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Topiramate (TPM) is widely used as monotherapy or add-on therapy in adults and children (aged 2 to 16 years) with primary generalized tonic-clonic seizures or focal-onset seizures. TPM has also expanded its treatment spectrum to other seizure types and epileptic encephalopathies. Moreover, TPM has beneficial effects in some comorbidities of epilepsy such as migraine/headache and obesity. Interestingly, it also exhibited neuroprotective effects in several preclinical studies. The most common side effects of TPM are generally mild to moderate, including somnolence, dizziness, fatigue, insomnia and weight loss, which may be reduced through starting with a low dose and slowing titration to effective dosages. The mechanisms underlying the antiepileptic effect and adverse reactions of TPM have been extensively studied in the past 14 years since the last comprehensive review of TPM. Multiple mechanisms including but not limited to: (1) blockade of voltage-gated Na

HDC interventions prevent hyperlipidemia by regulating intestinal microbiota and lipid absorption and metabolism in the intestine, and have a synergistic effect.

As the principal receptor that mediates both synaptic and tonic inhibition of neurons in the brain, the A-type gamma-aminobutyric acid receptor (GABA

Purpose Gastric cancer (GC) is aggressive cancer with a high mortality rate worldwide. N6-methyladenosine (m6A) RNA methylation is related to tumorigenesis, which is dynamically regulated by m6A modulators ("writer," "eraser," and "reader"). We conducted a comprehensive analysis of the m6A genes of GC patients in TCGA datasets to identify the potential diagnostic biomarkers. Materials and methods We analyzed the expression profile of m6A genes in the TCGA cohort and constructed a diagnostic-m6A-score (DMS) by the LASSO-logistic model. In addition, by consensus cluster analysis, we identified two different subgroups of GC risk individuals by the expression profile of m6A modulators, revealing that YTHDF1's expression variation profile in GC diagnosis. We also performed RT-qPCR and WB verification in 17 pairs of GC specimens and paired adjacent non-tumor tissues and GC cell lines, and verified the expression trend of YTHDF1 in five GEO GC datasets. YTHDF1 expression and clinical features of GC patients were assessed by the UALCAN. Results The DMS with high specificity and sensitivity (AUC = 0.986) is proven to distinguish cancer from normal controls better. Moreover, we found that the expression profile variation of YTHDF1 was significantly associated with the high-risk subtype of GC patients. RT-qPCR and Western blot results are consistent with silicon analysis, revealing that YTHDF1's potential oncogene role in GC tumor. Conclusion In conclusion, we developed the m6A gene-based diagnostic signature for GC and found that YTHDF1 was significantly correlated with the high-risk subtype of GC patients, suggesting that YTHDF1 might be a potential target in GC early diagnosis.

Correction for ‘Synergistic effect of polysaccharides and flavonoids on lipid and gut microbiota in hyperlipidemic rats’ by Yun-fei Bai et al., Food Funct., 2023, 14, 921–933, https://doi.org/10.1039/D2FO03031D.

The digestive system cancers are aggressive cancers with the highest mortality worldwide. In this study, we undertook a systematic investigation of the tumor immune microenvironment to identify diagnostic and prognostic biomarkers. The fraction of 22 immune cell types of patients were estimated using CIBERSORT. The least absolute shrinkage and selection operator (LASSO) analysis was carried out to identify important immune predictors. By comparing immune cell compositions in 801 tumor samples and 46 normal samples, we constructed the diagnostic immune score (DIS), showing high specificity and sensitivity in the training (area under the receiver operating characteristic curve [AUC] = 0.929), validation (AUC = 0.935), and different cancer type cohorts (AUC > 0.70 for all). We also established the prognostic immune score (PIS), which was an effective prognostic factor for relapse‐free survival in training, validation, and entire cohorts (P, Our study comprehensively analyzed the utility of consideration of immune cells in the diagnosis and prognosis of digestive system cancers. The diagnostic immune score and prognostic immune score signature might serve as biomarkers for early diagnosis and predicting survival.

The noradrenergic neurons of the locus coeruleus (LC) are associated with various brain functions and psychiatric disorders, such as addiction and depression. It has been shown that neuropeptide galanin (GAL) inhibits neuronal excitability in LC, but the mechanisms remain unclear. In the present study, we investigated the ionic and signal transduction mechanisms underlying inhibitory effect of GAL on LC neurons using whole-cell patch clamp recording in rat brain slices. Bath application of GAL decreased the spontaneous firings and induced a dose-dependent hyperpolarization of LC neurons and this effect was attenuated by knockdown of Galr1, but not Galr2, confirming that mainly GALR1 mediates the inhibition effect of GAL. The inhibitory effect of GAL was also blocked by treatments of pertussis toxin (PTX), GTP-γ-s or GDP-β-s, respectively, indicating that the functions of PTX sensitive Gi/o protein are required for GAL-induced hyperpolarization. Moreover, the blockers of GIRK (tertiapin-Q or SCH2 3390 hydrochloride) attenuated the GAL response while blocker of BK/SK/KATP channels or TASK-1/3 channels did not affect it significantly, suggesting that GIRK channels play an important role in GAL-induced hyperpolarization in LC neurons. Taken together, the inhibitory effect of GAL on LC neurons is mediated by GALR1 via PTX-sensitive Gi/o proteins, which activate GIRK channels.

It has previously been demonstrated that there are various voltage gated sodium channel (Nav) 1.5 splice variants expressed in brain tissue. A total of nine Nav1.5 isoforms have been identified, however, the potential presence of further Nav1.5 variants expressed in brain neurons remains to be elucidated. The present study systematically investigated the expression of various Nav1.5 splice variants and their associated electrophysiological properties in the rat brain tissue, via biochemical analyses and whole‑cell patch clamp recording. The results demonstrated that adult Nav1.5 was expressed in the rat, in addition to the neonatal Nav1.5, Nav1.5a and Nav1.5f isoforms. Further studies indicated that the expression level ratio of neonatal Nav1.5 compared with adult Nav1.5 decreased from 1:1 to 1:3 with age development from postnatal (P) day 0 to 90. This differed from the ratios observed in the developing rat hearts, in which the expression level ratio decreased from 1:4 to 1:19 from P0 to 90. The immunohistochemistry results revealed that Nav1.5 immunoreactivity was predominantly observed in neuronal cell bodies and processes, whereas decreased immunoreactivity was detected in the glial components. Electrophysiological analysis of Nav1.5 in the rat brain slices revealed that an Na current was detected in the presence of 300 nM tetrodotoxin (TTX), however this was inhibited by ~1 µM TTX. The TTX‑resistant Na current was activated at ‑40 mV and reached the maximum amplitude at 0 mV. The results of the present study demonstrated that neonatal and adult Nav1.5 were expressed in the rat brain and electrophysiological analysis further confirmed the functional expression of Nav1.5 in brain neurons.

We report the identification of a de novo GABRA1 (R214C) variant in a child with epileptic encephalopathy (EE), describe its functional characterization and pathophysiology, and evaluate its potential therapeutic options. The GABRA1 (R214C) variant was identified using whole exome sequencing, and the pathogenic effect of this mutation was investigated by comparing wild-type (WT) α1 and R214C α1 GABA

We report the identification of a de novo GABRA1 (R214C) variant in a child with epileptic encephalopathy (EE), describe its functional characterization and pathophysiology, and evaluate its potential therapeutic options. The GABRA1 (R214C) variant was identified using whole exome sequencing, and the pathogenic effect of this mutation was investigated by comparing wild-type (WT) α1 and R214C α1 GABAA receptor-expressing HEK cells. GABA-evoked currents in these cells were recorded using whole-cell, outside-out macro-patch and cell-attached single-channel patch-clamp recordings. Changes to surface and total protein expression levels of WT α1 and R214C α1 were quantified using surface biotinylation assay and western blotting, respectively. Finally, potential therapeutic options were explored by determining the effects of modulators, including diazepam, insulin, and verapamil, on channel gating and receptor trafficking of WT and R214C GABAA receptors. We found that the GABRA1 (R214C) variant decreased whole-cell GABA-evoked currents by reducing single channel open time and both surface and total GABAA receptor expression levels. The GABA-evoked currents in R214C GABAA receptors could only be partially restored with benzodiazepine (diazepam) and insulin. However, verapamil treatment for 24 h fully restored the function of R214C mutant receptors, primarily by increasing channel open time. We conclude that the GABRA1 (R214C) variant reduces channel activity and surface expression of mutant receptors, thereby contributing to the pathogenesis of genetic EE. The functional restoration by verapamil suggests that it is a potentially new therapeutic option for patients with the R214C variant and highlights the value of precision medicine in the treatment of genetic EEs.

Human neural stem cells (NSCs) hold great promise for research and therapy in neural diseases. Many studies have shown direct induction of NSCs from human fibroblasts, which require an invasive skin biopsy and a prolonged period of expansion in cell culture prior to use. Peripheral blood (PB) is routinely used in medical diagnoses, and represents a noninvasive and easily accessible source of cells. Here we show direct derivation of NSCs from adult human PB mononuclear cells (PB-MNCs) by employing episomal vectors for transgene delivery. These induced NSCs (iNSCs) can expand more than 60 passages, can exhibit NSC morphology, gene expression, differentiation potential, and self-renewing capability and can give rise to multiple functional neural subtypes and glial cells in vitro. Furthermore, the iNSCs carry a specific regional identity and have electrophysiological activity upon differentiation. Our findings provide an easily accessible approach for generating human iNSCs which will facilitate disease modeling, drug screening, and possibly regenerative medicine.

The γ-aminobutyric acid neurons (GABAergic neurons) in the inferior colliculus are classified into various patterns based on their intrinsic electrical properties to a constant current injection. Although this classification is associated with physiological function, the exact role for neurons with various firing patterns in acoustic processing remains poorly understood. In the present study, we analyzed characteristics of inferior colliculus neurons in vitro, and recorded responses to stimulation of the dorsal nucleus of the lateral lemniscus using the whole-cell patch clamp technique. Seven inferior colliculus neurons were tested and were classified into two firing patterns: sustained-regular (n = 4) and sustained-adapting firing patterns (n = 3). The majority of inferior colliculus neurons exhibited slight changes in response to stimulation and bicuculline. The responses of one neuron with a sustained-adapting firing pattern were suppressed after stimulation, but recovered to normal levels following application of the γ-aminobutyric acid receptor antagonist. One neuron with a sustained-regular pattern showed suppressed stimulation responses, which were not affected by bicuculline. Results suggest that GABAergic neurons in the inferior colliculus exhibit sustained-regular or sustained-adapting firing patterns. Additionally, GABAergic projections from the dorsal nucleus of the lateral lemniscus to the inferior colliculus are associated with sound localization. The different neuronal responses of various firing patterns suggest a role in sound localization. A better understanding of these mechanisms and functions will provide better clinical treatment paradigms for hearing deficiencies.

Previous studies demonstrated that Nav1.5 splice variants, including Nav1.5a and Nav1.5c, were expressed in dorsal root ganglia (DRG) neurons. However, since nine Nav1.5 isoforms have been identified, whether other Nav1.5 splice variants, especially the neonatal Nav1.5 splice variant, express in the DRG neurons is still unknown. In this study, we systematically investigated the expression of adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rats with spared nerve injury (SNI) by RT-PCR, DNA sequencing, restriction enzyme digestion, immunohistochemistry and immunofluorescence methods. The results demonstrated that both adult and neonatal Nav1.5 isoforms were expressed in the DRG neurons, but their expression ratio was ~2.5:1. In SNI rat models, the expression of both adult and neonatal Nav1.5 decreased by approximately a half in both mRNA and protein levels. In contrast, the expression of protein kinase C (PKC)-γ, one of the negative modulators for sodium currents, increased by ~1-fold. Taken together, this study first confirmed the expression of both adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rat, but their expression level decreased in pain models. The upregulation of PKC-γ may directly or indirectly downregulate the expression of Nav1.5 isoforms in SNI rat models, which may further involve in the pathological process of neuropathic pain.

Hyperuricaemia (HUA) is an independent risk factor for chronic kidney disease. Urate crystals are deposited in the kidney and can cause renal tubular interstitial fibrosis, leading to renal dysfunction. Chicory extract (hereafter referred to as chicory) clearly reduced serum uric acid levels in rats with HUA induced by 10% fructose. This is the first study to observe the effect of chicory on serum uric acid levels and renal function in rats with HUA and renal injury. In vivo studies using hyperuricaemic rats with renal injury induced by yeast and adenine demonstrated that chicory decreased serum uric acid level, and its effect of delaying the progression of kidney injury was better than that of benzbromarone. In vitro cell experiments showed that this effect is related to the inhibition of GLUT9 protein expression in renal tubules and that lowering blood uric acid concentrations is one of the factors that alleviates renal damage. The results of this study indicate that chicory can be used as an alternative for alleviating renal dysfunction in hyperuricaemia.

To evaluate the therapeutic efficacy and toxicity of hyperthermic intraperitoneal chemotherapy (HIPEC) plus high-frequency diathermic therapy (HFDT) followed by intravenous chemotherapy vs intravenous chemotherapy alone for adjuvant treatment of postoperative gastrointestinal neoplasms.Fifty-two gastrointestinal carcinoma patients who were radically operated were enrolled and divided into the treatment group and the control group. In the treatment group, 25 patients were treated with combination of HIPEC+HFDT and subsequent intravenous chemotherapy, while in the control group 27 patients received intravenous chemotherapy alone. Post-therapeutic complications and adverse reactions, time to progression (TTP) and overall survival (OS) were compared between these two groups.Difference in toxic reactions between the two groups was not statistically significant (p0.05). Postoperative progression- free survival (PFS) rate at 12 and 40 months after radical surgery was 72.0 and 54.0% respectively in the treatment group, and 65.8 and 11.5% respectively in the control group (p=0.108). TTP was statistically significantly longer in the treatment group than in the control group (median TTP 40.1 vs 18.5 months, p=0.027). Postoperative OS at 12 and 20 months after radical surgery was 88.0 and 78.0% respectively in the treatment group and 92.6 and 72.7% in the control group, without significant difference.After radical surgery, combination of HIPEC+HFDT and subsequent intravenous chemotherapy brings about superior PFS compared with intravenous adjuvant chemotherapy alone, while having no more complications and adverse reactions.

The large conductance Ca(2+)-activated K(+) (BK) channels are widely distributed in the brain, and act as intracellular calcium sensors in neurons. They play an important feedback role in controlling Ca(2+) flux and Ca(2+)-dependent processes, including neurotransmitter release and cellular excitability. In this study, the effects of the neuropeptide galanin on BK channels were examined by determining the whole-cell currents and single-channel activities in human embryonic kidney (HEK293) cells co-expressing GalR2 and the BK alpha subunit. Galanin enhanced the currents of BK channels, in a concentration-dependent and PTX-independent manner, with an ED50 value of 71.8±16.9 nM. This activation was mediated by GalR2, since its agonist AR-M1896 mimicked the effect of galanin, and since galanin did not facilitate BK currents in cells co-expressing cDNAs of BK and GalR1 or GalR3. The galanin-induced BK current persisted after replacement with Ca(2+)-free solution, suggesting that extracellular Ca(2+) is not essential. Chelating intracellular Ca(2+) by either the slow Ca(2+) buffer EGTA or the fast Ca(2+) buffer BAPTA abolished galanin-mediated activation of BK channels, indicating the important role of intracellular Ca(2+). The role of Ca(2+) efflux from the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) was confirmed by application of thapsigargin, an irreversible inhibitor that depletes Ca(2+) from SR/ER. Moreover, the inositol-1,4,5-triphosphate receptor (IP3R) was identified as the mediator responsible for increased intracellular Ca(2+) activating BK channels. Taken together, activation of GalR2 leads to elevation of intracellular Ca(2+) is due to Ca(2+) efflux from ER through IP3R sequentially opening BK channels.

In order to get information timely when elderly people fall down and need assistance, a kind of intelligent video surveillance system is designed and implemented. By using this system, the elderly dont need to wear any device. The H.264 video standard, the embedded technology, network technology, video surveillance technology and image processing technology are mixed used to detect human gesture in the video stream monitored. This system updates the background by the Gauss mixture model. The moving target is segmented by using the background subtraction algorithm. Experiments show that the system can be remote monitoring and detecting attitude. When the people falls down the system can automatically alarm, and satisfy the requirement of the timeliness, accuracy and stability.

Spatial patchiness and temporal variability in water availability are common in nature under global climate change, which can remarkably influence adaptive responses of clonal plants, i.e. clonal integration (translocating resources between connected ramets). However, little is known about the effects of spatial patchiness and temporal heterogeneity in water on growth and clonal integration between congeneric invasive and native Hydrocotyle species. In a greenhouse experiment, we subjected severed or no severed (intact) fragments of Hydrocotyle vulgaris, a highly invasive species in China, and its co-existing, native congener H. sibthorpioides to different spatial patchiness (homogeneous and patchy) and temporal interval (low and high interval) in water supply. Clonal integration had significant positive effects on growth of both species. In the homogeneous water conditions, clonal integration greatly improved the growth in fragments of both species under low interval in water. However, in the patchy water conditions, clonal integration significantly increased growth in both ramets and fragments of H. vulgaris under high interval in water. Therefore, spatial patchiness and temporal interval in water altered the effects of clonal integration of both species, especially for H. vulgaris. The adaptation of H. vulgaris might lead to invasive growth and potential spread under the global water variability.

Ferrite growth behavior in Fe-C-Mn alloys has been studied using controlled decarburization experiments. Two types of kinetic transition are considered. A first transition is proposed which involves a change from ParaEquibrium (PE) contact conditions at short times to Local-Equilibrium with Negligible Partitioning at longer times (LENP). This transition is attributed to the gradual build up of an alloying element spike due to the diffusion of Mn across the interface. The cross-interface mobility of Mn is estimated based on the experimental results. In some alloys, we observe a transition to extended PE states at high temperatures. A simple model which quantitatively describes the experimental observations over a range of composition and temperature is proposed. A key feature of this model is the introduction of an alloying element capacity of the moving ferrite/austenite interface, X*. The introduction of this quantity is purely guided by the experimental data and, at present, there is no physically based method for calculating it.

The transmission spectrum of four-level atoms in a cavity is calculated. It is shown that the four separate peaks associated with normal mode splitting and intra-cavity double dark states can be observed simultaneously. The position and intensity of the four peaks can be controlled by the intensity of the third interacting light. Therefore, the enhancement of normal mode splitting by a third coupling light of the intra-cavity four-level atoms is developed.

Based on optimized forecast method of unascertained classifying, a unascertained measurement classifying model (UMC) to predict mining induced goaf collapse was established. The discriminated factors of the model are influential factors including overburden layer type, overburden layer thickness, the complex degree of geologic structure, the inclination angle of coal bed, volume rate of the cavity region, the vertical goaf depth from the surface and space superposition layer of the goaf region. Unascertained measurement (UM) function of each factor was calculated. The unascertained measurement to indicate the classification center and the grade of waiting forecast sample was determined by the UM distance between the synthesis index of waiting forecast samples and index of every classification. The training samples were tested by the established model, and the correct rate is 100%. Furthermore, the seven waiting forecast samples were predicted by the UMC model. The results show that the forecast results are fully consistent with the actual situation.

Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with increasing prevalence and mortality, influenced by both environmental and genetic factors. ADAM33 gene has been found to be associated with asthma, declined lung function and COPD.The aim of this study was to find out if SNPs in ADAM33 (V4, T+1, T1, T2, S1, S2, Q-1 and F+1) play any role in genetic susceptibility to COPD in the Mongolian population of China.Two hundred and fifteen Mongolian COPD patients and 223 Mongolian healthy individuals were recruited for the study. Eight polymorphic loci (V4, T+1, T2, T1, S2, S1, Q-1, and F+1) of ADAM33 were selected for genotyping. Genotyping was carried out using the Polymerase Chain Reaction and Restriction Fragment Length polymorphism (PCR-RFLP) method.Seven SNPs in ADAM33 were associated with COPD (T+1, p = 0.014; T2, p = 0.018; T1, p = 0.048; S2, p = 0.003; S1, p = 0.000; Q-1, p = 0.000 and F+1, p = 0.000), even after Bonferroni correction, SNPs S2, S1, Q-1 and F+1 remained significant. Haplotype analysis showed that the frequencies of haplotype H1 (GGAGGGT), H5 (GGAGGGC) and H10 (GGGGAGT) were significantly higher in the COPD group than in the control group (p = 0.002, 0.031 and 0.009, respectively). In contrast, the haplotype H11 (GGACAGC) was more common in the control group than in the case group (p = 0.015).Seven SNPs in ADAM33 were associated with COPD in the Mongolian population of China.

microRNAs (miRNAs) play an important role in regulating normal organ physiology and development. Many miRNAs show spatially and temporally restricted expression patterns during embryogenesis and organogenesis. This study aimed to characterize the miRNA profile of the fetal mouse heart at 4 key time-points [embryonic day (E)12.5, E14.5, E16.5 and E18.5] in its development, by performing a sequencing by oligonucleotide ligation and detection (SOLiD) miRNA screen. The 4 time-points were designated as groups M1 (E18.5), M2 (E16.5), M3 (E14.5) and M4 (E12.5). miRNAs found to have consistent fold-changes of >2.0) between the 4 time-points were selected for further analysis. Ten miRNAs (mmu-miR-23b, mmu-miR-24, mmu-miR-23a, mmu-miR-375, mmu-miR-29a, mmu-miR-93, mmu-miR-21, mmu-miR-25, mmu-let-7b and mmu-miR-27b) that were the most highly expressed in the 4 groups, including the percentage >1% of total read counts, were identified. No miRNA was consistently downregulated or upregulated. There were 16 differentially expressed miRNAs between the later development group (M1+M2) and the early development group (M3+M4), which were validated by quantitative real-time PCR. Several members of the let-7 miRNA cluster (mmu-let-7a/7d/7e/7f) were upregulated in the later development group compared with the early development group. A network analysis of the predicted targets of mmu-let-7a/7d/7e/7f identified 5 target genes (FOXP1, TBX5, HAND1, AKT2 and PPARGC1A), known to be involved in cardiac development. Therefore, this study identified several miRNAs that are abundantly expressed in the developing heart, several of which are differentially expressed in the 4 time-points studied. Findings of this analysis may thus clarify the mechanisms of normal heart development and provide a physiological basis for future studies on congenital heart disease.

microRNAs (miRNAs) have emerged as key regulators in many biological processes, particularly cardiac growth and development, although the specific miRNA expression profile associated with this process remains to be elucidated. This study aimed to characterize the cellular microRNA profile involved in the development of congenital heart malformation, through the investigation of single ventricle (SV) defects. Comprehensive miRNA profiling in human fetal SV cardiac tissue was performed by deep sequencing. Differential expression of 48 miRNAs was revealed by sequencing by oligonucleotide ligation and detection (SOLiD) analysis. Of these, 38 were down-regulated and 10 were up-regulated in differentiated SV cardiac tissue, compared to control cardiac tissue. This was confirmed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. Predicted target genes of the 48 differentially expressed miRNAs were analyzed by gene ontology and categorized according to cellular process, regulation of biological process and metabolic process. Pathway-Express analysis identified the WNT and mTOR signaling pathways as the most significant processes putatively affected by the differential expression of these miRNAs. The candidate genes involved in cardiac development were identified as potential targets for these differentially expressed microRNAs and the collaborative network of microRNAs and cardiac development related-mRNAs was constructed. These data provide the basis for future investigation of the mechanism of the occurrence and development of fetal SV malformations.

One of the important applications of electromagnetically induced transparency (EIT) is to delay and store light in atomic ensembles. In this paper, the noise spectrum of the delayed quantum light throughout an EIT medium is investigated. With zero detection frequency, we can have minimum noise of delayed light in two-photon resonance of EIT, and the noise is larger than the minimum noise at off two-photon resonance due to the phase-to-amplitude noise conversion. It is shown that the noise for nonzero detection frequency can be suppressed by operating the system at off two-photon resonance, even when the unavoidable dephasing is included.

The learning problem of associative memory system (AMS) is investigated from the viewpoint of the approximation of input-to-output mapping function. In order to improve the generalization properties in learning multidimensional mappings of polynomial functions with order no more than 2, this paper proposes a novel associative memory system (AMS) based on a set of sharp-angled hat spline functions (SHSFs). The approximation capabilities of conventional AMS is evaluated at first, then a novel SHSF and the general structure of SHSF-AMS with corresponding interpolation and training algorithms are presented. Pertinent numerical simulations have shown the effectiveness of the proposed method.