intervene in sleep. Sleep-staging tracking is a shortcoming of this field. A total 368 sleep mHealth apps (233 newly developed and 135 existing) were examined in 313 papers; 323 grants supported 178 articles (56.9%). Only 12 of the newly developed apps are used in the real world, resulting in a 9% grant conversion rate. Conclusions: In the last decade, the field of tracking, diagnosing, and intervening in sleep disorders using mHealth apps has shown a trend of rapid development. However, the conversion rate of products from being funded and developed for use by end-users is low.

Correlation between the Human Development Index and the Incidence and Mortality of Non-Hodgkin Lymphoma.

OBJECTIVE: This study was to examine the relationship between socioeconomic status and the incidence and mortality of non-Hodgkin lymphoma (NHL). METHODS: We compared the age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and the ASMR to ASIR ratio (MIR) at national and regional levels and studied the correlation between the MIR and the human development index (HDI) in 2012 and 2018. RESULTS: The highest ASIR was in North America in 2012 and in Australia in 2018, and the lowest ASIR was in Central and South Asia in both 2012 and 2018. The highest ASMR was in North Africa in both 2012 and 2018, and the lowest ASMR was in Eastern Asia and South-Central Asia in 2012 and in South-Central Asia in 2018. The lowest MIR was in Australia in both 2012 and 2018, and the highest MIR was in Western Africa in both 2012 and 2018. HDI was strongly negatively correlated with MIR (r: -0.8810, P<0.0001, 2012; r: -0.8895, P<0.0001, 2018). Compared to the 2012 data, the MIR in the intermediate HDI countries significantly deceased and the HDI in low and high HDI countries significantly increased in 2018. CONCLUSION: The MIR is negatively correlated with HDI. Increasing the HDI in low and intermediate HDI countries may reduce the MIR and increase the survival of patients with NHL.

Sex differences in major cardiovascular outcomes and fractures in patients with subclinical thyroid dysfunction: a systematic review and meta-analysis.

OBJECTIVE: To evaluate whether sex differences in the associations of subclinical hypothyroidism (SH) and subclinical hyperthyroidism (SCH) with the risks of major adverse cardiovascular events (MACE) and fractures. METHODS: The PubMed, EmBase, and Cochrane Library databases were searched for eligible studies from inception until November 2021. The relative risk (RR) ratio with the 95% confidence interval (CI) was used to identify sex differences in the associations of SH and SCH with the risks of MACE and fractures. All analyses were performed using a random-effects model. RESULTS: Twenty-four cohort studies (in 3,480,682 patients) were selected for meta-analysis. There were no sex differences in the associations of SH and SCH with the risks of atrial fibrillation, all-cause mortality, cardiac death, coronary heart disease, heart failure, MACE, stroke, fracture. Subgroup analyses indicated a greater risk of MACE in men than in women with SH if follow-up was ≥10.0 years (RR ratio 2.44; 95% CI 1.17-5.10; P = 0.017). The risk of any fracture was greater in men than in women with SH if follow-up was <10.0 years (RR ratio 1.17; 95% CI 1.03-1.34; P = 0.017) and in studies with a high level of adjustment (RR ratio 1.16; 95% CI 1.02-1.32; P = 0.022). However, the risk of hip fracture was lower in men than in women with SH on pooling of studies with low adjustment (RR ratio 0.53; 95% CI 0.29-0.97; P = 0.039). CONCLUSIONS: There may be sex-related differences in the risks of MACE, any fracture, and hip fracture in patients with SH.

Risk Factors and Imaging Mechanisms of Fatigue After Mild Ischemic Stroke: An Exploratory Study From a Single Chinese Center.

Objective: To explore the biochemical risk factors and imaging mechanisms of post fatigue after mild ischemic stroke among a Chinese population. Methods: Forty consecutive patients with mild ischemic stroke within onset of 14 ± 2 days were enrolled between March and June 2018. The clinical information, scale data, biomarkers in peripheral venous blood, and imaging data during hospitalization and follow-up period were collected. Results: Patient age (range 34-78) was positively correlated with the prevalence of fatigue (p = 0.009). Both blood norepinephrine and serotonin levels during hospitalization were negatively correlated to the prevalence of post-stroke fatigue (model 1 p = 0.009 and model 2 P = 0.043, respectively). Infarct of right cerebral hemisphere is positively correlated with the occurrence of fatigue after mild ischemic stroke (p = 0.020). Compared to non-fatigue patients, amplitude of low-frequency fluctuation (ALFF) was lower in several areas of brain in stroke patients with fatigue, including the right orbital inferior frontal, right inner orbital frontal, right frontal, right triangular frontal inferior, right anterior and lateral cingulate, and right medial frontal gyruses. Analysis of the difference in functional connectivity between the fatigue and non-fatigue groups found no cluster. Conclusions: Frontal lobe-related neural pathways may play an essential role in the regulation of fatigue after mild ischemic stroke. Abnormal neural circuits may reduce the levels of neurotransmitters such as serotonin and norepinephrine and lead to post-stroke fatigue.

LINC00174 Facilitates Cell Proliferation, Cell Migration and Tumor Growth of Osteosarcoma via Regulating the TGF-ß/SMAD Signaling Pathway and Upregulating SSH2 Expression.

Osteosarcoma (OS), a frequent malignant tumor which mainly occurs in the bone. The roles of long noncoding RNAs (lncRNAs) have been revealed in cancers, including OS. LncRNA long intergenic non-protein coding RNA (LINC00174) has been validated as an oncogene in several cancers. However, the role of LINC00174 in OS has not been explored. In our research, loss-of-function assays were conducted to explore the function of LINC00174 in OS cells. Then, we explored the downstream pathway of LINC00174 in OS cells. Bioinformatics, RNA pull-down and RIP experiments investigated the downstream mechanism of LINC00174 in OS cells. Finally, in vivo assays clarified the effect of LINC00174 on tumorigenesis. We found that LINC00174 was upregulated in OS tissues and cells. LINC00174 knockdown repressed OS cell growth. Mechanistically, LINC00174 knockdown suppressed the TGF-ß/SMAD pathway. LINC00174 interacted with miR-378a-3p, and slingshot protein phosphatase 2 (SSH2) 3'UTR was targeted by miR-378a-3p in OS cells. Rescue assays showed that SSH2 upregulation or miR-378a-3p inhibition counteracted the inhibitory effect of LINC00174 depletion in OS cell growth. Additionally, LINC00174 depletion suppressed tumor growth in mice. In conclusion, LINC00174 promotes OS cellular malignancy and tumorigenesis via the miR-378a-3p/SSH2 axis and the TGF-ß/SMAD pathway, which might provide a novel insight for OS treatment.

Profile Screening of Differentially Expressed lncRNAs of Circulating Leukocytes in Type 2 Diabetes Patients and Differences From Type 1 Diabetes.

Long noncoding RNAs (lncRNAs) have been reported to have multiple functions and can be used as markers of various diseases, including diabetes. This study was conducted to determine the lncRNA profile in leukocytes from patients with type 2 diabetes (T2D). Differential expression of lncRNAs in T2D and type 1 diabetes (T1D) was also examined. RNA sequencing was performed in a critically grouped sample of leukocytes from T2D patients and healthy persons. A total of 845 significantly differentially expressed lncRNAs were identified, with 260 downregulated and 585 upregulated lncRNAs in T2D. The analysis of functions of DE-lncRNA and constructed co-expression networks (CNC) showed that 21 lncRNAs and 117 mRNAs harbored more than 10 related genes in CNC. Fourteen of 21 lncRNAs were confirmed to be significantly differentially expressed was detected by qPCR between the T2D and control validation cohorts. We also identified a panel of 4 lncRNAs showing significant differences in expression between T1D and T2D. Collectively, hundreds of novel DE-lncRNAs we identified in leukocytes from T2D patients will aid in epigenetic mechanism studies. Fourteen confirmed DE-lncRNAs can be regarded as diagnostic markers or regulators of T2D, including 4 lncRNAs that chould distinguish T1D and T2D in clinical practice to avoid misdiagnosis.

Impact of Sleep Duration on Depression and Anxiety After Acute Ischemic Stroke.

Background: Abnormal sleep duration predicts depression and anxiety. We seek to evaluate the impact of sleep duration before stroke on the occurrence of depression and anxiety at 3 months after acute ischemic stroke (AIS). Methods: Nationally representative samples from the Third China National Stroke Registry were used to examine cognition and sleep impairment after AIS (CNSR-III-ICONS). Based on baseline sleep duration before onset of stroke as measured by using the Pittsburgh Sleep Quality Index (PSQI), 1,446 patients were divided into four groups: >7, 6-7, 5-6, and <5 h of sleep. Patients were followed up with the General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) for 3 months. Poststroke anxiety (PSA) was defined as GAD-7 of ≥5 and poststroke depression (PSD) as PHQ-9 of ≥5. The association of sleep duration with PSA and PSD was evaluated using multivariable logistic regression. Results: The incidences of PSA and PSD were 11.2 and 17.6% at 3 months, respectively. Compared to a sleep duration of >7 h, 5-6 h, and <5 h of sleep were identified as risk factors of PSA [odds ratio (OR), 1.95; 95% confidence interval (CI), 1.24-3.07; P < 0.01 and OR, 3.41; 95% CI, 1.94-6.04; P < 0.01) and PSD (OR, 1.47; 95% CI, 1.00-2.17; P = 0.04 and OR, 3.05; 95% CI, 1.85-5.02; P < 0.01), while 6-7 h of sleep was associated with neither PSA (OR, 1.09; 95% CI, 0.71-1.67; P = 0.68) nor PSD (OR, 0.92; 95% CI, 0.64-1.30; P = 0.64). In interaction analysis, the impact of sleep duration on PSA and PSD was not affected by gender (P = 0.68 and P = 0.29, respectively). Conclusions: Sleep duration of shorter than 6 h was predictive of anxiety and depression after ischemic stroke.

Hepatic insulin resistance induced by mitochondrial oxidative stress can be ameliorated by sphingosine 1-phosphate.

The bioactive lipid mediator sphingosine 1-phosphate (S1P) is considered to be involved in the development of insulin resistance (IR) via effects on oxidative stress; the mechanism however is not yet fully revealed. To this end, we investigated the role and mechanism of S1P on hepatic IR. We found that treatment of the normal human liver cell LO2 with 1000 nM insulin for 48 h reduced glucose uptake and increased serine phosphorylation of insulin receptor substrate-1, indicating a reduction in insulin receptor signaling. Moreover, the same concentration of insulin caused accumulation of reactive oxygen species (ROS) in the cytosol and mitochondria, and enhanced expression of the antioxidant transcription factor (Nrf2) and upregulated Nrf2 nuclear translocation. Using known inhibitors and donors of ROS (H2O2, ·O2-, ·OH), the results demonstrated the differential roles for the specific ROS in regulating IR in LO2 cells, with H2O2 having a more significant inhibitory role compared with ·O2- and ·OH. Cell treatment with S1P at 0.1-5.0 µM reversed the effects of high insulin concentrations on ROS generation, glucose uptake, and insulin signaling. H2O2 also reversed the beneficial effects of S1P in alleviating IR. These results show that H2O2 signaling plays a key determinant in hepatic IR induced by insulin. S1P can ameliorate hepatic IR by reducing mitochondrial ROS generation, and the possible anti-IR effect mechanism may be involved in H2O2 signaling.

A Genome-Wide Analysis of Long Noncoding RNAs in Circulating Leukocytes and Their Differential Expression in Type 1 Diabetes Patients.

Long noncoding RNAs (lncRNAs) regulate gene expression at different levels in various diseases, including type 1 diabetes (T1D). However, the expression of circulating lncRNAs in leukocytes in T1D has not been well documented. To identify differentially expressed lncRNAs between T1D patients and healthy controls, RNA sequencing was performed on samples of leukocytes collected from both healthy persons and T1D patients. The categories, enriched pathways, coexpression networks, and the characteristics of novel lncRNAs were analyzed to provide an extensive profile. qPCR was adopted to validate the differential expression of lncRNAs in the validation cohort. A total of 14,930 lncRNAs and 16,063 mRNAs were identified in the peripheral blood leukocyte of T1D patients. After optimization using an adjusted p value (threshold of <0.05), 393 circulating lncRNAs were identified, of which 69 were downregulated and 324 were upregulated in T1D patients. Gene Ontology analysis indicated that these lncRNAs and mRNAs were enriched in the immune system category. Further analysis showed that 61.28% of the novel lncRNAs were conserved in humans. A set of 12 lncRNAs were selected for qPCR validation, and 9 of 12 lncRNAs were confirmed to show significant differential expression between the T1D and control validation cohorts. Among the 9 confirmed lncRNAs, lncRNA MSTRG.128697 and lncRNA MSTRG.128958 were novel and human-specific; however, further validation is required. lncRNA MSTRG.63013 has orthologous sequences in the mouse genome and was identified as a key node for etiology and pathophysiology in animal studies, which will help understand the epigenetic mechanisms of T1D complications.