Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in ...MTOR account for 15%–25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 100×–20,012×) of five important mTOR pathway genes—PIK3CA, PIK3R2, AKT3, TSC1, and TSC2—by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T p.Arg22Trp and c.610C>T p.Arg204Cys) and TSC2 (c.4639G>A p.Val1547Ile), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.
Candidates for high‐energy cathodes in potassium‐ion batteries (KIBs) are selected by fully screening the inorganic compound structure database. The compounds that satisfy the specific conditions for ...plausible KIB cathodes are further subjected to theoretical and electrochemical verification, and KVP2O7 is finally pinpointed. KVP2O7 can reversibly desert/insert ≈60% of K+ (60 mA h g−1) during either chemical or electrochemical oxidation/reduction. KVP2O7 shows an average discharge potential of ≈4.2 V versus K/K+, which corresponds to an energy density of 253 W h kg−1 at 0.25 C. This high energy density characteristic of KVP2O7 is maintained both during fast charge/discharge (C/D) and prolonged redox cycles. The C/D of KVP2O7 is also accompanied by a phase transition between a monoclinic KVP2O7 (P21/c) and a triclinic K1−xVP2O7(P1¯). The structure interpretation of a new K1−xVP2O7 phase indicates that K+‐extraction induces a conformational change of two tetrahedral PO4 units in pyrophosphates. The P1¯ phase of K1−xVP2O7 (x ≈0.6) remains stable during the C/D process, although it returns to the inborn P21/c phase after thermal treatment. It is believed that the data‐mining protocol designed for this study will provide a new strategy for materials discovery and that the pinpointed KVP2O7 can be utilized as a reliable KIB cathode.
The data‐mining of the inorganic registry and subsequent theoretical/experimental verification, is introduced to pinpoint KVP2O7 as a promising cathode material in potassium ion batteries. KVP2O7 delivers a high‐energy density of 253 W h kg−1, with excellent rate‐capability and stability. During charging, KVP2O7 of P21/c is transformed to K1−xVP2O7 (x ≈0.6) of P‐1, exhibiting good reversibility between the two phases during subsequent redox cycles.
A considerable portion of autoimmune encephalitis (AE) does not respond to conventional immunotherapies and subsequently has poor outcomes. We aimed to determine the efficacy of tocilizumab, an ...anti-interleukin-6 antibody, in rituximab-refractory AE compared with other treatment options. From an institutional cohort of AE, 91 patients with inadequate clinical response to first-line immunotherapy and following rituximab were retrospectively reviewed. Patients were grouped according to their further immunotherapy strategies. Thirty (33.0 %) patients were included in the tocilizumab group, 31 (34.0 %) in the additional rituximab group, and 30 (33.0 %) in the observation group. Outcomes were defined as the favorable modified Rankin Scale scores (≤2) at 1 and 2 months from the initiation of each treatment strategy and at the last follow-up. Favorable clinical response (improvement of the modified Rankin Scale scores by ≥ 2 points or achievement of the mRS scores ≤ 2) at the last follow-up was also analyzed. The tocilizumab group showed more frequent favorable mRS scores at 2 months from treatment initiation and at the last follow-up compared with those at the relevant time points of the remaining groups. The majority (89.5 %) of the patients with clinical improvement at 1 month from tocilizumab treatment maintained a long-term favorable clinical response. No serious adverse effects of rituximab or tocilizumab were reported. Therefore, we suggest that tocilizumab might be a good treatment strategy for treating AE refractory to conventional immunotherapies and rituximab. The tocilizumab-mediated clinical improvement manifests as early at 1 month after treatment initiation.
This feature article presents a short review of the recent developments in the synthesis of conjugated polyelectrolytes (CPEs) along with their applications in organic optoelectronic devices with ...particular focus on the molecular structures of CPEs with ionic functionality, synthetic approaches, and their utilization as an interfacial layer. The orthogonal solubility of the CPEs allows the simple preparation of multilayer organic devices by solution casting on top of a nonpolar organic photoactive layer without disturbing the interfaces, showing their effectiveness in tuning the electronic structures at the interfaces for improving the charge carrier transport and resulting device properties. These achievements highlight the dynamic nature of CPEs and their applicability to a wide range of optoelectronic devices.
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This year, France banned the application of titanium dioxide nanoparticles as a food additive (hereafter, E171) based on the insufficient oral toxicity data. Here, we investigated the subchronic ...toxic responses of E171 (0, 10, 100, and 1,000 mg/kg) and tried to elucidate the possible toxic mechanism using AGS cells, a human stomach epithelial cell line. There were no dose‐related changes in the Organisation for Economic Cooperation and Development test guideline‐related endpoints. Meanwhile, E171 deeply penetrated cells lining the stomach tissues of rats, and the IgM and granulocyte‐macrophage colony‐stimulating factor levels were significantly lower in the blood from rats exposed to E171 compared with the control. The colonic antioxidant protein level decreased with increasing Ti accumulation. Additionally, after 24‐h exposure, E171 located in the perinuclear region of AGS cells and affected expression of endoplasmic reticulum stress‐related proteins. However, cell death was not observed up to the used maximum concentration. A gene profile analysis also showed that immune response‐related microRNAs were most strongly affected by E171 exposure. Collectively, we concluded that the NOAEL of E171 for 90 days repeated oral administration is between 100 and 1,000 mg/kg for both male and female rats. Additionally, further study is needed to clarify the possible carcinogenesis following the chronic accumulation in the colon.
In this study, we found that E171 did not induce any dose‐related changes in the OECD test guideline‐related endpoints. Meanwhile, E171 deeply penetrated cells lining the stomach tissues of rats, and the colonic antioxidant protein level decreased with increasing Ti accumulation. After 24‐h exposure, E171 also located in the perinuclear region of AGS cells and affected expression of ER stress‐related proteins. Additionally, a gene profile analysis showed that immune response‐related microRNAs were most strongly affected by E171 exposure.
Objective
Autoimmune encephalitis (AE), represented by anti–leucine‐rich glioma‐inactivated 1 (anti‐LGI1) and anti–N‐methyl‐D‐aspartate receptor (anti‐NMDAR) encephalitis, has increasing clinical ...significance based on recent discoveries of neuronal autoantibodies. However, its immunopathogenesis is not fully understood. Here, we investigated whether AE is associated with the human leukocyte antigen (HLA) subtypes.
Methods
We compared the HLA genotypes of 11 anti‐LGI1 and 17 anti‐NMDAR encephalitis patients to the control groups, which consisted of 210 epilepsy patients and 485 healthy Koreans.
Results
Anti‐LGI1 encephalitis was associated with the DRB1*07:01–DQB1*02:02 haplotype (10 patients; 91%) in HLA class II genes, as well as with B*44:03 (8 patients; 73%) and C*07:06 (7 patients; 64%) in the HLA class I region. The prevalence of these alleles in anti‐LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti‐NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA‐peptide binding prediction algorithms and computational docking underpinned the close relationship.
Interpretation
This finding suggests that most anti‐LGI1 encephalitis develops in a population with specific HLA subtypes, providing insight into a novel disease mechanism. Ann Neurol 2017;81:183–192
The major obstacle to successful ABO blood group–incompatible kidney transplantation (ABOi KT) is antibody‐mediated rejection (AMR). This study aimed to investigate transcriptional profiles through ...RNA sequencing and develop a minimally invasive diagnostic tool for discrimination between accommodation and early acute AMR in ABOi KT. Twenty‐eight ABOi KT patients were selected: 18 with accommodation and 10 with acute AMR at the 10th day posttransplant protocol biopsy. Complete transcriptomes of their peripheral blood were analyzed by RNA sequencing. Candidate genes were selected by bioinformatics analysis, validated with quantitative polymerase chain reaction, and used to develop a classification model to diagnose accommodation. A total of 1385 genes were differentially expressed in accommodation compared with in AMR with P‐adjusted < .05. Functional annotation and gene set enrichment analysis identified several immune‐related and immunometabolic pathways. A 5‐gene classification model including COX7A2L, CD69, CD14, CFD, and FOXJ3 was developed by logistic regression analysis. The model was further validated with an independent cohort and discriminated between accommodation and AMR with 92.7% sensitivity, 85.7% specificity, and 91.7% accuracy. Our study suggests that a classification model based on peripheral blood transcriptomics may allow minimally invasive diagnosis of acute AMR vs accommodation and subsequent patient‐tailored immunosuppression in ABOi KT.
This study proposes and validates a 5‐gene classification model based on peripheral blood transcriptomics for minimally invasive diagnosis of early acute antibody‐mediated rejection versus accommodation in ABO‐incompatible kidney transplant patients.
Advanced glycation endproduct (AGE)-induced vascular smooth muscle cell (VSMC) proliferation and reactive oxygen species (ROS) production are emerging as important mechanisms of diabetic ...vasculopathy, but little is known about the molecular mechanism responsible for the antioxidative effects of statins on AGEs. It has been reported that statins exert pleiotropic effects on the cardiovascular system due to decreases in AGE-induced cell proliferation, migration, and vascular inflammation. Thus, in the present study, the authors investigated the molecular mechanism by which statins decrease AGE-induced cell proliferation and VSMC migration. In cultured VSMCs, statins upregulated Nrf2-related antioxidant gene, NQO1 and HO-1, via an ERK5-dependent Nrf2 pathway. Inhibition of ERK5 by siRNA or BIX02189 (a specific ERK5 inhibitor) reduced the statin-induced upregulations of Nrf2, NQO1, and HO-1. Furthermore, fluvastatin was found to significantly increase ARE promoter activity through ERK5 signaling, and to inhibit AGE-induced VSMC proliferation and migration as determined by MTT assay, cell counting, FACS analysis, a wound scratch assay, and a migration chamber assay. In addition, AGE-induced proliferation was diminished in the presence of Ad-CA-MEK5α encoding a constitutively active mutant form of MEK5α (an upstream kinase of ERK5), whereas depletion of Nrf2 restored statin-mediated reduction of AGE-induced cell proliferation. Moreover, fluvastatin suppressed the protein expressions of cyclin D1 and Cdk4, but induced p27, and blocked VSMC proliferation by regulating cell cycle. These results suggest statin-induced activation of an ERK5-dependent Nrf2 pathway reduces VSMC proliferation and migration induced by AGEs, and that the ERK5-Nrf2 signal module be viewed as a potential therapeutic target of vasculopathy in patients with diabetes and complications of the disease.
Given that individuals with latent tuberculosis (TB) infection represent the major reservoir of TB infection, latency-associated antigens may be promising options for development of improved ...multi-antigenic TB subunit vaccine. Thus, we selected RipA, a peptidoglycan hydrolase required for efficient cell division of Mycobacterium tuberculosis (Mtb), as vaccine candidate. We found that RipA elicited activation of dendritic cells (DCs) by induction of phenotypic maturation, increased production of inflammatory cytokines, and prompt stimulation of MAPK and NF-κB signaling pathways. In addition, RipA-treated DCs promoted Th1-polarzied immune responses of naïve CD4+ T cells with increased proliferation and activated T cells from Mtb-infected mice, which conferred enhanced control of mycobacterial growth inside macrophages. Moreover, mice immunized with RipA formulated in GLA-SE adjuvant displayed remarkable generation of Ag-specific polyfunctional CD4+ T cells in both lung and spleen. Following an either conventional or ultra-low dose aerosol challenges with 2 Mtb Beijing clinical strains, RipA/GLA-SE-immunization was not inferior to BCG by mediating protection as single Ag. Collectively, our findings highlighted that RipA could be a novel candidate as a component of multi-antigenic TB subunit vaccines.
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