Purification of gamma-cyclodextrin via selective coordination with potassium ions to form metal-organic frameworks.

Efficient purification of gamma-cyclodextrin (γ-CD) is always challenging due to its structural similarity to other CDs and low crystallinity in water. In addressing this issue, an approach was proposed based on the formation mechanism of cyclodextrin metal-organic frameworks (CD-MOFs). This method involved the selective coordination of CDs mixture with potassium ions in water, facilitated by ethanol-induced crystallization, leading to the purification of γ-CD. The results showed that potassium ions enhanced γ-CD crystallization, and ethanol was crucial to selectively coordinating potassium ions with γ-CD. The characterizations revealed that the resulting CD-MOFs exhibited a small particle size, high surface area, and high thermal stability, and was identical to γ-CD-MOF, further indicating the final γ-CD with high purity. The separation factors of γ-CD/α-CD and γ-CD/ß-CD were 309 and 260, respectively. Moreover, this method was validated through its application to the industrial enzymatic CDs mixture. The purification of γ-CD could achieve 99.99 ± 0.01 % after four crystallization cycles. Therefore, selectively coordinating with potassium ions to form MOFs provided a valuable reference for the purification of γ-CD and even the direct synthesis of γ-CD-MOF from CDs mixture. This advancement will also benefit the future production and application of γ-CD.

Supramolecular Structure of the ß-Cyclodextrin Metal-Organic Framework Optimizes Iodine Stability and Its Co-delivery with l-Menthol for Antibacterial Applications.

The spread of upper respiratory tract (URT) infections harms people's health and causes social burdens. Developing targeted treatment strategies for URT infections that exhibit good biocompatibility, stability, and strong antimicrobial effects remains challenging. The dual antimicrobial and antiviral effects of iodine (I2) in combination with the cooling sensation of l-menthol in the respiratory tract can simultaneously alleviate URT inflammation symptoms. However, as both I2 and l-menthol are volatile, addressing stability issues is crucial. In this study, a potassium iodide ß-cyclodextrin metal-organic framework [ß-CD-POF(I)] with appropriate particle size was used to coload and deliver I2 and l-menthol. Primarily, ß-CD-POF(I) was employed as the most efficient carrier to significantly enhance the stability of I2, surpassing any other known protection strategies in the pharmaceutical field (CD complexations, PVP conjugations, and cadexomer iodine). The mechanism underlying the improvement in stability of I2 by ß-CD-POF(I) was investigated through scanning electron microscopy with energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and molecular docking. The results revealed that the key processes involved in improving stability were the inclusion of I2 by ß-CD cavities in ß-CD-POF(I) and the formation of polyiodide anion between iodine ions and I2. Furthermore, the potential of ß-CD-POF(I) to load and deliver drugs was validated, and coloading of l-menthol and I2 demonstrated reliable stability. ß-CD-POF(I) achieved a rate of URT deposition ≥95% in vitro, and the combined antibacterial effects of coloaded I2 and l-menthol was better than I2 or PVP-I alone, with no irritation noted following URT administration in rabbits. Therefore, the stable coloading of drugs by ß-CD-POF(I), leading to enhanced antimicrobial effects, provides a new strategy for treating URT infections.

Normal distribution of H3K9me3 occupancy co-mediated by histone methyltransferase BcDIM5 and histone deacetylase BcHda1 maintains stable ABA synthesis in Botrytis cinerea TB-31.

Abscisic acid (ABA) is a conserved and important "sesquiterpene signaling molecule" widely distributed in different organisms with unique biological functions. ABA coordinates reciprocity and competition between microorganisms and their hosts. In addition, ABA also regulates immune and stress responses in plants and animals. Therefore, ABA has a wide range of applications in agriculture, medicine and related fields. The plant pathogenic ascomycete B. cinerea has been extensively studied as a model strain for ABA production. Nevertheless, there is a relative dearth of research regarding the regulatory mechanism governing ABA biosynthesis in B. cinerea. Here, we discovered that H3K9 methyltransferase BcDIM5 is physically associated with the H3K14 deacetylase BcHda1. Deletion of Bcdim5 and Bchda1 in the high ABA-producing B. cinerea TB-31 led to severe impairment of ABA synthesis. The combined analysis of RNA-seq and ChIP-seq has revealed that the absence of BcDIM5 and BcHda1 has resulted in significant global deficiencies in the normal distribution and level of H3K9me3 modification. In addition, we found that the cause of the decreased ABA production in the ΔBcdim5 and ΔBchda1 mutants was due to cluster gene repression caused by the emergence of hyper-H3K9me3 in the ABA gene cluster. We concluded that the ABA gene cluster is co-regulated by BcDIM5 and BcHda1, which are essential for the normal distribution of the B. cinerea TB-31 ABA gene cluster H3K9me3. This work expands our understanding of the complex regulatory network of ABA biosynthesis and provides a theoretical basis for genetic improvement of high-yielding ABA strains.

Predictors of seizure outcomes in stereo-electroencephalography-guided radio-frequency thermocoagulation for MRI-negative epilepsy.

Background: One-third of intractable epilepsy patients have no visually identifiable focus for neurosurgery based on imaging tests [magnetic resonance imaging (MRI)-negative cases]. Stereo-electroencephalography-guided radio-frequency thermocoagulation (SEEG-guided RF-TC) is utilized in the clinical treatment of epilepsy to lower the incidence of complications post-open surgery. Objective: This study aimed to identify prognostic factors and long-term seizure outcomes in SEEG-guided RF-TC for patients with MRI-negative epilepsy. Design: This was a single-center retrospective cohort study. Methods: We included 30 patients who had undergone SEEG-guided RF-TC at Sanbo Brain Hospital, Capital Medical University, from April 2015 to December 2019. The probability of remaining seizure-free and the plotted survival curves were analyzed. Prognostic factors were analyzed using log-rank tests in univariate analysis and the Cox regression model in multivariate analysis. Results: With a mean time of 31.07 ± 2.64 months (median 30.00, interquartile range: 18.00-40.00 months), 11 out of 30 patients (36.7%) were classified as International League Against Epilepsy class 1 in the last follow-up. The mean time of remaining seizure-free was 21.33 ± 4.55 months [95% confidence interval (CI) 12.41-30.25], and the median time was 3.00 ± 0.54 months (95% CI 1.94-4.06). Despite falling in the initial year, the probability of remaining seizure-free gradually stabilizes in the subsequent years. The patients were more likely to obtain seizure freedom when the epileptogenic zone was located in the insular lobe or with one focus on the limbic system (p = 0.034, hazard ratio 5.019, 95% CI 1.125-22.387). Conclusion: Our findings may be applied to guide individualized surgical interventions and help clinicians make better decisions.

Filter-Informed Spectral Graph Wavelet Networks for Multiscale Feature Extraction and Intelligent Fault Diagnosis.

Intelligent fault diagnosis has been increasingly improved with the evolution of deep learning (DL) approaches. Recently, the emerging graph neural networks (GNNs) have also been introduced in the field of fault diagnosis with the goal to make better use of the inductive bias of the interdependencies between the different sensor measurements. However, there are some limitations with these GNN-based fault diagnosis methods. First, they lack the ability to realize multiscale feature extraction due to the fixed receptive field of GNNs. Second, they eventually encounter the over-smoothing problem with increase of model depth. Finally, the extracted features of these GNNs are hard to understand due to the black-box nature of GNNs. To address these issues, a filter-informed spectral graph wavelet network (SGWN) is proposed in this article. In SGWN, the spectral graph wavelet convolutional (SGWConv) layer is established upon the spectral graph wavelet transform, which can decompose a graph signal into scaling function coefficients and spectral graph wavelet coefficients. With the help of SGWConv, SGWN is able to prevent the over-smoothing problem caused by long-range low-pass filtering, by simultaneously extracting low-pass and band-pass features. Furthermore, to speed up the computation of SGWN, the scaling kernel function and graph wavelet kernel function in SGWConv are approximated by the Chebyshev polynomials. The effectiveness of the proposed SGWN is evaluated on the collected solenoid valve dataset and aero-engine intershaft bearing dataset. The experimental results show that SGWN can outperform the comparative methods in both diagnostic accuracy and the ability to prevent over-smoothing. Moreover, its extracted features are also interpretable with domain knowledge.

Higher Expression of Human Endogenous Retrovirus-K was Observed in Peripheral B Lymphocytes of Leukemia and Lymphoma Patients.

Hematological malignant tumors (HMTs) are serious diseases that threaten human health and life with high mortality. Therefore, it is necessary to develop novel strategies for diagnosis and treatment. Human endogenous retroviruses (HERVs) have recently attracted increasing attention as potential targets for cancer diagnosis and therapy. In this study, we explored the association between HERV-K expression levels and HMTs development. Clinical data and peripheral blood samples were collected from 236 leukemia, 384 lymphoma patients, and 69 healthy controls. Quantitative polymerase chain reaction was used to detect the expression of HERV-K gag, pol, and env genes in peripheral blood mononuclear cells or different cell subpopulations. Differently expressed HERV-K genes were further tested by using deep sequencing method, and further analyzed with gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. B cell- and T cell-related cytokines in patients were also detected by enzyme-linked immunosorbent assay (ELISA). The results showed that the expression levels of the HERV-K gag, pol, and env genes in patients were significantly higher than in healthy controls. There was a correlation between the expression level of HERV-K and the clinicopathological parameters of leukemia patients. HERV-K expression was increased in the B lymphocytes of leukemia and lymphoma patients, but not in the T cells or neutrophils. The GO and KEGG analyses showed that abnormal expression of the HERV-K locus in patients affected immune regulation. The analysis of cytokines proved that the B cell-related cytokines, including interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon-gamma, were significantly decreased in patients, while the T cell-related cytokines, including IL-3, IL-12, and TNF-ß, were not significantly changed. In conclusion, HERV-K genes might participate in the occurrence and development of leukemia and lymphoma, and might be biomarkers for the detection or evaluation of leukemia and lymphoma.

Structural and functional specializations of human fast-spiking neurons support fast cortical signaling.

Fast-spiking interneurons (FSINs) provide fast inhibition that synchronizes neuronal activity and is critical for cognitive function. Fast synchronization frequencies are evolutionary conserved in the expanded human neocortex despite larger neuron-to-neuron distances that challenge fast input-output transfer functions of FSINs. Here, we test in human neurons from neurosurgery tissue, which mechanistic specializations of human FSINs explain their fast-signaling properties in human cortex. With morphological reconstructions, multipatch recordings, and biophysical modeling, we find that despite threefold longer dendritic path, human FSINs maintain fast inhibition between connected pyramidal neurons through several mechanisms: stronger synapse strength of excitatory inputs, larger dendrite diameter with reduced complexity, faster AP initiation, and faster and larger inhibitory output, while Na+ current activation/inactivation properties are similar. These adaptations underlie short input-output delays in fast inhibition of human pyramidal neurons through FSINs, explaining how cortical synchronization frequencies are conserved despite expanded and sparse network topology of human cortex.

In Situ Characterization of 17-4PH Stainless Steel by Small-Angle Neutron Scattering.

17-4PH martensitic steel is usually used as valve stems in nuclear power plants and it suffers from thermal aging embrittlement due to long-time service in a high-temperature and high-pressure environment. Here, we characterized the evolution of microstructures at the nano-scale in 17-4PH steel by in situ small-angle neutron scattering (SANS) with a thermo-mechanically coupled loading device. The device could set different temperatures and tensile so that an in situ SANS experiment could dynamically characterize the process of nanoscale structural changes. The results showed that with increasing thermal aging time, the ε-Cu phase precipitates and grows as the temperature is 475 °C and 590 °C, and the ε-Cu phase is spherical at 475 °C but became elongated cylinders at 590 °C. Moreover, the loading stress could aid in the growth of the ε-Cu phase at 475 °C.

Ectopic expression of neuronal adenosine kinase, a biomarker in mesial temporal lobe epilepsy without hippocampal sclerosis.

AIMS: Mesial temporal lobe epilepsy without hippocampal sclerosis (no-HS MTLE) refers to those MTLE patients who have neither magnetic resonance imaging (MRI) lesions nor definite pathological evidence of hippocampal sclerosis. They usually have resistance to antiepileptic drugs, difficulties in precise seizure location and poor surgical outcomes. Adenosine is a neuroprotective neuromodulator that acts as a seizure terminator in the brain. The role of adenosine in no-HS MTLE is still unclear. Further research to explore the aetiology and pathogenesis of no-HS MTLE may help to find new therapeutic targets. METHODS: In surgically resected hippocampal specimens, we examined the maladaptive changes of the adenosine system of patients with no-HS MTLE. In order to better understand the dysregulation of the adenosine pathway in no-HS MTLE, we developed a rat model based on the induction of focal cortical lesions through a prenatal freeze injury. RESULTS: We first examined the adenosine system in no-HS MTLE patients who lack hippocampal neuronal loss and found ectopic expression of the astrocytic adenosine metabolising enzyme adenosine kinase (ADK) in hippocampal pyramidal neurons, as well as downregulation of neuronal A1 receptors (A1 Rs) in the hippocampus. In the no-HS MTLE model rats, the transition of ADK from neuronal expression to an adult pattern of glial expression in the hippocampus was significantly delayed. CONCLUSIONS: Ectopic expression of neuronal ADK might be a pathological hallmark of no-HS MTLE. Maladaptive changes in adenosine metabolism might be a novel target for therapeutic intervention in no-HS MTLE.

WPConvNet: An Interpretable Wavelet Packet Kernel-Constrained Convolutional Network for Noise-Robust Fault Diagnosis.

Deep learning (DL) has present great diagnostic results in fault diagnosis field. However, the poor interpretability and noise robustness of DL-based methods are still the main factors limiting their wide application in industry. To address these issues, an interpretable wavelet packet kernel-constrained convolutional network (WPConvNet) is proposed for noise-robust fault diagnosis, which combines the feature extraction ability of wavelet bases and the learning ability of convolutional kernels together. First, the wavelet packet convolutional (WPConv) layer is proposed, and constraints are imposed to convolutional kernels, so that each convolution layer is a learnable discrete wavelet transform. Second, a soft threshold activation is proposed to reduce the noise component in feature maps, whose threshold is adaptively learned by estimating the standard deviation of noise. Third, we link the cascaded convolutional structure of convolutional neutral network (CNN) with wavelet packet decomposition and reconstruction using Mallat algorithm, which is interpretable in model architecture. Extensive experiments are carried out on two bearing fault datasets, and the results show that the proposed architecture outperforms other diagnosis models in terms of interpretability and noise robustness.

Dynamic evolution of the anterior cingulate-insula network during seizures.

OBJECTIVES: In physiological situations, the anterior cingulate cortex (ACC) and anterior insular cortex (AIC) are prone to coactivation. The functional connectivity and interaction between ACC and AIC in the context of epilepsy remain unclear. This study aimed to investigate the dynamic coupling between these two brain regions during seizures. METHODS: Patients who underwent stereoelectroencephalography (SEEG) recording were included in this study. The SEEG data were visually inspected and quantitatively analyzed. The narrowband oscillations and aperiodic components at seizure onset were parameterized. The frequency-specific non-linear correlation analysis was applied to the functional connectivity. The excitation/inhibition ratio (E:I ratio) reflected by the aperiodic slope was performed to evaluate the excitability. RESULTS: Twenty patients were included in the study, with 10 diagnosed with anterior cingulate epilepsy and 10 with anterior insular epilepsy. In both types of epilepsy, the correlation coefficient (h2 ) between the ACC and AIC at seizure onset exhibited a significantly higher value than that during interictal and preictal periods (p < 0.05). The direction index (D) showed a significant increase at seizure onset, serving as an indicator for the direction of information flow between these two brain regions with up to 90% accuracy. The E:I ratio increased significantly at seizure onset, with the seizure-onset zone (SOZ) demonstrating a more pronounced increase compared to non-SOZ (p < 0.05). For seizures originating from AIC, the E:I ratio was significantly higher in the AIC than in the ACC (p = 0.0364). CONCLUSIONS: In the context of epilepsy, the ACC and AIC are dynamically coupled during seizures. The functional connectivity and excitability exhibit a significant increase at seizure onset. By analyzing connectivity and excitability, the SOZ in ACC and AIC can be identified. The direction index (D) serves as an indicator for the direction of information flow from SOZ to non-SOZ. Notably, the excitability of SOZ changes more significantly than that of non-SOZ.

Effects of altered excitation-inhibition imbalance by repetitive transcranial magnetic stimulation for self-limited epilepsy with centrotemporal spikes.

Objectives: Patients with self-limited epilepsy with centrotemporal spikes (SeLECTS) with electrical status epilepticus in sleep (ESES) have generalized cognitive impairment, yet treatment options are limited. Our study aimed to examine the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on SeLECTS with ESES. In addition, we applied electroencephalography (EEG) aperiodic components (offset and slope) to investigate the improvement of rTMS on the excitation-inhibition imbalance (E-I imbalance) in the brain of this group of children. Methods: Eight SeLECTS patients with ESES were included in this study. Low-frequency rTMS (≤1 Hz) was applied for 10 weekdays in each patient. To assess the clinical efficacy and changes in E-I imbalance, EEG recordings were performed both before and after rTMS. Seizure-reduction rate and spike-wave index (SWI) were measured to investigate the clinical effects of rTMS. The aperiodic offset and slope were calculated to explore the effect of rTMS on E-I imbalance. Results: Five of the eight patients (62.5%) were seizure-free within 3 months after stimulation, with treatment effects decreasing with longer follow-ups. The SWI decreased significantly at 3 and 6 months after rTMS compared with the baseline (P = 0.0157 and P = 0.0060, respectively). The offset and slope were compared before rTMS and within 3 months after stimulation. The results showed a significant reduction in the offset after stimulation (P < 0.0001). There was a remarkable increase in slope after the stimulation (P < 0.0001). Conclusion: Patients achieved favorable outcomes in the first 3 months after rTMS. The ameliorative effect of rTMS on SWI may last up to 6 months. Low-frequency rTMS could reduce firing rates in neuronal populations throughout the brain, which was most pronounced at the site of stimulation. A significant reduction in the slope after rTMS treatment suggested an improvement in the E-I imbalance in the SeLECTS.

Protocol of a prospective multicenter randomized controlled trial of robot-assisted stereotactic lesioning in the treatment of focal drug-resistant epilepsy.

BACKGROUND: This protocol describes the design of a multicenter randomized controlled trial of robot-assisted stereotactic lesioning versus epileptogenic foci resection. Typical causes of focal epilepsy include hippocampal sclerosis and focal cortical dysplasia. These patients usually present with drug resistance and require surgical treatment. Although epileptogenic foci resection is still the most commonly used treatment for such focal epilepsy, there is increasing evidence that epileptogenic focus resection may lead to neurological impairment. The treatment of epilepsy with a robot-assisted stereotactic lesioning mainly includes two new minimally invasive surgical methods: radiofrequency thermocoagulation (RF-TC) and laser interstitial thermal therapy (LITT). Seizure-free is less likely to be achieved by these two procedures, but neurologic preservation is better. In this study, we aimed to compare the safety and efficacy of RF-TC, LITT, and epileptogenic foci resection for focal drug-resistant epilepsy. METHODS: This is a multicenter, three-arm, randomized controlled clinical trial. The study will include patients older than 3 years of age with epilepsy who have had medically refractory seizures for at least 2 years and are eligible for surgical treatment with an epileptogenic focus as determined by multidisciplinary evaluation prior to randomization. The primary outcome measure is seizure outcome (quantified by seizure remission rate) at 3-month, 6-month, and 1-year follow-up after treatment. Postoperative neurologic impairment, spectrum distribution change of video electroencephalogram, quality of life, and medical costs will also be assessed as secondary outcomes. TRIAL REGISTRATION: Chinese Clinical Trials Registry ChiCTR2200060974. Registered on June 14, 2022. The status of the trial is recruiting, and the estimated study completion date is December 31, 2024.

Identification of differentially expressed HERV-K(HML-2) loci in colorectal cancer.

Colorectal cancer is one of the malignant tumors with the highest mortality rate in the world. Survival rates vary significantly among patients at various stages of the disease. A biomarker capable of early diagnosis is required to facilitate the early detection and treatment of colorectal cancer. Human endogenous retroviruses (HERVs) are abnormally expressed in various diseases, including cancer, and have been involved in cancer development. Real-time quantitative PCR was used to detect the transcript levels of HERV-K(HML-2) gag, pol, and env in colorectal cancer to systematically investigate the connection between HERV-K(HML-2) and colorectal cancer. The results showed that HERV-K(HML-2) transcript expression was significantly higher than healthy controls and was consistent at the population and cell levels. We also used next-generation sequencing to identify and characterize HERV-K(HML-2) loci that were differentially expressed between colorectal cancer patients and healthy individuals. The analysis revealed that these loci were concentrated in immune response signaling pathways, implying that HERV-K impacts the tumor-associated immune response. Our results indicated that HERV-K might serve as a screening tumor marker and a target for tumor immunotherapy in colorectal cancer.

Aberrant adenosine signaling in patients with focal cortical dysplasia.

Focal cortical dysplasia (FCD), a common malformation of cortical development, is frequently associated with pharmacoresistant epilepsy in both children and adults. Adenosine is an inhibitory modulator of brain activity and a prospective anti-seizure agent with potential for clinical translation. Our previous results demonstrated that the major adenosine-metabolizing enzyme adenosine kinase (ADK) was upregulated in balloon cells (BCs) within FCD type IIB lesions, suggesting that dysfunction of the adenosine system is implicated in the pathophysiology of FCD. In our current study, we therefore performed a comprehensive analysis of adenosine signaling in surgically resected cortical specimens from patients with FCD type I and type II via immunohistochemistry and immunoblot analysis. Adenosine enzyme signaling was assessed by quantifying the levels of the key enzymes of adenosine metabolism, i.e., ADK, adenosine deaminase (ADA), and ecto-5'-nucleotidase (CD73). Adenosine receptor signaling was assessed by quantifying the levels of adenosine A2A receptor (A2AR) and putative downstream mediators of adenosine, namely, glutamate transporter-1 (GLT-1) and mammalian target of rapamycin (mTOR). Within lesions in FCD specimens, we found that the adenosine-metabolizing enzymes ADK and ADA, as well as the adenosine-producing enzyme CD73, were upregulated. We also observed an increase in A2AR density, as well as a decrease in GLT-1 levels and an increase in mTOR levels, in FCD specimens compared with control tissue. These results suggest that dysregulation of the adenosine system is a common pathologic feature of both FCD type I and type II. The adenosine system might therefore be a therapeutic target for the treatment of epilepsy associated with FCD.

SEEG-based reevaluation of epileptogenic networks and the predictive role for reoperation in MTLE patients with surgical failure.

OBJECTIVE: Approximately 20%-30% of mesial temporal lobe epilepsy (MTLE) patients got unfavorable seizure control after surgery, and there was a discrepancy about the reasons for the surgical failure. The functional connectivity (FC) patterns obtained from stereo-electroencephalography (SEEG) reveal information about the dynamics of the epileptic brain and the added value of extracting information that was not identifiable in the SEEG data using FC analysis. This study aims to find out the patterns of the potential epileptogenic network of failure patients and the electrophysiological predictors of reoperation. METHODS: From January 2012 to December 2019, the MTLE patients with surgical failure were reviewed, and all patients underwent SEEG-guided reoperation. The epileptogenic network was quantified by calculating FC indicators, including phase slope index (PSI), mutual information (MI) strength, imaginary coherence (icoh), and Granger causality. RESULTS: Ten patients with 13 seizures were included in the analysis, and 7 of them achieved a favorable outcome after the SEEG-guided reoperation. The surgical zone (SZ) with a favorable prognosis showed greater outward information flow than the non-SZ, whereas the SZ with an unfavorable prognosis showed greater inward information flow. The recurrent patients with favorable prognosis had strong connectivity between the posterior hippocampus, temporal neocortex, and insula, whereas the patients with unfavorable prognosis showed strong functional connectivity between the insula and temporal-parietal-occipital junction. The power spectrum of patients with favorable prognosis was significantly lower than that of patients with unfavorable prognosis, especially showing a more oscillation power of low frequency. SIGNIFICANCE: The SEEG-guided reoperation could achieve favorable seizure control outcomes for recurrent patients. The FCs were a potential indicator to help construct the temporal epileptic network and predictor for the reoperative prognosis in the recurrent patients.

Deep brain stimulation suppresses epileptic seizures in rats via inhibition of adenosine kinase and activation of adenosine A1 receptors.

AIMS: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus, is an effective therapy for patients with drug-resistant epilepsy, yet, its mechanism of action remains elusive. Adenosine kinase (ADK), a key negative regulator of adenosine, is a potential modulator of epileptogenesis. DBS has been shown to increase adenosine levels, which may suppress seizures via A1 receptors (A1 Rs). We investigated whether DBS could halt disease progression and the potential involvement of adenosine mechanisms. METHODS: Control group, SE (status epilepticus) group, SE-DBS group, and SE-sham-DBS group were included in this study. One week after a pilocarpine-induced status epilepticus, rats in the SE-DBS group were treated with DBS for 4 weeks. The rats were monitored by video-EEG. ADK and A1 Rs were tested with histochemistry and western blot, respectively. RESULTS: Compared with the SE group and SE-sham-DBS group, DBS could reduce the frequency of spontaneous recurrent seizures (SRS) and the number of interictal epileptic discharges. The DPCPX, an A1 R antagonist, reversed the effect of DBS on interictal epileptic discharges. In addition, DBS inhibited the overexpression of ADK and the downregulation of A1 Rs. CONCLUSION: The findings indicate that DBS can reduce SRS in epileptic rats via inhibition of ADK and activation of A1 Rs. A1 Rs might be a potential target of DBS for the treatment of epilepsy.

The clinicopathological features of ganglioglioma with CD34 expression and BRAF mutation in patients with epilepsy.

Objective: The aim of the study was to evaluate the clinicopathological features, as well as the surgical prognosis, of epilepsy-associated gangliogliomas (GG) with CD34 expression and BRAFV600E mutation. Methods: Clinical data of patients who underwent epilepsy surgery for GG were retrospectively studied. Univariate and multivariate analyses were performed to evaluate the correlations of clinical and pathological factors with molecular markers of CD34 expression and BRAFV600E mutation in GG. Results: A total of 208 patients with GG had immunohistochemical detection of CD34 expression (positive/negative: 184/24), and among them, 89 patients had immunohistochemical detection of BRAFV600E mutation (positive/negative: 54/35). By univariate and multivariate analyses, seizure aura (p = 0.025), concordance of ictal electroencephalogram (EEG) findings (p = 0.045) and medial temporal tumor (p = 0.030) were found to be related to CD34 expression, but only hospitalization time (p = 0.042) was different for BRAF-mutated status. In addition, drug-resistant epilepsy (p = 0.040) and concordance of interictal EEG findings (p = 0.009) were found to be associated with tumor progression-free survival (PFS) in univariate analysis, but only concordance of interictal EEG findings was with significance in multivariate analysis. However, CD34 expression or BRAFV600E mutation in GG was not found to be associated with surgical outcomes of seizure control and tumor PFS. Conclusion: The CD34 expression or BRAFV600E mutation in GG may partly influence the distribution of clinicopathological features of patients with epilepsy, but they may be not able to predict the surgical prognosis of seizure outcome and tumor recurrence.

The endothelial-enriched lncRNA LINC00607 mediates angiogenic function.

Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates, post-atherosclerotic cultured endothelial cells from patients and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1 to ultimately mediate angiogenesis.