A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice.

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

Insight into the Role of Ferroptosis in Epilepsy.

Excessively high or synchronized neuronal activity in the brain is the underlying cause of epilepsy, a condition of the central nervous system. Epilepsy is caused mostly by an imbalance in the activity of inhibitory and excitatory neural networks. Recurrent or prolonged seizures lead to neuronal death, which in turn promotes epileptogenesis and epileptic seizures. Ferrous ion-mediated cell death is known as ferroptosis, which is due to the accumulation of lipid peroxidation products resulting from compromise of the glutathione (GSH)-dependent antioxidant system. The pathophysiology of epilepsy has been linked to anomalies in the glutathione peroxidase 4 (GPX4)/GSH redox pathway, lipid peroxidation, and iron metabolism. Studies have shown that inhibiting ferroptosis may alleviate cognitive impairment and decrease seizures, indicating that it is neuroprotective. With the hope of aiding the development of more novel approaches for the management of epilepsy, this research aimed to examine the role of ferroptosis in this disease.

Causal relationship between addictive behaviors and epilepsy risk: A mendelian randomization study.

BACKGROUND: Previous studies have reported inconsistent results regarding the potential relationships between addictive behaviors and the risk of epilepsy. OBJECTIVE: To assess whether genetically predicted addictive behaviors are causally associated with the risk of epilepsy outcomes. METHODS: The causation between five addictive behaviors (including cigarettes per day, alcoholic drinks per week, tea intake, coffee intake, and lifetime cannabis use) and epilepsy was evaluated by using a two-sample Mendelian Randomization (MR) analysis. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (MR Egger, weighted median, simulation extrapolation corrected MR-Egger, and Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO)) were performed to complement IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis. RESULTS: The IVW analysis method indicated an approximately 20% increased risk of epilepsy per standard deviation increase in lifetime cannabis use (odds ratio [OR], 1.20; 95% confidence interval [CI]), 1.02-1.42, P = 0.028). However, there is no causal association between the other four addictive behaviors and the risk of epilepsy (cigarettes per day: OR, 1.04; 95% CI, 0.92-1.18, P = 0.53; alcoholic drinks per week: OR, 1.31; 95% CI, 0.93-1.84, P = 0.13; tea intake: OR, 1.15; 95% CI, 0.84-1.56, P = 0.39; coffee intake: OR, 0.86; 95% CI, 0.59-1.23, P = 0.41). The other MR analysis methods and further leave-one-out sensitivity analysis suggested the results were robust. CONCLUSION: This MR study indicated a potential genetically predicted causal association between lifetime cannabis use and higher risk of epilepsy. As for the other four addictive behaviors, no evidence of a causal relationship with the risk of epilepsy was found in this study.

Clinical Heterogeneity in Acute Symptomatic Seizures due to Autoimmune Encephalitis Related to GAD65 Antibodies.

INTRODUCTION: This study aimed to explore the diversity and clinical features of acute symptomatic seizures due to autoimmune encephalitis related to anti-glutamate decarboxylase (GAD) 65 antibodies. METHODS: Clinical data of a series of 6 patients positive for anti-GAD65 antibodies were retrospectively analyzed. RESULTS: Five of the patients were male and 1 was a female, with a median age of 44.1 years (range 18-70 years). Seizure forms were varied in 6 patients when they were admitted to the hospital: 3 cases of seizures only and 3 accompanied by other symptoms, such as mental disorder, cognitive impairment, cerebellar ataxia, and ocular movement disorder. Three patients (50%) had coexisting systemic autoimmune diseases, including diabetes mellitus, vitiligo, and hyperthyroidism. Five patients (83%) had abnormal brain MRI findings. They were all treated by immunotherapy, 5 of 6 patients improved significantly but relapsed after withdrawing methylprednisolone, and 1 patient got deteriorated. None of them were diagnosed with tumors. CONCLUSIONS: Clinical features of acute symptomatic seizures related to GAD65 antibodies are diverse, and early and continuous immunotherapy is necessary for patients.

Research progress on oxidative stress regulating different types of neuronal death caused by epileptic seizures.

Clinical and experimental data hints that prolonged and repeated epileptic seizures can lead to molecular, biochemical, metabolic, and structural changes in the brain, a continuous process of chronic brain injury that ultimately leads to neuronal death. The histological characteristics of hippocampal structure determine its high sensitivity to excitotoxicity and present different types of neuronal death, including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Hippocampal neuronal death promotes the progression of epileptogenesis, seizures, and epilepsy and is closely related to the impairment of cognitive function. Massive evidence indicates that oxidative stress plays a critical role in different forms of neuronal death induced by epileptic seizures. The brain is particularly vulnerable to damage caused by oxidative stress, and an increase in oxidative stress biomarkers was found in various epilepsy types. The purpose of this review is to elucidate the molecular mechanism of neuronal death and explore the moderating effect of oxidative stress on epileptic seizure-induced neuronal death patterns so as to find potential intervention targets for neuroprotective treatment after epileptic seizures.

Lentivirus-mediated microRNA-26a-modified neural stem cells improve brain injury in rats with cerebral palsy.

This study is launched to investigate the effect of lentivirus-mediated microRNA-26a (miR-26a)-modified neural stem cells (NSCs) in brain injury in rats with cerebral palsy (CP). The successfully constructed miR-26a lentivirus expression vector and empty vector virus were used to modify NSCs. The model of CP with ischemia and anoxia was established in rats. NSCs and miR-26a-NSCs were stereoscopically injected into the cerebral cortex of the modeled rats, respectively. The survival and migration of NSCs infected with recombinant lentivirus expressing green fluorescence in vivo was observed under a light microscope. The neurobehavioral functions, morphology, and ultrastructure of cerebral cortex and hippocampus, apoptosis of brain cells, expression of apoptosis-related protein caspase-3 and Bax, together with the expression of the glial fibrillary acidic protein (GFAP) in cerebral cortex and hippocampus were determined. Expression of miR-26a in NSCs infected with plVTHM-miR-26a increased significantly. After NSCs transplantation, the neurobehavioral status of CP rats was improved, the degree of brain pathological injury was alleviated, the apoptotic index of cells in cerebral cortex and hippocampus and the expression of the apoptotic protein (caspase-3 and Bax) were decreased, the expression of GFAP were significantly decreased. After miR-26a-NSCs transplantation, these aforementioned results further improved or decreased. Our study suggests that miR-26a-modified NSCs mediated by lentivirus can improve brain injury, inhibit apoptosis of brain cells and activation of astrocytes in CP rats.

Assessment of left ventricular systolic function by non-invasive pressure-strain loop area in young male strength athletes.

BACKGROUND: The health of athletes has been recognized as a worldwide public concern with more reported sudden cardiac deaths (SCD). Therefore, early detection of abnormal heart function in athletes can help reduce the risk of exercise. A novel valid non-invasive method to evaluate left ventricular (LV) myocardial work (MW) using LV pressure-strain loop (PSL), was used in this paper to explore LV systolic function in young male strength athletes. METHODS: Thirty-six professional young male strength athletes (the athlete group) and 32 healthy, age-matched young men (the control group) were involved in the study. The LVMW parameters were calculated as the area of PSL by two-dimensional speckle tracking echocardiography (2D-STE) and peak systolic LV pressure. The differences between two groups of data and the predictive efficacy of MW parameters for LV systolic function were analyzed. RESULTS: The athlete group had significantly higher values of global wasted myocardial work (GWW) and peak strain dispersion (PSD) than did the control group (P<0.05). Global myocardial work index (GWI), global constructive myocardial work (GCW) and global longitudinal strain (GLS) were lower in the athlete group than that in the control group, although statistical significance was not reached (P>0.05). Due to the proportion of GWW and GCW, statistically significant reduction was found in global myocardial work efficiency (GWE) in the athlete group. Conventional echocardiography parameters were well correlated with GWW and GWE (P<0.05). The best predictor of LV myocardial contractile performance in the athletes using receiver operating characteristic curve (ROC) was GWE, with the area under ROC (AUC) of 0.733, sensitivity of 83.3% and specificity of 59.4%. CONCLUSIONS: Subclinical changes have appeared in the hearts of young male strength athletes after long-term intensive exercise and LVMW parameters by PSL play an important role in the evaluation of athlete's LV contractile performance.

Clinical characteristics, treatment, and long-term outcomes in children suffering from benign convulsions with mild gastroenteritis: a retrospective study.

BACKGROUND: Benign convulsions with mild gastroenteritis (BCWG) is a common condition in children in Asia and is generally not associated with pH or electrolyte imbalances. When BCWG is diagnosed, a lumbar puncture is usually recommended to rule out potential intracranial infections. This study examined the clinical characteristics of BCWG and evaluated the necessity of lumbar puncture. METHODS: Medical records of children admitted to the First Hospital of Jilin University with BCWG between January 2018 and May 2019 were reviewed and analyzed. Children were stratified by rotavirus positivity or lumbar puncture status. Clinical characteristics and long-term outcomes were compared between groups. RESULTS: A total of 51 children were included in the analyses (55.1% rotavirus [HRV] positive). The average age of convulsion onset was 21.12 ± 7.44 months, the male-to-female ratio was 1.8:1, and convulsions occurred primarily between October 2018 and April 2019. The main clinical presentations of BCWG were convulsions, vomiting, diarrhea, and fever. Convulsions occurred predominantly two days after diagnosis of gastroenteritis, were mainly generalized tonic-clonic with 88.2% of children having ≤ 3 convulsions per episode, and had a mean duration of 2.0 minutes (interquartile range [IQR]: 1.0, 3.0). Children with BCWG had mild metabolic acidosis (HCO3- 17.82 ± 3.63 mmol/L) with an elevated anion gap (AG; 20.98 ± 3.00 mmol/L), mild hyponatremia (134.56 ± 2.85 mmol/L), and slightly increased levels of creatine kinase myocardial band (CKMB). HRV + children had more severe acidosis and higher CKMB levels. Cerebrospinal fluid (CSF) samples collected via lumbar puncture were normal. No developmental abnormalities were noted as assessed by the Social Life Ability Scale. CONCLUSIONS: BCWG is a situation-related seizure, with clinical presentations of tonic-clonic or focal convulsions and mild gastroenteritis (vomiting, diarrhea). Mild metabolic acidosis and hyponatremia may exist. The prognosis of the disease is favorable; lumbar puncture and long-term antiepileptics are unnecessary and should not be recommended.

A Functional Polymorphism rs145204276 in the Promoter of Long Noncoding RNA GAS5 Is Associated with an Increased Risk of Ischemic Stroke.

Long noncoding RNAs (lncRNAs) play crucial roles in the regulation of pathological process of ischemic stroke (IS) via affecting cell apoptosis, inflammation, cell death, and angiogenesis. LncRNA growth arrest-specific 5 (GAS5) was observed to be up-regulated in IS, acting as a competing endogenous RNA for miR-137 to mediate the Notch1 signaling pathway. In this study, we aimed to whether an insertion/deletion polymorphism (rs145204276) in the promoter of GAS5 was related to the risk of IS. The rs145204276 was genotyped using polymerase chain reaction (PCR)-polyacrylamide gel electrophoresis in 509 patients with IS and 668 healthy controls with frequencies matched to cases regarding age, gender, living area, and ethnicity. The GAS5 expression levels were determined using qPCR and relative luciferase activity was measured using the Dual Luciferase assay system. The presence of del/del genotype and del allele was associated with an increased risk of IS [del/del versus ins/ins: adjusted odds ratio (OR) = 2.06, 95% confidence interval (CI): 1.37-3.11; recessive model: adjusted OR = 2.07, 95% CI: 1.41-3.04; del versus ins: adjusted OR = 1.31, 95% CI: 1.08-1.57]. Results from logistic regression analysis identified risk factors for IS, including hypertension, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and rs145204276 del/del genotype. Furthermore, patients carrying rs145204276 del/del genotype had significantly higher levels of GAS5 and cells transfected with rs145204276 del allele exhibited a larger increase in luciferase activity. These findings indicate that rs145204276 del allele exhibited a significant association with an increased IS susceptibility by elevating the transcriptional activity and subsequently enhancing the expression of lncRNA GAS5.

Characterization of the Key Aroma Compounds in Proso Millet Wine Using Headspace Solid-Phase Microextraction and Gas Chromatography-Mass Spectrometry.

The volatile compounds in proso millet wine were extracted by headspace solid-phase microextraction (85 µm polyacrylate (PA), 100 µm polydimethylsiloxane (PDMS), 75 µm Carboxen (CAR)/PDMS, and 50/30 µm divinylbenzene (DVB)/CAR/PDMS fibers), and analyzed using gas chromatography-mass spectrometry; the odor characteristics and intensities were analyzed by the odor activity value (OAV). Different sample preparation factors were used to optimize this method: sample amount, extraction time, extraction temperature, and content of NaCl. A total of 64 volatile compounds were identified from the wine sample, including 14 esters, seven alcohols, five aldehydes, five ketones, 12 benzene derivatives, 12 hydrocarbons, two terpenes, three phenols, two acids, and two heterocycles. Ethyl benzeneacetate, phenylethyl alcohol, and benzaldehyde were the main volatile compounds found in the samples. According to their OAVs, 14 volatile compounds were determined to be odor-active compounds (OAV > 1), and benzaldehyde, benzeneacetaldehyde, 1-methyl-naphthalene, 2-methyl-naphthalene, and biphenyl were the prominent odor-active compounds (OAV > 50), having a high OAV. Principal component analysis (PCA) showed the difference of distribution of the 64 volatile compounds and 14 odor-active compounds with four solid-phase microextraction (SPME) fibers.

Assessment of active and inactive sacroiliitis in patients with ankylosing spondylitis using quantitative dynamic contrast-enhanced MRI.

PURPOSE: To investigate the feasibility of using quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to differentiate the active and inactive stage of sacroiliitis and the correlation between quantitative parameters and disease activity as measured by clinical scores. MATERIALS AND METHODS: Forty-two patients with ankylosing spondylitis underwent DCE-MRI on a 3.0T MRI unit. According to the results of the blood sedimentation rate (ESR), C-reactive protein (CRP), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the patients were grouped into inactive and active groups. Pharmacokinetic models were used to generate the semiquantitative and quantitative hemodynamic parameters of DCE-MRI. The between-group differences were analyzed using the Wilcoxon rank sum test, and the correlations between the pharmacokinetic parameters and BASDAI score were analyzed using Spearman's correlation coefficient. The efficacies of different parameters in differentiating the active and inactive phase of sacroiliitis were evaluated and compared using receiver operator characteristics (ROC) curve analysis. RESULTS: Ktrans , Kep , Ve , time to peak (TTP), max concentration (MAX Conc), and area under the curve (AUC) of the active group were significantly higher than those of the inactive stage group (P < 0.05). There were significant correlations between all parameters and BASDAI (P < 0.05). AUC of the receiver operator characteristics curve (AUCR ) of different parameters were not statistically different (P >0.05), except between AUC and MAX Conc (P = 0.0012). CONCLUSION: Quantitative DCE-MRI parameters can differentiate between active and inactive ankylosing spondylitis. Among those, Ktrans had the highest correlation coefficient with the BASDAI score. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:71-78.

ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation.

The gene encoding a DNA/RNA binding protein FUS/TLS is frequently mutated in amyotrophic lateral sclerosis (ALS). Mutations commonly affect its carboxy-terminal nuclear localization signal, resulting in varying deficiencies of FUS nuclear localization and abnormal cytoplasmic accumulation. Increasing evidence suggests deficiencies in FUS nuclear function may contribute to neuron degeneration. Here we report a novel FUS autoregulatory mechanism and its deficiency in ALS-associated mutants. Using FUS CLIP-seq, we identified significant FUS binding to a highly conserved region of exon 7 and the flanking introns of its own pre-mRNAs. We demonstrated that FUS is a repressor of exon 7 splicing and that the exon 7-skipped splice variant is subject to nonsense-mediated decay (NMD). Overexpression of FUS led to the repression of exon 7 splicing and a reduction of endogenous FUS protein. Conversely, the repression of exon 7 was reduced by knockdown of FUS protein, and moreover, it was rescued by expression of EGFP-FUS. This dynamic regulation of alternative splicing describes a novel mechanism of FUS autoregulation. Given that ALS-associated FUS mutants are deficient in nuclear localization, we examined whether cells expressing these mutants would be deficient in repressing exon 7 splicing. We showed that FUS harbouring R521G, R522G or ΔExon15 mutation (minor, moderate or severe cytoplasmic localization, respectively) directly correlated with respectively increasing deficiencies in both exon 7 repression and autoregulation of its own protein levels. These data suggest that compromised FUS autoregulation can directly exacerbate the pathogenic accumulation of cytoplasmic FUS protein in ALS. We showed that exon 7 skipping can be induced by antisense oligonucleotides targeting its flanking splice sites, indicating the potential to alleviate abnormal cytoplasmic FUS accumulation in ALS. Taken together, FUS autoregulation by alternative splicing provides insight into a molecular mechanism by which FUS-regulated pre-mRNA processing can impact a significant number of targets important to neurodegeneration.

Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China.

OBJECTIVE: The pharmacokinetics of lamotrigine (LTG) varies significantly among individuals and particularly among different ethnic groups. This is in part due to the presence of genetic polymorphisms affecting genes that metabolize LTG. UGT1A4 is a major metabolizing enzyme of LTG. The aim of this study was to investigate the effect of two UGT1A4 gene polymorphisms, UGT1A4 (70C > A) and UGT1A4 (142 T > G), on the levels and efficacy of LTG in Han Chinese patients with epilepsy. METHODS: The study cohort comprised 106 Han Chinese patients patients with epilepsy who were receiving LTG monotherapy. Blood samples were taken and LTG levels measured. The presence of UGT1A4 (70C > A) and UGT1A4 (142 T > G) was determined. The therapeutic efficacy of LTG at the 1-year time-point was assessed. RESULTS: All patients were homozygous for the CC genotype of UGT1A4 (70C > A), while the distribution of UGT1A4 (142 T > G) varied among patients. Two patients had a single nucleotide deletion at position 127 (UGT1A4 127delA). To evaluate the effect of the UGT1A4 (142 T > G) polymorphism on LTG pharmacokinetics, patients were divided into two groups. Group A included patients with the 142TG or 142GG polymorphism and Group B patients had the 142TT polymorphism. The normalized blood concentration and the efficacy of LTG were higher in Group B patients than in Group A patients (P < 0.05). The two patients with UGT1A4 127delA genotype had extremely high blood levels of LTG, and treatment was discontinued in one of these patients due to a severe LTG-associated rash. CONCLUSION: Patients with the UGT1A4 142TT polymorphism had a higher blood LTG concentration and better therapeutic efficacy, suggesting that this polymorphism influences LTG activity. The UGT1A4 127delA polymorphism significantly affected LTG levels and increased one of our patient's susceptibility to LTG-related adverse events.

Association between human blood metabolites and cerebral cortex architecture: evidence from a Mendelian randomization study.

Background: Dysregulation of circulating metabolites may affect brain function and cognition, associated with alterations in the cerebral cortex architecture. However, the exact cause remains unclear. This study aimed to determine the causal effect of circulating metabolites on the cerebral cortex architecture. Methods: This study utilized retrieved data from genome-wide association studies to investigate the relationship between blood metabolites and cortical architecture. A total of 1,091 metabolites and 309 metabolite ratios were used for exposure. The brain cortex surface area and cortex thickness were selected as the primary outcomes in this study. In this study, the inverse variance weighting method was used as the main analytical method, complemented by sensitivity analyses that were more robust to pleiotropy. Furthermore, metabolic pathway analysis was performed via MetaboAnalyst 6.0. Finally, reverse Mendelian randomization (MR) analysis was conducted to assess the potential for reverse causation. Results: After correcting for the false discovery rate (FDR), we identified 37 metabolites and 9 metabolite ratios that showed significant causal associations with cortical structures. Among these, Oxalate was found to be most strongly associated with cortical surface area (ß: 2387.532, 95% CI 756.570-4018.495, p = 0.037), while Tyrosine was most correlated with cortical thickness (ß: -0.015, 95% CI -0.005 to -0.025, p = 0.025). Furthermore, pathway analysis based on metabolites identified six significant metabolic pathways associated with cortical structures and 13 significant metabolic pathways based on metabolite ratios. Conclusion: The identified metabolites and relevant metabolic pathways reveal potential therapeutic pathways for reducing the risk of neurodegenerative diseases. These findings will help guide health policies and clinical practice in treating neurodegenerative diseases.

Causal relations between ischemic stroke and epilepsy: A bidirectional Mendelian randomization study.

Background: Although previous studies have reported a bidirectional relationship between ischemic stroke (IS) and epilepsy, the existence of a causal nexus and its directionality remains a topic of controversy. Methods: The single nucleotide polymorphisms (SNPs) associated with IS were extracted from the Genome-Wide Association Study (GWAS) database. Pooled genetic data encompassing all epilepsy cases, as well as generalized and focal epilepsy subtypes, were acquired from the International League Against Epilepsy's GWAS study. In this study, the primary analysis approach utilized the inverse variance weighting (IVW) method as the main analytical technique. To enhance the robustness of the findings against potential pleiotropy, additional sensitivity analyses were conducted. Results: In the forward analysis, the IVW method demonstrated that IS was associated with an increased risk of all epilepsy (odds ratio (OR) = 1.127, 95 % confidence interval (CI) = 1.038-1.224, P = 0.004) and generalized epilepsy (IVW: OR = 1.340, 95 % CI = 1.162-1.546, P = 5.70 × 10-5). There was no substantial causal relationship observed between IS and focal epilepsy (P > 0.05). Furthermore, generalized epilepsy, focal epilepsy, and all epilepsy did not show a causal relationship with IS. Conclusion: This Mendelian randomization (MR) analysis demonstrates that IS increases the risk of developing epilepsy, especially generalized epilepsy. Conversely, no clear causal association was found between epilepsy and the onset of stroke. Therefore, the possible mechanisms of the effect of epilepsy on the pathogenesis of IS still need to be further investigated.

RELN gene-related drug-resistant epilepsy with periventricular nodular heterotopia treated with radiofrequency thermocoagulation: a case report.

An increasing number of gene mutations associated with epilepsy have been identified, some linked to gray matter heterotopia-a common cause of drug-resistant epilepsy. Current research suggests that gene mutation-associated epilepsy should not be considered a contraindication for surgery in epilepsy patients. At present, stereoelectroencephalography-guided radiofrequency thermocoagulation is an important method to treat periventricular nodular heterotopia-associated drug-resistant epilepsy. We present a case of drug-resistant epilepsy, accompanied by periventricular nodular heterotopia and a heterozygous mutation of the RELN gene, successfully treated with radiofrequency thermocoagulation, resulting in a favorable outcome.

Diet-derived circulating antioxidants and risk of epilepsy: A study combining metabolomics and mendelian randomization.

Background: Previous studies offer inconclusive results on the association between diet-derived circulating antioxidants and epilepsy. Objective: This study aims to assess oxidative stress presence in epilepsy patients' circulation and investigate the causal link between diet-derived circulating antioxidants and epilepsy. Methods: Untargeted metabolomics analysis was conducted on plasma samples from 62 epileptic patients and 20 healthy individuals to evaluate oxidative stress based on metabolite alterations in epilepsy patients' circulation. Two-sample Mendelian Randomization (MR) analysis examined the causation between diet-derived circulating antioxidants (measured by absolute levels and relative metabolite concentrations) and epilepsy, utilizing the inverse-variance weighted (IVW) method as the primary outcome, with complementary MR analysis methods (MR Egger, weighted median, weighted mode, and simple mode). Results: Untargeted metabolomics analysis revealed elevated circulating oxidizing metabolites (palmitic acid, oleic acid, linoleic acid, and myristic acid) and reduced reducing metabolites (glutamine) in epilepsy patients, providing robust evidence of oxidative stress. The IVW analysis indicated significantly reduced epilepsy risk (odds ratio: 0.552; 95% confidence interval: 0.335-0.905, P = 0.018) with genetically determined higher absolute circulating ß-carotene. However, other diet-derived circulating antioxidants (lycopene, retinol, ascorbic acid, and selenium) and antioxidant metabolites (α-tocopherol, γ-tocopherol, ascorbic acid, and retinol) did not significantly associate with epilepsy risk. Additional MR analysis methods and heterogeneity assessments confirmed the results' robustness. Conclusion: This study provides compelling evidence of oxidative stress in epilepsy patients' circulation. However, the majority of diet-derived circulating antioxidants (lycopene, retinol, ascorbic acid, vitamin E, and selenium) are unlikely to causally associate with reduced epilepsy risk, except for ß-carotene.

Insights into the starch and proteins molecular structure changes of foxtail millet sourdough: Effect of fermentation from grains of cereal to pre-meal.

This study investigated the effects of foxtail millet sourdough fermentation time (0, 8, 16, and 24 h) on the protein structural properties, thermomechanical, fermentation, dynamic rheological, starch granules crystalline regions molecular mobility, and starch microstructural characteristics. The fermentation led to a significant increase in the concentration of free amino acids from protein hydrolysis. Fourier transform infrared spectroscopy (FTIR) revealed changes in protein secondary structure and the presence of functional groups of different bioactive compounds. The result of thermomechanical properties showed a significant increase in the stability (0.70-0.79 min) and anti-retrogradation ability (2.29-3.14 Nm) of lactic acid bacteria (LAB) sourdough compared to the control dough, showing a wider processing applicability with radar profiler index. In contrast, sourdoughs with lower tan δ values had higher elasticity and strength. Scanning electron microscopy showed that the surface of the starch appeared from smooth to uneven with patchy shapes and cavities, which declined the crystallinity from 34.00 % to 21.57 %, 23.64 %, 25.09 %, and 26.34 % respectively. Fermentation changed the To, Tp, Tc, and ΔH of the starch. The results of the study will have great potential for application in the whole grain sourdough industry.

The IKMC web portal: a central point of entry to data and resources from the International Knockout Mouse Consortium.

The International Knockout Mouse Consortium (IKMC) aims to mutate all protein-coding genes in the mouse using a combination of gene targeting and gene trapping in mouse embryonic stem (ES) cells and to make the generated resources readily available to the research community. The IKMC database and web portal (www.knockoutmouse.org) serves as the central public web site for IKMC data and facilitates the coordination and prioritization of work within the consortium. Researchers can access up-to-date information on IKMC knockout vectors, ES cells and mice for specific genes, and follow links to the respective repositories from which corresponding IKMC products can be ordered. Researchers can also use the web site to nominate genes for targeting, or to indicate that targeting of a gene should receive high priority. The IKMC database provides data to, and features extensive interconnections with, other community databases.