Imbalance in Glucose Metabolism Regulates the Transition of Microglia from Homeostasis to Disease-Associated Microglia Stage 1.

Microglia undergo two-stage activation in neurodegenerative diseases, known as disease-associated microglia (DAM). TREM2 mediates the DAM2 stage transition, but what regulates the first DAM1 stage transition is unknown. We report that glucose dyshomeostasis inhibits DAM1 activation and PKM2 plays a role. As in tumors, PKM2 was aberrantly elevated in both male and female human AD brains, but unlike in tumors, it is expressed as active tetramers, as well as among TREM2+ microglia surrounding plaques in 5XFAD male and female mice. snRNAseq analyses of microglia without Pkm2 in 5XFAD mice revealed significant increases in DAM1 markers in a distinct metabolic cluster, which is enriched in genes for glucose metabolism, DAM1, and AD risk. 5XFAD mice incidentally exhibited a significant reduction in amyloid pathology without microglial Pkm2 Surprisingly, microglia in 5XFAD without Pkm2 exhibited increases in glycolysis and spare respiratory capacity, which correlated with restoration of mitochondrial cristae alterations. In addition, in situ spatial metabolomics of plaque-bearing microglia revealed an increase in respiratory activity. These results together suggest that it is not only glycolytic but also respiratory inputs that are critical to the development of DAM signatures in 5XFAD mice.

Mouse models of Slc35a2 brain mosaicism reveal mechanisms of mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy.

OBJECTIVE: Brain somatic variants in SLC35A2 were recently identified as a genetic marker for mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). The role of SLC35A2 in cortical development and the contributions of abnormal neurons and oligodendrocytes to seizure activity in MOGHE remain largely unexplored. METHODS: Here, we generated a novel Slc35a2 floxed allele, which we used to develop two Slc35a2 conditional knockout mouse lines targeting (1) the Emx1 dorsal telencephalic lineage (excitatory neurons and glia) and (2) the Olig2 lineage (oligodendrocytes). We examined brain structure, behavior, and seizure activity. RESULTS: Knockout of Slc35a2 from the Emx1 lineage, which targets both cortical neurons and oligodendrocytes, resulted in early lethality and caused abnormal cortical development, increased oligodendroglial cell density, early onset seizures, and developmental delays akin to what is observed in patients with MOGHE. By tracing neuronal development with 5-Ethynyl-2'-deoxyuridine (EdU) birthdating experiments, we found that Slc35a2 deficiency disrupts corticogenesis by delaying radial migration of neurons from the subventricular zone. To discern the contributions of oligodendrocytes to these phenotypes, we knocked out Slc35a2 from the Olig2 lineage. This recapitulated the increased oligodendroglial cell density and resulted in abnormal electroencephalographic activity, but without a clear seizure phenotype, suggesting Slc35a2 deficiency in neurons is required for epileptogenesis. SIGNIFICANCE: This study presents two novel Slc35a2 conditional knockout mouse models and characterizes the effects on brain development, behavior, and epileptogenesis. Together, these results demonstrate a direct causal role for SLC35A2 in MOGHE-like phenotypes, including a critical role in neuronal migration during brain development, and identify neurons as key contributors to SLC35A2-related epileptogenesis.

Detection of brain somatic variation in epilepsy-associated developmental lesions.

OBJECTIVE: Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. METHODS: We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high-depth targeted DNA sequencing. RESULTS: We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen-activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B-raf proto-oncogene, serine/threonine kinase [BRAF], and KRAS proto-oncogene, GTPase [KRAS]) was associated with low-grade epilepsy-associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes not yet associated with focal cortical dysplasia. SIGNIFICANCE: These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

SynGAP is expressed in the murine suprachiasmatic nucleus and regulates circadian-gated locomotor activity and light-entrainment capacity.

The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master circadian clock. The phasing of the SCN oscillator is locked to the daily solar cycle, and an intracellular signaling cassette from the small GTPase Ras to the p44/42 mitogen-activated protein kinase (ERK/MAPK) pathway is central to this entrainment process. Here, we analyzed the expression and function of SynGAP-a GTPase-activating protein that serves as a negative regulator of Ras signaling-within the murine SCN. Using a combination of immunohistochemical and Western blotting approaches, we show that SynGAP is broadly expressed throughout the SCN. In addition, temporal profiling assays revealed that SynGAP expression is regulated over the circadian cycle, with peak expression occurring during the circadian night. Further, time-of-day-gated expression of SynGAP was not observed in clock arrhythmic BMAL1 null mice, indicating that the daily oscillation in SynGAP is driven by the inherent circadian timing mechanism. We also show that SynGAP phosphorylation at serine 1138-an event that has been found to modulate its functional efficacy-is regulated by clock time and is responsive to photic input. Finally, circadian phenotypic analysis of Syngap1 heterozygous mice revealed enhanced locomotor activity, increased sensitivity to light-evoked clock entrainment, and elevated levels of light-evoked MAPK activity, which is consistent with the role of SynGAP as a negative regulator of MAPK signaling. These findings reveal that SynGAP functions as a modulator of SCN clock entrainment, an effect that may contribute to sleep and circadian abnormalities observed in patients with SYNGAP1 gene mutations.

An Online SBAS Service to Improve Drone Navigation Performance in High-Elevation Masked Areas.

Owing to the high demand for drone operation in high-elevation masked areas, it is necessary to develop a more effective method of transmitting and applying Satellite-Based Augmentation System (SBAS) messages for drones. This study proposes an onboard module including correction conversion, integrity information calculation, and fast initialization requests, which can enable the application of an online SBAS to drone operation. The proposed system not only improves the position accuracy with timely and proper protection levels in an open sky, but also reduces the initialization time from 70-100 s to 1 s, enabling a drone of short endurance to perform its mission successfully. In SBAS signal-denied cases, the position accuracy was improved by 40% and the uncorrected 13.4 m vertical error was reduced to 5.6 m by applying an SBAS message delivered online. The protection levels calculated with the accurate position regardless of the current location could denote the thrust level and availability of the navigation solution. The proposed system can practically solve the drawbacks of the current SBAS, considering the characteristics of the low-cost receivers on the market. Our proposed system is expected to be a useful and practical solution to integrate drones into the airspace in the near future.

Lack of Retirement Preparation is Associated with Increased Depressive Symptoms in the Elderly: Findings from the Korean Retirement and Income Panel Study.

The aim of this study was to investigate the relationship between retirement preparation and depressive symptoms among Koreans 50 years of age or older. We used data from the 2009 to 2013 Korean Retirement and Income Panel Study (KReIS), which included data from the 365 baseline participants of 50 years of age or older. Our sample included only newly retired participants who worked in 2009, but had retired in the 2011 and 2013. To monitor the change in depressive symptoms according to retirement preparation, we used repeated measurement data. We measured depressive symptoms using the Center for Epidemiological Studies Depression (CES-D) 20-item scale. In addition, we measured retirement preparation using a single self-report question asking whether the participant was financially ready for retirement. We evaluated relationship between retirement preparation and depressive symptoms after multivariable adjustment. Compared to subjects who had prepared for retirement (reference group), participants who had not prepared for retirement had increased depression scores (ß = 2.49, P < 0.001). In addition, individuals who had not prepared for retirement and who had low household income had the highest increase in depression scores (ß = 4.43, P < 0.001). Individuals, who had not prepared for retirement and without a national pension showed a considerable increase in depression scores (ß = 3.02, P < 0.001). It is suggested that guaranteed retirement preparation is especially important for mental health of retired elderly individuals with low economic strata.

In situ non-aqueous nucleation and growth of next generation rare-earth-free permanent magnets.

Using a controllable wet chemical approach, the polyol process, we developed a cobalt carbide nanomagnet consisting of an assembly of Co2C and Co3C nanoparticles as an alternative to rare earth permanent magnets (PMs). The thermodynamically stable mixed phase cobalt carbide nanoparticles are shown to be acicular in morphology. Their exchange-coupled magnetic interaction possessing high maximum energy product of 20.7 kJ m(-3) and room temperature coercivity (2.9 kOe) has been confirmed through vibrating sample magnetometer (VSM) and first order reversal curves (FORCs). These metastable carbide nanoparticles offer improved magnetic properties compared to their pure bulk form. An understanding of the formation mechanism, using in situ time-resolved X-ray spectroscopy (TR-XAS), and the correlation between phase contributions to the properties are described in detail. Our strategy presents a controllable route to preparing the cobalt carbide nanomagnets, which could be potentially useful in permanent magnet clean energy applications. Additionally, the in situ apparatus offers a promising way to directly explore the effects of reaction variables for high-temperature wet chemical reactions.

Somatic Mosaicism in Brain Disorders.

Research efforts over the past decade have defined the genetic landscape of somatic variation in the brain. Neurons accumulate somatic mutations from development through aging with potentially profound functional consequences. Recent studies have revealed the contribution of somatic mosaicism to various brain disorders including focal epilepsy, neuropsychiatric disease, and neurodegeneration. One notable finding is that the effect of somatic mosaicism on clinical outcomes can vary depending on contextual factors, such as the developmental origin of a variant or the number and type of cells affected. In this review, we highlight current knowledge regarding the role of somatic mosaicism in brain disorders and how biological context can mediate phenotypes. First, we identify the origins of brain somatic variation throughout the lifespan of an individual. Second, we explore recent discoveries that suggest somatic mosaicism contributes to various brain disorders. Finally, we discuss neuropathological associations of brain mosaicism in different biological contexts and potential clinical utility.

Loss of Slc35a2 alters development of the mouse cerebral cortex.

Brain somatic variants in SLC35A2, an intracellular UDP-galactose transporter, are commonly identified mutations associated with drug-resistant neocortical epilepsy and developmental brain malformations, including focal cortical dysplasia type I and mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). However, the causal effects of altered SLC35A2 function on cortical development remain untested. We hypothesized that focal Slc35a2 knockout (KO) or knockdown (KD) in the developing mouse cortex would disrupt cortical development and change network excitability. Through two independent studies, we used in utero electroporation (IUE) to introduce CRISPR/Cas9/targeted guide RNAs or short-hairpin RNAs into the embryonic mouse brain at day 14.5-15.5 to achieve Slc35a2 KO or KD, respectively, from neural precursor cells. Slc35a2 KO or KD caused disrupted radial migration of electroporated neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter. Slc35a2 KO in neurons did not induce changes in oligodendrocyte number, importantly suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects of Slc35a2 mutations. Adult KO mice were implanted with EEG electrodes for 72-hour continuous recording. Spontaneous seizures were not observed in focal Slc35a2 KO mice, but there was reduced seizure threshold following pentylenetetrazol injection. Here we demonstrate that focal Slc35a2 KO or KD in vivo disrupts corticogenesis through altered neuronal migration and that KO leads to reduced seizure threshold. Together these results demonstrate a direct causal role for SLC35A2 in cortical development.

Long interspersed nuclear elements safeguard neural progenitors from precocious differentiation.

Long interspersed nuclear element-1 (L1 or LINE-1) is a highly abundant mobile genetic element in both humans and mice, comprising almost 20% of each genome. L1s are silenced by several mechanisms, as their uncontrolled expression has the potential to induce genomic instability. However, L1s are paradoxically expressed at high levels in differentiating neural progenitor cells. Using in vitro and in vivo techniques to modulate L1 expression, we report that L1s play a critical role in both human and mouse brain development by regulating the rate of neural differentiation in a reverse-transcription-independent manner.

Ribosomal S6 Kinase Regulates the Timing and Entrainment of the Mammalian Circadian Clock Located in the Suprachiasmatic Nucleus.

Previous work in the suprachiasmatic nucleus (SCN), the locus of the principal circadian clock, has shown that the activation state of the ERK/MAPK effector p90 ribosomal S6 kinase (RSK) is responsive to photic stimulation and is modulated across the circadian cycle. These data raise the prospect that RSK signaling contributes to both SCN clock timing and entrainment. Here, we found marked expression of the three main RSK isoforms (RSK1/2/3) within the SCN of C57/Bl6 mice. Further, using a combination of immunolabeling and proximity ligation assays, we show that photic stimulation led to the dissociation of RSK from ERK and the translocation of RSK from the cytoplasm to the nucleus. To test for RSK functionality following light treatment, animals received an intraventricular infusion of the selective RSK inhibitor, SL0101, 30 min prior to light (100 lux) exposure during the early circadian night (circadian time 15). Notably, the disruption of RSK signaling led to a significant reduction (∼45 min) in the phase delaying effects of light, relative to vehicle-infused mice. To test the potential contribution of RSK signaling to SCN pacemaker activity, slice cultures from a per1-Venus circadian reporter mouse line were chronically treated with SL0101. Suppression of RSK signaling led to a significant lengthening of the circadian period (∼40 min), relative to vehicle-treated slices. Together, these data reveal that RSK functions as a signaling intermediate that regulates light-evoked clock entrainment and the inherent time keeping properties of the SCN.

Loss of Slc35a2 alters development of the mouse cerebral cortex.

Brain somatic variants in SLC35A2 are associated with clinically drug-resistant epilepsy and developmental brain malformations, including mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). SLC35A2 encodes a uridine diphosphate galactose translocator that is essential for protein glycosylation; however, the neurodevelopmental mechanisms by which SLC35A2 disruption leads to clinical and histopathological features remain unspecified. We hypothesized that focal knockout (KO) or knockdown (KD) of Slc35a2 in the developing mouse cortex would disrupt cerebral cortical development through altered neuronal migration and cause changes in network excitability. We used in utero electroporation (IUE) to introduce CRISPR/Cas9 and targeted guide RNAs or short-hairpin RNAs to achieve Slc35a2 KO or KD, respectively, during early corticogenesis. Following Slc35a2 KO or KD, we observed disrupted radial migration of transfected neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter. Slc35a2 KO in neurons did not induce changes in oligodendrocyte number, suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects. Spontaneous seizures were not observed, but intracranial EEG recordings after focal KO showed a reduced seizure threshold following pentylenetetrazol injection. These results demonstrate that Slc35a2 KO or KD in vivo disrupts corticogenesis through altered neuronal migration.

Updated general exposure factors for risk assessment in the Korean population.

BACKGROUND: There has been an increasing need to update the recommended values of Korean exposure factors for adults aged 19 and older, as using exposure factors developed over a decade ago could reduce risk assessment reliability. OBJECTIVE: Exposure factor data have been compiled and standardized using the latest national statistical reports and academic literature, as well as studies conducted from 2016 to 2018. METHODS: The updated data contained anthropometric parameters, inhalation rates, food and drinking water ingestion rates, and time-activity patterns and provided technical information on Koreans' exposure factors classified by sex, age group, per capita and general population, and doer-only for various exposure assessments. RESULTS: Although the average life expectancy, body weight, body surface area, and inhalation rate increased slightly compared to the 2007 Korean Exposure Factor Handbook, differences various in food consumption were remarkable. Because of Asians' similar food preferences, the intake rate of grain products and vegetables in Koreans, Chinese, and Japanese contributed much toward total intake. Koreans spent half their times outdoors compared to Americans and Chinese. SIGNIFICANCE: This study provided the currently updated exposure factor information for Koreans and could be compared with recommendations provided by exposure factor resources in various countries. IMPACT STATEMENT: Exposure to environmental pollutants may significantly vary depending on the exposure factors related to human behaviors and characteristics. Therefore the exposure factors need to be continuously updated along with more extensive survey areas and improved measurement methods. We utilized the existing data with the aim to develop general exposure factors for risk assessment in Korean aged ≥19 years. Measurements and questionnaire surveys were also performed if there were no existing data. This study provided the currently updated exposure factor information for Koreans and could be compared to those of other countries.

Comparison of the exposure assessment of di(2-ethylhexyl) phthalate between the PBPK model-based reverse dosimetry and scenario-based analysis: A Korean general population study.

Di (2-ethylhexyl) phthalate (DEHP), classified as a reproductive toxicant, is a ubiquitous pollutant in foodstuffs, dust, and commercial products. In this study, to provide a useful cross-check on the accuracy of the exposure assessment, the estimated daily intake of DEHP was compared using reverse dosimetry with a physiologically-based pharmacokinetic (PBPK) model and a scenario-based probabilistic estimation model for six subpopulations in Korea. For reverse dosimetry analysis, the concentrations of urinary DEHP metabolites, namely mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono (2-ethyl-5-oxohexyl)phthalate (MEOHP), from three human biomonitoring program datasets were used. For the scenario-based model, we evaluated the various exposure sources of DEHP, including diet, air, indoor dust, soil, and personal care products (PCPs), and also determined its levels based on the literature review and measurements of indoor dust. The DEHP exposure doses using both exposure assessment approaches were similar in all cases, except for the 95th percentile exposure doses in toddlers (1-2 years) and young children (3-6 years). The PBPK-reverse dosimetry estimated daily intakes at the 95th percentile ranged between 22.53 and 29.90 µg/kg/day for toddlers and young children. These exceeded the reference dose (RfD) of 20 µg/kg bw/day of the US Environmental Protection Agency (EPA) based on the increased relative liver weight. Although, food was considered the primary source of DEHP, contributing to a total exposure of 50.8-75.1%, the effect of exposure to indoor dust should not be overlooked. The occurrence of high levels of DEHP in indoor dust collected from Korean homes suggests the use of a wide variety of consumer products containing DEHP. Furthermore, more attention should be paid to the high exposure levels of DEHP, especially in young children. Therefore, it is necessary to perform continuous monitoring of the indoor dust, consumer products, and the body burden of children.

Development of General Exposure Factors for Risk Assessment in Korean Children.

There has been an increasing need for the risk assessment of external environmental hazards in children because they are more sensitive to hazardous chemical exposure than adults. Therefore, the development of general exposure factors is required for appropriate risk assessment in Korean children. This study aimed to determine the general exposure factors among Korean children aged ≤18 years. We developed the recommended exposure factors across five categories: physiological variables, inhalation rates, food and drinking water intake, time-activity patterns, and soil and dust ingestion. National databases were used, and direct measurements and questionnaire surveys of representative samples were performed to calculate the inhalation rate, water intake, and soil ingestion rate. With regard to the time-activity patterns, the daily inhalation rates ranged from 9.49 m3/day for children aged 0-2 years to 14.98 m3/day for those aged 16-18 years. This study found that Korean children spent an average of 22.64 h indoors, 0.63 h outdoors, and 0.73 h in-transit on weekdays. The general exposure factors of Korean children were studied for the first time, and these results could be used to assess children's exposure and risk. They also suggest the differences compared with the results of international results.

Behavioral characteristics to airborne particles generated from commercial spray products.

Commercial spray products are commonly used in daily life and airborne particles generated by these products may cause adverse health effects. Our study was aimed to characterize the behaviors of airborne particles from spray products and to determine the deposition loss rate. Four categories of spray products with highly frequent use - air fresheners, fabric deodorants, window cleaners, and a bathroom cleaner - were selected for the study. The products were applied in a cleanroom according to the instructions for use. Airborne particles (10-10,000 nm) were measured within the breathing zone of a user with a scanning mobility particle sizer and an optical particle spectrometer. Additionally, filter sampling was performed to examine the morphological characteristics of the particles using a field emission-scanning electron microscope (FE-SEM). The initial concentration and particle size distribution varied among different spray types and products. Two propellant-type air fresheners that we tested showed a high initial concentration of smaller sized particles. However, one of these and all hand-pressure type propellants showed a low initial concentration in all size ranges. We observed that particles in nucleation mode (10-31.6 nm) decreased and aggregated particles shifted to accumulation mode (100-1,000 nm) over time. The FS-SEM analysis confirmed the aggregation of nano-sized particles for all products. The deposition loss rates of various particle sizes depended on the initial concentration and distribution of particle sizes. For two air fresheners with high initial concentrations, the loss rate of small-sized particles was higher than that of the other products whereas the particle loss rate of large-sized particles was higher, regardless of initial concentration. The results of this study can give us useful information in the behaviors of airborne particles in the consumer spray products and resulting exposure assessment especially in the application to the exposure modeling of spray products.

Hovenia dulcis Extract Attenuates High-Fat Diet-Induced Hepatic Lipid Accumulation and Hypertriglyceridemia in C57BL/6 Mice.

The effects of dietary supplementation with aqueous Hovenia dulcis Thunb. extract (HDE) (20 weeks) on high-fat diet (HFD)-induced nonalcoholic fatty liver disease and dyslipidemia were evaluated in mice. Supplementation with 200 and 800 mg/kg feed HDE (HDE200 and HDE800, respectively) resulted in no significant difference in growth in the HFD-fed groups. The triglyceride (TG) levels and free fatty acids were significantly decreased, whereas high-density lipoprotein cholesterol was increased in the HDE800 group (P < .05). The hepatic intracellular TGs were significantly decreased in the HDE-fed groups and lipogenic enzymes (acetyl CoA carboxylase, fatty acid synthase, stearoyl CoA desaturase, and diacylglycerol transferase) in the liver were significantly downregulated by HDE supplementation (P < .05). The diminished serum antioxidant enzyme activities in the HFD group were effectively restored by HDE supplementation, which also contributed to the attenuation of hyperlipidemia.

Health risk assessment of dermal and inhalation exposure to deodorants in Korea.

In Korea, humidifiers that include biocidal ingredients have caused serious lung injuries and deaths. After these incidents, public concern regarding the use of chemicals in products (i.e., chemical phobia) increased. Frequent health risk assessments and stringent management of consumer products are, therefore, of paramount importance to reduce these serious occurrences. In this study, the irritative and respiratory health effects of deodorants were assessed in relation to dermal and inhalation exposure. In total, 64 deodorants were divided into 5 groups by application type, and health risk assessments were conducted on each group. In total, 26 fragrance ingredients and 27 biocidal ingredients were analyzed and assessed according to their risk to human health. Exposure assessment was performed in two steps. In the tiered 1 assessment (screening), the 95th exposure factor values were used to estimate exposure to assume the worst-case scenario. The maximum concentration in the deodorants was used without considering the application type. In the tiered 2 assessment (detail assessment), the 75th exposure factor values were used to estimate the assumed reasonable exposure to ingredients. In these assessments, the maximum concentration used in the exposure models was determined by the product purpose and application type. The values input into the exposure algorithms were developed via the exposure route. Of the selected fragrance and biocidal active ingredients, 18 fragrance and 13 biocidal ingredients were detected in the deodorants that were assessed. From the results of the tiered 1 assessment, it was necessary for tiered 2 risk assessments to be conducted for 6 ingredients for the inhalation route, and 13 ingredients for the dermal route. The inhalation margin of exposure of ingredients in deodorants of gel/trigger/spray types for home/car and fabric/air usage was above the target margin of exposure. The health risk of 6 evaluated ingredients was relatively low for the inhalation route of exposure. This study showed that the assessed ingredients have no health risks at their maximum concentrations in deodorants. The approach discussed in this study should be used to establish improved guidelines for specific ingredients in consumer products, and for setting limits for newly developed raw materials that may pose dermal and inhalation hazard.

The Phosphorylation of CREB at Serine 133 Is a Key Event for Circadian Clock Timing and Entrainment in the Suprachiasmatic Nucleus.

Within the suprachiasmatic nucleus (SCN)-the locus of the master circadian clock- transcriptional regulation via the CREB/CRE pathway is implicated in the functioning of the molecular clock timing process, and is a key conduit through which photic input entrains the oscillator. One event driving CRE-mediated transcription is the phosphorylation of CREB at serine 133 (Ser133). Indeed, numerous reporter gene assays have shown that an alanine point mutation in Ser133 reduces CREB-mediated transcription. Here, we sought to examine the contribution of Ser133 phosphorylation to the functional role of CREB in SCN clock physiology in vivo. To this end, we used a CREB knock-in mouse strain, in which Ser133 was mutated to alanine (S/A CREB). Under a standard 12 h light-dark cycle, S/A CREB mice exhibited a marked alteration in clock-regulated wheel running activity. Relative to WT mice, S/A CREB mice had highly fragmented bouts of locomotor activity during the night phase, elevated daytime activity, and a delayed phase angle of entrainment. Further, under free-running conditions, S/A CREB mice had a significantly longer tau than WT mice and reduced activity amplitude. In S/A CREB mice, light-evoked clock entrainment, using both Aschoff type 1 and 6 h "jet lag" paradigms, was markedly reduced relative to WT mice. S/A CREB mice exhibited attenuated transcriptional drive, as assessed by examining both clock-gated and light-evoked gene expression. Finally, SCN slice culture imaging detected a marked disruption in cellular clock phase synchrony following a phase-resetting stimulus in S/A CREB mice. Together, these data indicate that signaling through CREB phosphorylation at Ser133 is critical for the functional fidelity of both SCN timing and entrainment.

Determining Exposure Factors of Anti-Fogging, Dye, Disinfectant, Repellent, and Preservative Products in Korea.

Reliable exposure factors are essential to determine health risks posed by chemicals in consumer products. We analyzed five risk-concerned product categories (anti-fogging, dye, disinfectant, repellent, and preservative products) for 13 products (three car anti-fogging products, a lens anti-fogging product, two car dye products, two drain disinfectants, an air conditioner disinfectant, a chlorine-based disinfectant, a fabric repellent, an insect repellent for food, and a wood preservative) considered to be of high risk in order to determine exposure factors via web surveys and estimation of amount of product. Among the 3000 participants (1482 (49%) men) aged ≥19 years, drain disinfectants were used most frequently (38.2%); the rate of usage of the other products ranged between 1.1-24.0%. The usage rates for the consumer products differed by sex, age, income, and education. Some consumer products such as car and lens anti-fogging products, chlorine-based disinfectants, fabric repellents, and drain disinfectants were regularly used more than once a month, while car dye products, air conditioner disinfectants, insect repellents for food, and wood preservatives were not regularly used owing to the specific product purposes and seasonal needs. Our results could be used for managing or controlling chemical substances in consumer products and conducting accurate exposure assessments.