TGF-ß score based on silico analysis can robustly predict prognosis and immunological characteristics in lower-grade glioma: the evidence from multicenter studies.

INTRODUCTION: Nowadays, mounting evidence shows that variations in TGF-ß signaling pathway-related components influence tumor development. Current research has patents describing the use of anti-TGF-ß antibodies and checkpoint inhibitors for the treatment of proliferative diseases. Importantly, TGF-ß signaling pathway is significant for lower-grade glioma (LGG) to evade host immunity. Loss of particular tumor antigens and shutdown of professional antigen-presenting cell activity may render the anti-tumor response ineffective in LGG patients. However, the prognostic significance of TGF-ß related genes in LGG is still unknown. METHODS: We collected RNA-seq data from the GTEx database (normal cortical tissues), the Cancer Genome Atlas database (TCGA-LGG), and the Chinese Glioma Genome Atlas database (CGGA-693 and CGGA-325) for conducting our investigation. RESULTS: In addition, previous publications were explored for the 223 regulators of the TGF-ß signaling pathway, and 30 regulators with abnormal expression in TCGA and GTEx database were identified. In order to identify hub prognostic regulators, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were used to screen from differentially expressed genes (DEGs). On the basis of 11 genes from LASSO-Cox regression analysis (NEDD8, CHRD, TGFBR1, TP53, BMP2, LRRC32, THBS2, ID1, NOG, TNF, and SERPINE1), TGF-ß score was calculated. Multiple statistical approaches verified the predictive value of the TGF-ß score for the training cohort and two external validation cohorts. Considering the importance of the TGF-ß signaling pathway in immune regulation, we evaluated the prediction of the TGF-ß score for immunological characteristics and the possible application of the immunotherapeutic response using six algorithms (TIMER, CIBERSORT, QUANTISEQ, MCP-counter, XCELL and EPIC) and three immunotherapy cohorts (GSE78820, Imvigor-210 and PRJEB23709). Notably, we compared our risk signature with the signature in ten publications in the meta-cohort (TCGA-LGG, CGGA-693 and CGGA-325), and the TGF-ß score had the best predictive efficiency (C-index =0.812). CONCLUSION: In conclusion, our findings suggest that TGF-ß signaling pathway-related signatures are prognostic biomarkers in LGG and provide a novel tool for tumor microenvironment (TME) assessment.

LINC01234 Sponging of the miR-513a-5p/AOX1 Axis is Upregulated in Osteoporosis and Regulates Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells.

Non-coding RNAs, including long-chain non-coding RNA (lncRNA) and micro-RNA (miRNA), have been implicated in osteoporosis (OP) progression by regulating osteoblast-dependent bone metabolism. Herein, we investigated whether LINC01234, miR-513a-5p, and AOX1 regulate osteogenic differentiation and proliferation of human bone marrow mesenchymal stem cells (hMSCs). The expression of LINC01234, miR-513a-5p, and AOX1 was monitored using RT-qPCR or western blotting. Cell proliferation was assessed using a CCK8 assay. Alkaline phosphatase activity (ALP) and alizarin red dye staining were performed to determine osteogenic differentiation. Furthermore, the expression of osteoblast differentiation markers, such as ALP, BMP1 (bone morphogenetic protein 1), osteocalcin (OCN), and osteopontin (OPN), was determined by RT-qPCR. Luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to verify the interplay between miR-513a-5p and LINC01234 or AOX1. Compared with the plasma of healthy controls, LINC01234 and AOX1 were highly expressed in the plasma of patients with OP, whereas miR-513a-5p showed low expression. In contrast, LINC01234 and AOX1 expression displayed a gradual decrease in induced differentiated hMSCs, while miR-513a-5p expression was upregulated with induction time. The predicted binding sites between miR-513a-5p and LINC01234 or AOX1 were verified by luciferase reporter and RIP assays. LINC01234 silencing induced osteogenic differentiation and proliferation in vitro, and miR-513a-5p silencing blunted osteogenic differentiation and proliferation modulated by LINC01234. AOX1 silencing caused by miR-513a-5p enhances osteogenic proliferation and differentiation. LINC01234 sponging of the miR-513a-5p/AOX1 axis impeded the osteogenic differentiation of hMSCs, favoring OP progression.

Handheld robotic needle holder training: slower but better.

BACKGROUND: Handheld robotic laparoscopic instruments fill the gap between robotic and conventional instruments, combining the advantages of degrees of freedom and low price. The difficulty and value in learning these new instruments require detailed investigation. METHODS: Forty novice surgeons with no laparoscopic experience were randomly assigned to two groups: conventional instrument group (Group Conv) and robotic instrument group (Group Rob). The same training protocol was used in both groups: after viewing a standard operation film, laparoscopic suture training was administered using the corresponding instruments. After each training period, surgeons were tested using a force-sensing test platform. Maximum force (MF) and impulse (IMP) of operators through each ring were recorded. Learning curves based on MF and IMP for both instruments were compared. Institutional review board approval is not needed for this study. RESULTS: MF and IMP of both groups decreased with increased training time; the learning curve of Group Conv decreased faster than that of Group Rob. When training time reached 13 h, the MF of Group Rob was significantly lower than that of Group Conv (P < 0.05), while IMP showed no significant difference between the two groups. CONCLUSIONS: Effective training reduces operator MF and IMP, possibly decreasing damage to tissues with both conventional and handheld robotic needle holders. Group Rob took longer to reach a plateau, but subsequently had lower suture tension than did Group Conv. MF is more sensitive than IMP for measuring performance progress.

Identification of a novel series of azabenzimidazole-derived inhibitors of spleen tyrosine kinase.

Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits. Lead compound 23 from this novel ABI series has a SYK IC50 = 0.21 nM in a biochemical assay and inhibits growth of SUDHL-4 cells at a GI50 = 210 nM.

Handheld laparoscopic robotized instrument: progress or challenge?

BACKGROUND: Handheld laparoscopic robotized instruments have been developed to combine the advantages of a robotic operation system and conventional laparoscopic instruments. Direct objective standards are needed to quantify surgeons' skill level and validate the advantages of new instruments. This study describes and objectively evaluates the use of a robotized instrument using a force-sensing test platform. METHODS: The test platform consists of 12 rings on a hypersensitive force sensor. Forty volunteers were recruited: the expert group included 20 laparoscopic experts and the novice group included 20 medical students in their 4th year without laparoscopic skills. The baseline of the two groups was identified using a conventional needle holder. Participants then repeated the test with the robotized needle holder after training. The maximum force and impulse of each ring were analyzed for each group. Institutional review board approval is not needed for this study. RESULTS: Significantly lower maximum force and impulse were observed in the expert group than in the novice group during the baseline test (all P < 0.05). After training, a significant difference remained in maximum force and impulse between the two groups using the robotized needle holder (all P < 0.05). Within each group, there was no difference in maximum force or impulse using the robotized needle holder after training compared to that on using the conventional needle holder (all P > 0.05). CONCLUSIONS: The maximum force and impulse recorded by a test platform can accurately identify participants' laparoscopic skill level. Six hours' training can ensure that experts master the use of the robotized needle holder, but this training session is too short for novices to improve their performance with a new instrument. The force-sensing test platform can reflect the suturing characteristics of users based on the skill level and is useful for laparoscopic suture training.

Long noncoding RNA FLVCR1-AS1 aggravates biological behaviors of glioma cells via targeting miR-4731-5p/E2F2 axis.

Long noncoding RNAs (lncRNAs) display essential roles in cancer progression. FLVCR1-AS1 is a rarely investigated lncRNAs involved in various human cancers, such as hepatocellular carcinoma and lung cancer. However, its function in glioma has not been clarified. In our study, we found that FLVCR1-AS1 was highly expressed in glioma tissues and cell lines. And upregulation of FLVCR1-AS1 predicted poor prognosis in patients with glioma. Moreover, FLVCR1-AS1 knockdown inhibited proliferation, migration and invasion of glioma cells. Through bioinformatics analysis, we identified that FLVCR1-AS1 was a sponge for miR-4731-5p to upregulate E2F2 expression. Moreover, rescue assays indicated that FLVCR1-AS1 modulated E2F2 expression to participate in glioma progression. Altogether, our research demonstrates that the FLVCR1-AS1/miR-4731-5p/E2F2 axis is a novel signaling in glioma and may be a potential target for tumor therapy.

Design and Evaluation of FBG-Based Tension Sensor in Laparoscope Surgical Robots.

Due to the narrow space and a harsh chemical environment in the sterilization processes for the end-effector of surgical robots, it is difficult to install and integrate suitable sensors for the purpose of effective and precise force control. This paper presents an innovative tension sensor for estimation of grasping force in our laparoscope surgical robot. The proposed sensor measures the tension of cable using fiber gratings (FBGs) which are pasted in the grooves on the inclined cantilevers of the sensor. By exploiting the stain measurement characteristics of FBGs, the small deformation of the inclined cantilevers caused by the cable tension can be measured. The working principle and the sensor model are analyzed. Based on the sensor model, the dimensions of the sensor are designed and optimized. A dedicated experimental setup is established to calibrate and test the sensor. The results of experiments for estimation the grasping force validate the sensor.

Suppression of NLRP3 inflammasome attenuates stress-induced depression-like behavior in NLGN3-deficient mice.

Depression, regulated by central nervous system (CNS), is a significant inflammatory disorder. Neuroligin3 (NLGN3) has been implicated in brain functions. In the study, a chronic unpredictable mild stress (CUMS) model in wild type (WT) or NLGN3-knockout (KO) mice was established to explore the role of NLGN3 in regulating depression and to reveal the underlying molecular mechanism. The results indicated that NLGN3-knockout markedly reversed the loss of body weight, the reduction of sucrose consumption, the decrease of immobile time in the forced swimming tests (FST) and tail suspension tests (TST) induced by CUMS paradigm. CUMS up-regulated corticosterone (CORT) in serum, and down-regulated serotonin (5-HT), norepinephrine (NE) and brain-derived neurotrophic factor (BDNF) in hippocampus of mice, which were significantly reversed by NLGN3 deficiency. The results further demonstrated that NLGN3-knockout improved the degenerative neurons in cortex and hippocampus of CUMS-treated mice, accompanied with a significant decrease of ionized calciumbinding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) expressions. Additionally, NLGN3-KO mice challenged with CUMS showed a significant reduction of pro-inflammatory cytokines and chemokine, including tumor necrosis factor-alpha (TNF-α), interleukin-18 (IL-18), interleukin-1 beta (IL-1ß), interleukin-4 (IL-4), CC-chemokine ligand-1 (CCL-1) and CXC-chemokine ligand-1 (CXCL-1), in cortex, hippocampus and amygdala tissue samples. Western blot analysis suggested that NLGN3-knockout inhibited the activation of nod-like receptor protein 3 (NLRP3) inflammasome and its adaptor of apoptosis-associated speck like protein (ASC), and reduced the expression of Caspase-1, along with the inactivation of nuclear factor-κB (NF-κB) in CUMS-challenged mice. The role of NLGN3 in regulating depression in mice was confirmed in vitro using astrocytes stimulated by LPS that NLGN3 knockdown reduced LPS-induced inflammation. Importantly, the suppressive effects of NLGN3-knockdown on inflammatory response were reversed by NLRP3 or ASC over-expression in AST exposed to LPS. In sum, our findings indicated that suppressing NLGN3 played a potential antidepressant role in CUMS animal model by inactivating NLRP3 inflammasome, providing a new therapeutic avenue for depression.

Variable Admittance Control Based on Fuzzy Reinforcement Learning for Minimally Invasive Surgery Manipulator.

In order to get natural and intuitive physical interaction in the pose adjustment of the minimally invasive surgery manipulator, a hybrid variable admittance model based on Fuzzy Sarsa(λ)-learning is proposed in this paper. The proposed model provides continuous variable virtual damping to the admittance controller to respond to human intentions, and it effectively enhances the comfort level during the task execution by modifying the generated virtual damping dynamically. A fuzzy partition defined over the state space is used to capture the characteristics of the operator in physical human-robot interaction. For the purpose of maximizing the performance index in the long run, according to the identification of the current state input, the virtual damping compensations are determined by a trained strategy which can be learned through the experience generated from interaction with humans, and the influence caused by humans and the changing dynamics in the robot are also considered in the learning process. To evaluate the performance of the proposed model, some comparative experiments in joint space are conducted on our experimental minimally invasive surgical manipulator.

Iron-Catalyzed Oxidative C-H/C-H Cross-Coupling between Electron-Rich Arenes and Alkenes.

A novel oxidative C-H/C-H cross-coupling reaction between electron-rich arenes and alkenes is established utilizing FeCl3 as the catalyst and DDQ as the oxidant. Interestingly, direct arylation products are obtained with diaryl-ethylenes and double arylation products are obtained with styrene derivatives, which show high chemoselectivity and good substrate scope. A radical trapping experiment and EPR (electron paramagnetic resonance) experiments indicate that this reaction proceeds through a radical pathway in which DDQ plays a key role in the aryl radical formation. XAFS (X-ray absorption fine structure) experiments reveal that the oxidation state of the iron catalyst does not change during the reaction, suggesting that FeCl3 might be used as a Lewis acid. Finally, a detailed mechanism is proposed for this transformation.