Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity

Aberrant glutamatergic, dopaminergic, and GABAergic neurotransmission has been implicated in schizophrenia. Cariprazine reverses the behavioral effects observed in the rat phencyclidine (PCP)-induced model of schizophrenia; however, little is known about its in vivo neurochemistry. The study aims to compare the effects of cariprazine and aripiprazole on PCP-induced changes in the extracellular levels of glutamate, dopamine, serotonin, noradrenaline, and GABA in the rat medial prefrontal cortex (mPFC), and on locomotor activation. Microdialysis was performed in awake rats with probes placed into the mPFC. Rats (n = 7/group) received vehicle (saline), cariprazine (0.05, 0.2, or 0.8 mg/kg), or aripiprazole (3 or 20 mg/kg) via gavage. After 60 min, 5 mg/kg PCP was administered intraperitoneally (i.p.). Samples were taken before drug administration, during pretreatment, and after PCP injection. Locomotor activity recording and microdialysis sampling occurred simultaneously. PCP treatment increased extracellular levels of all the neurotransmitters tested except GABA, for which there were no significant changes. Cariprazine and aripiprazole dose-dependently inhibited the PCP-induced increases of tested neurotransmitters. Overall effects were significant for higher cariprazine doses and both aripiprazole doses for glutamate and noradrenaline, for higher cariprazine doses and 20 mg/kg aripiprazole for dopamine, and for 0.8 mg/kg cariprazine and 20 mg/kg aripiprazole for serotonin and locomotor activity. Both cariprazine and aripiprazole dose-dependently attenuated PCP-induced hyperlocomotion and acute increases in glutamate, dopamine, noradrenaline, and serotonin levels in the mPFC; cariprazine was approximately 5-fold more potent than aripiprazole

Prediction of causative genes in inherited retinal disorder from fundus photography and autofluorescence imaging using deep learning techniques

Background/Aims: To investigate the utility of a data-driven deep learning approach in patients with inherited retinal disorder (IRD) and to predict the causative genes based on fundus photography and fundus autofluorescence (FAF) imaging. / Methods: Clinical and genetic data from 1302 subjects from 729 genetically confirmed families with IRD registered with the Japan Eye Genetics Consortium were reviewed. Three categories of genetic diagnosis were selected, based on the high prevalence of their causative genes: Stargardt disease (ABCA4), retinitis pigmentosa (EYS) and occult macular dystrophy (RP1L1). Fundus photographs and FAF images were cropped in a standardised manner with a macro algorithm. Images for training/testing were selected using a randomised, fourfold cross-validation method. The application program interface was established to reach the learning accuracy of concordance (target: >80%) between the genetic diagnosis and the machine diagnosis (ABCA4, EYS, RP1L1 and normal). / Results: A total of 417 images from 156 Japanese subjects were examined, including 115 genetically confirmed patients caused by the three prevalent causative genes and 41 normal subjects. The mean overall test accuracy for fundus photographs and FAF images was 88.2% and 81.3%, respectively. The mean overall sensitivity/specificity values for fundus photographs and FAF images were 88.3%/97.4% and 81.8%/95.5%, respectively. / Conclusion: A novel application of deep neural networks in the prediction of the causative IRD genes from fundus photographs and FAF, with a high prediction accuracy of over 80%, was highlighted. These achievements will extensively promote the quality of medical care by facilitating early diagnosis, especially by non-specialists, access to care, reducing the cost of referrals, and preventing unnecessary clinical and genetic testing

Prediction of Causative Genes in Inherited Retinal Disorders from Spectral-Domain Optical Coherence Tomography Utilizing Deep Learning Techniques

Purpose. To illustrate a data-driven deep learning approach to predicting the gene responsible for the inherited retinal disorder (IRD) in macular dystrophy caused by ABCA4 and RP1L1 gene aberration in comparison with retinitis pigmentosa caused by EYS gene aberration and normal subjects. Methods. Seventy-five subjects with IRD or no ocular diseases have been ascertained from the database of Japan Eye Genetics Consortium; 10 ABCA4 retinopathy, 20 RP1L1 retinopathy, 28 EYS retinopathy, and 17 normal patients/subjects. Horizontal/vertical cross-sectional scans of optical coherence tomography (SD-OCT) at the central fovea were cropped/adjusted to a resolution of 400 pixels/inch with a size of 750 × 500 pix2 for learning. Subjects were randomly split following a 3 : 1 ratio into training and test sets. The commercially available learning tool, Medic mind was applied to this four-class classification program. The classification accuracy, sensitivity, and specificity were calculated during the learning process. This process was repeated four times with random assignment to training and test sets to control for selection bias. For each training/testing process, the classification accuracy was calculated per gene category. Results. A total of 178 images from 75 subjects were included in this study. The mean training accuracy was 98.5%, ranging from 90.6 to 100.0. The mean overall test accuracy was 90.9% (82.0–97.6). The mean test accuracy per gene category was 100% for ABCA4, 78.0% for RP1L1, 89.8% for EYS, and 93.4% for Normal. Test accuracy of RP1L1 and EYS was not high relative to the training accuracy which suggests overfitting. Conclusion. This study highlighted a novel application of deep neural networks in the prediction of the causative gene in IRD retinopathies from SD-OCT, with a high prediction accuracy. It is anticipated that deep neural networks will be integrated into general screening to support clinical/genetic diagnosis, as well as enrich the clinical education

Investigation of the mechanism of chromium removal in (3-aminopropyl)trimethoxysilane functionalized mesoporous silica

We are proposed that a possible mechanism for Cr(VI) removal by functionalized mesoporous silica. Mesoporous silica was functionalized with (3-aminopropyl)trimethoxysilane (APTMS) using the post-synthesis grafting method. The synthesized materials were characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), N-2 adsorption-desorption analysis, Fourier-transform infrared (FT-IR), thermogravimetric analyses (TGA), and X-ray photoelectron spectroscopy (XPS) to confirm the pore structure and functionalization of amine groups, and were subsequently used as adsorbents for the removal of Cr(VI) from aqueous solution. As the concentration of APTMS increases from 0.01 M to 0.25 M, the surface area of mesoporous silica decreases from 857.9 m(2)/g to 402.6 m(2)/g. In contrast, Cr(VI) uptake increases from 36.95 mg/g to 83.50 mg/g. This indicates that the enhanced Cr(VI) removal was primarily due to the activity of functional groups. It is thought that the optimum concentration of APTMS for functionalization is approximately 0.05 M. According to XPS data, NH3+ and protonated NH2 from APTMS adsorbed anionic Cr(VI) by electrostatic interaction and changed the solution pH. Equilibrium data are well fitted by Temkin and Sips isotherms. This research shows promising results for the application of amino functionalized mesoporous silica as an adsorbent to removal Cr(VI) from aqueous solution

Clinical and genetic characteristics of 10 Japanese patients with PROM1-associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population

Variants in the PROM1 gene are associated with cone (-rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (-rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population

Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency

Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders

Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association

Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15–77/25–94). The median visual acuity in the right/left eye was 0.52/0.40 (range, −0.08–2.00/−0.18–1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD in ADCORD was determined in the Japanese cohort (39.1%), often showing the mild phenotype (CORD) with late-onset disease (sixth decade). Frequently found heterozygous missense variants located within the homeodomain underlie this mild phenotype. This large cohort study delineates the disease spectrum of CRX-RD in the Japanese population

Licking planets and stomping on buildings: children’s interactions with curated spaces in virtual reality

This visual essay draws upon data from a commercially funded project on which I was the lead researcher (Yamada-Rice et al. 2017). The study was undertaken to develop a set of best practices for the production of Virtual Reality (VR) content for children. The project combined large-scale quantitative data from a global survey with qualitative methods used to observe and interview a smaller sample of 8–12 year-olds. There was also a health and safety element that tested for changes in vision and balance pre and post VR use. This article draws from the qualitative dataset that investigated children’s interaction with a range of VR content and devices, the aspects that engaged them and how easy it was to use