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Perinatal exposure to valproic acid is commonly used for autism spectrum disorder (ASD) animal model development. The inhibition of histone deacetylases by VPA has been proposed to induce epigenetic changes during neurodevelopment, but the specific alterations in genetic expression underlying ASD-like behavioral changes remain unclear. We used qPCR-based gene expression and epigenetics tools and Western blotting in the hippocampi of neonatal valproic acid-exposed animals at 4 weeks of age and conducted the social interaction test to detect behavioral changes. Significant alterations in gene expression were observed in males, particularly concerning mRNA expression of Foxo3, which was significantly associated with behavioral changes. Moreover, notable differences were observed in H3K27ac chromatin immunoprecipitation, quantitative PCR (ChIP-qPCR), and methylation-sensitive restriction enzyme-based qPCR targeting the Foxo3 gene promoter region. These findings provide evidence that epigenetically regulated hippocampal Foxo3 expression may influence social interaction-related behavioral changes. Furthermore, identifying sex-specific gene expression and epigenetic changes in this model may elucidate the sex disparity observed in autism spectrum disorder prevalence. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is a known drug for treating epilepsy and mood disorders; however, it is not recommended for pregnant women because of its possible teratogenicity. VPA affects neurotransmission and gene expression through epigenetic mechanisms by acting as a histone deacetylase inhibitor and has been used to establish animal models of autism spectrum disorder (ASD). However, studies on the long-term effects of early exposure to VPA on glucocorticoid and neurosteroid synthesis in the brain are lacking. Therefore, this study aimed to investigate the long-term changes in metabolic alterations and gene expression regulation according to sex, using metabolic steroid profiling data from cerebral cortex samples of rats four weeks after VPA exposure (400 mg/kg). In neonatal VPA-exposed models, estradiol levels decreased, and cytochrome P450 19A1 gene (Cyp19a1) expression was reduced in the prepubertal male cortex. Progesterone and allopregnanolone levels decreased, and 3β-hydroxysteroid dehydrogenase 1 gene (Hsd3b1) expression was also downregulated in the prepubertal female cortex. Furthermore, cortisol levels increased, and mRNA expression of the nuclear receptor subfamily 3 group C member 1 gene (Nr3c1) was downregulated in the cortices of both sexes. Unlike the neonatal VPA-exposed models, although a decrease in progestin and estradiol levels was observed in females and males, respectively, no differences were observed in cortisol levels in the cortex tissues of 8-week-old adult rats administered VPA for four weeks. These results indicate that early environmental chemical exposure induces long-term neurosteroid metabolic effects in the brain, with differences according to sex. [ABSTRACT FROM AUTHOR]

Previous studies have investigated the role of inflammatory markers in suicidality of patients with major depressive disorder (MDD) or panic disorder (PD). However, few studies have investigated associations between serum inflammatory cytokine levels and suicidality. We hypothesized that MDD and PD status might be significantly associated with serum inflammatory cytokines and that we could predict levels of improvement in suicide ideation intensity using serum inflammatory biomarkers in patients with MDD and PD. For this study, 41 patients with MDD, 52 patients with PD, and 59 healthy control (HC) subjects were enrolled. Psychological measurements and serum inflammatory markers such as interleukin (IL) −6, −10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and C reactive protein (CRP) were examined. A total of five visits were completed during 12 weeks. After controlling for confounding factors, log-transformed IL-6 (ln_IL-6) at baseline (MDD: 0.297 ± 0.626; PD: 0.342 ± 0.723; HC: −0.121 ± 0.858; p = 0.007, >0.0017, 0.05/30) and mean ln_IL-6 (MDD: 0.395 ± 0.550, PD: 0.249 ± 0.544, HC: −0.139 ± 0.622, p = 0.002, >0.0017, 0.05/30) levels were trends towards significantly higher in patients with MDD and PD than in HC. In MDD patients, a higher level of basal ln_TNF-α was a significant predictor of ΔSSI (changes in SSI scores between baseline and week 12) even after controlling for changes of depression symptoms and baseline SSI scores (standardized β = 0.541, p = 0.002 < 0.0028, 0.05/18). In conclusion, we could predict ΔSSI using baseline inflammatory biomarkers for patients with MDD. [ABSTRACT FROM AUTHOR]

We report on the synthesis and characterization of highly monodisperse amorphous silica nanoparticles (ASNs) and mesoporous silica nanoparticles (MSNs) with particle sizes of 15–60 nm. We demonstrate adsorption of Cr(VI) ions on amino-functionalized ASNs (NH2–ASNs) and MSNs (NH2–MSNs) and their removal from aqueous environments and show the specific surface area (SSA) of NH2–MSNs is four times as larger as that of NH2–ASNs and that more than 70% of the total SSA of NH2–MSNs is due to the presence of nanopores. Analyses of Cr(VI) adsorption kinetics on NH2–ASNs and NH2–MSNs exhibited relatively rapid adsorption behavior following pseudo-second order kinetics as determined by nonlinear fitting. NH2–ASNs and NH2–MSNs exhibited significantly higher Cr(VI) adsorption capacities of 34.0 and 42.2 mg·g−1 and removal efficiencies of 61.9 and 76.8% than those of unfunctionalized ASNs and MSNs, respectively. The Langmuir model resulted in best fits to the adsorption isotherms of NH2–ASNs and NH2–MSNs. The adsorption of Cr(VI) on NH2–ASNs and NH2–MSNs was an endothermic and spontaneous process according to the thermodynamic analyses of temperature-dependent adsorption isotherms. The removal efficiencies of NH2–ASNs and NH2–MSNs exhibited a moderate reduction of less than 25% of the maximum values after five regeneration cycles. Furthermore, NH2–MSNs were also found to reduce adsorbed Cr(VI) into less harmful Cr(III). [ABSTRACT FROM AUTHOR]

Background: A link between brain-derived neurotrophic factor (BDNF) expression and the mood regulatory effect of leptin has been suggested in the pathophysiology of major depressive disorder (MDD). We investigated treatment response and pre-treatment leptin and BDNF in patients with MDD and with panic disorder (PD).Methods: We recruited 41 patients with MDD, 52 patients with PD, and 59 matched healthy controls. All subjects completed five visits (at baseline, 2, 4, 8, and 12 weeks), and both MDD and PD patients were treated with standard pharmacotherapy for 12 weeks. Plasma BDNF (pBDNF) and blood leptin levels were obtained along with a 17-item Hamilton Depression Scale rating (HDRS-17) score at every visit.Results: The ratio of pre-treatment pBDNF to leptin was significantly lower in patients with MDD and PD compared to healthy controls (p = 0.024), but was not associated with severity of depressive or anxiety symptoms. Pre-treatment pBDNF:leptin ratio was significantly higher in treatment responders than in non-responders (p = 0.012) in MDD but not in PD. This difference was larger in MDD patients with appetite loss (p = 0.034). In multivariate analysis, pre-treatment pBDNF:leptin ratio was significantly associated with treatment responsiveness (Adjusted Odds Ration [AOR] = 2.50, 95% CI 1.02-6.14) in MDD.Limitation: small sample size; limited information on detailed pharmacological effects.Conclusions: A relatively higher ratio of pre-treatment pBDNF to leptin was associated with greater treatment response in MDD but not in PD. Further research should focus on exploration of a link between BDNF and leptin underlying neuronal plasticity in depression. [ABSTRACT FROM AUTHOR]

• Mitochondrial dysfunction was observed in the PPA-treated SH-SY5Y cells. • Mitochondrial biogenesis-related protein expression was increased by PPA treatment. • PPA treatment induce ASCL1 and LFNG gene expression change. Studies in animal models have shown that the short-chain fatty acid, propionic acid (PPA), interferes with mitochondrial metabolism leading to mitochondrial dysfunction and behavioral abnormalities. The aim of this study was to investigate the effects of PPA on mitochondrial function and gene expression in neuronal cells. SH-SY5Y cells and normal human neural progenitor (NHNP) cells were exposed to 1, 5 mM PPA for 4 or 24 h and we found that the mitochondrial potential measured in SH-SY5Y cells decreased in a dose-dependent manner after PPA treatment. Electron microscopy analysis revealed that the size of the mitochondria was significantly reduced following PPA treatment. A dose-dependent increase in the mitochondrial DNA copy number was observed in the PPA-treated cells. The expression of the mitochondrial biogenesis-related proteins PGC-1α, TFAM, SIRT3, and COX4 was significantly increased after PPA treatment. Transcriptome analysis revealed that mRNA expression in the notch signaling-related genes ASCL1 and LFNG changed after PPA treatment and the positive correlated protein expression changes were also observed. These results revealed that PPA treatment may affect neurodevelopment by altering mitochondrial function and notch signaling-related gene expression. [ABSTRACT FROM AUTHOR]

Depressive symptoms are related to abnormalities in the autonomic nervous system (ANS), and physiological signals that can be used to measure and evaluate such abnormalities have previously been used as indicators for diagnosing mental disorder, such as major depressive disorder (MDD). In this study, we investigate the feasibility of developing an objective measure of depressive symptoms that is based on examining physiological abnormalities in individuals when they are experiencing mental stress. To perform this, we recruited 30 patients with MDD and 31 healthy controls. Then, skin conductance (SC) was measured during five 5-min experimental phases, comprising baseline, mental stress, recovery from the stress, relaxation, and recovery from the relaxation, respectively. For each phase, the mean amplitude of the skin conductance level (MSCL), standard deviations of the SCL (SDSCL), slope of the SCL (SSCL), mean amplitude of the non-specific skin conductance responses (MSCR), number of non-specific skin conductance responses (NSCR), and power spectral density (PSD) were evaluated from the SC signals, producing 30 parameters overall (six features for each phase). These features were used as input data for a support vector machine (SVM) algorithm designed to distinguish MDD patients from healthy controls based on their physiological responses. Statistical tests showed that the main effect of task was significant in all SC features, and the main effect of group was significant in MSCL, SDSCL, SSCL, and PSD. In addition, the proposed algorithm achieved 70% accuracy, 70% sensitivity, 71% specificity, 70% positive predictive value, 71% negative predictive value in classifying MDD patients and healthy controls. These results demonstrated that it is possible to extract meaningful features that reflect changes in ANS responses to various stimuli. Using these features, detection of MDD was feasible, suggesting that SC analysis has great potential for future diagnostics and prediction of depression based on objective interpretation of depressive states. [ABSTRACT FROM AUTHOR]

Background: Heart Rate Variability (HRV) parameters have been used to evaluate the autonomic nervous system. We hypothesized that patients with major depressive disorder (MDD) and panic disorder (PD) showed different HRV profiles compared to healthy controls. We also hypothesized that we could predict the responder groups in the MDD and PD patients, using differences in HRV indices between the stress and rest phases.Methods: 28 MDD patients and 29 PD patients were followed for 12 weeks, and we also followed 39 healthy control subjects. We measured HRV parameters at the rest, stress, and recovery phases.Results: Patients with MDD and PD demonstrated lower pNN50 than controls during the stress (F = 7.49, p = 0.001), and recovery phases (F = 9.43, p = 0.0001). Patients with MDD and PD also showed higher LF/HF ratio than controls during the stress phase (F = 6.15, p = 0.002). Responders in the PD group presented a lower level of LF/HF ratio during the stress phase compared to non-responders (F = 10.14, p = 0.002), while responders in the MDD group showed a lower level of heart rate during all three phases, compared to non-responders. Additionally, we could predict treatment response in patients with MDD using ΔLF/HF ratio (OR: 1.33, 95% CI = 1.07-1.65, p = 0.011) and ΔpNN50 (OR: 1.49, 95% CI 1.09-1.77, p = 0.014).Conclusion: The changes of HRV parameters of pNN50 and LF/HF ratio between the stress and recovery phase may be clinical markers of predictors of treatment responsiveness in MDD and PD patients. [ABSTRACT FROM AUTHOR]

• FOXO3 induction by acute valproate exposure was confirmed at in vivo model in juvenile male hippocampus only. • Proneural gene expression, ASCL1 and NGN2, were upregulated by FOXO3 down expression in FOXO3 siRNA treated PC12 cells. • Mitochondria biogenesis related gene expressions were regulated by FOXO3 expression in FOXO3 siRNA treated PC12 cells. Valproic acid (VPA), an anticonvulsant and mood stabilizer, may affect Notch signaling and mitochondrial function. In a previous study, acute VPA exposure induced increased expression of FOXO3, a transcription factor that shares common targets with pro-neuronal ASCL1. In this study, intraperitoneal acute VPA (400 mg/kg) administration in 4-week-old mice increased and decreased FOXO3 and ASCL1 expression, respectively, in the hippocampus, associated with sex-based differences. Treatment of Foxo3 siRNA increased the mRNA expression levels of Ascl1, Ngn2, Hes6, and Notch1 in PC12 cells. Furthermore, VPA exposure induced significant expression changes of mitochondria-related genes, including COX4 and SIRT1 , in hippocampal tissues, associated with sex-based differences. This study suggests that acute VPA exposure differently affects proneural gene expression via FOXO3 induction in the hippocampus based on sex. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is an antiepileptic drug found to induce mitochondrial dysfunction and autophagy in cancer cell lines. We treated the SH-SY5Y cell line with various concentrations of VPA (1, 5, and 10 mM). The treatment decreased cell viability, ATP production, and mitochondrial membrane potential and increased reactive oxygen species production. In addition, the mitochondrial DNA copy number increased after VPA treatment in a dose-dependent manner. Western blotting showed that the levels of mitochondrial biogenesis-related proteins (PGC-1α, TFAM, and COX4) increased, though estrogen-related receptor expression decreased after VPA treatment. Further, VPA treatment increased the total and acetylated FOXO3a protein levels. Although SIRT1 expression was decreased, SIRT3 expression was increased, which regulated FOXO3 acetylation in the mitochondria. Furthermore, VPA treatment induced autophagy via increased LC3-II levels and decreased p62 expression and mTOR phosphorylation. We suggest that VPA treatment induces mitochondrial biogenesis and autophagy via changes in FOXO3a expression and posttranslational modification in the SH-SY5Y cell line. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a common psychiatric disorder and the leading cause of disability worldwide. However, current methods used to diagnose depression mainly rely on clinical interviews and self-reported scales of depressive symptoms, which lack objectivity and efficiency. To address this challenge, we present a machine learning approach to screen for MDD using electrodermal activity (EDA). Participants included 30 patients with MDD and 37 healthy controls. Their EDA was measured during five experimental phases consisted of baseline, mental arithmetic task, recovery from the stress task, relaxation task, and recovery from the relaxation task, which elicited multiple alterations in autonomic activity. Selected EDA features were extracted from each phase, and differential EDA features between two distinct phases were evaluated. By using these features as input data and performing feature selection with SVM-RFE, 74% accuracy, 74% sensitivity, and 71% specificity could be achieved by our decision tree classifier. The most relevant features selected by SVM-RFE included differential EDA features and features from the stress and relaxation tasks. These findings suggest that automatic detection of depression based on EDA features is feasible and that monitoring changes in physiological signal when a subject is experiencing autonomic arousal and recovery may enhance discrimination power. [ABSTRACT FROM AUTHOR]

Background: The current method to evaluate major depressive disorder (MDD) relies on subjective clinical interviews and self-questionnaires.Objective: Autonomic imbalance in MDD patients is characterized using entropy measures of heart rate variability (HRV). A machine learning approach for screening depression based on the entropy is demonstrated.Methods: The participants experience five experimental phases: baseline (BASE), stress task (MAT), stress task recovery (REC1), relaxation task (RLX), and relaxation task recovery (REC2). The four entropy indices, approximate entropy, sample entropy, fuzzy entropy, and Shannon entropy, are extracted for each phase, and a total of 20 features are used. A support vector machine classifier and recursive feature elimination are employed for classification.Results: The entropy features are lower in the MDD group; however, the disease does not have a significant effect. Experimental tasks significantly affect the features. The entropy did not recover during REC1. The differences in the entropy features between the two groups increased after MAT and showed the largest gap in REC2. We achieved 70% accuracy, 64% sensitivity, and 76% specificity with three optimal features during RLX and REC2.Conclusion: Monitoring of HRV complexity changes when a subject experiences autonomic arousal and recovery can potentially facilitate objective depression recognition. [ABSTRACT FROM AUTHOR]

Background/Aims: A limited number of studies addressed MRI-based neurodegenerative changes in subjective memory impairment (SMI). We investigated changes in white matter (WM) microstructures as well as gray matter (GM) macrostructures in subjects with SMI of high and low risk for progression. Methods: A modeling scale (score range, 0-6) developed for prediction of SMI progression was used to divide SMI subjects (n = 46) into two groups: a high risk of progression (score ⩾ 3; n = 19) and a low risk of progression (score ⩽ 2; n = 27). Cross-sectional comparisons were performed using a region-of-interest-based diffusion tensor imaging (DTI) analysis, cortical thickness analysis, and hippocampal volumetry. Results: The high-risk group had more microstructural disruption shown by lower fractional anisotropy in the hippocampus, parahippocampal gyrus, supramarginal gyrus, and parts of frontotemporal lobes. On the other hand, GM macrostructural changes did not differ between the groups and were not associated with modeling scale scores. Conclusion: SMI subjects with a high risk of progression had more WM microstructural disruption than those with a low risk, and the changes were not explained by GM atrophy. Our findings suggest that the degree of microstructural alterations in SMI may be distinctive according to the risk factors and may precede GM atrophy. [ABSTRACT FROM AUTHOR]

Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the total times spent in the center, corner, or border zones in the male prenatal TMT-exposed mice were less than those of control unexposed mice in the open-field test. Female TMT-exposed mice scored lower on total numbers of arm entries and percentages of alternations than controls in the Y-maze test with lower body weight. We found that only TMT-exposed males had fewer copies of mtDNA in the hippocampus and prefrontal cortex region than controls. Additional epigenetic changes, including increased 5-methyl cytosine/5-hydroxymethyl cytosine levels in the male TMT hippocampus, were observed. After methylation binding domain (MBD) sequencing, multiple signaling pathways related to metabolism and neurodevelopment, including FoxO signaling, were identified by pathway analysis for differentially methylated regions (DMRs). Increased FOXO3 and decreased ASCL1 expression were also observed in male TMT hippocampi. This study suggests that sex differences and epigenetics should be more carefully considered in prenatal toxicology studies. [ABSTRACT FROM AUTHOR]

Herein, we developed a facile one-pot approach to prepare amphiphilic aggregation-induced emission (AIE)-active hyperbranched fluorescent nanoparticles with a core–shell structure. This was conducted via the addition reaction between tetraphenylethylene (TPE)-OH, isophorone diisocyanate, and hyperbranched polyglycidol (HPG) using a one-pot method. The resultant AIE-active hyperbranched polymer structure was characterized by 1H nuclear magnetic resonance and Fourier-transform infrared spectroscopy. The amphiphilic AIE-active polymer was prone to self-assemble in an aqueous solution to form core–shell type nanoparticles with a TPE core and hydroxyl groups on the core surface. The self-assembly of nanoparticles in the aqueous solution was characterized using dynamic light scattering, ultraviolet–visible spectroscopy, fluorescence spectroscopy, and transmission electron microscopy. Aggregation behavior of TPE-HPG polymer in water and diethyl ether was studied by dissipative particle dynamics simulation. Furthermore, these TPE-HPG nanoparticles exhibited a strong blue luminescence in the aqueous solution due to the aggregation of the AIE feature of TPE. These polymeric nanoparticles showed high water solubility, good photostability, and biological imaging properties. The cell viability assay and confocal microscopy imaging results suggested that the TPE-HPG fluorescent polymeric organic nanoparticles (FPNs) have low cytotoxicity and excellent biocompatibility. Thus, TPE-HPG FPNs are excellent candidates for biomedical applications. Image 1 • Aggregation-induced emission (AIE)-active hyperbranched polymer is synthesized. • The amphiphilic polymer is self-assembled to form AIE-active nanoparticles (NPs). • The AIE-active NPs show excellent water dispersibility and biocompatibility for bioimaging applications. [ABSTRACT FROM AUTHOR]

• Classification of panic disorder vs. major depressive disorder and controls using a 2-channel EEG system (FP1, FP2). • Panic disorder and major depressive disorder subjects show reduced cortical complexity. • Presents a rapid and practical paradigm for use in primary care settings. The current study aimed to investigate the possibility of rapid and accurate diagnoses of Panic disorder (PD) and Major depressive disorder (MDD) using machine learning. The support vector machine method was applied to 2-channel EEG signals from the frontal lobes (Fp1 and Fp2) of 149 participants to classify PD and MDD patients from healthy individuals using non-linear measures as features. We found significantly lower correlation dimension and Lempel-Ziv complexity in PD patients and MDD patients in the left hemisphere compared to healthy subjects at rest. Most importantly, we obtained a 90% accuracy in classifying MDD patients vs. healthy individuals, a 68% accuracy in classifying PD patients vs. controls, and a 59% classification accuracy between PD and MDD patients. In addition to demonstrating classification performance in a simplified setting, the observed differences in EEG complexity between subject groups suggest altered cortical processing present in the frontal lobes of PD patients that can be captured through non-linear measures. Overall, this study suggests that machine learning and non-linear measures using only 2-channel frontal EEGs are useful for aiding the rapid diagnosis of panic disorder and major depressive disorder. [ABSTRACT FROM AUTHOR]

Abstract: Background: The genetic factors that determine the heterogeneity of cognitive impairment in Alzheimer's disease (AD) patients have been rarely reported. We aimed to investigate the association between top hits of genome-wide association studies (GWAS) and specific cognitive domains in AD patients. Methods: We investigated 86 single nucleotide polymorphisms (SNPs) selected from 12 genes (ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, LRAT, MS4A6A, PCDH11X, and PICALM) based on results of the recent GWAS and genotyped in 211 AD cases. We also analyzed results of comprehensive neuropsychological evaluations in all cases. We performed multiple regression analyses. Results: There were four significant associations between genotypes and phenotypes of AD patients: CR1 SNP rs11803956 correlated with Mini-Mental State Examination (MMSE) score (β=1.718, Pcorrected =0.002); ABCA7 SNP rs3752232 correlated with Rey Complex Figure Test (RCFT) copy score (β=−6.861, Pcorrected =0.013); APOE SNP rs2075650 correlated with the percentile of RCFT copy score (β=14.005, Pcorrected =0.021) and the percentile of total score in phonemic fluency (β=11.052, Pcorrected =0.035). Conclusion: Our results suggest that CR1, ABCA7, and APOE correlate with specific aspects of cognitive impairments in AD patients. [Copyright &y& Elsevier]

Highlights: [•] We investigated brain MD changes in Parkinson's disease patients. [•] MD changes in corticofugal tract, cingulum and other white matter tracts in PD. [•] MD changes in left putamen, caudate, pallidum and thalamus in PD [Copyright &y& Elsevier]

We report an enhancement in light emission efficiency form Si nanocrystal (NC) light-emitting diodes (LEDs) via surface plasmons (SPs) by employing Au nanoparticles (NPs). Photoluminescence intensity of Si NCs with Au NPs was enhanced by 2 factors of magnitude due to the strong coupling of Si NCs and SP resonance modes of Au NPs. The electrical characteristics of Si NC LED were significantly improved, which was attributed to an increase in an electron injection into the Si NCs due to the formation of inhomogeneous Schottky barrier at the SiC-indium tin oxide interface. Moreover, light output power from the Si NC LED was enhanced by 50% due to both SP coupling and improved electrical properties. The results presented here can provide a very promising way to significantly enhance the performance of Si NC LED. [ABSTRACT FROM AUTHOR]