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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.

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.

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.

Background A proper restoration of sagittal alignment is essential in AIS patients, but few studies provided a formula to predict an optimal surgical thoracic kyphosis (TK) gain in adolescent idiopathic scoliosis (AIS) patients. A formula was recently proposed (LL = (PI+TK)/2 + 10) to predict the optimal lumbar lordosis (LL) in adult spinal deformity patients, which has not been validated in adolescents. The aim of this study is to establish a formula with TK and pelvic parameters in normal adolescents and predict an optimal TK with this formula pre- and post-operatively in Lenke 1 AIS patients. Methods A total of 60 asymptomatic adolescents were used to validate the proposed formula. The subject was considered to match with the formula, if the difference between the virtual TK and the theoretical TK was less than 10°. Then regression analysis was performed to establish a new formula to predict TK in adolescents. The predictive efficiency of the new formula was also validated in 40 Lenke 1 AIS patients. Results Of the 60 asymptomatic adolescents, only 26 (43.33%) asymptomatic adolescents matched with the adjusted formula: TK = 2 × (LL-10)-PI. The paired t test revealed a significantly different theoretical TK (tTK) compared to the virtual TK (41.23 ± 18.29° vs. 24.80 ± 8.75°, P

Background The factors associated with lateral curve flexibility in degenerative scoliosis have not been well documented. Disc degeneration could result in significant change in stiffness and range of motion in lateral bending films. The osteophytes could be commonly observed in degenerative spine but the relationship between osteophyte formation and curve flexibility remains controversial. The aim of the current study is to clarify if the disc degeneration and osteophyte formation were both associated with curve flexibility of degenerative scoliosis. Methods A total of 85 patients were retrospectively analyzed. The inclusion criteria were as follow: age greater than 45 years, diagnosed as degenerative scoliosis and coronal Cobb angle greater than 20°. Curve flexibility was calculated based on Cobb angle, and range of motion (ROM) was based on disc angle evaluation. Regional disc degeneration score (RDS) was obtained according to Pfirrmann classification and osteophyte formation score (OFS) was based on Nanthan classification. Spearman correlation was performed to analyze the relationship between curve flexibility and RDS as well as OFS. Results Moderate correlation was found between RDS and curve flexibility with a Spearman coefficient of −0.487 (P = 0.009). Similarly, moderate correlation was observed between curve flexibility and OFS with a Spearman coefficient of −0.429 (P = 0.012). Strong correlation was found between apical ROM and OFS compared to the relationship between curve flexibility and OFS with a Spearman coefficient of −0.627 (P