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Three long-chain oligomeric acceptors with a stepwise increase in conjugation length are obtained via three successive one-pot reactions and a systematic structure–property–performance relationship study was carried out.

The excellent reactivity toward C–H direct arylation, water wettability and O–C p–π conjugation endow EDOT to be an attractive electron donor unit for CP photocatalysts, yielding an unprecedented hydrogen evolution rate up to 0.95 mmol h−1/6 mg catalyst.

A library of STP-based CP photocatalysts with –CN groups at varied positions were designed and facilely synthesized by an atom- and step-economic one-component direct arylation polymerization for a structure–property–performance correlation study.

Five carbazole and diketopyrrolopyrrole-based donor-acceptor (D-A) new π-conjugated oligomers (π-COs) with gradually elongated lengths are facilely synthesized via a single pot of direct C–H arylation with merits of atom- and step-economy. The structure-property-performance correlations of these π-COs and their parent polymer are studied in detail by opto-electronic characterizations and bulk heterojunction (BHJ) organic photovoltaic (OPV) devices. It is found that the π-COs having longer lengths enable better performance in OPVs owing to the enhanced intermolecular interaction with the elongation of the conjugations. The above results not only highlight the powerful synthetic strategy here provided, but also reveal that π-COs with unique properties might find promising application in OPVs.

2-Styrylthiophene-based donor-acceptor linear conjugated polymers with tunable cyano substituents are atom-economically obtained

Facile synthesis without involvement of toxic reagents is of great significance in the practical application of photovoltaic materials. In this work, four acceptor-donor-acceptor (A-D-A) type unfused-ring acceptors (UFRAs) with stepwise extension in π-conjugation, i. e., CPFB-IC-n (n=1-4), involving cyclopentadithiophene (CPDT) and 1,4-difluorobenzene (DFB) as cores, are facilely synthesized by an atom-, step-economic and labor-saving method through direct arylation of C-H bond (DACH). Among them, CPFB-IC-4 has the longest conjugation lengths among the molecular UFRA ever reported. The dependence of optoelectronic properties and photovoltaic performances of CPFB-IC-n (n=1-4) on conjugation length were systematically investigated. CPFB-IC-2 with near zero highest occupied molecular orbital (HOMO) offsets (ΔE

Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) are typical causes of developmental delay and refractory epilepsy. G‐protein‐coupled receptor 30 (GPR30) is a specific estrogen receptor that is critical in neurodevelopment, neuroinflammation, and neuronal excitability, suggesting that it plays a potential role in the epilepsy of patients with FCDIIb and TSC. Therefore, we investigated the role of GPR30 in patients with FCDIIb and TSC. We found that the expression of GPR30 and its downstream protein kinase A (PKA) pathway were decreased and negatively correlated with seizure frequency in female patients with FCDIIb and TSC, but not in male patients. GPR30 was widely distributed in neurons, astrocytes, and microglia, and its downregulation was especially notable in microglia. The GPR30 agonist G‐1 increased the expression of PKA and p‐PKA in cultured cortical neurons, and the GPR30 antagonist G‐15 exhibited the opposite effects of G‐1. The NF‐κB signaling pathway was also activated in the specimens of female patients with FCDIIb and TSC, and was regulated by G‐1 and G‐15 in cultured cortical neurons. We also found that GPR30 regulated cortical neuronal excitability by altering the frequency of spontaneous excitatory postsynaptic currents and the expression of NR2A/B. Further, the relationship between GPR30 and glycometabolism was evaluated by analyzing the correlations between GPR30 and 18F‐FDG PET‐CT values (standardized uptake values, SUVs). Positive correlations between GPR30 and SUVs were found in female patients, but not in male patients. Intriguingly, GPR30 expression and SUVs were significantly decreased in the epileptogenic tubers of female TSC patients, and ROC curves indicated that SUVs could predict the localization of epileptogenic tubers. Taken together, our results suggest a potential protective effect of GPR30 in the epileptogenesis of female patients with FCDIIb and TSC.

Epilepsy is a highly prevalent and drug-refractory neurological disorder characterized by spontaneous recurrent seizures. Estrogen is identified to be proconvulsant and lowers the seizure threshold of female epilepsy. Estrogen receptor β (ERβ) has been proposed to mediate neuroprotection in epilepsy, although the underlying mechanism remains unknown. Rationale: In this study, we investigated the role of ERβ in the epileptogenesis of female temporal lobe epilepsy (TLE). Methods: Immunohistochemistry, immunofluorescence, western blots, Golgi staining, 1H MRS and whole-cell patch-clamp were used to evaluate ERβ expression, pathological changes, and synaptic excitation /inhibition (E/I) balance in female TLE patients and ovariectomized (OVX) chronic epileptic mice. Electroencephalogram (EEG) recordings were recorded to evaluate the epileptic susceptibility in OVX WT and ERβ-/- mice. And high-throughput RNA-sequence was performed to identify differential expression genes (DEGs) which can elucidate the potential mechanism of ERβ regulating the seizure susceptibility. Results: ERβ expression was decreased in the brains of female TLE patients and OVX chronic epileptic mice. ERβ deletion enhanced seizure susceptibility and exacerbated the imbalance of synaptic E/I in hippocampal CA1 area of OVX epileptic mice. In line with these observations, RNA-sequence data further identified glutamine ligase (GLUL) as the target of ERβ involved in regulating synaptic E/I in CA1. Furthermore, ERβ agonist WAY-200070 markedly suppressed epileptic phenotypes and normalized GLUL expression in CA1 region of kainic acid (KA) induced OVX chronic epileptic model. Conclusions: Our data provide novel insight into the pathogenesis of female TLE, and indicate ERβ provides a new therapeutic strategy for female TLE patients.

Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood. Our previous studies revealed that the expression of vascular endothelial growth factor-C (VEGF-C) and corresponding receptors VEGFR-2, VEGFR-3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy. Here, we showed that the expression of VEGF-C, VEGFR-2, and VEGFR-3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF-C, VEGFR-2 and VEGFR-3 was located in the micro-columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked-EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor- and AMPA receptor-mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X-ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF-C, however, could be antagonized by ki8751, the blocker of VEGFR-2. These results suggest that VEGF-C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor-mediated currents.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems. The TSC1 and TSC2 genes have been identified as the genetic basis of TSC. Two gene tests were used for definitive genetic diagnosis. In our study, the case of a Chinese pediatric patient with seizures, hypomelanotic macules, hyperpigmented patches, multiple parenchymal lesions in the ventricle, and developmental retardation is detailed. Whole-genome sequencing (WGS) and multiplex ligation-dependent probe amplification (MLPA) were employed to detect genetic variations and copy number variations of TSC1 and TSC2. A novel heterozygous nonsense mutation in the TSC2 gene (c.3751A>T, p.Lys1251Ter) was identified in a Chinese pediatric patient suffering from TSC, whose unaffected parents did not carry this mutation. The mutation was classified as “pathogenic” according to the American College of Medical Genetics (ACMG) guidelines. WGS was carried out to definitively diagnose and detect variations in the exon and noncoding region of the gene and copy number variations in the whole genome simultaneously. For diseases with complex genetic mechanisms, WGS as the first-line test can be efficient and cost-effective for clinical diagnosis.

Aim Nod-like receptor protein 3 (NLRP3) inflammasome-mediated inflammation has emerged as a contributor to epileptogenesis. Endoplasmic reticulum stress (ERS) plays an important role in epilepsy-induced neurodegeneration. NLRP3 activation and ERS reactions share the same induction factors, suggesting that these processes may be interdependent. However, the correlation between NLRP3 and ERS in TLE has not been confirmed. Methods The expression patterns of NLRP3 inflammasome and ERS-related markers in the temporal neocortices of TLE patients were investigated by western blotting, immunohistochemistry and immunofluorescent labelling. Correlations between the protein levels of NLRP3 and the expression of ERS-related markers were assessed using Spearman's rank correlation test. To observe the relationship between the NLRP3 inflammasome and ERS, inhibitors were used in a status epilepticus (SE) model. Results Our results show that NLRP3 inflammasome components and ERS-related markers were upregulated in the temporal neocortices of TLE patients, and were mainly localized to neurons, astrocytes and microglia. We found a positive correlation between the protein levels of NLRP3 and the expression of ERS-related markers in the temporal neocortices of 20 TLE patients. Furthermore, after blocking the NLRP3 inflammasome with MCC950, the expression of ERS-related markers was markedly decreased in the hippocampi of SE mice. Moreover, TUDCA, a specific ERS inhibitor, also reduced the expression of NLRP3 components in the hippocampus under SE conditions. Conclusion Taken together, our data reveal the interdependence of the NLRP3 inflammasome and ERS in the epileptogenic zone of TLE patients and in the hippocampi of mice in the early post-SE phase.

BackgroundA hallmark of temporal lobe epilepsy (TLE) is brain inflammation accompanied by neuronal demise. Accumulating evidence demonstrates that Rev-Erbα is involved in regulating neuroinflammation and determining the fate of neurons. Therefore, we studied the expression and cellular distribution of Rev-Erbα in the epileptogenic zone of TLE and the effect of treatment with the Rev-Erbα specific agonist SR9009 in the pilocarpine model.MethodsThe expression pattern of Rev-Erbα was investigated by western blotting, immunohistochemistry, and immunofluorescence labeling in patients with TLE. Next, the effects of SR9009 on neuroinflammation, neuronal apoptosis, and neuronal loss in the mouse hippocampus 7 days after status epilepticus (SE) were assessed by western blotting, immunofluorescence labeling staining, and TUNEL staining.ResultsThe western blotting, immunohistochemistry, and immunofluorescence labeling results revealed that Rev-Erbα was downregulated in the epileptogenic zone of TLE patients and mainly localized in neurons, astrocytes, and presumably microglia. Meanwhile, the expression of Rev-Erbα was decreased in the hippocampus and temporal neocortex of mice treated with pilocarpine in the early post-SE and chronic phases. Interestingly, the expression of Rev-Erbα in the normal hippocampus showed a 24-h rhythm; however, the rhythmicity was disturbed in the early phase after SE, and this disturbance was still present in epileptic animals. Our further findings revealed that treatment with SR9009 inhibited NLRP3 inflammasome activation, inflammatory cytokine (IL-1β, IL-18, IL-6, and TNF-α) production, astrocytosis, microgliosis, and neuronal damage in the hippocampus after SE.ConclusionsTaken together, these results suggested that a decrease in Rev-Erbα in the epileptogenic zone may contribute to the process of TLE and that the activation of Rev-Erbα may have anti-inflammatory and neuroprotective effects.

Background Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults, with pathological mechanisms remaining to be fully elucidated. Fibroblast Growth Factor 13 (FGF13) encodes an intracellular protein involved in microtubule stabilization and regulation of voltage-gated sodium channels (VGSCs) function. FGF13 mutation has been identified in patients with inherent seizure, suggesting a potential association between FGF13 and the etiology of TLE. Here, we set to explore the pathological role of FGF13 in the etiology of TLE. Results We found that the expression of FGF13 was increased in the cortical lesions and CA1 region of sclerotic hippocampus and correlated with the seizure frequency in TLE patients. Also, Fgf13 expression was increased in the hippocampus of chronic TLE mice generated by kainic acid (KA) injection. Furthermore, Fgf13 knockdown or overexpression was respectively found to attenuate or potentiate the effects of KA on axonal length, somatic area and the VGSCs-mediated current in the hippocampal neurons. Conclusions Taken together, these findings suggest that FGF13 is involved in the pathogenesis of TLE by modulating microtubule activity and neuronal excitability.

3,4-Ethylene dioxythiophene (EDOT), as a monomer of commercial conductive poly(3,4-ethylene dioxythiophene) (PEDOT), has been facilely incorporated into a series of new π-conjugated polymer-based photocatalysts

Objective: Central nervous system infections (CNSIs), especially viral encephalitis and meningitis, are well-recognized causes of medically refractory epilepsy. Although surgery is an effective and durable intervention against these infections, the seizure control outcomes described in previous surgical series have been variable. Accordingly, it is not clear which variables are most valuable in predicting seizure control following surgery for CNSI. The aim of this meta-analysis was to identify the predictors of favorable surgical outcomes in CNSI-related epilepsy.Methods: The PubMed, EMBASE, Cochrane Library, WANGFANG, VIP, CBM, and CNKI databases were searched for studies according to the inclusion criteria. Prognostic factors, surgical outcomes, and patient characteristics were extracted. Heterogeneity was detected by the I2 and Q statistics.Results: Seventeen studies were included in our meta-analysis. Eight predictors of favorable outcomes (Engel Class I/II) were determined, including abnormal MRI findings, meningitis, temporal location only, regional ictal pattern, unilateral ictal pattern, older age at epilepsy, longer silent period, and longer time from infection, as follows: OR = 3.34 (95% CI 1.44–7.74), OR = 0.31 (95% CI 0.13–0.70), OR = 0.34 (95% CI 0.16–0.74), OR = 5.65 (95% CI 1.75–18.30), and OR = 9.53 (95% CI 2.36–38.48), respectively, and MD = 2.15 (95% CI 0.20–4.11), MD = 2.40 (95% CI 0.09–4.70), and MD = 8.49 (95% CI 1.50–15.48), respectively. A subgroup analysis found the following associations: regional and unilateral ictal patterns in viral encephalitis, a younger age at infection in parasitic encephalopathy, an older age at surgery, a longer time from onset, and a longer time from infection in unexplained meningitis. A sensitivity analysis restricted to studies that included each variable yielded robust results. Little evidence of publication bias was observed.Conclusions: This meta-analysis suggests that abnormal MRI findings, meningitis, temporal location only, regional and unilateral ictal patterns, older age at epilepsy, longer silent period, and longer time from infection are predictive factors in patients with favorable surgical outcomes in CNSI-related epilepsy. In addition, different infective agents influenced the results in regional and unilateral ictal patterns in ictal electroencephalography, as well as the relationship between age at infection and surgery and the time from epilepsy onset and infection.

Temporal lobe epilepsy (TLE) is defined as the sporadic occurrence of spontaneous recurrent seizures, and its pathogenesis is complex. SHP‐2 (Src homology 2‐containing protein tyrosine phosphatase 2) is a widely expressed cytosolic tyrosine phosphatase protein that participates in the regulation of inflammation, angiogenesis, gliosis, neurogenesis and apoptosis, suggesting a potential role of SHP‐2 in TLE. Therefore, we investigated the expression patterns of SHP‐2 in the epileptogenic brain tissue of intractable TLE patients and the various effects of treatment with the SHP‐2‐specific inhibitor SHP099 on a pilocarpine model. Western blotting and immunohistochemistry results confirmed that SHP‐2 expression was upregulated in the temporal neocortex of patients with TLE. Double‐labeling experiments revealed that SHP‐2 was highly expressed in neurons, astrocytes, microglia and vascular endothelial cells in the epileptic foci of TLE patients. In the pilocarpine‐induced C57BL/6 mouse model, SHP‐2 upregulation in the hippocampus began one day after status epilepticus, reached a peak at 21 days and then maintained a significantly high level until day 60. Similarly, we found a remarkable increase in SHP‐2 expression at 1, 7, 21 and 60 days post‐SE in the temporal neocortex. In addition, we also showed that SHP099 increased reactive gliosis, the release of IL‐1β, neuronal apoptosis and neuronal loss, while reduced neurogenesis and albumin leakage. Taken together, the increased expression of SHP‐2 in the epileptic zone may be involved in the process of TLE.

Background Meningiomas typically manifest on magnetic resonance imaging (MRI) as iso- to hypointense on T1-weighted imaging and iso- to hyperintense on T2-weighted imaging. After contrast administration, they usually homogeneously enhance and exhibit a visible dural tail. Meningiomas with atypical findings may be misdiagnosed. Case presentation We report a 50-year-old female patient with a pathologically diagnosed fibrous meningioma (World Health Organization grade I) that exhibited ring enhancement on MRI. Conclusions Meningiomas may rarely present with ring enhancement on MRI. The natural history and mechanisms of cystic degeneration and enhancement in the various types of meningioma require further study.

Correction for ‘EDOT-based conjugated polymers accessed via C–H direct arylation for efficient photocatalytic hydrogen production’ by Zhi-Rong Tan et al., Chem. Sci., 2022, DOI: 10.1039/d1sc05784g.

Cortical tubers in patients with tuberous sclerosis complex (TSC) are highly associated with intractable epilepsy. Recent evidence suggests a close relationship between FGF13 and seizures. To understand the role of FGF13 in the pathogenesis of cortical tubers, we investigated the expression pattern of FGF13 in cortical tubers of TSC compared with normal control cortices (CTX). We found that both the mRNA and protein levels of FGF13 were significantly higher in the cortical tubers from patients with TSC than in the control cortices. The immunohistochemical results showed strong FGF13 immunoreactivity in abnormal cells, including dysplastic neurons (DNs) and giant cells (GCs). Moreover, double-label immunofluorescence analyses confirmed that FGF13 was mainly localized in neurons and nearly absent in glia-like cells. The protein levels of FGF13 in the TSC samples were positively correlated with the frequency of seizures before surgery. Taken together, these results suggest that the overexpression and distribution pattern of FGF13 may be related to intractable epilepsy caused by TSC.

Focal cortical dysplasias (FCDs) are well recognized as important causes of medically intractable epilepsy in both children and adults. To explore the potential role of fibroblast growth factor 13 (FGF13) in intractable epilepsy caused by FCDs, we examined the expression of FGF13 in cortical lesions from 23 patients with FCD type Ia (FCDIa), 24 patients with FCD type IIa (FCDIIa), and 12 patients with FCD type IIb (FCDIIb), and we compared the results with the FGF13 expression levels in control cortex (CTX) brain tissues from 12 nonepileptic normal subjects. Both the mRNA levels and protein levels of FGF13 were significantly higher in the cortical lesions from patients with FCD than in the control cortices. The immunohistochemical results showed that strong FGF13 immunoreactivity was observed in misshapen cells, including neuronal microcolumns, hypertrophic neurons, dysmorphic neurons, and most balloon cells. Moreover, double-label immunofluorescence analyses confirmed that FGF13 was mainly localized in neurons and nearly absent in glia-like cells. Taken together, our results suggest that the overexpression of FGF13 in FCDs and the cell-specific distribution patterns of FGF13 in misshapen neurons in FCDs could potentially contribute to intractable epilepsy caused by FCDs.

Focal cortical dysplasia (FCD) is one of the main causes of medically intractable epilepsy. Some studies have reported that transient receptor potential canonical channel 3 (TRPC3) may play an important role in the occurrence of seizures. In this study, we investigated the expression patterns of TRPC3 in different types of FCD. Forty-five FCD specimens and 12 control samples from autopsies were used in our study. Western blotting, immunohistochemistry, and immunofluorescence staining were employed to detect protein expression and distribution. The amount of TRPC3 protein was markedly elevated in the FCD group. The immunohistochemistry results revealed that TRPC3 staining was strong in the malformed cells and microcolumns. Most of the TRPC3-positive cells were colabeled with glutamatergic and GABAergic markers. The overexpression and altered cellular distribution of TRPC3 in the FCD samples suggest that TRPC3 may be related to epileptogenesis in FCD.

Background Temporal lobe epilepsy (TLE) is the most common intractable epilepsy in adults, and elucidation of the underlying pathological mechanisms is needed. Voltage-gated chloride channels (ClC) play diverse physiological roles in neurons. However, less is known regarding their functions in the epilepogenesis of TLE. Methods ClC-mediated current and the spontaneous inhibitory synaptic currents (sIPSC) in hippocampal neurons of epileptic lesions were investigated by electrophysiological recording. The EEG data were analyzed by Z-scored wavelet and Fourier transformations. The expression of ClC-3, a member of ClC gene family, was detected by immunostaining and western blot. Findings ClC-mediated current was increased in the hippocampal neurons of chronic TLE mice. Application of chloride channel blockers, NPPB (5-Nitro-2- [3-phenylpropylamino] benzoic acid) and DIDS (4,4’-Diisothiocyanato-2,2’-stilbenedisulfonic acid disodium salt) reduced ClC-mediated current and increased inhibitory synaptic transmission in TLE mice. NPPB and DIDS reduced the seizure frequency and the average absolute power of ictal high-frequency oscillations (HFOs, 80-500 Hz) in TLE mice. In addition, both drugs induced outwardly rectified currents, which might be tonic inhibitory currents in the hippocampal neurons of TLE patients. Furthermore, the expression of ClC-3 was increased in the hippocampus of TLE mice and patients and positively correlated with both the absolute power and number of ictal HFOs per seizure in the sclerotic hippocampus. Interpretation These data suggest that ClC participate in the epilepogenetic process of TLE and the inhibition of ClC may have anti-epileptic effect. Funding This work was supported by National Natural Science Foundation of China (No. 81601143, No. 81771217).

Focal cortical dysplasia type II (FCD II) and tuberous sclerosis complex (TSC) are well-known causes of chronic refractory epilepsy in children. Canonical transient receptor potential channels (TRPCs) are non-selective cation channels that are commonly activated by phospholipase C (PLC) stimulation. Previous studies found that TRPC4 may participate in the process of epileptogenesis. This study aimed to examine the expression and distribution of TRPC4 in FCD II (n = 24) and TSC (n = 11) surgical specimens compared with that in age-matched autopsy control samples (n = 12). We found that the protein levels of TRPC4 and its upstream factor, PLC delta 1 (PLCD1), were elevated in FCD II and TSC samples compared to those of control samples. Immunohistochemistry assays revealed that TRPC4 staining was stronger in malformed cells, such as dysmorphic neurons, balloon cells and giant cells. Moderate-to-strong staining of the upstream factor PLCD1 was also identified in abnormal neurons. Moreover, double immunofluorescence staining revealed that TRPC4 was colocalised with glutamatergic and GABAergic neuron markers. Taken together, our results indicate that overexpression of TRPC4 protein may be involved in the epileptogenesis of FCD II and TSC.

In this work, we present two new electron acceptors, TriPDI and Fused-TriPDI, in which three perylene diimide (PDI) moieties are tethered to a benzotrithiophene (BTT) core via either single bonds (TriPDI) or ring-fusion (Fused-TriPDI). TriPDI connects three PDIs to BTT via carbon–carbon single bonds, resulting in a rotatable and highly twisted skeleton. Instead, Fused-TriPDI, made through oxidative ring-fusion of TriPDI, exhibits good structural rigidity and planarity, as well as effective conjugation between PDI and BTT. As a result, the fused molecule shows up-shifted energy levels, and enhanced absorption and charge mobility over the unfused one. The polymer solar cells (PSCs) with a PTB7-Th:Fused-TriPDI blend show the best power conversion efficiency of 6.19%, which is around three times higher than that with PTB7-Th:TriPDI.

// Song Li 1 , Zhenle Zang 1 , Jiaojiang He 2 , Xin Chen 1 , Sixun Yu 3 , Yuchun Pei 1 , Zhi Hou 1 , Ning An 1 , Hui Yang 1 , Chunqing Zhang 1 , Shiyong Liu 1 1 Epilepsy Research Center of PLA, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China 2 Department of Neurosurgery, General Hospital of the People's Liberation Army Lanzhou Military Region, Lanzhou, Gansu, 730050, China 3 Department of Neurosurgery, General Hospital of the People's Liberation Army Chengdu Military Region, Chengdu, Sichuan, 610083, China Correspondence to: Chunqing Zhang, email: cqzhang@tmmu.edu.cn Shiyong Liu, email: shiyongxinqiao@163.com Keywords: focal cortical dysplasia, epileptogenesis, pathogenesis, pannexin 1, pannexin 2 Received: May 16, 2016 Accepted: December 16, 2016 Published: December 28, 2016 ABSTRACT Focal cortical dysplasia (FCD) is a major cause of intractable epilepsy in children however the mechanisms underlying the pathogenesis of FCD and FCD induced epilepsy remain unclear. Increasing evidence suggests that the large-pore ion channels, pannexin 1 (Panx1) and 2 (Panx2), are involved in epilepsy and brain development. In this study, we investigated the expression of Panx1 and Panx2 in surgical samples from patients with FCD type Ia (FCDIa), type IIa (FCDIIa), and type IIb (FCDIIb) and in age-matched autopsy control samples. We found Panx1 mRNA and protein levels were both increased in all these FCD samples. Immunohistochemical analyses revealed that Panx1 was mainly distributed in microcolumn neurons, dysmorphic neurons (DNs), balloon cells (BCs) and reactive astrocytes. Double-labeled staining showed that the Panx1-positive neurons were mostly glutamatergic DNs and occasionally GABAergic normal-appearing neurons. Importantly, the protein levels of Panx1 positively correlated with the frequency of seizures. Intriguingly, the Panx2 mRNA and protein levels were only upregulated in FCDIIb lesions and characteristically expressed on SOX2-positive multipotential BCs. Immunofluorescent experiments identified that Panx2-positive BCs mainly expressed the neuronal differentiation transcription factor MASH1 but not the immature glial marker vimentin. Taken together, our results established a potential role of the specific expression and cellular distribution patterns of Panx1 and Panx2 in FCD-associated epileptogenesis and pathogenesis.

Exploring sustainable chemistry for renewable energy plays a key role in meeting the ever increasing energy demand without sacrificing the environment. In this study, two novel diketopyrrolopyrrol(DPP)-based π-conjugated oligomers (named as TPE-DPP4 and BP-DPP4) have been readily synthesized via a ligand-free Pd-catalyzed sequential activation of C H bond in two steps with good yields starting from simple building blocks. Poly(3-hexylthiophene) is employed as an electron donor to blend with the new DPP-derived electron acceptors for the fullerene-free bulk heterojunction organic photovoltaics. The power conversion efficiency of 2.49% has been achieved, corresponding with an open-circuit voltage of 1.16 V, which is among the highest open-circuit voltages for the single-junction organic photovoltaics. The facilely accessible electron acceptors blended with cost-effective poly(3-hexylthiophene) donor for fullerene-free organic photovoltaics opens a new pathway to access renewable solar energy via sustainable chemistry.

Introduction: Lennox-Gastaut syndrome (LGS) is a severe subtype of childhood-onset epileptic encephalopathy with drug-resistant and poor surgical prognosis. However, electroencephalogram (EEG) patterns of symptomatic LGS or LG phenotypes with structural brain lesions including focal abnormalities or asymmetric slow-spike-wave (SSW) patterns remain largely unknown. Due to the contradictory lateralization difference between MRI lesions and EEG pattern in symptomatic LGS or LG phenotypes, it is difficult to determine the precise lateralization of epileptic lesions, which is crucial to better surgical prognosis. This study is aim to ascertain the clinical characteristics of the EEG patterns, and its relationship with MRI lesions and to evaluate its prognostic value of surgical treatment in symptomatic LGS or LG phenotypes. Methods: Twenty-four symptomatic LGS cases with asymmetric EEG SSW patterns and contralaterally independent or contralaterally dominant MRI lesions were collected, and their clinical features were analyzed retrospectively. Results: In this cohort, most of lesions were perinatal or acquired during the first 6 months of life. The most common etiology was intracerebral hemorrhage. The LGS patients with both asymmetric SSW and focal sporadic epileptic waves (SEW) patterns showed the best surgical outcome with Engel class I level. Asymmetric SSW patterns with maximal discharges contralateral to MRI lesions were frequently observed in most of symptomatic LGS or LG phenotypes. Predominantly diffuse destructive lesions led to an attenuated voltage of ipsilateral scalp EEG producing an asymmetric SSW pattern in those patients with symptomatic LGS or LG phenotypes. Conclusions: Our study reveals a special SEW EEG pattern in symptomatic LG patients with asymmetric SSW and MRI lesions contralateral to the dominant EEG patterns. Contradictory lateralization difference between MRI and EEG probably arises from the relative voltage attenuation presenting in EEG ipsilateral to huge destructive lesions from early life. Our study suggests that the independent focal SEW activity remaining ipsilateral to the MRI lesion can potentially predict better surgical prognosis in symptomatic LGS or LG phenotypes.

Backgrounds Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are very frequently associated with epilepsy in pediatric patients. Human leukocyte immunoglobulin-like receptor B2 (LILRB2) participates in the process of neurite growth, synaptic plasticity, and inflammatory reaction, suggesting a potential role of LILRB2 in epilepsy. However, little is known about the distribution and expression of LILRB2 in cortical lesions of FCD IIb and cortical tubers of TSC. Methods In this study, we have described the distribution and expression of LILRB2 signaling pathway in cortical lesions of pediatric patients with FCD IIb (n = 15) and TSC (n = 12) relative to age-matched autopsy control samples (CTX, n = 10), respectively. The protein levels of LILRB2 pathway molecules were assessed by western blotting and immunohistochemistry. The expression pattern was investigated by immunohistochemistry and double labeling experiment. Spearman correlation analysis to explore the correlation between LILRB2 protein level and seizure frequency. Results The protein levels of LILRB2 and its downstream molecules POSH, SHROOM3, ROCK1, ROCK2 were increased in cortices of patients compared to CTX. Protein levels of LILRB2 negatively correlated with the frequency of seizures in FCD IIb and TSC patients, respectively. Moreover, all LILRB2 pathway molecules were strongly expressed in dysmorphic neurons, balloon cells, and giant cells, LILRB2 co-localized with neuron marker and astrocyte marker. Conclusion Taken together, the special expression patterns of LILRB2 signaling pathway in cortical lesions of FCD IIb and TSC implies that it may be involved in the process of epilepsy.

At least 50% of patients with tuberous sclerosis complex present with intractable epilepsy; for these patients, resective surgery is a treatment option. Here, we report a nationwide multicentre retrospective study and analyse the long-term seizure and neuropsychological outcomes of epilepsy surgery in patients with tuberous sclerosis complex. There were 364 patients who underwent epilepsy surgery in the study. Patients’ clinical data, postoperative seizure outcomes at 1-, 4-, and 10-year follow-ups, preoperative and postoperative intelligence quotients, and quality of life at 1-year follow-up were collected. The patients’ ages at surgery were 10.35 ± 7.70 years (range: 0.5–47). The percentage of postoperative seizure freedom was 71% (258/364) at 1-year, 60% (118/196) at 4-year, and 51% (36/71) at 10-year follow-up. Influence factors of postoperative seizure freedom were the total removal of epileptogenic tubers and the presence of outstanding tuber on MRI at 1- and 4-year follow-ups. Furthermore, monthly seizure (versus daily seizure) was also a positive influence factor for postoperative seizure freedom at 1-year follow-up. The presence of an outstanding tuber on MRI was the only factor influencing seizure freedom at 10-year follow-up. Postoperative quality of life and intelligence quotient improvements were found in 43% (112/262) and 28% (67/242) of patients, respectively. Influence factors of postoperative quality of life and intelligence quotient improvement were postoperative seizure freedom and preoperative low intelligence quotient. The percentage of seizure freedom in the tuberectomy group was significantly lower compared to the tuberectomy plus and lobectomy groups at 1- and 4-year follow-ups. In conclusion, this study, the largest nationwide multi-centre study on resective epilepsy surgery, resulted in improved seizure outcomes and quality of life and intelligence quotient improvements in patients with tuberous sclerosis complex. Seizure freedom was often achieved in patients with an outstanding tuber on MRI, total removal of epileptogenic tubers, and tuberectomy plus. Quality of life and intelligence quotient improvements were frequently observed in patients with postoperative seizure freedom and preoperative low intelligence quotient.

SummaryAim Infantile spasms (IS) are an age-specific epileptic syndrome with specific clinical symptom and electroencephalogram (EEG) features, lacking treatment options, and a poor prognosis. Excessive endogenous corticotropin-releasing hormone (CRH) in infant brain might result in IS. However, the data from human IS are limited. In our study, we investigated the expressions of CRH and its receptor type 1 (CRHR1) in surgical tissues from patients with IS and autopsy controls. Methods Specimens surgically removed from 17 patients with IS, and six autopsy controls were included in the study. Real-time PCR, Western blotting, and immunostaining were used to detect the expressions of mRNA, protein expression, and distribution. The correlation between variates was analyzed by Spearman rank correlation. Results The expressions of CRH and CRHR1 were significantly upregulated in the epileptogenic tissues of IS patients compared with the control group. CRH was distributed mainly in neurons, while CRHR1 was distributed in neurons, astrocytes, and microglia. The expression levels of CRH and CRHR1 were positively correlated with the frequency of epileptic spasms. Moreover, the expression of protein kinase C (PKC), which was an important downstream factor of CRHR1, was significantly upregulated in the epileptogenic tissues of patients with IS and was positively correlated with the CRHR1 expression levels and the frequency of epileptic spasms. Conclusion These results suggest that the CRH signal transduction pathway might participate in the epileptogenesis of IS, supporting the hypothesis that CRH is related to the pathogenesis of IS.

Summary Aim Focal cortical dysplasia (FCD) represents a well-known cause of medically intractable epilepsy. Studies found that transient receptor potential vanilloid receptor 4 (TRPV4) may participate in the occurrence of seizures. This study investigated the expression patterns of TRPV4 in FCD and the cascade that regulate functional state of TRPV4 in cortical neurons. Methods Thirty-nine surgical specimens from FCD patients and 10 age-matched control samples from autopsies were included in this study. Protein expression and distribution were detected by Western blot, immunohistochemistry, and immunofluorescence staining. Calcium imaging was used to detect the TRPV4-mediated Ca2+ influx in cortical neurons. Results (1) The protein levels of TRPV4 and of an upstream factor, protein kinase C (PKC), were markedly elevated in FCD. (2) TRPV4 staining was stronger in the dysplastic cortices of FCD and mainly observed in neuronal microcolumns and malformed cells. (3) The activation of TRPV4 was central for [Ca2+]i elevation in cortical neurons, and this activity of TRPV4 in cortical neurons was regulated by the PKC, but not the PKA, pathway. Conclusion The overexpression and altered cellular distribution of TRPV4 in FCD suggest that TRPV4 may potentially contribute to the epileptogenesis of FCD.

Focal cortical dysplasias (FCDs) are major brain malformations that commonly lead to medically intractable epilepsy. The purinergic ionotropic P2X7 receptor (P2X7R) is an atypical P2X subtype that gates calcium and sodium ions. Previous animal studies have suggested that P2X7R is a contributing factor in epileptogenesis. This study aimed to define the distribution and expression of P2X7R in 35 FCD patient-surgical-resection specimens relative to autopsy control samples (n = 8). Immunohistochemical colocalization assays revealed that P2X7R was primarily expressed in neurons, astrocytes, and microglia. In FCD samples, P2X7R protein levels were increased in abnormal cell types such as dysmorphic neurons and balloon cells, which are characteristic of FCD. By real-time PCR and Western blotting, P2X7R mRNA and protein expression levels were elevated in FCD patient samples vs control samples; P2X7R expression was also higher in FCDII vs FCDIa patient samples. Because interleukin-1β is a downstream factor of the P2X7R signaling pathway, we determined that there was also moderate-to-strong interleukin-1β expression in the dysmorphic neurons, balloon cells, and microglia in FCD patient lesions. These results indicate that increasing P2X7R levels may contribute to the pathogenesis of human FCD and that P2X7R represents a potential anti-epileptogenic target.

The aim of this study was to determine the predictors of seizure recurrence in surgery for focal cortical dysplasia (FCD) by conducting a meta-analysis. Publications that met the pre-stated inclusion criteria were selected from PubMed and CNKI databases. Two authors extracted data independently about prognostic factors, surgical outcome, and clinical characteristics of participants. A fixed-effects model was used to calculate the summary of odds ratio (OR) with 95% confidence interval (CI). Forty-eight studies were included in our meta-analysis. Three predictors of seizure recurrence (Engel class III/IV)—histological FCD type I, incomplete resection, and extratemporal location were determined; combined OR with 95% CI were 1.94 (95%CI 1.53–2.46), 12.06 (95%CI 7.32–19.88), and 1.91 (95%CI 1.06–3.44), respectively. Trial sequential analysis revealed that the outcomes had a sufficient sample size to reach firm conclusions. Furthermore, seizure location was not substantially modified by geographic region, while histological FCD type I and incomplete resection showed a significant association with seizure recurrence in different continents except Asia for incomplete resection. Sensitivity analyses restricted to studies for each variable yielded robust results. Little evidence of publication bias was observed. Meanwhile, the difference in the standard for outcome failed to influence the results for prognosis. Network meta-analysis including 13 trials comparing subtypes of FCD found the FCD IIb had the lowest seizure recurrence rate. This meta-analysis suggests that histological FCD type I, incomplete resection, and extratemporal location are recurrence factors in patients with epilepsy surgery for FCD. In addition, FCD IIb is associated with the highest rates of postoperative seizure control among the subtypes of FCD, type I and type II.

Focal cortical dysplasia (FCD) is the main cause of medically intractable pediatric epilepsy. Previous studies have suggested that alteration of cortical interneurons and abnormal cytoarchitecture have been linked to initiation and development for seizure. However, whether each individual subpopulation of cortical interneurons is linked to distinct FCD subtypes remains largely unknown. Here, we retrospectively analyzed both control samples and epileptic specimens pathologically diagnosed with FCD types Ia, IIa, or IIb. We quantified three major interneuron (IN) subpopulations, including parvalbumin (PV)-, somatostatin (Sst)-, and vasoactive intestinal peptide (Vip)-positive INs across all the subgroups. Additionally, we calculated the ratio of the subpopulations of INs to the major INs (mINs) by defining the total number of the PV-, Sst-, and Vip-INs as mINs. Compared with the control, the density of the PV-INs in FCD type IIb was significantly lower, and the ratio of PV/mINs was lower in the superficial part of the cortex of the FCD type Ia and IIb groups. Interestingly, we found a significant increase in the ratio of Vip/mINs only in FCD type IIb. Overall, these results suggest that in addition to a reduction in PV-INs, the increase in Vip/mINs may be related to the initiation of epilepsy in FCD type IIb. Furthermore, the increase in Vip/mINs in FCD type IIb may, from the IN development perspective, indicate that FCD type IIb forms during earlier stages of pregnancy than FCD type Ia.

Toll-like receptors (TLRs) that mediate inflammatory responses play an important role in epilepsy; however, whether TLR1 is also involved in epileptogenesis remains unclear. Thus, in this study, we investigated the extent and pattern of TLR1 expression in epileptic tissues. One-hundred and thirty-two mice were intra-cerebroventricularly injected with PBS or kainic acid (KA) and were examined at 1, 3, 8 and 24 h. The expression pattern and distribution of TLR1 were examined by reverse-transcriptase polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemistry staining. The mRNA and protein levels of TLR1 were significantly upregulated in the hippocampus and temporal cortex of epileptic mice compared with those of controls. TLR1 expression was increased as early as 1 h following KA treatment and peaked at 8 and 24 h. Immunohistochemistry staining demonstrated that TLR1 was distributed in the CA1-3, dentate gyrus and hilus regions of the hippocampus and different cortical regions. Immunofluorescent staining further revealed that TLR1 was primarily expressed in the neurons, microglia, and astrocytes of epileptogenic tissue. These results demonstrate that cortical and hippocampal sub-regional expression of TLR1 is altered during epileptogenesis in a time- and location-specific manner, suggesting a close association with the process of epilepsy.

Non-fullerene acceptor based organic photovoltaic devices (OPVs) reported so far are inferior to those derived from fullerenes. This increases the speculation on whether donors need to be tailored for advancing non-fullerene OPVs. We explored herein two direct arylation-derived diketopyrrolopyrrole (DPP)-based three-dimensional (3D) donors that can deliver respectable power conversion efficiencies (PCEs) of 4.64% and 4.02% with polymeric acceptor N2200 blends, surpassing those obtained from PC71BM (3.56% and 3.22%, respectively). It is found that these 3D-shaped molecular donors can yield improved photo-to-current conversion and balanced charge transport when blending with the linear N2200 polymer. This finding suggests that engineering molecular geometry can be a promising approach for developing high-performance materials.

Increasing evidence indicates that inflammatory processes play a crucial role in the etiopathology of epilepsy and seizure disorders. The Toll/IL-1R domain-containing adapter-inducing IFN-β (TRIF) activated several transcriptions leading to the production of pro-inflammatory cytokines in the central nervous system, which suggests a potential role for TRIF in the epileptogenesis of epilepsy. In this study, we investigated the roles of TRIF in human and mice epileptogenic tissues. Western blot and immunohistochemistry assays showed that the expression of TRIF was significantly upregulated in neurons and glial cells in both human epileptic tissues and mouse models, and positively correlated with seizure frequency. TRIF expression positively correlated with high-mobility group box 1 (HMGB1) expression. In TRIF-deficient mice, electroencephalograms displayed a significant decrease in seizure frequency and duration time, while KA induced seizures compared with wild-type (WT) mice. The number and duration time of spontaneous seizures were also decreased in the chronic KA-induced TRIF-deficient mouse models. In TLR4-deficient hippocampal neurons and mouse models, TRIF expression was lower compared with WT mice during HMGB1 and KA stimulation. Meanwhile, in KA-induced TRIF-deficient mouse models, microglia activation was significantly suppressed; pro-inflammatory factors including IL-1β, TNF-α, iNOS, HMGB1 and IFN-β were reduced; and the survival of the neurons in the hippocampus increased compared with WT mice. Our findings suggested that TRIF may be involved in the epileptogenesis of temporal lobe epilepsy, which would make it a potential therapeutic target for the treatment of epilepsy.