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Primary intraocular lymphoma is a lymphoma that occurs in the eye, and is a subtype of primary central nervous system lymphoma that occurs in the brain, spinal cord, and meninges. It is composed of diffuse large B cell type. The pathophysiology and cause are not known exactly, and future research is needed. However, viral infection is thought to be the cause in immunocompromised patients. Diagnostic methods include fluorescein angiography, retinal tomography, and ocular magnetic resonance imaging. The main diagnostic method is cytopathology, but due to its false-negative rates the interleukin (IL)-10 cytokine, known as a growth factor for malignant B-lymphocytes in primary intraocular lymphoma, can be helpful in diagnosis. In the case of primary intraocular lymphoma, intravitreal methotrexate injection can be performed. Ratio of IL-10/IL-6 is greater than 1 before treatment and decreases to less than 1 after treatment. Although the prognosis is poor, it is expected to increase the survival rate through research on diagnostic methods and intraocular injection treatment combined with systemic chemotherapy and radiation therapy.

The implementation of an energy storage system (ESS) as a container-type package is common due to its ease of installation, management, and safety. The control of the operating environment of an ESS mainly considers the temperature rise due to the heat generated through the battery operation. However, the relative humidity of the container often increases by over 75% in many cases because of the operation of the air conditioner which pursues temperature-first control. Humidity is a major factor which can cause safety issues such as fires owing to insulation breakdown caused by condensation. However, the importance of humidity control in ESS is underestimated compared to temperature control. In this study, temperature and humidity monitoring and management issues were addressed for a container-type ESS by building sensor-based monitoring and control systems. Furthermore, a rule-based air conditioner control algorithm was proposed for temperature and humidity management. A case study was conducted to compare the conventional and proposed control algorithms and verify the feasibility of the proposed algorithm. The results showed that the proposed algorithm reduced the average humidity by 11.4% compared to the value achieved with the existing temperature control method while also maintaining the temperature.

Purpose: We report a case of spontaneous closure of a carotid-cavernous fistula (CCF) after contrast-enhanced orbit computed tomography (CT).Case summary: A 80-year-old female was referred to our clinic under suspicion of chronic angle- closure glaucoma because of persistently high intraocular pressure commencing one month prior. Slit-lamp examination revealed a conjunctival injection and corkscrew-like vessel dilatation in the left eye, and a high intraocular pressure. Dilated fundus examination revealed central retinal vein occlusion in that eye. Contrast-enhanced orbit CT revealed a dilated, superior ophthalmic vein in the left orbit, and she was transferred to our department of neurosurgery for digital subtraction angiography (DSA); this is the gold standard imaging modality for the diagnosis of direct and indirect CCFs. DSA was performed two weeks after orbit CT; however, no CCF was visible. Thereafter, the conjunctival injection and the elevated intraocular pressure improved gradually over eight months. We suspect that the CCF closed spontaneously.Conclusions: Our case highlights the fact that a CCF can close spontaneously after contrast-enhanced orbit CT; ophthalmologists may wish to bear this in mind.

Purpose: We compared the accuracy of central corneal thickness (CCT) measurements according to CCT measured by noncontact Tono-pachymetry and ultrasound pachymetry (USP). Methods: CCT was measured in 90 eyes of 90 subjects by two optometrists. The CCT measurements were compared and the correlations between the measurements were analyzed. To evaluate whether the measurements varied depending on CCT, the subjects were classified into three groups according to CCT (group 1: thin thickness group; group 2: medium thickness group; and group 3: thick thickness group). The differences in CCT obtained by the two devices (△CCT = Tono-pachymetry-USP) were compared and analyzed among the three groups. Results: The average CCT measurements by Tono-pachymetry and USP were 523.26 ± 32.93 μm and 527.08 ± 37.33 μm, respectively. CCT by Tono-pachymetry was significantly thinner than by USP (△CCT= -3.82 ± 15.34, p = 0.020). The two measurements were strongly correlated (r = 0.912, p < 0.001). The △CCT values were 5.40 ± 12.13 μm in group 1, -6.37 ± 15.07 μm in group 2, and -10.50 ± 14.39 μm in group 3 (p < 0.001). Conclusions: CCT measured by tono-pachymetry was thinner on average compared to the value measured by USP and the differences in measurements between the two devices were different according to CCT. The thinner the CCT, the thicker the measurement, and the thicker the CCT, the thinner the measurement. Therefore, this trend should be considered when interpreting tono- pachymetry results in clinical practice.

Background Neuroinflammation plays an important role in cognitive decline and memory impairment in neurodegenerative disorders. Previously, we demonstrated that Humulus japonicus (HJ) has anti-inflammatory effects in rodent models of Alzheimer’s disease and Parkinson’s disease. The present study aimed to examine the protective potential of HJ extracts against lipopolysaccharide (LPS)-induced cognitive impairment and scopolamine-induced amnesia in mouse models. Cognitive improvement of mice was investigated by novel object recognition test. For analyzing effects on neuroinflammation, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed. Results We found that the oral administration of HJ significantly improved cognitive dysfunction induced by LPS in a novel object recognition test. The LPS-induced activation of microglia was notably decreased by HJ treatment in the cortex and hippocampus. HJ administration with LPS also significantly increased the mRNA expression of interleukin (IL)-10 and decreased the mRNA expression of IL-12 in the parietal cortex of mice. The increased expression of LPS-induced complement C1q B chain (C1bq) and triggering receptor expressed on myeloid cells 2 (Trem2) genes was significantly suppressed by HJ treatment. In addition, HJ administration significantly improved novel object recognition in a scopolamine-induced amnesia mouse model. Conclusions These findings revealed that HJ has a beneficial effect on cognitive impairment and neuroinflammation induced by systemic inflammation and on amnesia induced by scopolamine in mice.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation and presence of amyloid plaques (Aβ), tangles, dementia, and cognitive impairment. Currently, there is no known cure for AD; however, recently, the association between alteration of the gut microbiota and AD pathology has been explored to find novel therapeutic approaches. Microbiota-targeted intervention has been suggested as an attractive therapeutic approach for AD. Agathobaculum butyriciproducens (SR79) is a strict anaerobic and butyric acid-producing bacteria. We hypothesized that administration of SR79 might have a beneficial effect on cognitive deficits and AD pathologies. To determine the therapeutic effects of SR79 on AD pathologies, APP/PS1 transgenic and lipopolysaccharide -induced cognitive impairment mouse models were used. In the lipopolysaccharide -induced cognitive deficit model, the administration of SR79 improved cognitive function and decreased microglia activation. In addition, the administration of SR79 to APP/PS1 mice significantly improved novel object recognition and percent alteration results in novel object recognition and Y-maze alteration tests. Furthermore, Aβ plaque deposition and microglial activation were markedly reduced in the parietal cortex and hippocampus after SR79 treatment in APP/PS1 mice. SR79 treatment significantly decreased gene expression levels of IL-1β and C1QB and increased the gene expression levels of IGF-1 and thereby the downstream signaling pathway in the cortex of APP/PS1 mice. In conclusion, SR79 administration improved cognitive function and AD pathologies through the regulation of neuroinflammation and IGF-1 signaling in an animal model.

AIMS/INTRODUCTION The purpose of this study was to investigate the impact of vision and hearing impairments on the risk of adverse cardiovascular outcomes and mortality in patients with type 2 diabetes using a nationwide longitudinal cohort. MATERIALS AND METHODS We enrolled 771,128 patients with type 2 diabetes who underwent the National Health Screening Program in 2009. We carried out Cox proportional hazards regression analyses to calculate the hazard ratios (HR) of myocardial infarction (MI), stroke, and mortality in those with or without vision and hearing impairments. Subgroup analyses of patients stratified by age, sex and diabetic retinopathy were carried out. RESULTS Diabetes patients with either vision or hearing impairment showed higher risk of MI, stroke or death compared with those without. Among the combinations of impairments, patients with both vision and hearing impairments had the highest risk for MI (adjusted HR [aHR] 1.362, 95% confidence interval [CI] 1.252-1.481) and mortality (aHR 1.591, 95% CI 1.532-1.651). Those with only vision impairment showed higher risk of MI (aHR 1.324, 95% CI 1.275-1.375 and aHR 1.117, 95% CI 1.066-1.170, respectively), stroke (aHR 1.318, 95% CI 1.276-1.362 and aHR 1.134 95% CI 1.089-1.180, respectively) and mortality (aHR 1.417, 95% CI 1.390-1.446 and aHR 1.163, 95% CI 1.135-1.191, respectively) compared with those with only hearing impairment. CONCLUSIONS Vision and hearing impairments are independently important risk factors for adverse cardiovascular events and mortality in patients with type 2 diabetes. Vision and hearing impairments synergistically increased the risk of MI and all-cause deaths, but not stroke. In addition, in patients aged

Sub-micron pixels have been widely adopted in recent CMOS image sensors to implement high resolution cameras in small form factors, i.e. slim mobile-phones. Even with shrinking pixels, customers demand higher image quality, and the pixel performance must remain comparable to that of the previous generations. Conventionally, to suppress the optical crosstalk between pixels, a metal grid has been used as an isolation structure between adjacent color filters. However, as the pixel size continues to shrink to the sub-micron regime, an optical loss increases because the focal spot size of the pixel’s microlens does not downscale accordingly with the decreasing pixel size due to the diffraction limit: the light absorption inevitably occurs in the metal grid. For the first time, we have demonstrated a new lossless, dielectric-only grid scheme. The result shows 29 % increase in sensitivity and +1.2-dB enhancement in Y-SNR when compared to the previous hybrid metal-and-dielectric grid.

Sustainable development principles are being increasingly incorporated into university planning and design education. This paper evaluates how university planning and design programs teach sustainability and how these various approaches may influence future planners and designers. This systematic review quantitatively analyzes 5639 empirical research documents published from 2011 to 2020, including peer-reviewed papers and reports related to planning and design disciplines in higher education institutions. Key findings include differences in how planning and design curricula include and emphasize sustainability topics, as well as how various modes and teaching approaches correlate with sustainability values. This research offers a comprehensive understanding of how sustainable development approaches and teaching methods may influence how students and emerging professionals approach complex planning and design problems.

Ethylenethiourea (ETU) is one of the main metabolite of ethylenebisdithiocarbamate fungicides and potential exposure is highest for workers involved in rubber and fungicide production. Exposure of ETU induces endocrine disruption, teratogenesis, carcinogenicity, and goitrogenicity. ETU was administrated at concentration of 2 mg/kg/day for 58 weeks in C57BL/6 mice. After 58 weeks, blood samples were analyzed serum lipid profile, hepatic function dices, and plasma levels of creatine and blood urea nitrogen. Isolated kidneys were stained with haematoxylin-eosin. Analysis of miRNA expression profile was conducted on Affymetrix miRNA 4.0 Array. Chronic diet of ETU induced body weight loss, increased serum triglyceride and total cholesterol, increased plasma creatine and blood urea nitrogen, injured glomerulus and nephron tubule, induced severe hydronephrosis and polycystic kidney. ETU diet increased expression levels of the biomarker of renal injury and fibrosis in kidney. miR-17~92 cluster and miR-182-5p associated with cyst progression were increased in expression levels on the kidney. Chronic exposure to ETU at low concentrations results in functional and structural damage to the kidney, and increases cyst formation in the kidney.

Humulus japonicus (HJ) is a traditional herbal medicine that exhibits anti-inflammatory, antimicrobial and anti-tumor effects that is used for the treatment of hypertension, pulmonary disease and leprosy. Recently, it has also been reported that HJ demonstrates neuroprotective properties in animal models of neurodegenerative diseases. The current study hypothesised that the administration of HJ would exhibit therapeutic effects in autism spectrum disorder (ASD), a neurodevelopmental disorder with lifelong consequences. The BTBR T+ Itpr3tf/J mouse model of ASD was used to investigate the anti-autistic like behavioural effects of HJ. Chronic oral administration of the ethanolic extract of HJ significantly increased social interaction, attenuated repetitive grooming behaviour and improved novel-object recognition in BTBR mice. Anti-inflammatory effects of HJ in the brain were analysed using immunohistochemistry and reverse-transcription quantitative PCR analysis. Microglia activation was markedly decreased in the striatum and hippocampus, and pro-inflammatory cytokines, including C-C Motif Chemokine Ligand 2, interleukin (IL)-1β and IL-6, were significantly reduced in the hippocampus following HJ treatment. Moreover, HJ treatment normalised the phosphorylation levels of: N-methyl-D-aspartate receptor subtype 2B and calcium/calmodulin-dependent protein kinase type II subunit α in the hippocampus of BTBR mice. The results of the present study demonstrated that the administration of HJ may have beneficial potential for ameliorating behavioural deficits and neuroinflammation in ASD.

The dopamine precursor 3,4-dihydroxyphenyl- l-alanine (L-DOPA) is the most widely used symptomatic treatment for Parkinson's disease (PD); however, its prolonged use is associated with L-DOPA-induced dyskinesia in more than half of patients after 10 years of treatment. The present study investigated whether co-treatment with β-Lapachone, a natural compound, and L-DOPA has protective effects in a 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. Unilateral 6-OHDA-lesioned mice were treated with vehicle or β-Lapachone (10 mg/kg/day) and L-DOPA for 11 days. Abnormal involuntary movements (AIMs) were scored on days 5 and 10. β-Lapachone (10 mg/kg) co-treatment with L-DOPA decreased the AIMs score on both days 5 and 10. β-Lapachone was demonstrated to have a beneficial effect on the axial and limb AIMs scores on day 10. There was no significant suppression in dopamine D1 receptor-related and ERK1/2 signaling in the DA-denervated striatum by β-Lapachone-cotreatment with L-DOPA. Notably, β-Lapachone-cotreatment with L-DOPA increased phosphorylation at the Ser9 site of glycogen synthase kinase 3β (GSK-3β), indicating suppression of GSK-3β activity in both the unlesioned and 6-OHDA-lesioned striata. In addition, astrocyte activation was markedly suppressed by β-Lapachone-cotreatment with L-DOPA in the striatum and substantia nigra of the unilateral 6-OHDA model. These findings suggest that β-Lapachone cotreatment with L-DOPA therapy may have therapeutic potential for the suppression or management of the development of L-DOPA-induced dyskinesia in patients with PD.

Sirtuin1 (Sirt1) is an unusual target for aging and aging-associated diseases. During the screening for Sirt1 activators from natural compounds, piperlongumine (PL), one of the major constituents of Piper longum, potently activated the deacetylase ability of Sirt1 in vitro. Treatment with PL, which regulated the gene transcription of antioxidant response element in hippocampal neurons, attenuated the cytotoxicity induced by intraneuronal Aβ1-42 expression. The oral administration of PL, at a dose of 50 mg/kg/day for 2.5 months, significantly reduced the occupied area of beta-amyloid in parietal cortex of APP/PS1 mice. Novel object recognition and working memory impairment also markedly improved. Moreover, activated microglia and astrocytes in the cortex notably decreased, indicating the anti-inflammatory activity of PL. Finally, vesicular glutamate transporter 1 significantly increased in the hippocampus of APP/PS1 mice following PL treatment. These results suggested the beneficial effects PL and its therapeutic potential to ameliorate AD-like pathology.

Metformin is a medication that is widely prescribed for the management of type 2 diabetes. In addition to its anti-diabetic uses, metformin has been proposed as a therapeutically effective drug candidate in various central nervous system disorders, including Parkinson's disease (PD). PD is characterized by severe movement defects and is commonly treated with the dopamine (DA) precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA). However, prolonged use of L-DOPA can lead to the development of L-DOPA-induced dyskinesia (LID). Here, we hypothesized that metformin co-treatment would improve LID in the 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Metformin did not interfere the pharmacotherapeutic effects of L-DOPA in the cylinder test. Furthermore, metformin co-treatment with L-DOPA attenuated the development of LID in unilaterally 6-OHDA-lesioned mice. Metformin showed a long-lasting effect on axial, limb, and orofacial abnormal involuntary movement scores for up to 20 days after treatment initiation. Interestingly, persistent enhancement of the mammalian target of rapamycin, dopamine D1 receptor, and extracellular signaling-regulated kinase 1/2 signaling was maintained in the DA-denervated striatum during metformin treatment. Metformin globally normalized the increased glycogen synthase kinase 3β activity induced by chronic treatment of L-DOPA in a manner associated with Akt activation in unilaterally 6-OHDA-lesioned mice. These findings suggest that metformin may have therapeutic potential for the suppression or management of L-DOPA-induced motor complications in patients with PD.

배경 및 목적 : 본 연구의 목적은 말더듬 아동들을 대상으로 통사 복잡성에 따른 문장표현능력에 차이가 있는지 알아보고, 이러한 능력이 비유창성에 어떠한 영향을 미치는지 살펴보고자 하였다. 또한 문장표현능력과 작업기억용량과의 관계에 대해 알아보고자 하였다. 방법: 학령기 말더듬 아동과 일반 아동 총 20명을 대상으로 하였다. 문장표현검사과제는 구문점화와...

Humulus japonicus (HJ), popularly known as Japanese hops, is a traditional herbal medicine widely used for the treatment of pulmonary disease, skin disease, and hypertension in Korea. HJ exerts scavenging effects against reactive oxygen species (ROS), such as superoxide radical, hydroxyl radical, and hydrogen peroxide. Moreover, dysfunction and damage of mitochondria elicited by ROS are of critical importance in the pathogenesis of Parkinson's disease (PD). The present study aimed to examine neuroprotective potential of extracts of HJ using in vitro and in vivo 6-hydroxydopamine (6-OHDA) models. SH-SY5Y cells were cultured to explore the mechanisms for the neuroprotective effect of HJ in vitro. Unilateral 6-OHDA-induced mouse model of PD was established to investigate the neuroprotective effect of HJ on dopaminergic neurons in substantia nigra pars compacta (SNc) and striatum in vivo. Methanol extract of HJ (HJM) significantly attenuated cytotoxicity and the mitochondrial apoptosis pathway caused by 6-OHDA in SH-SY5Y cells. In addition, HJM significantly increased glutathione levels and decreased phosphorylation of ERK1/2 in SH-SY5Y cells exposed to 6-OHDA. In the in vivo study, the administration of methanol or ethanol extract of HJ improved the motor dysfunction and notably reduced dopaminergic cell death and fiber loss in the SNc and striatum caused by 6-OHDA. Our findings demonstrate that HJ may have therapeutic potential to protect dopaminergic neuron degeneration in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms. Despite the remarkable improvements in the management of PD in recent decades, many patients remain significantly disabled. Metformin is a primary medication for the management of type 2 diabetes. We previously showed that co-treatment with metformin and 3,4-dihydroxyphenyl-l-alanine (l-DOPA) prevented the development of l-DOPA-induced dyskinesia in a 6-hydroxydopamine (6-OHDA)-lesioned animal model of PD. However, effects of metformin on PD- and aging-induced genes in reactive astrocytes remain unknown. In this study, we assessed the effect of metformin on motor function, neuroprotection, and reactive astrocytes in the 6-OHDA-induced PD animal model. In addition, the effects of metformin on the genes expressed by specific types of astrocytes were analyzed in PD model and aged mice. Here, we showed that metformin treatment effectively improves the motor symptoms in the 6-OHDA-induced PD mouse model, whereas metformin had no effect on tyrosine hydroxylase-positive neurons. The activation of AMPK and BDNF signaling pathways was induced by metformin treatment on the 6-OHDA-lesioned side of the striatum. Metformin treatment caused astrocytes to alter reactive genes in a PD animal model. Moreover, aging-induced genes in reactive astrocytes were effectively regulated or suppressed by metformin treatment. Taken together, these results suggest that metformin should be evaluated for the treatment of Parkinson's disease and related neurologic disorders characterized by astrocyte activation.

Humulus japonicus Siebold & Zucc. (HJ) has traditionally been administered to patients with pulmonary disease, skin disease and hypertension in Korea, and it is considered to exert anti-inflammatory, antioxidant, antimicrobial and anti-mycobacterial effects. However, its effects against Alzheimer's disease (AD) have yet to be explored. Thus, this study was carried out to investigate whether HJ has a beneficial effect on the progression of AD in an animal model. A methanolic extract of HJ (500 mg/kg/day) was intragastrically administered to 5-month-old APP/PS1 transgenic (Tg-APP/PS1) mice for 2.5 months. Novel object recognition and Y-maze alteration tests were used to assess cognitive function, and an immunohistochemical assay was performed to assess amyloid β (Aβ) deposition, tau phosphorylation and gliosis. An in vitro assay using a microglial cell line was also performed to investigate the anti-inflammatory effects of HJ. Our results revealed that HJ significantly decreased the mRNA and protein expression levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide in the microglial cell line. The administration of HJ for 2 months improved the cognitive function of Tg-APP/PS1 mice. HJ notably reduced the area occupied by Aβ and neurofibrillary tangles, and the number of activated astrocytes and microglia in the cortex of Tg-APP/PS1 mice. The findings of our study suggest that HJ has the therapeutic potential to inhibit the progression of AD and to improve cognitive deterioration in Tg-APP/PS1 mice.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated. To investigate whether PA-5HT relieve LID in PD and decrease hyperactivation of dopamine D1 receptors, we used the 6-hydroxydopomine (6-OHDA)-lesioned mouse model of PD and treated the L-DOPA (20 mg/kg) for 10 days with PA-5HT (0.3 mg/kg/day). The number of wall contacts with the forelimb in the cylinder test was significantly decreased by 6-OHDA lesion in mice and the pharmacotherapeutic effect of L-DOPA was also revealed in PA-5HT-treated mice. Moreover, in AIMs test, PA-5HT-treated mice showed significant reduction of locomotive, axial, limb, and orofacial AIMs score compared to the vehicle-treated mice. LID-induced hyper-phosphorylation of ERK1/2 and overexpression of FosB/ΔFosB was markedly decreased in 6-OHDA-lesioned striatum of PA-5HT-treated mice, indicating that PA-5HT decreased the dopamine D1 receptor-hyperactivation induced by chronic treatment of L-DOPA in dopamine-denervated striatum. These results suggest that PA-5HT effectively attenuates the development of LID and enhance of ERK1/2 phosphorylation and FosB/ΔFosB expression in the hemi-parkinsonian mouse model. PA-5HT may have beneficial effect on the LID in PD.

The dopamine precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA) is currently the most efficacious pharmacotherapy for Parkinson's disease (PD). However, long-term L-DOPA treatment leads to the development of abnormal involuntary movements (AIMs) in patients and animal models of PD. Recently, involvement of growth arrest and DNA damage-inducible 45β (Gadd45β) was reported in neurological and neurobehavioral dysfunctions. However, little is known about the role of Gadd45β in the dopaminergic nigrostriatal pathway or L-DOPA-induced dyskinesia (LID). To address this issue, we prepared an animal model of PD using unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra of Gadd45β(+/+) and Gadd45β(-/-) mice. Dyskinetic symptoms were triggered by repetitive administration of L-DOPA in these 6-OHDA-lesioned mice. Whereas dopamine denervation in the dorsal striatum decreased Gadd45β mRNA, chronic L-DOPA treatment significantly increased Gadd45β mRNA expression in the 6-OHDA-lesioned striatum of wild-type mice. Using unilaterally 6-OHDA-lesioned Gadd45β(+/+) and Gadd45β(-/-) mice, we found that mice lacking Gadd45β exhibited long-lasting increases in AIMs following repeated administration of L-DOPA. By contrast, adeno-associated virus-mediated expression of Gadd45β in the striatum reduced AIMs in Gadd45β knockout mice. The deficiency of Gadd45β in LID increased expression of ΔFosB and c-Fos in the lesioned striatum 90 min after the last administration of L-DOPA following 11days of daily L-DOPA treatments. These data suggest that the increased expression of Gadd45β induced by repeated administration of L-DOPA may be beneficial in patients with PD.

The NAD(P)H:quinone oxidoreductase 1 (NQO1) gene encodes a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones to hydroquinones. A polymorphic form of NQO1 is associated with mood disorders such as schizophrenia. However, the role of NQO1 in dopaminergic system has not yet been elucidated. To determine the role of NQO1 in the dopaminergic system, we investigated pharmaco-behavioral effects of d-amphetamine using NQO1-deficienct mice. According to our comparative study involving NQO1+/+ and NQO1-/- mice, NQO1 deficiency increased d-amphetamine-induced psychomotor activity and psychological dependency compared to wild-type mice. Basal and d-amphetamine-induced dopamine levels were also enhanced by NQO1 deficiency. In NQO1-/- mice, neural activation induced by d-amphetamine was higher in dorsolateral striatum, but not in dorsomedial and ventral striata. Although protein level of CaMKIIα, which is a key player in amphetamine-induced dopamine efflux, was decreased in striata of NQO1-/- mice, phosphorylation of CaMKIIα was markedly enhanced in NQO1-/- mice compared to wild-type mice. Interestingly, experiments with pharmacological antagonist showed that D2 antagonist-induced suppression of locomotion required activation of NQO1. Moreover, the rewarding effect in response to D1 agonist was increased by NQO1 deficiency. These results suggest that striatal NQO1 is of considerable interest to understand the mechanism of dopaminergic regulation of psychiatric disorders.

Purpose To analyze the differences in the vitreous cytokine profiles in epiretinal membrane eyes with and without an ectopic inner foveal layer (EIFL). Methods Sixty eyes with epiretinal membrane (32 eyes without EIFL and 28 eyes with EIFL) were included. The vitreous samples were collected during surgery for epiretinal membrane. The cytokine levels of the vitreous were measured using a multiplex bead analysis. Results The mean logMAR visual acuity was worse (0.42 vs. 0.37; P = 0.331) and the central foveal thickness was higher in the EIFL group (496.9 µm vs. 434.2 µm; P = 0.007) than they were in the group without EIFL. The mean EIFL thickness was 164.1 ± 67.7 µm in the EIFL group. On multiplex analysis of the vitreous cytokines, the levels of CD163 (21529 pg/dL vs. 10877 pg/dL; P = 0.002) and macrophage colony-stimulating factor (206 pg/dL vs. 159 pg/dL, P = 0.004) were significantly higher in the EIFL group than they were in the group without EIFL. Conclusions Eyes with EIFL had increased vitreous levels of M2 macrophage markers. The activation of glial cell proliferation by M2 macrophages may contribute to EIFL formation.

Histone acetylation is a key regulatory factor for gene expression in cells. Modulation of histone acetylation by targeting of histone acetyltransferases (HATs) effectively alters many gene expression profiles and synaptic plasticity in the brain. However, the role of HATs on l-DOPA-induced dyskinesia of Parkinson’s disease (PD) has not been reported. Our aim was to determine whether HAT inhibitors such as anacardic acid, garcinol, and curcumin from natural plants reduce severity of l-DOPA-induced dyskinesia using a unilaterally 6-hydroxydopamine (6-OHDA)-lesioned PD mouse model. Anacardic acid 2 mg/kg, garcinol 5 mg/kg, or curcumin 100 mg/kg co-treatment with l-DOPA significantly reduced the axial, limb, and orofacial (ALO) score indicating less dyskinesia with administration of HAT inhibitors in 6-OHDA-lesioned mice. Additionally, l-DOPA’s efficacy was not altered by the compounds in the early stage of treatment. The expression levels of c-Fos, Fra-2, and Arc were effectively decreased by administration of HAT inhibitors in the ipsilateral striatum. Our findings indicate that HAT inhibitor co-treatment with l-DOPA may have therapeutic potential for management of l-DOPA-induced dyskinesia in patients with PD.

The dopamine precursorl-3,4-dihydroxyphenylalanine (l-DOPA) is widely used as a therapeutic choice for the treatment of patients with Parkinson's disease. However, the long-term use ofl-DOPA leads to the development of debilitating involuntary movements, calledl-DOPA-induced dyskinesia (LID). The cAMP/protein kinase A (PKA) signaling in the striatum is known to play a role in LID. However, from among the nine known adenylyl cyclases (ACs) present in the striatum, the AC that mediates LID remains unknown. To address this issue, we prepared an animal model with unilateral 6-hydroxydopamine lesions in the substantia nigra in wild-type and AC5-knock-out (KO) mice, and examined behavioral responses to short-term or long-term treatment withl-DOPA. Compared with the behavioral responses of wild-type mice, LID was profoundly reduced in AC5-KO mice. The behavioral protection of long-term treatment withl-DOPA in AC5-KO mice was preceded by a decrease in the phosphorylation levels of PKA substrates ERK (extracellular signal-regulated kinase) 1/2, MSK1 (mitogen- and stress-activated protein kinase 1), and histone H3, levels of which were all increased in the lesioned striatum of wild-type mice. Consistently, FosB/ΔFosB expression, which was induced by long-terml-DOPA treatment in the lesioned striatum, was also decreased in AC5-KO mice. Moreover, suppression of AC5 in the dorsal striatum with lentivirus-shRNA-AC5 was sufficient to attenuate LID, suggesting that the AC5-regulated signaling cascade in the striatum mediates LID. These results identify the AC5/cAMP system in the dorsal striatum as a therapeutic target for the treatment of LID in patients with Parkinson's disease.

Approximately 40-50% of all patients with Parkinson׳s disease (PD) show symptoms and signs of depressive disorders, for which neither pathogenic understanding nor rational treatment are available. Using Pit3x-deficient mice, a model for selective nigrostriatal dopaminergic neurodegeneration, we tested depression-related behaviors and acute stress responses to better understand how a nigrostriatal dopaminergic deficit increases the prevalence of depressive disorders in PD patients. Pitx3-deficient mice showed decreased sucrose consumption and preference in the two-bottle free-choice test of anhedonia. Acute restraint stress increased c-Fos (known as a neuronal activity marker) expression levels in various brain regions, including the prefrontal cortex, striatum, nucleus accumbens, and paraventricular nucleus of the hypothalamus (PVN), in both Pitx3+/+ and -/- mice. However, the stress-induced increases in c-Fos levels in the cortex, dorsal striatum, and PVN were significantly greater in Pitx3-/- than +/+ mice, suggesting that signs of depressive disorders in parkinsonism are related to altered stress vulnerability. Based on these results, we propose that Pitx3-/- mice may serve as a useful genetic animal model for co-morbid depressive disorder and parkinsonism.

Background Despite recent advancements in human genomics and identifying hundreds of risk loci for psychiatric disorders, drug development in psychiatry remains a challenge. While Genome-Wide Association Studies (GWAS) provide us with a great starting point by highlighting risk regions of the genome, translating disease-associated DNA variants to physiological function has been quite sluggish. This is mostly due to polygenic and multifactorial nature of psychiatric diseases which in turn have made development of relevant cellular and in vivo models particularly difficult. One recent GWAS identified over hundred genes that are strongly associated with schizophrenia but contribution of each gene to the disease seems to be small. Each risk gene is identified with tens of SNPs, most of which are common SNPs residing in the intronic regions of DNA. Methods Therefore, establishing cellular models to understand the directionality (loss or gain) and functional defect caused by each risk SNP within each gene can be an enormous undertaking. On the other hand, rare exon variants found in the disease population can serve as a more reliable starting point to understand how the function of a risk gene is affected in the disease. Results Here we examined effects of rare variants reported for CACNA1C, a top schizophrenia GWAS hit, in cellular models. CACNA1C is also linked to bipolar disorder, ADHD, depression and autism where schizophrenia GWAS identified over 160 risk SNPs for this gene. We used linkage disequilibrium information to identify a small number of risk SNPs that have the highest chance of affecting the overall function of CACNA1C gene. We have combined these two approaches, built neuronal functional assays and identified several important disease related phenotypes. Discussion These studies show a proof of concept in the context of the CACNA1C gene but this approach can be used as a platform to characterize other GWAS hits several other disease areas.

SummaryProteasomes drive the selective degradation of protein substrates with covalently linked ubiquitin chains in eukaryotes. Although proteasomes are distributed throughout the cell, specific biological functions of the proteasome in distinct subcellular locales remain largely unknown. We report that proteasomes localized at the centrosome regulate the degradation of local ubiquitin conjugates in mammalian neurons. We find that the proteasomal subunit S5a/Rpn10, a ubiquitin receptor that selects substrates for degradation, is essential for proteasomal activity at centrosomes in neurons and thereby promotes the elaboration of dendrite arbors in the rodent brain in vivo. We also find that the helix-loop-helix protein Id1 disrupts the interaction of S5a/Rpn10 with the proteasomal lid and thereby inhibits centrosomal proteasome activity and dendrite elaboration in neurons. Together, our findings define a function for a specific pool of proteasomes at the neuronal centrosome and identify a biological function for S5a/Rpn10 in the mammalian brain.

Functional active packaging materials were successfully developed by incorporating antioxidant agents into corn-zein-laminated linear low-density polyethylene (LLDPE) film. The minimum effective concentrations of the active compounds (for example, thymol, carvacrol, eugenol) were determined and these compounds were then laminated into LLDPE films to develop corn-zein-laminated films with antioxidant agents. The release rate of antioxidant agents in gas and liquid media were determined along with the mechanical and water barrier properties of the films containing these compounds. Tensile strength and percentage elongation at break were reduced in the corn-zein-laminated LLDPE films when compared to typical LLDPE film. Furthermore, the ability of the corn-zein-laminated films to repel moisture decreased by approximately 12.2%, but was improved by incorporating hydrophobic antioxidant compounds in the corn-zein layer. Examination of release kinetics in the gas and liquid phases verified that antioxidants were effectively released from the films and inhibited oxidation during testing. Finally, the films were used for fresh ground beef packaging, and effectively inhibited lipid oxidation and had a positive effect on the color stability of beef patties during storage. These results indicate that the developed antioxidant films are a novel active packaging material that can be effectively implemented by the food industry to improve the quality and safety of foods. Practical Application: Zein protein, a by-product of corn processing industry, was laminated into plastic films in combination with natural phenolic compounds to develop antioxidant packaging films. The films demonstrated their efficient release patterns of antioxidant compounds, which are suitable for packaging applications and food protection.