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Background Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas. Methods As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry. Results Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade. Conclusions We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.

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Purpose:Unlike most cancers, no clear epidemiological correlation between diabetes (Db) and malignant glioma progression exists. Because hyperglycemia activates proinflammatory pathways through the receptor for advanced glycation endproducts (RAGE), we hypothesized that Db can also promote malignant glioma progression.Experimental Design:We compared the growth of two phenotypically diverse syngeneic glioma models in control and diabetic mice. Tumor growth and antitumor immune responses were evaluated in orthotopic and heterotopic models and correlated to RAGE and RAGE ligand expression.Results:Irrespective of tumor implantation site, growth of a “classical” glioma model, GL261, increased in hyperglycemic mice and was mediated by upregulation of RAGE and its ligand, HMGB1. However, growth of a “mesenchymal” glioma subtype, K-Luc, depended on tumor implantation site. Whereas heterotopic K-Luc tumors progressed rapidly in Db mice, intracranial K-Luc tumors grew slower. We further showed that hyperglycemia inhibited the innate antitumor inflammatory responses in both models. Although this contributed to the accelerated growth of heterotopic tumors, suppression of tumor inflammatory responses dampened the growth of orthotopic K-Luc gliomas.Conclusions:Hyperglycemia may enhance glioma growth through promotion of RAGE expression and suppression of antitumor immune responses. However, abrogation of the proinflammatory milieu in tumors may also dampen the growth of inflammatory glioma subtypes in the brains of diabetic mice. This dichotomy in glioma growth response to hyperglycemia may partly explain why conflicting epidemiological studies show both an increased risk and a protective effect of Db in patients with malignant gliomas.

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Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood–brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01207-w.

Density is one of the auxiliary indicators for judging the internal quality of tomatoes. However, in the density measurement process, it is often difficult to measure the volume of the tomatoes accurately. To solve this problem, first, this study proposed a novel tomato volume measurement method based on machine vision. The proposed method uses machine vision to measure the geometric feature parameters of tomatoes, and inputs them into the LabVIEW software to convert the calculation of irregular tomato volume into a BP neural network (BPNN) model that calculates the plane pixel area and pixel volume, thereby realizing the modeling, analysis, design and simulation of tomato volume; then, an experimental platform was constructed to compare the results of the proposed method with the results predicted by the 3D wireframe model. When the number of photos taken was n = 5, the average error of the tomato volume prediction results of the 3D wireframe model was 8.22%, and the highest accuracy was 92.93%; while the average error of the tomato volume prediction results of the BPNN was 4.60%, and the highest accuracy was 95.60%. Increasing the number of orthographic projections can improve the accuracy of the model, but when the number of photos was more than 7, the accuracy improvement was not significant. Also, increasing the number of nodes in the hidden layer can improve the accuracy of the model, however, considering that increasing the number of nodes will increase the host operating cost, it is suggested to choose a node number of 12 for the tomato volume measurement. In the end, the final experimental results showed that the proposed method achieved better measurement results. However, the volume measured by the two models is larger than the real volume of tomatoes. For this reason, we added a correction coefficient to the BPNN model, and its highest accuracy has increased by 1.3%.

INTRODUCTION Malignant gliomas consist of heterogenous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment (TME). Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth, invasion, and immune escape. OBJECTIVE We aimed to demonstrate that blockade of RAGE expression may tackle resistance pathways by inhibiting GBM progression, invasion, and immune evasion. METHODS We evaluated genetic ablation of RAGE on the tumorigenicity of two syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by immunohistochemistry, qPCR, ELISA, western blotting, NanoString, flow cytometry, and in vivo survival analysis. RESULTS Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition also enhanced tumor inflammatory responses by downregulating the expression of galectin-3, rendered the immunotherapy resistant K-Luc gliomas responsive to immune checkpoint blockade therapy, and significantly increased survival. CONCLUSION This study is the first to link RAGE expression with galactin-3 as an immune modulator in glioblastoma and revealed that the effect of glioma RAGE expression on TME was mediated through downregulation of Gal-3 and subsequent polarization of Tumor-associated macrophages. The therapeutic significance of RAGE downregulation was demonstrated by sensitizing a highly invasive and immune-resistant glioma model to immune checkpoint blockade and strongly supports the development of RAGE ablation as a complementary treatment strategy for malignant gliomas.

Enterovirus D68 (EV-D68) is a respiratory viral pathogen that causes severe respiratory diseases and neurologic manifestations. Since the 2014 outbreak, EV-D68 has been reported to cause severe complications worldwide. However, there are currently no approved antiviral agents or vaccines for EV-D68. In this study, we found that zinc ions exerted substantial antiviral activity against EV-D68 infection in vitro. Zinc salt treatment potently suppressed EV-D68 RNA replication, protein synthesis, and infectious virion production and inhibited cytopathic effects without producing significant cytotoxicity at virucidal concentrations (EC50=0.033mM). Zinc chloride (ZnCl2) treatment moderately inhibited EV-D68 attachment. Time-dose analysis of EV-D68 structural protein VP1 synthesis showed stronger suppression of VP1 in the culture medium than that in the cell lysates. Furthermore, a zinc ionophore, pyrrolidine dithiocarbamate, which can transport zinc ions into cells, also enhanced the anti-EV-D68 activity of ZnCl2 treatment. Taken together, our results demonstrated that the enhancement of zinc influx could serve as a powerful strategy for the therapeutic treatment of EV-D68 infections.

Under the background of the continuous improvement of artificial intelligence technology, the research technology of intelligent networked vehicle has become one of the hot topics in the global automotive technology research. It is not only a brand-new attempt for automobile structure and development, but also has a huge development space in the field of artificial intelligence technology. In this paper, the development status of intelligent network connected vehicle is analyzed and some suggestions are put forward.

S100B, a member of the multigene family of Ca 2+ -binding proteins, is overexpressed by most malignant gliomas but its biological role in gliomagenesis is unclear. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of STAT3. Furthermore, S100B downregulation in a murine glioma model inhibited macrophage trafficking and tumor growth. Based on these observations, we hypothesized that S100B inhibitors may have antiglioma properties through modulation of tumor microenvironment. To discover novel S100B inhibitors, we developed a high-throughput screening cell-based S100B promoter-driven luciferase reporter assay. Initial screening of 768 compounds in the NIH library identified 36 hits with >85% S100B inhibitory activity. Duloxetine (Dul, an SNRI) was selected for the initial proof-of-concept studies. At low concentrations (1–5 μM) Dul inhibited S100B and CCL2 production in mouse GL261 glioma cells, but had minimal cytotoxic activity in vitro . In vivo , however, Dul (30 mg/kg/14 days) inhibited S100B production, altered the polarization and trafficking of tumor-associated myeloid-derived cells, and inhibited the growth of intracranial GL261 gliomas. Dul therapeutic efficacy, however, was not observed in the K-Luc glioma model that expresses low levels of S100B. These findings affirm the role of S100B in gliomagenesis and justify the development of more potent S100B inhibitors for glioma therapy.

Over the past decade, the surgical treatment of adolescent idiopathic scoliosis (AIS) has established new techniques to reduce curve severity and shifted to include the regular use of pedicle screws. Few studies have focused on this evolving trend in AIS correction surgery. In this study, we investigated how the operative approach, instrumentation, and surgical techniques have changed over the past 15 years and to quantify the related improvements in AIS surgical treatment.This is a retrospective review of a prospective AIS registry in a single center. Patient data were reviewed from January 2001 to December 2015. The age and surgical case distribution were recorded for each year. Trends in classification use, instrumentation types, levels of fusion, and surgical approaches were analyzed by year. The major Cobb angles and correction rates were compared between different instrumentations and surgical approaches.A total of 2530 patients with AIS (83.0% female) were included, with a mean age of 15.14 years. Most patients underwent surgery at 14 years of age (473 patients, 18.7%), followed by 15 years of age (468 patients, 18.5%). In our center, the classification of patients with AIS shifted from the King classification to the Lenke classification in 2005. The major baseline Cobb angle of the entire cohort averaged 50.99° and this mean Cobb angle decreased to 14.41° after surgery. The correction rates for the first 3 years (2001-2003) were less than 70%, whereas the correction rates for the rest of the years were all greater than 70%. In addition, significantly higher correction rates were observed in patients with Cobb angles90° (72.93% vs. 55.61%, P0.001). A total of 218 anterior-only surgeries and 109 combined anteroposterior surgeries were performed; the remaining 2205 surgeries were performed with a posterior-only approach. The use of anterior-only and anteroposterior approaches trended to decrease after 2005. The correction rate of anterior-only approaches was significantly greater than posterior-only and anteroposterior approaches (77.86%, 72.51%, and 59.37%, respectively). In patients corrected with a posterior-only approach, the screw-hook hybrid construct was used in 342 patients, whereas the all-pedicle-screw construct was used in 1835 patients. The shift from hybrid to all-screw construct occurred in 2006. In patients with thoracic AIS, the correction rate was significantly higher in the all-screw group (73.26% vs. 67.76%; P0.001).Consistent improvement of major curve correction has been achieved by the spine community over 15 years. After stabilized coronal correction and fewer fusion levels, the next steps in this evolution are the restoration of sagittal profiles, especially the hypokyphosis seen in patients with Lenke 1, the posterior minimally invasive approach, and a fast-track return to activity.

Several genes are associated with increased risk for autism spectrum disorder (ASD), neurodevelopmental disorders that present with repetitive movements and restricted interests along with deficits in social interaction/communication. While genetic alterations associated with ASD are present early in life, ASD-like behaviors are difficult to detect in early infancy. This raises the issue of whether reversal of an ASD-associated genetic alteration early in life can prevent the onset of ASD-like behaviors. Genetic alterations ofSHANK3, a well-characterized gene encoding a postsynaptic scaffolding protein, are estimated to contribute to ∼0.5% of ASD and remain one of the more replicated and well-characterized genetic defects in ASD. Here, we investigate whether early genetic reversal of aShank3mutation can prevent the onset of ASD-like behaviors in a mouse model. Previously, we have demonstrated that mice deficient inShank3display a wide range of behavioral abnormalities such as repetitive grooming, social deficits, anxiety, and motor abnormalities. In this study, we replicate many of these behaviors inShank3mutant mice. With early genetic restoration of wild-type (WT)Shank3, we rescue behaviors including repetitive grooming and social, locomotor, and rearing deficits. Our findings support the idea that the underlying mechanisms involving ASD behaviors in mice deficient inShank3are susceptible to early genetic correction ofShank3mutations.

TGF-β signal pathway activation is vital in the pathogenesis of DKD. We aim to investigate the role of Yishenhuoxue formula on TGF-β/Smad signal transduction in DKD rats. 60 male adult Wistar rats were enrolled and randomly allocated into four groups: N group, M group (given STZ 60mg/kg, ip), H group (given Yishenhuoxue formula 1.0g/kg/day, ig) and L group (given Yishenhuoxue formula 0.5g/kg/day, ig). The levels of BW, 24h UV, SCr, UCr, mALB were measured after 8 weeks treatment, while the levels of KW/BW index, CCr and UAER were calculated by relevant formula. The rats' left kidneys were harvested to detect histological changes by PAS staining and right kidneys were harvested to detect the levels of TGF-β, Smad2/3, phosphorylated Smad 2/3, Smad 7 and CTGF by western blot analysis. We found that Yishenhuoxue formula treatment can protect kidneys from DKD injury, which is illustrated with following criteria: 1) a significant decrement in KW/BW index, 24h UV, SCr, mALB and UAER, while a significant increment in BW, UCr, CCr (p0.05 vs. M group); 2) minor and segmental changes as slight expansion of the glomerular basement membrane compared with M group; 3) an apparent decrease in levels of TGF-β1, phosphorylated Smad 2/3 and CTGF, while an apparent increase in levels of Smad 2/3 and Smad7 compared with M group (p0.05). The studies confirm that Yishenhuoxue formula has strong inhibitory effect on TGF-β/Smad signal transduction in DKD rats' kidneys by decreasing expression of TGF-β1, weakening of Smad 2/3 phosphorylation and increasing expression of Smad 7.

Research and analysis a self-balancing obstacle-crossing vehicle to walk on unstructured and complex ground. In this paper, the overall design scheme is analyzed, and the innovative points of the design research are put forward. The mechanical structure of self-balancing obstacle-crossing chassis was designed, modeled and assembled by using CATIA three-dimensional drawing software. The results of the final datas show that the strength and stiffness of the model design system meet the requirements of static design. The simulation results of ADAMS show that the maximum obstacle-crossing height is 210 mm and the maximum swing angle of swing arm is 37.2°, which verifies that the data designed in this paper meets the original design requirements.

Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders1–6 and are among the most prevalent in autism spectrum disorders1,2,7. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes8,9. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study8, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.

Neuroligin-3 (NLGN3) is a postsynaptic cell adhesion protein that interacts with presynaptic ligands including neurexin-1 (NRXN1) [Ichtchenko et al., Journal of Biological Chemistry, 271, 2676-2682, 1996]. Mice harboring a mutation in the NLGN3 gene (NL3R451C) mimicking a mutation found in two brothers with autism spectrum disorder (ASD) were previously generated and behaviorally phenotyped for autism-related behaviors. In these NL3R451C mice generated and tested on a hybrid C57BL6J/129S2/SvPasCrl background, we observed enhanced spatial memory and reduced social interaction [Tabuchi et al., Science, 318, 71-76, 2007]. Curiously, an independently generated second line of mice harboring the same mutation on a C57BL6J background exhibited minimal aberrant behavior, thereby providing apparently discrepant results. To investigate the origin of the discrepancy, we previously replicated the original findings of Tabuchi et al. by studying the same NL3R451C mutation on a pure 129S2/SvPasCrl genetic background. Here we complete the behavioral characterization of the NL3R451C mutation on a pure C57BL6J genetic background to determine if background genetics play a role in the discrepant behavioral outcomes involving NL3R451C mice. NL3R451C mutant mice on a pure C57BL6J background did not display spatial memory enhancements or social interaction deficits. We only observed a decreased startle response and mildly increased locomotor activity in these mice suggesting that background genetics influences behavioral outcomes involving the NL3R451C mutation. Autism Res 2018, 11: 234-244. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay summary Behavioral symptoms of autism can be highly variable, even in cases that involve identical genetic mutations. Previous studies in mice with a mutation of the Neuroligin-3 gene showed enhanced learning and social deficits. We replicated these findings on the same and different genetic backgrounds. In this study, however, the same mutation in mice on a different genetic background did not reproduce our previous findings. Our results suggest that genetic background influences behavioral symptoms of this autism-associated mutation.

Study design Retrospective study. Objective To investigate if the surgical outcome of young adults was equivalent to adolescents for surgical correction of thoracic adolescent idiopathic scoliosis (AIS). Summary of background data Despite numerous reports on the satisfactory surgical correction, some AIS patients or families still have the assumption that delay of surgery into young adulthood may be more beneficial. Hence, the strict paired analysis of clinical outcome between AIS and adult idiopathic scoliosis (AdIS) is required, which lacks report in the current literature. Methods This is a retrospective 1:1 matched cohort. A total of 80 pairs were recruited with the following inclusion criteria: (A) female Lenke Type 1A or 1B idiopathic scoliosis; (B) selective fusion; (C) adolescents aged 10 to 18 years and young adults aged 19 to 29 years; (D) one-stage posterior approach; (E) all-pedicle-screws instrumentations; (F) major Cobb angle 45° to 80°. AIS patients and AdIS patients were matched for apex, major thoracic curve magnitude (±5°), lumbar curve magnitude (±5°), time of surgery (±6 month), and follow-up (±6 month). Results The age at the time of surgery in AdIS patients averaged 22.21years, significantly larger than that of AIS patients (22.21 vs. 14.47 yr). AdIS patients had significant lower curve flexibility. Accordingly, lower correction rate and larger postoperative main Cobb angle were found in AdIS patients. Regarding quality of life, no significant difference was observed between the two groups during follow-up. Conclusion The results may provide evidence for spine surgeons to communicate with AIS patients and their families regarding pros and cons of the delay of surgery into young adulthood. AIS patients would gain better radiographic curve correction compared with matched AdIS patients due to more flexibility. When considering potential curve progression, the radiographic outcome of AdIS may be even worse. Whereas delaying to adulthood may have similar health-related quality of life and reduce the risk of adding-on phenomenon. Level of evidence 3.

SHANK3(ProSAP2) is among the most common genes mutated in autism spectrum disorders (ASD) and is the causative gene in Phelan–McDermid syndrome (PMS). We performed genetic rescue ofShank3mutant phenotypes in adult mice expressing aShank3exon 21 insertion mutation (Shank3G). We used a tamoxifen-inducible Cre/loxP system (CreTam) to revertShank3Gto wild-type (WT)Shank3+/+. We found that tamoxifen treatment in adultShank3GCreTam+mice resulted in complete rescue of SHANK3 protein expression in the brain and appeared to rescue synaptic transmission and some behavioral differences compared toShank3+/+CreTam+controls. However, follow-up comparisons between vehicle-treated, WT Cre-negative mice (Shank3+/+CreTam−andShank3+/+CreTam+) demonstrated clear effects ofCreTamon baseline synaptic transmission and some behaviors, making apparently positive genetic reversal effects difficult to interpret. Thus, while theCreTamtamoxifen-inducible system is a powerful tool that successfully rescuesShank3expression in ourShank3G/Greversible mutants, one must exercise caution and use appropriate control comparisons to ensure sound interpretation.

This paper uses the depth learning method to settle the question of robot detection and capture in the RGB-D view of the sight comprising the object. A large number of candidates can be evaluated by using a two-step cascade system, which is faster and more effective than manual design. There are two deep-step cascade system network, a top value of the first detection system is reappraised by the second system. The first meshwork runs faster because of its fewer functions and can prune a large number of candidate fetches effectively. The second network is more powerful, so the speed is relatively slow, and the top-level detection value of the first system can be re-evaluated. To deal with multimodal input effectively, e propose a weighted structure regularization method in view of multichannel group regularization. The experimental results indicate the depth learning arithmetic can effectively improve the performance of RGBD robot grasping data sets, And the new objects can also be captured successfully.

Introduction: DMP-1 supplement has a satisfactory effect on diabetic kidney disease in patients with whether T1DM or T2DM. Oxidative stress and TGF-β signal pathway activation are essential in the pathogenesis of DKD. We aim to investigate the effect of DMP-1 on oxidative stress and TGF-β activation in rats with DKD. Materials and methods: Male Wistar rats were enrolled and randomly allocated into five groups: Control group, STZ group (60 mg/kg, ip), DMP-1 low dose group (0.5 g/kg/day, ig), DMP-1 medium dose group (1.0 g/kg/day, ig) and DMP-1 high dose group (2.0 g/kg/day, ig). The levels of UREA, BUN, UCr, β2-MG, mALB, NOS, CAT, MDA and T-AOC were measured after 8 weeks treatment. And rats’ left kidneys were harvested to detect the expression of TGF-β, Smad2/3 and Smad7 by immunohistochemical analysis. Results: DMP-1 treatment has protective effects on kidney injury induced by STZ, which is demonstrated as following criteria: (1) a significant reduction in levels of UREA (p

Mutations/deletions in the SHANK3 gene are associated with autism spectrum disorders and intellectual disability. Here, we present electrophysiological and behavioral consequences in novel heterozygous and homozygous mice with a transcriptional stop cassette inserted upstream of the PDZ domain-coding exons in Shank3 (Shank3E13 ). Insertion of a transcriptional stop cassette prior to exon 13 leads to loss of the two higher molecular weight isoforms of Shank3. Behaviorally, both Shank3E13 heterozygous (HET) and homozygous knockout (KO) mice display increased repetitive grooming, deficits in social interaction tasks, and decreased rearing. Shank3E13 KO mice also display deficits in spatial memory in the Morris water maze task. Baseline hippocampal synaptic transmission and short-term plasticity are preserved in Shank3E13 HET and KO mice, while both HET and KO mice exhibit impaired hippocampal long-term plasticity. Additionally, Shank3E13 HET and KO mice display impaired striatal glutamatergic synaptic transmission. These results demonstrate for the first time in this novel Shank3 mutant that both homozygous and heterozygous mutation of Shank3 lead to behavioral abnormalities with face validity for autism along with widespread synaptic dysfunction. Autism Res 2017, 10: 42-65. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Enterovirus D68 (EV-D68) is a member of the Picornavirus family and a causative agent of respiratory diseases in children. The incidence of EV-D68 infection has increased worldwide in recent years. Thus far, there are no approved antiviral agents or vaccines for EV-D68. Here, we show that methyl-β-cyclodextrin (MβCD), a common drug that disrupts lipid rafts, specifically inhibits EV-D68 infection without producing significant cytotoxicity at virucidal concentrations. The addition of exogenous cholesterol attenuated the anti-EV-D68 activity of MβCD. MβCD treatment had a weak influence on the attachment of viral particles to the cell membrane but significantly inhibited EV-D68 entry into host cells. We demonstrated that EV-D68 facilitated the translocation of the viral receptor ICAM-5 to membrane rafts in infected cells. The colocalization of viral particles with ICAM-5 in lipid rafts was thoroughly abolished in cells after treatment with MβCD. Finally, we showed that MβCD inhibited the replication of isolated circulating EV-D68 strains. In summary, our results demonstrate that MβCD suppresses EV-D68 replication by perturbing the accumulation of virus particles and ICAM-5 in lipid rafts. This mechanism represents a promising strategy for drug development.

Aims The aim of this study was to investigate the impact of maturity status at the time of surgery on final spinal height in patients with an adolescent idiopathic scoliosis (AIS) using the spine-pelvic index (SPI). The SPI is a self-control ratio that is independent of age and maturity status. Patients and Methods The study recruited 152 female patients with a Lenke 1 AIS. The additional inclusion criteria were a thoracic Cobb angle between 45° and 70°, Risser 0 to 1 or 3 to 4 at the time of surgery, and follow-up until 18 years of age or Risser stage 5. The patients were stratified into four groups: Risser 0 to 1 and selective fusion surgery (Group 1), Risser 0 to 1 and non-selective fusion (Group 2), Risser 3 to 4 and selective fusion surgery (Group 3), and Risser 3 to 4 and non-selective fusion (Group 4). The height of spine at follow-up (HOSf) and height of pelvis at follow-up (HOPf) were measured and the predicted HOS (pHOS) was calculated as 2.22 (SPI) × HOPf. One-way analysis of variance (ANOVA) was performed for statistical analysis. Results Of the 152 patients, there were 32 patients in Group 1, 27 patients in Group 2, 48 patients in Group 3, and 45 patients in Group 4. Significantly greater HOSf was observed in Group 3 compared with Group 1 (p = 0.03) and in Group 4 compared with Group 2 (p = 0.02), with similar HOPf (p = 0.75 and p = 0.83, respectively), suggesting that patients who undergo surgery at Risser grade of 0 to 1 have a shorter spinal height at follow-up than those who have surgery at Risser 4 to 5. HOSf was similar to pHOS in both Group 1 and Group 2 (p = 0.62 and p = 0.45, respectively), indicating that undergoing surgery at Risser 0 to 1 does not necessarily affect final spinal height. Conclusion This study shows that fusion surgery at Risser 0 may result in growth restriction unlike fusion surgery at Risser 3 to 4. Despite such growth restriction, AIS patients could reach their predicted or ‘normal’ spinal height after surgery regardless of baseline maturity status due to the longer baseline spinal length in AIS patients and the remaining growth potential at the non-fusion levels. Cite this article: Bone Joint J 2018;100-B:1372–6.

Objective To analyze postoperative changes in cervical alignment in patients with adolescent idiopathic scoliosis (AIS) with different curve patterns. Methods Radiographic data were retrospectively reviewed in 43 patients with AIS with right thoracic major curve versus 39 with major lumbar curve with a minimum of 2 years’ follow-up. Radiographic parameters analyzed in this study included cervical sagittal parameters (cervical lordosis [CL], T1 slope, T1 slope minus C2–C7 lordosis, T1–spine, T1 pelvic angle, and C2–C7 sagittal vertical axis) and spinopelvic sagittal parameters obtained from radiographs. Paired t tests were used for comparison with 0.05 as a statistically significant threshold. Results At baseline, larger CL (5.69° vs. −5.12°, P = 0.002) and smaller T1 slope minus C2–C7 lordosis (9.26° vs. 17.09°, P = 0.001) was noted in patients with lumbar-curve adolescent idiopathic scoliosis (L-AIS), whereas preoperative thoracic kyphosis (TK) was not different between the 2 groups. When the immediate postoperative sagittal profiles were compared between the 2 groups, larger TK (23.72° vs. 18.86°, P = 0.009) and more obvious CL (7.26° vs. −2.60°, P = 0.001) were noticed in the L-AIS group. During the follow-up, larger TK and CL were still maintained in the L-AIS group. In addition, a significant correlation was found between the improvement of CL and TK restoration in patients with L-AIS (r = −0.473, P = 0.002). Conclusions Correlations between the improvement of CL and TK highlight the importance of restoration of patients with normal TK or AIS. Reciprocal changes in cervical alignment may happen if the TK was also simultaneously restored in patients with AIS. For patients with different curve patterns, the cervical sagittal parameters tend to be similar during follow-up.

Even when treated with aggressive current therapies, patients with glioblastoma usually survive less than two years and exhibit a high rate of recurrence. CpG is an oligonucleotide that activates the innate immune system via Toll-like receptor 9 (TLR9) activation. Injection of CpG into glioblastoma tumors showed promise as an immunotherapy in mouse models but proved disappointing in human trials. One aspect of glioma that is not addressed by CpG therapy alone is the highly invasive nature of glioma cells, which is associated with resistance to radiation and chemotherapy. Here, we demonstrate that single-walled carbon nanotubes noncovalently functionalized with CpG (SWNT/CpG), which retain the immunostimulatory property of the CpG, selectively inhibit the migration of glioma cells and not macrophages without affecting cell viability or proliferation. SWNT/CpG also selectively decreased NF-κB activation in glioma cells, while activating macrophages by induction of the TLR9/NF-κB pathway, as we have previously reported. The migration inhibition of glioma cells was correlated with selective reduction of intracellular levels of reactive oxygen species (ROS), suggesting that an antioxidant-based mechanism mediates the observed effects. To the best of our knowledge, SWNT/CpG is the first nanomaterial that inhibits the migration of cancer cells while stimulating the immune system.