Chlorinated persistent organic pollutants in human breast milk in the Miyagi Prefecture disaster-affected area 1 year after the Great East Japan Earthquake of 2011.

BACKGROUND: In the Great East Japan Earthquake of 11 March 2011, an earthquake and accompanying tsunami struck the Tohoku region of northeastern Japan. Buildings collapsed and the tsunami spread waste, including hazardous materials. This study aimed to determine the concentrations of persistent organic pollutants (POPs) in the breast milk of mothers living in the disaster-affected area of Sendai 1 year after the earthquake. Temporal trends in the POPs concentrations were evaluated by comparison with previous studies. METHODS: One hundred breast milk samples were obtained from lactating mothers at a hospital in Sendai in 2012. The results were compared with those from other years to examine whether there were changes in the POPs concentrations after the earthquake. We measured polychlorinated biphenyls (PCBs) and organochlorine pesticides, such as chlordanes, using gas chromatography-mass spectrometer (GC-MS) with negative chemical ionization, and dichlorodiphenyl trichloroethane (DDT) and its metabolites using GC-MS with electron impact ionization. RESULTS: The mean total PCBs (11 congeners), total chlordane, and total DDT concentrations were 76.2 ng/g lipid, 39.8 ng/g lipid, and 73.5 ng/g lipid, respectively. For the samples collected in 2012, the concentrations of POPs in breast milk showed minimal changes compared with results from previous years for samples collected at the same hospital in Sendai. CONCLUSIONS: Our study demonstrates that 1 year after the earthquake and tsunami, the concentrations of chlorinated POPs in breast milk had not changed substantially.

Age-Related Changes in the Characteristics of the Elderly Females Using the Signal Features of an Earlobe Photoplethysmogram.

Non-invasive measurement of physiological parameters and indicators, specifically among the elderly, is of utmost importance for personal health monitoring. In this study, we focused on photoplethysmography (PPG), and developed a regression model that calculates variables from the second (SDPPG) and third (TDPPG) derivatives of the PPG pulse that can observe the inflection point of the pulse wave measured by a wearable PPG device. The PPG pulse at the earlobe was measured for 3 min in 84 elderly Korean women (age: 71.19 ± 6.97 years old). Based on the PPG-based cardiovascular function, we derived additional variables from TDPPG, in addition to the aging variable to predict the age. The Aging Index (AI) from SDPPG and Sum of TDPPG variables were calculated in the second and third differential forms of PPG. The variables that significantly correlated with age were c/a, Tac, AI of SDPPG, sum of TDPPG, and correlation coefficient 'r' of the model. In multiple linear regression analysis, the r value of the model was 0.308, and that using deep learning on the model was 0.839. Moreover, the possibility of improving the accuracy of the model using supervised deep learning techniques, rather than the addition of datasets, was confirmed.

Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner.

Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive occlusion of the internal carotid arteries. Genetic studies originally identified RNF213 as an MMD susceptibility gene that encodes a large 591 kDa protein with a functional RING domain and dual AAA+ ATPase domains. As the functions of RNF213 and its relationship to MMD onset are unknown, we set out to characterize the ubiquitin ligase activity of RNF213, and the effects of MMD patient mutations on these activities and on other cellular processes. In vitro ubiquitination assays, using the RNF213 RING domain, identified Ubc13/Uev1A as a key ubiquitin conjugating enzyme that together generate K63-linked polyubiquitin chains. However, nearly all MMD patient mutations in the RING domain greatly reduced this activity. When full-length proteins were overexpressed in HEK293T cells, patient mutations that abolished the ubiquitin ligase activities conversely enhanced nuclear factor κB (NFκB) activation and induced apoptosis accompanied with Caspase-3 activation. These induced activities were dependent on the RNF213 AAA+ domain. Our results suggest that the NFκB- and apoptosis-inducing functions of RNF213 may be negatively regulated by its ubiquitin ligase activity and that disruption of this regulation could contribute towards MMD onset.

Development of the main olfactory system and main olfactory epithelium-dependent male mating behavior are altered in Go-deficient mice.

In mammals, initial detection of olfactory stimuli is mediated by sensory neurons in the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). The heterotrimeric GTP-binding protein Go is widely expressed in the MOE and VNO of mice. Early studies indicated that Go expression in VNO sensory neurons is critical for directing social and sexual behaviors in female mice [Oboti L, et al. (2014) BMC Biol 12:31]. However, the physiological functions of Go in the MOE have remained poorly defined. Here, we examined the role of Go in the MOE using mice lacking the α subunit of Go Development of the olfactory bulb (OB) was perturbed in mutant mice as a result of reduced neurogenesis and increased cell death. The balance between cell types of OB interneurons was altered in mutant mice, with an increase in the number of tyrosine hydroxylase-positive interneurons at the expense of calbindin-positive interneurons. Sexual behavior toward female mice and preference for female urine odors by olfactory sensory neurons in the MOE were abolished in mutant male mice. Our data suggest that Go signaling is essential for the structural and functional integrity of the MOE and for specification of OB interneurons, which in turn are required for the transmission of pheromone signals and the initiation of mating behavior with the opposite sex.

AKT-independent Reelin signaling requires interactions of heterotrimeric Go and Src.

Reelin, a large secreted extracellular matrix glycoprotein, plays a key role in neuronal migration during cortical development and promotes neuronal maturation. The signaling pathway regulating neuronal maturation in the postnatal period are relatively less well understood. In this study, we demonstrated that a heterotrimeric G protein, Go, is a novel target of Reelin-induced signaling to promote neurite outgrowth. In primary hippocampal neurons of Reelin-deficient reeler mice, neurite outgrowth was significantly reduced and rescued upon addition of Reelin. Pertussis toxin (PTX) treatment or transfection with Gαo-siRNA suppressed Reelin-mediated neurite outgrowth in wild-type neurons. Additionally, Reelin treatment led to increased phosphorylation of AKT, GSK3ß, and JNK, which were all effectively blocked by the PI3K inhibitor, LY294002. By comparison, PTX specifically blocked JNK activation, but not AKT and GSK3ß. Immunoprecipitation assays disclosed that Reelin increases the active forms of both Src and Gαo and promotes their direct association. Notably, Dab1, a cytoplasmic adaptor molecule that mediates Reelin signaling, did not interact with Gαo. Neurite outgrowth by Reelin was induced via activating Src kinase, which directly stimulated Gαo, activity, leading to JNK activation. Based on the collective findings, we suggest that Reelin-dependent signaling mechanisms may be split into Src-AKT-dependent and Src-Go-dependent pathways. Our results additionally provide evidence that Reelin receptors cross-communicate with heterologous G protein-coupled receptors (GPCR) independently of the cognate ligands of GPCR.

Effects of bathing in different hot spring types on Japanese gut microbiota.

Hot springs have been used for a variety of purposes, including the treatment and amelioration of illness and recreation. Japan has ten different types of therapeutic springs (described here as spa types), which are traditionally believed to have different efficacy. However, more research must be conducted to determine how they affect healthy people. Therefore, this study focused on the gut microbiota and aimed to investigate changes in the gut microbiota in healthy people after bathing in different spa types. Using Beppu's hot springs (simple, chloride, bicarbonate, sulfur, and sulfate types), 136 healthy Japanese adults living in the Kyushu area participated in the study and bathed in the same hot spring for seven days. Fecal samples were collected before and after the 7-day bathing period, and the relative abundance of the gut microbiota was determined by 16S rRNA sequencing. The results showed that the relative abundance of Bifidobacterium bifidum increased significantly after seven consecutive days of bathing in the bicarbonate spring. Significant increases in other gut microbiota were also observed after bathing in simple, bicarbonate, and sulfur springs. These results suggest that bathing in different hot springs may affect the gut microbiota in healthy individuals differently.

Evaluation of the effect of photoplethysmograms on workers' exposure to methyl bromide using second derivative.

Methyl bromide (MB) is worldwide the only effective fumigant heavily used for quarantine pre-shipment treatment and has a critical use exemption for soil fumigations due to its excellent permeability and insecticidal effect. However, MB should be replaced as it is an an ozone-depleting substance and also highly toxic to humans. Recently, MB has been shown to be hazardous even for asymptomatic workers, affecting their central and autonomic nervous systems. However, the effects of MB exposure on vascular health have not been explored. This study aimed to determine whether MB affects the arterial system of asymptomatic workers. We measured the second derivative of the photoplethysmogram (SDPTG) indices, which are indicators of vascular load and aging, and urinary bromide ion (Br-) concentrations in 44 fumigators (study group) and 20 inspectors (control group) before and after fumigation. In fumigators, the mean values of post-work SDPTG indices (b/a, c/a, d/a, e/a, and SDPTG aging index) and Br- levels were significantly changed compared to their pre-work values (p < 0.05), indicating a negative effect on their cardiovascular health. In contrast, SDPTG indices and Br- levels in inspectors did not show any differences before and after work. All SDPTG indices except c/a showed significant correlations with Br- levels in all individuals (p < 0.05). In conclusion, the Br- levels and SDPTG indices of fumigators varied after MB work, and they experienced negative effects on their health despite being asymptomatic.

Prefrontal EEG slowing, synchronization, and ERP peak latency in association with predementia stages of Alzheimer's disease.

Background: Early screening of elderly individuals who are at risk of dementia allows timely medical interventions to prevent disease progression. The portable and low-cost electroencephalography (EEG) technique has the potential to serve it. Objective: We examined prefrontal EEG and event-related potential (ERP) variables in association with the predementia stages of Alzheimer's disease (AD). Methods: One hundred elderly individuals were recruited from the GARD cohort. The participants were classified into four groups according to their amyloid beta deposition (A+ or A-) and neurodegeneration status (N+ or N-): cognitively normal (CN; A-N-, n = 27), asymptomatic AD (aAD; A + N-, n = 15), mild cognitive impairment (MCI) with AD pathology (pAD; A+N+, n = 16), and MCI with non-AD pathology (MCI(-); A-N+, n = 42). Prefrontal resting-state eyes-closed EEG measurements were recorded for five minutes and auditory ERP measurements were recorded for 8 min. Three variables of median frequency (MDF), spectrum triangular index (STI), and positive-peak latency (PPL) were employed to reflect EEG slowing, temporal synchrony, and ERP latency, respectively. Results: Decreasing prefrontal MDF and increasing PPL were observed in the MCI with AD pathology. Interestingly, after controlling for age, sex, and education, we found a significant negative association between MDF and the aAD and pAD stages with an odds ratio (OR) of 0.58. Similarly, PPL exhibited a significant positive association with these AD stages with an OR of 2.36. Additionally, compared with the MCI(-) group, significant negative associations were demonstrated by the aAD group with STI and those in the pAD group with MDF with ORs of 0.30 and 0.42, respectively. Conclusion: Slow intrinsic EEG oscillation is associated with MCI due to AD, and a delayed ERP peak latency is likely associated with general cognitive impairment. MCI individuals without AD pathology exhibited better cortical temporal synchronization and faster EEG oscillations than those with aAD or pAD. Significance: The EEG/ERP variables obtained from prefrontal EEG techniques are associated with early cognitive impairment due to AD and non-AD pathology. This result suggests that prefrontal EEG/ERP metrics may serve as useful indicators to screen elderly individuals' early stages on the AD continuum as well as overall cognitive impairment.

Resting-state prefrontal EEG biomarker in correlation with postoperative delirium in elderly patients.

Postoperative delirium (POD) is associated with adverse outcomes in elderly patients after surgery. Electroencephalography (EEG) can be used to develop a potential biomarker for degenerative cerebral dysfunctions, including mild cognitive impairment and dementia. This study aimed to explore the relationship between preoperative EEG and POD. We included 257 patients aged >70 years who underwent spinal surgery. We measured the median dominant frequency (MDF), which is a resting-state EEG biomarker involving intrinsic alpha oscillations that reflect an idle cortical state, from the prefrontal regions. Additionally, the mini-mental state examination and Montreal cognitive assessment (MoCA) were performed before surgery as well as 5 days after surgery. For long-term cognitive function follow up, the telephone interview for cognitive status™ (TICS) was performed 1 month and 1 year after surgery. Fifty-two (20.2%) patients were diagnosed with POD. A multivariable logistic regression analysis that included age, MoCA score, Charlson comorbidity index score, Mini Nutritional Assessment, and the MDF as variables revealed that the MDF had a significant odds ratio of 0.48 (95% confidence interval 0.27-0.85). Among the patients with POD, the postoperative neurocognitive disorders could last up to 1 year. Low MDF on preoperative EEG was associated with POD in elderly patients undergoing surgery. EEG could be a novel potential tool for identifying patients at a high risk of POD.

Preclinical Study on Biodistribution of Mesenchymal Stem Cells after Local Transplantation into the Brain.

Therapeutic efficacy of mesenchymal stem cells (MSCs) is determined by biodistribution and engraftment in vivo. Compared to intravenous infusion, biodistribution of locally transplanted MSCs are partially understood. Here, we performed a pharmacokinetics (PK) study of MSCs after local transplantation. We grafted human MSCs into the brains of immune-compromised nude mice. Then we extracted genomic DNA from brains, lungs, and livers after transplantation over a month. Using quantitative polymerase chain reaction with human Alu-specific primers, we analyzed biodistribution of the transplanted cells. To evaluate the role of residual immune response in the brain, MSCs expressing a cytosine deaminase (MSCs/CD) were used to ablate resident immune cells at the injection site. The majority of the Alu signals mostly remained at the injection site and decreased over a week, finally becoming undetectable after one month. Negligible signals were transiently detected in the lung and liver during the first week. Suppression of Iba1-positive microglia in the vicinity of the injection site using MSCs/CD prolonged the presence of the Alu signals. After local transplantation in xenograft animal models, human MSCs remain predominantly near the injection site for limited time without disseminating to other organs. Transplantation of human MSCs can locally elicit an immune response in immune compromised animals, and suppressing resident immune cells can prolong the presence of transplanted cells. Our study provides valuable insights into the in vivo fate of locally transplanted stem cells and a local delivery is effective to achieve desired dosages for neurological diseases.

The SGLT2 inhibitor empagliflozin improves cardiac energy status via mitochondrial ATP production in diabetic mice.

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor developed, has been shown to reduce cardiovascular events in patients with type 2 diabetes and established cardiovascular disease. Several studies have suggested that empagliflozin improves the cardiac energy state which is a partial cause of its potency. However, the detailed mechanism remains unclear. To address this issue, we used a mouse model that enabled direct measurement of cytosolic and mitochondrial ATP levels. Empagliflozin treatment significantly increased cytosolic and mitochondrial ATP levels in the hearts of db/db mice. Empagliflozin also enhanced cardiac robustness by maintaining intracellular ATP levels and the recovery capacity in the infarcted area during ischemic-reperfusion. Our findings suggest that empagliflozin enters cardiac mitochondria and directly causes these effects by increasing mitochondrial ATP via inhibition of NHE1 and Nav1.5 or their common downstream sites. These cardioprotective effects may be involved in the beneficial effects on heart failure seen in clinical trials.

Variations in the Second Derivative of a Photoplethysmogram with Age in Healthy Korean Adults.

Second derivative of photoplethysmogram (SDPTG) indices correlate with aging and vascular health. The trend of SDPTG indices with age has not yet been studied in the Korean population. Various SDPTG indices were measured in 300 healthy Koreans (150 men and 150 women), aged 19−69 years, stratified into five age groups consisting of 60 people (30 men and 30 women) in each age group from their 20s to 60s. The values of the SDPTG indices clearly showed distinct variations with age in healthy Korean groups (p < 0.001 for all indices). b/a increased linearly with age (y = 0.0045x − 0.803), as did SDPTG aging index (SDPTG-AI) (y = 0.0162x − 1.1389). c/a decreased linearly with age (y = −0.0044x + 0.1017), as did d/a (y = −0.0062x + 0.034) and e/a (y = −0.001x + 0.2002). A significant sex difference was shown in b/a and e/a ratios and SDPTG-AI (p < 0.001 for all indices); women had a higher b/a ratio (−0.55 ± 0.14 versus −0.65 ± 0.13) and SDPTG-AI (−0.33 ± 0.3 versus −0.52 ± 0.33) and a lower e/a ratio (0.13 ± 0.06 versus 0.18 ± 0.07) than men. A linear regression model of diverse SDPTG indices was provided according to the age of healthy Koreans, which may be valuable in preventing diseases related to vascular conditions by estimating the degradation of arterial function.

Heart Rate Variability Analysis in Workers Exposed to Methyl Bromide as a Quarantine Treatment.

OBJECTIVE: To determine whether methyl bromide (MB) fumigation work for plants imported in Korea affects workers' health by assessing heart rate variability (HRV). METHODS: We measured HRV indices (TP, VLF, LF, HF, HR, SDNN, pNN50 and HRV-index) and urinary bromide ion (Br-) in 62 fumigators (study group) and 34 inspectors (the control group) before and after fumigation work. In addition, the relationship between Br- concentration and HRV indices was analysed. RESULTS: The fumigators' post-work HRV indices and Br- level were changed compared with their pre-work values (P < 0.001). Conversely, inspectors' values were not shown a difference before and after work. The HRV indices in all subjects were negatively correlated with the Br- levels (P < 0.05). CONCLUSIONS: Fumigators with high Br- concentrations and low post-work HRV indices following MB fumigation work experienced adverse effects on their autonomic nervous systems.

Predicting Dementia With Prefrontal Electroencephalography and Event-Related Potential.

Objective: To examine whether prefrontal electroencephalography (EEG) can be used for screening dementia. Methods: We estimated the global cognitive decline using the results of Mini-Mental Status Examination (MMSE), measurements of brain activity from resting-state EEG, responses elicited by auditory stimulation [sensory event-related potential (ERP)], and selective attention tasks (selective-attention ERP) from 122 elderly participants (dementia, 35; control, 87). We investigated that the association between MMSE and each EEG/ERP variable by using Pearson's correlation coefficient and performing univariate linear regression analysis. Kernel density estimation was used to examine the distribution of each EEG/ERP variable in the dementia and non-dementia groups. Both Univariate and multiple logistic regression analyses with the estimated odds ratios were conducted to assess the associations between the EEG/ERP variables and dementia prevalence. To develop the predictive models, five-fold cross-validation was applied to multiple classification algorithms. Results: Most prefrontal EEG/ERP variables, previously known to be associated with cognitive decline, show correlations with the MMSE score (strongest correlation has |r| = 0.68). Although variables such as the frontal asymmetry of the resting-state EEG are not well correlated with the MMSE score, they indicate risk factors for dementia. The selective-attention ERP and resting-state EEG variables outperform the MMSE scores in dementia prediction (areas under the receiver operating characteristic curve of 0.891, 0.824, and 0.803, respectively). In addition, combining EEG/ERP variables and MMSE scores improves the model predictive performance, whereas adding demographic risk factors do not improve the prediction accuracy. Conclusion: Prefrontal EEG markers outperform MMSE scores in predicting dementia, and additional prediction accuracy is expected when combining them with MMSE scores. Significance: Prefrontal EEG is effective for screening dementia when used independently or in combination with MMSE.

Cell Type-specific Knockout with Gli1-mediated Cre Recombination in the Developing Cerebellum.

The inducible Cre-loxP system provides a useful tool for inducing the selective deletion of genes that are essential for proper development and enables the study of gene functions in properly developed animals. Here, we show that inducible Cre-loxP driven by the Gli1-promoter can induce cell-type-specific deletion of target genes in cerebellar cortical neurons. We used reporter mice containing the YFP (yellow fluorescence protein) gene at the Gt(ROSA)26Sor locus with a loxP-flanked transcriptional stop sequence, in which successful Cre-mediated excision of the stop sequence is indicated by YFP expression in Cre-expressing cells. Administration of tamoxifen during early postnatal days (P4~7) induces Cre-dependent excision of stop sequences and allows YFP expression in proliferating neuronal progenitor cells in the external granule layer and Bergmann glia in the Purkinje cell layer. A substantial number of YFP-positive progenitor cells in the external granule layer migrated to the internal granule cell layer and became granule cell neurons. By comparison, injection of tamoxifen during late postnatal days (P19~22) induces YFP expression only in Bergmann glia, and most granule cell neurons were devoid of YFP expression. The results indicate that the Gli1 promoter is temporarily active in progenitor cells in the external granule layer during the early postnatal period but constitutively active in Bergmann glia. We propose that the Gli1-mediated CreER system can be applied for the conditional deletion of genes of interest from cerebellar granule cell neurons and/or Bergmann glia.

Psycho-Electrophysiological Benefits of Forest Therapies Focused on Qigong and Walking with Elderly Individuals.

We developed two distinct forest therapy programs (FTPs) and compared their effects on dementia prevention and related health problems for older adults. One was focused on Qigong practice in the forest (QP) and the other involved active walking in the forest (WP). Both FTPs consisted of twelve 2-h sessions over six weeks and were conducted in an urban forest. We obtained data from 25, 18, and 26 participants aged 65 years or above for the QP, WP, and control groups, respectively. Neuropsychological scores via cognition (MoCA), geriatric depression (GDS) and quality of life (EQ-5D), and electrophysiological variables (electroencephalography, bioimpedance, and heart rate variability) were measured. We analyzed the intervention effects with a generalized linear model. Compared to the control group, the WP group showed benefits in terms of neurocognition (increases in the MoCA score, and alpha and beta band power values in the electroencephalogram), sympathetic nervous activity, and bioimpedance in the lower body. On the other hand, the QP group showed alleviated depression and an increased bioimpedance phase angle in the upper body. In conclusion, both active walking and Qigong in the forest were shown to have distinctive neuropsychological and electrophysiological benefits, and both had beneficial effects in terms of preventing dementia and relieving related health problems for elderly individuals.

Declining Trends of Heart Rate Variability According to Aging in Healthy Asian Adults.

Heart rate variability (HRV) indices correlate with aging and are related to the autonomic nervous system. However, the trend of HRV with age has not been explored for the Asian population. Therefore, we proposed a linear regression model of HRV indices that decreased with aging in healthy Asian adults. HRV parameters [High frequency (HF), Low frequency (LF), Very low frequency (VLF), Total power (TP), HRV triangular index (HRV-index), Standard deviation of the normal-to-normal interval (SDNN), and Proportion of normal-to-normal intervals greater than 50 ms (pNN50)] were measured in a total of 300 healthy participants (150 men and 150 women) aged 19-69 years stratified into five age groups: 19-29, 30-39, 40-49, 50-59, and 60-69 years comprising 60 people each in Seoul, South Korea. A simple regression analysis was performed to reveal the linear declining trend of HRV indices with age. Independent t-tests were conducted to investigate the gender differences in HRV values depending on each age group. The values of all HRV indices showed a decreasing trend with age in healthy Korean adults, as observed in the Western population (P < 0.001 for all indices); HF (Y = -0.039x + 6.833, R 2 = 0.287), LF (Y = -0.047x + 7.197, R 2 = 0.414), VLF (Y = -0.025x + 6.861, R 2 = 0.177), TP (Y = -0.034x + 8.082, R 2 = 0.352), HRV-index (Y = -0.125x + 15.628, R 2 = 0.298), SDNN (Y = -0.502x + 53.907, R 2 = 0.343), and pNN50 (Y = -0.650x + 53.852, R 2 = 0.345) all decreased with age. There was no significant gender difference in any HRV parameter. A linear regression model of various HRV indices has been presented considering the age of healthy Asians, which may be useful to prevent diseases related to the autonomic nervous system by estimating or tracking autonomic functional degeneration in the Asian population.

Assessing the Retest Reliability of Prefrontal EEG Markers of Brain Rhythm Slowing in the Eyes-Closed Resting State.

Objective. We examined whether prefrontal lobe EEG markers of slower brain rhythms, which are correlated with functional brain aging, can reliably reflect those of other brain lobes, as measured by a multichannel device. Methods. EEG measurements were taken of 112 healthy individuals aged 20 to 69 years in the eyes-closed resting state. A 5-minute measurement was taken at 8 regions (Fp1, Fp2, F3, F4, T3, T4, O1, O2). Indices (median frequency [MDF], peak frequency [PF]) that quantitatively reflect the characteristics of EEG slowing, and traditional commonly used spectral indices (absolute powers as delta, theta, alpha, beta, and relative power as alpha-to-theta ratio [ATR]), were extracted from the EEG signals. For these indices, the differences between the prefrontal lobe and other areas were analyzed and the test-retest reproducibility was investigated. Results. The EEG slowing indicators showed high conformity over all brain lobes and stable reproducibility. On the other hand, the typical EEG spectral indicators delta, theta, alpha, beta, and ATR differed between brain regions. Conclusion. It was found that EEG slowing markers, which were used for assessing the aging or degeneration of brain functions, could be reliably extracted from a prefrontal EEG alone. Significance. These findings suggest that EEG prefrontal markers may reflect markers of other brain regions when a multi-channel device is used. Thus, this method may constitute a low-cost, wearable, wireless, easily accessible, and noninvasive tool for neurological assessment that could be used in the early detection of cognitive decline and in the prevention of dementia.

Negative effect of methyl bromide fumigation work on the central nervous system.

Methyl bromide (MB) is a fumigant that has been widely used for killing pests on plants in trade, soils, and structures worldwide due to its excellent permeability and insecticidal effect; however, MB should be replaced because it is an ozone-depleting substance. It is well-known that MB is highly toxic and hazardous to workers, but the effects of exposure in asymptomatic workers have not been explored. The purpose of this study is to investigate the impact of MB fumigation on the health of fumigators at a sensitive level. The electroencephalogram (EEG) and urinary bromide ion levels of 44 fumigators (the study group) and 20 inspectors (the control) were measured before and after fumigation work from February to August 2019 in Busan, Korea. The mean post-work concentration of bromide ion (18.311 µg/mg CRE) in the fumigators was significantly increased from the pre-work level (7.390 µg/mg CRE) (P<0.001). The fumigator post-work median frequencies (MDF) and alpha-to-theta ratios (ATR) of EEG index were significantly decreased compared to the pre-work values (P<0.05 for all indices). In contrast, there were no significant differences in inspector EEG indices and urinary bromide ion. The urinary bromide ion levels in all the subjects were negatively correlated with MDF (P = 0.032). In conclusion, fumigators' EEG indices and urinary bromide ion suggested that occupational exposure to MB negatively affected the health of workers, although the workers were asymptomatic.

ERK Regulates NeuroD1-mediated Neurite Outgrowth via Proteasomal Degradation.

Neurogenic differentiation 1 (NeuroD1) is a class B basic helix-loop-helix (bHLH) transcription factor and regulates differentiation and survival of neuronal and endocrine cells by means of several protein kinases, including extracellular signal-regulated kinase (ERK). However, the effect of phosphorylation on the functions of NeuroD1 by ERK has sparked controversy based on context-dependent differences across diverse species and cell types. Here, we evidenced that ERK-dependent phosphorylation controlled the stability of NeuroD1 and consequently, regulated proneural activity in neuronal cells. A null mutation at the ERK-dependent phosphorylation site, S274A, increased the half-life of NeuroD1 by blocking its ubiquitin-dependent proteasomal degradation. The S274A mutation did not interfere with either the nuclear translocation of NeuroD1 or its heterodimerization with E47, its ubiquitous partner and class A bHLH transcription factor. However, the S274A mutant increased transactivation of the E-box-mediated gene and neurite outgrowth in F11 neuroblastoma cells, compared to the wild-type NeuroD1. Transcriptome and Gene Ontology enrichment analyses indicated that genes involved in axonogenesis and dendrite development were downregulated in NeuroD1 knockout (KO) mice. Overexpression of the S274A mutant salvaged neurite outgrowth in NeuroD1-deficient mice, whereas neurite outgrowth was minimal with S274D, a phosphomimicking mutant. Our data indicated that a longer protein half-life enhanced the overall activity of NeuroD1 in stimulating downstream genes and neuronal differentiation. We propose that blocking ubiquitin-dependent proteasomal degradation may serve as a strategy to promote neuronal activity by stimulating the expression of neuron-specific genes in differentiating neurons.