C-C chemokine receptor 5 is essential for conventional NK cell trafficking and liver injury in a murine hepatitis virus-induced fulminant hepatic failure model.

BACKGROUND: Previous studies have demonstrated that natural killer (NK) cells migrated into the liver from peripheral organs and exerted cytotoxic effects on hepatocytes in virus-induced liver failure. AIM: This study aimed to investigate the potential therapeutic role of chemokine receptors in the migration of NK cells in a murine hepatitis  virus strain 3 (MHV-3)-induced fulminant hepatic failure (MHV-3-FHF) model and its mechanism. RESULTS: By gene array analysis, chemokine (C-C motif) receptor 5 (CCR5) was found to have remarkably elevated expression levels in hepatic NK cells after MHV-3 infection. The number of hepatic CCR5+ conventional NK (cNK) cells increased and peaked at 48 h after MHV-3 infection, while the number of hepatic resident NK (rNK) cells steadily declined. Moreover, the expression of CCR5-related chemokines, including macrophage inflammatory protein (MIP)-1α, MIP-1ß and regulated on activation, normal T-cell expressed and secreted (RANTES) was significantly upregulated in MHV-3-infected hepatocytes. In an in vitro Transwell migration assay, CCR5-blocked splenic cNK cells showed decreased migration towards MHV-3-infected hepatocytes, and inhibition of MIP-1ß or RANTES but not MIP-1α decreased cNK cell migration. Moreover, CCR5 knockout (KO) mice displayed reduced infiltration of hepatic cNK cells after MHV-3 infection, accompanied by attenuated liver injury and improved mouse survival time. Adoptive transfer of cNK cells from wild-type mice into CCR5 KO mice resulted in the abundant accumulation of hepatic cNK cells and aggravated liver injury. Moreover, pharmacological inhibition of CCR5 by maraviroc reduced cNK cell infiltration in the liver and liver injury in the MHV-3-FHF model. CONCLUSION: The CCR5-MIP-1ß/RANTES axis played a critical role in the recruitment of cNK cells to the liver during MHV-3-induced liver injury. Targeted inhibition of CCR5 provides a therapeutic approach to ameliorate liver damage during virus-induced acute liver injury.

Cav3.1-driven bursting firing in ventromedial hypothalamic neurons exerts dual control of anxiety-like behavior and energy expenditure.

The central nervous system has evolved to coordinate the regulation of both the behavior response to the external environment and homeostasis of energy expenditure. Recent studies have indicated the dorsomedial ventromedial hypothalamus (dmVMH) as an important hub that regulates both innate behavior and energy homeostasis for coping stress. However, how dmVMH neurons control neuronal firing pattern to regulate chronic stress-induced anxiety and energy expenditure remains poorly understood. Here, we found enhanced neuronal activity in VMH after chronic stress, which is mainly induced by increased proportion of burst firing neurons. This enhancement of VMH burst firing is predominantly mediated by Cav3.1 expression. Optogenetically evoked burst firing of dmVMH neurons induced anxiety-like behavior, shifted the respiratory exchange ratio toward fat oxidation, and decreased food intake, while knockdown of Cav3.1 in the dmVMH had the opposite effects, suggested that Cav 3.1 as a crucial regulator. Interestingly, we found that fluoxetine (anxiolytics) could block the increase of Cav3.1 expression to inhibit the burst firing, and then rescued the anxiety-like behaviors and energy expenditure changes. Collectively, our study first revealed an important role of Cav3.1-driven bursting firing of dmVMH neurons in the control of anxiety-like behavior and energy expenditure, and provided potential therapeutic targets for treating the chronic stress-induced emotional malfunction and metabolism disorders.

3D surface reconstruction of transparent objects using laser scanning with a four-layers refinement process.

Acquiring the 3D geometry of objects has been an active research topic, wherein the reconstruction of transparent objects poses a great challenge. In this paper, we present a fully automatic approach for reconstructing the exterior surface of a complex transparent scene. Through scanning a line laser by a galvo-mirror, images of the scene are captured from two viewing directions. Due to the light transmission inside the transparent object, the captured feature points and the calibrated laser plane can produce large number of 3D point candidates with large incorrect points through direct triangulation. Various situations of laser transmission inside the transparent object are analyzed and the reconstructed 3D laser point candidates are classified into two types: first-reflection points and non-first-reflection points. The first-reflection points means the first reflected laser points on the front surface of measured objects. Then, a novel four-layers refinement process is proposed to extract the first-reflection points step by step from the 3D point candidates through optical geometric constraints, including (1) Layer-1 : fake points removed by single camera, (2) Layer-2 : ambiguity points removed by the dual-camera joint constraint, (3) Layer-3 : retrieve the missing first-reflection exterior surface points by fusion and (4) Layer-4 : severe ambiguity points removed by contour-continuity. Besides, a novel calibration model about this imaging system is proposed for 3D point candidates reconstruction through triangulation. Compared with traditional laser scanning method, we pulled in the viewing angle information of the second camera and a novel four-layers refinement process is adopted for reconstruction of transparent objects. Various experiments on real objects demonstrate that proposed method can successfully extract the first-reflection points from the candidates and recover the complex shapes of transparent and semitransparent objects.

WITHDRAWN: CRISPR/Cas9 mediated HPV and PD1 inhibition produces a synergistic anti-tumor effect on cervical cancer.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Low-dose endothelial monocyte-activating polypeptide-II increases permeability of blood-tumor barrier via a PKC-ζ/PP2A-dependent signaling mechanism.

Our previous study demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) induces blood-tumor barrier (BTB) opening via the RhoA/Rho kinase/protein kinase C (PKC)-α/ß signaling pathway and that PKC-ζ is involved in this process via other mechanisms. In the present study, using an in vitro BTB model, we detected the exact signaling mechanisms by which PKC-ζ activation affects EMAP-II-induced BTB hyperpermeability. Our results showed that three types of serine/threonine (Ser/Thr) protein phosphatases (PPs), namely PP1, PP2A, and PP2B, were expressed by rat brain microvascular endothelial cells (RBMECs). There was an interaction between PKC-ζ and PP2A in RBMECs. In addition, EMAP-II induced a significant increase in both the expression and the activity of PP2A in RBMECs. Inhibition of PKC-ζ with PKC-ζ pseudosubstrate inhibitor (PKC-ζ-PI) completely blocked EMAP-II-induced PP2A activation. Conversely, inhibition of PP2A with okadaic acid (OA) had no effect on EMAP-II-induced PKC-ζ activation. Like PKC-ζ-PI, OA partially prevented EMAP-II-induced BTB hyperpermeability and occludin redistribution in RBMECs. Neither PKC-ζ-PI nor OA affected EMAP-II-induced phosphorylation of myosin light chain and redistribution of actin cytoskeleton in RBMECs. Taken together, our present study demonstrated that low-dose EMAP-II increases BTB permeability by activating the PKC-ζ/PP2A signaling pathway, which consequently leads to the disruption of TJs and impairment of endothelial barrier function.

CRM197 in Combination With shRNA Interference of VCAM-1 Displays Enhanced Inhibitory Effects on Human Glioblastoma Cells.

CRM197 is a naturally nontoxic diphtheria toxin mutant that binds and inhibits heparin-binding epidermal growth factor-like growth factor. CRM197 serves as carrier protein for vaccine and other therapeutic agents. CRM197 also inhibits the growth, migration, invasion, and induces apoptosis in various tumors. Vascular cell adhesion molecule-1 (VCAM-1) is an important cell surface adhesion molecule associated with malignancy of gliomas. In this work, we aimed to investigate the role and mechanism of CRM197 combined with shRNA interference of VCAM-1 (shRNA-VCAM-1) on the migration, invasion, and apoptosis of glioblastoma cells. U87 and U251 human glioblastoma cells were treated with CRM197 (10 µg/ml) and shRNA interfering technology was employed to silence VCAM-1 expression. Cell viability, migration, invasiveness, and apoptosis were assessed with CCK8, Transwell and Annexin V-PE/7-AAD staining. Activation of cleaved caspase-3, 8, and 9, activity of matrix metalloproteinase-2/9 (MMP-2/9), and expression of phosphorylated Akt (p-Akt) were also checked. Results showed that CRM197 and shRNA-VCAM-1 not only significantly inhibited the cell proliferation, migration, invasion, but also promoted the apoptosis of U87 and U251 cells. Combined treatment of both displayed enhanced inhibitory effects on the malignant biological behavior of glioma cells. The activation of cleaved caspase-3, 8, 9 was promoted, activity of MMP-2 and MMP-9 and expression of p-Akt were inhibited significantly by the treatment of CRM197 and shRNA-VCAM-1 alone or in combination, indicating that the combination of CRM197 with shRNA-VCAM-1 additively inhibited the malignant behavior of human glioblastoma cells via activating caspase-3, 8, 9 as well as inhibiting MMP-2, MMP-9, and Akt pathway.

MiR-661 inhibits glioma cell proliferation, migration and invasion by targeting hTERT.

In this study, we analyzed the functional role of miR-661 in glioma cell proliferation, migration and invasion. We found that overexpression of miR-661 obviously suppressed the proliferation, migration and invasion of glioma cells. MiRNA target prediction algorithms implied that hTERT is a candidate target gene for miR-661. A fluorescent reporter assay confirmed that miR-661 could lead to hTERT gene silencing by recognizing and specifically binding to the predicted site of the hTERT mRNA 3' untranslated region (3'UTR) specifically. Furthermore, hTERT knockdown significantly decreased the growth and viability of glioma cells. These results indicate that miR-661 can inhibit glioma cell proliferation, migration and invasion by targeting hTERT.

MiR-143 enhances the antitumor activity of shikonin by targeting BAG3 expression in human glioblastoma stem cells.

Therapeutic applications of microRNAs (miRNAs) in chemotherapy were confirmed to be valuable, but there is rare to identify their specific roles and functions in shikonin treatment toward tumors. Here, for the first time, we reported that miR-143 played a critical role in the antitumor activity of shikonin in glioblastoma stem cells (GSCs). The results showed that the expression of miR-143 was downregulated in shikonin treated GSCs within 24 h. MiR-143 overexpression significantly enhanced the inhibitory effect of shikonin toward GSCs on cell viability. Besides, miR-143 overexpression caused a significant increase in the apoptotic fraction and made apoptosis occur earlier. Further investigation identified that BAG3, an apoptotic regulator, was a functional target of miR-143 in shikonin treated GSCs. The expression of BAG3 was upregulated in shikonin treated GSCs within 24 h. MiR-143 overexpression significantly reversed the high expression of BAG3 in shikonin treated GSCs. Moreover, it was confirmed that the enhanced cytotoxicity of shikonin by miR-143 overexpression was reversed by BAG3 overexpression both in vitro and in vivo, suggesting that the enhanced tumor suppressive effects by miR-143 overexpression was at least partly through the regulation of BAG3. Taken together, for the first time, our results demonstrate that miR-143 could enhance the antitumor activity of shikonin toward GSCs through reducing BAG3 expression, which may provide a novel therapeutic strategy for enhancing the treatment efficacy of shikonin toward GSCs.

Enhanced antitumor effect of shikonin by inhibiting Endoplasmic Reticulum Stress via JNK/c-Jun pathway in human glioblastoma stem cells.

Though previous study demonstrated that shikonin could exert its antitumor activity by inducing apoptosis and necrosis, the pro-survival mechanisms involved in its antitumor process are still little to know. In the present study, for the first time, we found a protective mechanism was simultaneously activated which caused the reduced sensitivity of glioblastoma stem cells (GSCs) to the cytotoxicity of shikonin. Reduced active caspase-9 expression and enhanced mitochondrial membrane potential (MMP) were intriguingly observed within 24 h treatment by shikonin in GSCs. Further investigation identified that Endoplasmic Reticulum Stress (ERS) was involved in its antitumor process, which compromised the cytotoxicity of shikonin toward GSCs. Inhibiting ERS by 4-phenylbutyric acid (4-PBA) markedly enhanced the cytotoxicity of shikonin in GSCs. The consistent result was simultaneously observed in the GSCs-xenografted mice. Furthermore, our results identified that JNK/c-Jun pathway was involved in the antitumor process of shikonin, providing a mechanism by which ERS reduced the cytotoxicity of shikonin toward GSCs. Altogether, the novel observation in the present study identified that inhibiting ERS would be an attractive new approach to enhance the therapeutic potency of shikonin toward GSCs.

Endothelial-monocyte-activating polypeptide II induces rat C6 glioma cell apoptosis via the mitochondrial pathway.

The present study was performed to examine whether Endothelial-monocyte-activating polypeptide II (EMAP II) could inhibit glioma growth by inducing rat brain glioma C6 cells apoptosis. The results revealed that the EMAP II decreased cell viability of rat C6 glioma cells in a time-dependent manner. Apoptotic proportion was increased gradually after EMAP II. EMAP II induced the decrease in mitochondrial membrane potential and the release of cytochrome c into the cytosol, followed by activation of caspase-9 and caspase-3. Meanwhile, EMAP II-induced apoptosis was accompanied by an increase of reactive oxygen species (ROS). The significant up-regulation in the expressions of Bax and Apaf-1 as well as down-regulation in the expression of Bcl-2 was observed. The time course change of ROS was prior to the changes of above investigated indexes. All of these results strongly suggest that EMAP II could induce rat C6 glioma cells apoptosis via the mitochondrial pathway, and ROS, Bax/Bcl-2 might be involved in this processing.

Bradykinin increased the permeability of BTB via NOS/NO/ZONAB-mediating down-regulation of claudin-5 and occludin.

After demonstrating bradykinin (BK) could increase the permeability of blood-tumor barrier (BTB) via opening the tight junction (TJ), and that the possible mechanism is unclear, we demonstrated that BK could increase the expressions of eNOS and nNOS and promote ZONAB translocation into nucleus. NOS inhibitors l-NAME and 7-NI could effectively block the effect of BK on increasing BTB permeability, decreasing the expressions of claudin-5 and occludin and promoting the translocation of ZONAB. Overexpression of ZONAB could significantly enhance BK-mediating BTB permeability. Meanwhile, chromatin immunoprecipitation verified ZONAB interacted with the promoter of claudin-5 and occludin respectively. This study indicated NOS/NO/ZONAB pathway might be involved in BK's increasing the permeability of BTB.

Overexpression of miR-18a negatively regulates myocyte enhancer factor 2D to increase the permeability of the blood-tumor barrier via Krüppel-like factor 4-mediated downregulation of zonula occluden-1, claudin-5, and occludin.

miR-18a represses angiogenesis and tumor evasion by weakening vascular endothelial growth factor and transforming growth factor-ß signaling to prolong the survival of glioma patients, although it is thought to be an oncogene. This study investigates the potential effects of miR-18a on the permeability of the blood-tumor barrier (BTB) and its possible molecular mechanisms. An in vitro BTB model was successfully established. The endogenous expression of miR-18a in glioma vascular endothelial cells (GECs) was significantly lower than that in normal vascular ECs, and the overexpression of miR-18a significantly increased the permeability of the BTB as well as downregulating the mRNA and protein expressions of tight junction-related proteins zonula occluden-1 (ZO-1), claudin-5, and occludin in GECs. Dual luciferase reporter assays revealed that miR-18a bound to the 3'-untranslated region (3'UTR) of myocyte enhancer factor 2D (MEF2D). The overexpression of both miR-18a and MEF2D with the 3'UTR significantly weakened the effect caused by miR-18a of decreasing the mRNA and protein expressions of ZO-1, claudin-5 and occludin and of increasing the permeability of the BTB. Chromatin immunoprecipitation showed that MEF2D could directly bind to KLF4 promoter. This study shows that miR-18a targets and negatively regulates MEF2D, which further regulates tight junction-related proteins ZO-1, claudin-5, and occludin through transactivation of KLF4 and, finally, changes the permeability of the BTB. MiR-18a should garner growing attention because it might serve as a potential target in opening the BTB and providing a new strategy for the treatment of gliomas.

MiR-21 up-regulation mediates glioblastoma cancer stem cells apoptosis and proliferation by targeting FASLG.

To investigate whether miR-21 can affect the apoptosis and proliferation of glioblastoma cancer stem cells (GSCs) from down-regulating FASLG. The expression of miRNA-21 was detected by quantitative real-time PCR in normal brain tissue and glioblastoma samples, and the changes of miRNA-21 expression between GSCs and non-GSCs were also detected. The apoptosis and proliferation ability of miR-21 in GSCs were analyzed by MTT and flow cytometry assay after anti-miR-21 transfection. For the regulation mechanism analysis of miR-21, TargetScan, PicTar and microRNA were selected to predict some potential target genes of miR-21. The predicted gene was identified to be the direct and specific target gene of miR-21 by luciferase activities assay and western blot. RNA interference technology was used to confirm the apoptosis and proliferation effects of miR-21 were directly induced by FASLG. The expression of miR-21 increased significantly in glioblastoma contrast to normal brain tissue, and miR-21 up-regulated in GSCs remarkably. The proliferation of GSCs cell could be inhibited with high-expression of miR-21 and this effect could be restored by miR-21 knocked down. Mechanism analysis revealed that FASLG was a specific and direct target gene of miR-21. The advanced effects of anti-miR-21 on GSCs apoptosis and proliferation were mediated by expression of silenced FASLG. In summary, aberrantly expressed miR-21 regulates GSCs apoptosis and proliferation partly through directly down-regulating FASLG protein expression in GSCs and this might offer a new potential therapeutic stratagem for glioblastoma.

Silencing of Bmi-1 gene enhances chemotherapy sensitivity in human glioblastoma cells.

BACKGROUND: The aim of this study was to determine the influence of the BMI1 gene on chemotherapy sensitivity in human glioma cells. MATERIAL/METHODS: The expression of the BMI1 gene in 41 cases of human brain glioma was determined by quantitative real-time PCR. The silencing effect of RNA interference on the BMI1 gene was detected by Western blot. Methyl thiazolyl tetrazolium assay (MTT) and flow cytometry methods were used to determine the cell viability and apoptosis rate of the U251 cells with BMI1 silencing. After those U251 cells were treated with Cisplatin (DDP), the cell viability and apoptosis rate were further detected. RESULTS: The BMI1 mRNA in glioma was remarkably up-regulated, 176.3% as much as that in peri-cancerous tissues (P<0.05). The siRNA-BMI1 significantly and effectually inhibited the expression of BMI1 protein (P<0.05). The cell viability decreased in U251 cells with BMI1 silenced, and the apoptosis rate upgraded significantly (P<0.05 for both). After treating with DDP at various concentrations (1, 3, and 5 µg/ml), the cell viability in the BMI1-slienced U251 cells was much lower than that in corresponding control U251 cells at each DDP concentration (P<0.05 for all), and the apoptosis rate showed the opposite changing trends (P<0.05 for all). CONCLUSIONS: There is a notable relationship between the over-expression of BMI1 and the carcinogenesis of gliomas. The silence of BMI1 inhibited cell proliferation and enhanced the apoptosis of the U251 cells, and increased the chemotherapy sensitivity of U251 cells to DDP.

Shikonin Inhibits the Migration and Invasion of Human Glioblastoma Cells by Targeting Phosphorylated ß-Catenin and Phosphorylated PI3K/Akt: A Potential Mechanism for the Anti-Glioma Efficacy of a Traditional Chinese Herbal Medicine.

Shikonin is an anthraquinone derivative extracted from the root of lithospermum. Shikonin is traditionally used in the treatment of inflammatory and infectious diseases such as hepatitis. Shikonin also inhibits proliferation and induces apoptosis in various tumors. However, the effect of shikonin on gliomas has not been fully elucidated. In the present study, we aimed to investigate the effects of shikonin on the migration and invasion of human glioblastoma cells as well as the underlying mechanisms. U87 and U251 human glioblastoma cells were treated with shikonin at 2.5, 5, and 7.5 µmol/L and cell viability, migration and invasiveness were assessed with CCK8, scratch wound healing, in vitro Transwell migration, and invasion assays. The expression and activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) and the expression of phosphorylated ß-catenin (p-ß-catenin) and phosphorylated PI3K/Akt were also checked. Results showed that shikonin significantly inhibited the cell proliferation, migration, invasion, and expression of MMP-2 and MMP-9 in U87 and U251 cells. The expression of p-ß-catenin showed contrary trends in two cell lines. It was significantly inhibited in U87 cells and promoted in U251 cells. Results in this work indicated that shikonin displayed an inhibitory effect on the migration and invasion of glioma cells by inhibiting the expression and activity of MMP-2 and -9. In addition, shikonin also inhibited the expression of p-PI3K and p-Akt to attenuate cell migration and invasion and MMP-2 and MMP-9 expression in both cell lines, which could be reversed by the PI3K/Akt pathway agonist, insulin-like growth factor-1 (IGF-1).

In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9.

Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy.

Permeability of the blood-tumor barrier is enhanced by combining vascular endothelial growth factor with papaverine.

This study aims to determine the effects of vascular endothelial growth factor (VEGF), papaverine (PA), and the combination of VEGF and PA on the permeability of the blood-tumor barrier (BTB) and to determine possible molecular mechanisms contributing to the effects. In the rat C6 glioma model, the extravasation of Evans blue (EB) through the BTB was increased significantly by VEGF and PA. VEGF-induced and PA-induced increase of EB extravasation was further increased after combining VEGF with PA infusion. Transmission electron microscopy (TEM) showed that the combination of VEGF and PA not only opened tight junctions (TJ) dramatically but increased the presence of pinocytotic vesicles of brain microvascular endothelial cells (BMECs) significantly. Meanwhile, the downregulation of the TJ-associated proteins occludin and claudin-5 and the upregulation of the caveolae structure proteins caveolin-1 and caveolin-2 caused by the combination of VEGF and PA were observed by Western blot and immunohistochemistry, which were more remarkable than those by the two strategies separately. In addition, after VEGF and PA infusion, the results of radioimmunoassay, Western blot, and enzyme-linked immunosorbent assay (ELISA) revealed a significant increase in expression levels of cGMP and protein kinase G-1 (PKG-1) and the activation of nuclear factor-κB (NF-κB) p65. This study demonstrates that combination of VEGF and PA can increase the permeability of the BTB by a paracellular pathway (downregulation of occludin and claudin-5) and a transcellular pathway (upregulation of caveolin-1 and caveolin-2) and that the cGMP/PKG/NF-κB signal pathway might be involved in the modulation process.

MiR-210 up-regulation inhibits proliferation and induces apoptosis in glioma cells by targeting SIN3A.

BACKGROUND: The aim of this study was to determine whether miR-210 can affect the apoptosis and proliferation of human U251 glioma cells from down-regulating SIN3A. MATERIAL AND METHODS: The expression of miRNA-210 was detected by quantitative real-time PCR in normal brain tissue and glioma samples. The apoptosis and proliferation ability of U251 cells were analyzed by MTT and flow cytometry assay after anti-miR-210 transfection. For the regulation mechanism analysis of miR-210, TargetScan, PicTar, and microRNA were selected to predict some potential target genes of miR-210. The predicted gene was identified to be the direct and specific target gene of miR-210 by luciferase activities assay and Western blot. RNA interference technology was used to confirm that the apoptosis and proliferation effects of miR-210 were directly induced by SIN3A. RESULTS: The expression of miR-210 increased significantly in glioma in comparison with normal brain tissue. The silence of miR-210 expression could inhibit the proliferation of U251 cells and induce the apoptosis. Mechanism analysis revealed that SIN3A was a specific and direct target gene of miR-210. The siRNA-SIN3A could down-regulate the expression of SIN3A protein, which was up-regulated in U251 cells by anti-miR-210 transfection, and our experiments found that silence of SIN3A could inhibit the apoptosis and sharply increase the proliferation of U251 cells. The regulation effects of anti-miR-210 on apoptosis and proliferation can be reversed respectively by the expression silence of SIN3A. CONCLUSIONS: Aberrantly expressed miR-210 regulates human U251 glioma cells apoptosis and proliferation partly through directly down-regulating SIN3A protein expression. This might offer a new potential therapeutic stratagem for glioma.

[Changes of plasma glucagon level in individuals with different glucose metabolism].

OBJECTIVE: To determine the levels of plasma glucagon and associated factors in individuals with different glucose metabolism. METHODS: One hundred and ten outpatient patients received an oral glucose tolerance test (OGTT) voluntarily. The patients were divided into three groups according to their OGTT results: normal glucose golerance (NGT) group (n=33), impaired glucose regulation (IGR) group (n=35), newly diagnosed type 2 diabetes (DM2) group (n=42). Plasma glucagon (GLC) and insulin (INS) at 0 min (0 h), 30 min (0.5 h), 60 min (1 h) and 120 min (2 h) were measured by radio immunity and electrochemiluminescence assay, respectively. We calculated the area of glucagon under the curve (AUCglc), the value of early phase glucagon secretion (deltaGLC = GLC(0.5 h) - GLC(0 h)) and the ratio of insulin to glucagon (INS/GLC). RESULTS: (1) There was no significant difference in the level of GLC(0 h) among the three groups (P > 0.05). (2) Patients in the IGR group had higher levels of GLC(0.5 h) and GLC(1 h), greater values of AUC(glc), and deltaGLC, and lower values of INS(0.5 h)/GLC(0.5 h) than those in the NGT group (P < 0.05). (3) Patients in the DM2 group had higher levels of GLC(0.5 h) and GLC(1 h), greater values of AUC(glc) and deltaGLC, and lower values of INS(0.5 h)/GLC(0.5 h) and INS(1 h)/GLC(1 h) than those in the NGT group (P < 0.05). (4) Patients in the DM2 group had higher levels of GLC(1 h), greater values of AUC(glc), and lower values of INS(0.5 h)/GLC(0.5 h), INS(1 h)/GLC(1 h), and INS(2 h)/GLC(2 h), than those in the IGR group (P < 0.05). (5) The multiple linear regression analysis showed that the value of AUC(glc). was positively correlated with HOMA-IR (adjust R2 = 0.219, P = 0.001). CONCLUSION: There are no significant differences in fasting plasma glucagon levels among the individuals with different glucose metabolism. Hypersecretion of glucagon and reduced glucagon suppressing effect of insulin occur in IGR patients, which is exacerbated when DM2 are developed. HOMA-IR is an important factor associated with glucagon hypersecretion.

Efficient and Robust Point Cloud Registration via Heuristics-guided Parameter Search.

Estimating the rigid transformation with 6 degrees of freedom based on a putative 3D correspondence set is a crucial procedure in point cloud registration. Existing correspondence identification methods usually lead to large outlier ratios (> 95% is common), underscoring the significance of robust registration methods. Many researchers turn to parameter search-based strategies (e.g., Branch-and-Bround) for robust registration. Although related methods show high robustness, their efficiency is limited to the high-dimensional search space. This paper proposes a heuristics-guided parameter search strategy to accelerate the search while maintaining high robustness. We first sample some correspondences (i.e., heuristics) and then just need to sequentially search the feasible regions that make each sample an inlier. Our strategy largely reduces the search space and can guarantee accuracy with only a few inlier samples, therefore enjoying an excellent trade-off between efficiency and robustness. Since directly parameterizing the 6-dimensional nonlinear feasible region for efficient search is intractable, we construct a three-stage decomposition pipeline to reparameterize the feasible region, resulting in three lower-dimensional sub-problems that are easily solvable via our strategy. Besides reducing the searching dimension, our decomposition enables the leverage of 1-dimensional interval stabbing at all three stages for searching acceleration. Moreover, we propose a valid sampling strategy to guarantee our sampling effectiveness, and a compatibility verification setup to further accelerate our search. Extensive experiments on both simulated and real-world datasets demonstrate that our approach exhibits comparable robustness with state-of-the-art methods while achieving a significant efficiency boost.