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2-Dimensional (2D) metal oxides have many potential industrial applications including heterogeneous catalysis, water splitting, renewable energy conversion, supercapacitor applications, biomaterials, gas separation and gas storage. Herein we report a simple and scalable method for the preparation of 2D TiO 2 nanostructures by reaction of titanium isopropoxide with acetic acid at 333 K in isopropanol, followed by calcination at 673 K to remove the organic ligands. Both the products and reaction intermediates have been studied using electron microscopy, X-ray diffraction, N 2 physisorption, nuclear magnetic resonance, thermogravimetric analysis, and X-ray photoelectron, Raman, and infrared spectroscopy. The anisotropic condensation of the planar Ti 6 O 4 (O i Pr) 8 (OAc) 8 complex is believed to be responsible for the formation of the 2D structure, where O i Pr and OAc represent isopropoxide and acetate ligands, respectively. This research demonstrates that the metal complexes are promising building blocks for desired architectures, and the self-assembly of an acetate bidentate ligand is a versatile tool for manipulating the shape of final products.

Acquired middle ear cholesteatoma leads to hearing loss, ear discharge, ear pain, and more serious intracranial complications. However, there is still no effective treatment other than surgery. TFIIB-related factor 2 (BRF2) acted as a redox sensor overexpressing in oxidative stress which linked endoplasmic reticulum (ER) stress, while glucose-regulated protein 78 (GRP78) was a biomarker of ER stress in cancer, atherosclerosis and inflammation. In our study, we investigated the roles of BRF2 and GRP78 in acquired middle ear cholesteatoma. Our results revealed that the expression of BRF2 was significant increased in acquired middle ear cholesteatoma, and which was positively correlated with the expression of GRP78. In addition, BRF2 and GRP78 showed colocalization in epithelium of acquired middle ear cholesteatomas and HaCaT cells. Prolongation of LPS stimulation in HaCaT cells escalated the expression of BRF2 and GRP78. To confirm the role of BRF2 and GRP78, we transfected si-BRF2 into HaCaT cells. All results indicated that BRF2 expression positively regulates the expression of GRP78 and may participate in the pathogenesis of acquire middle ear cholesteatoma., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

PNPLA6-related disorders include several phenotypes, such as Boucher-Neuhäuser syndrome, Gordon Holmes syndrome, spastic paraplegia, photoreceptor degeneration, Oliver-McFarlane syndrome and Laurence-Moon syndrome. In this study, detailed clinical evaluations and genetic testing were performed in five (4 Chinese and 1 Caucasian/Chinese) syndromic retinal dystrophy patients. Genotype-phenotype correlations were analyzed based on review of the literatures of previously published PNPLA6-related cases. The mean age of patients and at first visit were 20.8 years (11, 12, 25, 28, 28) and 14.2 years (4, 7, 11, 24, 25), respectively. They all presented with severe chorioretinal dystrophy and profoundly decreased vision. The best corrected visual acuity (BCVA) ranged from 20/200 to 20/2000. Systemic manifestations included cerebellar ataxia, hypogonadotropic hypogonadism and hair anomalies. Six novel and three reported pathogenic variants in PNPLA6 (NM_001166111) were identified. The genotypes of the five cases are: c.3134C > T (p.Ser1045Leu) and c.3846+1G > A, c.3547C > T (p.Arg1183Trp) and c.1841+3A > G, c.3436G > A (p.Ala1146Thr) and c.2212-10A > G, c.3436G > A (p.Ala1146Thr) and c.2266C > T (p.Gln756*), c.1238_1239insC (p.Leu414Serfs*28) and c.3130A > G (p.Thr1044Ala). RT-PCR confirmed that the splicing variants indeed led to abnormal splicing. Missense variants p.Thr1044Ala, p.Ser1045Leu, p.Ala1146Thr, p.Arg1183Trp and c.3846+1G > A are located in Patatin-like phospholipase (Pat) domain. In conclusion, we report the phenotypes in five patients with PNPLA6 associated syndromic retinal dystrophy with variable systemic involvement and typical choroideremia-like fundus changes. Ocular manifestations may be the first and the only findings for years. All of our patients carried one severe deleterious variant (stop-gain or splicing variant) and one milder variant (missense variant). Retinal involvement was significantly correlated with severe deleterious variants and variants in Pat domain., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

ABCA4 gene associated retinal dystrophies (ABCA4-RD) are a group of inherited eye diseases caused by ABCA4 gene mutations, including Stargardt disease, cone-rod dystrophy and retinitis pigmentosa. With the development of next-generation sequencing (NGS), numerous clinical and genetic studies on ABCA4-RD have been performed, and the genotype and phenotype spectra have been elucidated. However, most of the studies focused on the Caucasian population and limited studies of large Chinese ABCA4-RD cohorts were reported. In this study, we summarized the phenotypic and genotypic characteristics of 129 Chinese patients with ABCA4-RD. We found a mutation spectrum of Chinese patients which is considerably different from that of the Caucasian population and identified 35 novel ABCA4 mutations. We also reported some rare and special cases, such as, pedigrees with patients in two generations, patients diagnosed with cone-rod dystrophy or retinitis pigmentosa, patients with subretinal fibrosis and patients with preserved foveal structure. At the same time, we focused on the correlation between the genotypes and phenotypes. By the comprehensive analysis of multiple clinical examinations and the application of multiple regression analysis, we proved that patients with two "null" variants had a younger onset age and reached legal blindness earlier than patients with two "none-null" variants. Patients with one or more "none-null" variants tended to have better visual acuity and presented with milder fundus autofluorescence changes and more preserved rod functions on the full-field electroretinography than patients with two "null" variants. Furthermore, most patients with the p.(Phe2188Ser) variant shared a mild phenotype with a low fundus autofluorescence signal limited to the fovea and with normal full-field electroretinography responses. Our findings expand the variant spectrum of the ABCA4 gene and enhance the knowledge of Chinese patients with ABCA4-RD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To describe the functional phenotypic features of East Asian patients with RP1L1-associated occult macular dystrophy (ie, Miyake disease)., Design: An international multicenter retrospective cohort study., Methods: Twenty-eight participants (53 eyes) with Miyake disease were enrolled at 3 centers (in Japan, China, and South Korea). Ophthalmologic examinations including spectral-domain optical coherence tomography (SDOCT) and multifocal electroretinogram (mfERG) were performed. Patients were classified into 3 functional groups based on mfERG: Group 1, paracentral dysfunction with relatively preserved central/peripheral function; Group 2, homogeneous central dysfunction with preserved peripheral function; and Group 3, widespread dysfunction over the recorded area. Three functional phenotypes were compared in clinical parameters and SDOCT morphologic classification (severe phenotype, blurred/flat ellipsoid zone and absence of the interdigitation zone; mild phenotype, preserved ellipsoid zone)., Results: There were 8 eyes in Group 1, 40 eyes in Group 2, and 5 eyes in Group 3. The patients in Group 1 showed significantly later onset (P = .005) and shorter disease duration (P = .002), compared with those in Group 2. All 8 eyes in Group 1 showed the mild morphologic phenotype, while 43 of 45 eyes in Groups 2 and 3 presented the severe phenotype, which identified a significant association between the functional grouping and the morphologic classification (P < .001)., Conclusions: A spectrum of functional phenotypes of Miyake disease was first documented with identification of 3 functional subtypes. Patients with paracentral dysfunction had the mildest phenotype, and those with homogeneous central or widespread dysfunction showed overlapping clinical findings with severe photoreceptor changes, suggesting various extents of visual impairment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The GUCY2D gene encodes the photoreceptor guanylate cyclase (GC-E) and different pathogenic variants can lead to Leber congenital amaurosis (LCA) or cone-rod dystrophy (CRD). In this study, we describe three unrelated families who carried different mutations at codon 838 of the GUCY2D gene, and presented different phenotypes of retinal degeneration., Materials and Methods: Family and personal histories were collected, and the patients underwent best corrected visual acuity (BCVA), fundus photography (FP), electroretinography (ERG), optical coherence tomography (OCT) and fundus autofluorescence (FAF). Venous blood was drawn from patients and family members, and genomic DNA was extracted. Next-generation sequencing of known ocular genes was applied to the proband to find pathogenic variants. Polymerase chain reaction (PCR) and Sanger sequencing were conducted for validation and segregation., Results: Six patients from three unrelated families were enrolled. All the patients manifested decreased vision, photophobia and myopia from childhood. ERG recordings demonstrated a significant reduction in cone responses for all patients, while rod responses ranged widely from normal to moderately reduced. All patients were diagnosed with CRD, but the disease severity and progression rates in the three families were significantly different. Three pathogenic variants in the GUCY2D gene (c.2512 C > T (p.R838C), c.2512 C > A (p.R838S) and c.2513 G > A (p.R838H)) were identified., Conclusions: We presented the phenotypes of three Chinese adCRD families carrying different variants at codon 838 of the GUCY2D gene. The R838S variant is a novel genotype associated with GUCY2D -CRD. The R838H variant can cause severe retinal features. Our findings enhance the understanding of GUCY2D phenotypic diversity.

Purpose: To describe the clinical and molecular genetic characteristics of a large cohort of Chinese patients with choroideremia (CHM)., Methods: Forty-eight Chinese participants from 35 families with a clinical diagnosis of CHM who harbored sequence variants in the CHM gene were enrolled. Comprehensive clinical evaluations and molecular genetic analysis of the CHM gene were performed., Results: The median age of the 48 patients was 31.5 years (range, 5-78 years). There were 30 different sequence variants detected in 35 families; of which, 13 sequence variants were novel. The mean (±SD) best-corrected visual acuity best in logarithm of the minimum angle of resolution equivalents was 0.71 (±0.87) (range, 0.00-2.80) or approximately 20/100 in Snellen visual acuity. A significant correlation was revealed between best-corrected visual acuity best and age (P < 0.001). The trend in the change in the best-corrected visual acuity over age showed that relatively good vision remained until 20 years old. The patterns of fundus photography and fundus autofluorescence finding demonstrated that residual retinal pigment epithelium areas significantly declined in patients at the age of 20 years or older. The results of visual field and full-field electroretinography showed that these measures might be of limited value for evaluating the condition of the late stage of CHM in Chinese patients., Conclusion: This study described for the first time the clinical and molecular genetic characteristics of a large cohort of Chinese patients with CHM. The findings from best-corrected visual acuity best and visual field showed that the impairment of visual function in CHM might be more severe in Chinese patients than in western patients.

Background: Wagner vitreoretinopathy (WVR) is a rare non-syndromic autosomal dominant inherited vitreoretinopathy. We studied the phenotypes of two Chinese families with WVR and identified the pathogenic variants., Materials and Methods: Four affected individuals were involved in this study. Three of them underwent detailed ophthalmic examinations, including best-corrected visual acuity (BCVA), dilated ophthalmoscopy, optical coherence tomography (OCT), visual field testing, and electroretinograms (ERG). The DNA sample of the proband was sequenced using our customized capture panel, which includes 338 retinal disease genes. Sanger sequencing was performed for validation and segregation., Results: Affected subjects manifested typical WVR features, including an optically empty vitreous with vitreoretinal membranes and veils, chorioretinal atrophy, and presenile cataracts. One patient was complicated with retinal detachment. BCVA ranged from light perception to 20/33. Reduced retinal thickness, loss, or discontinuation of ellipsoid and interdigitation zone were shown by OCT. Visual field testing displayed various degrees of peripheral vision loss. ERG recorded moderate to severe decline of both rod and cone responses. Next generation sequencing (NGS) combined with segregation test revealed two splice-site pathogenic variants (c.9265 + 2 T > A and c.4004-1 G > T) in VCAN gene., Conclusions: Clinical manifestations are highly variable among WVR patients. Retinal detachment is common in WVR and the most vision-threatening complication. Next generation sequencing is a useful tool in precise diagnosis of this spectrum of diseases with highly heterogeneous or overlapped phenotypes.

1D and 2D metal oxide nanostructures are important for potential applications in alternative energy, batteries, supercapacitors, catalysts, biomaterials, and electronic nanodevices. Many current approaches for making the desired nanomaterials require multiple steps, which are often exotic and complex for production on a commercial scale. In contrast, the sol-gel reactions between metal alkoxides and organic acids have emerged as a simple protocol for producing metal oxides and inorganic/organic hybrid materials with a controllable 1D or 2D architecture. Our knowledge of this process continues to evolve through the fundamental goal of designing a desired nanostructure from the corresponding molecular building blocks. Our research was driven by the discovery of various morphologies by fine-tuning the synthesis parameters, such as the reaction temperature and molar ratio of the reactants, as well as switching solvents. These discoveries lead to several quesions: What are the building blocks of the 1D and 2D nanostructures and how does the self-assembly occur? What are the reaction kinetics and the mechanisms of nanostructure formation? What role does the solvent play in the assembly process? What are the effects of reaction temperature and pressure? How can we manipulate the nanostructure-for example, the parallel growth of 1D semiconductors-from a substrate surface? And lastly, what are the industrial applications of macroporous aerogels and xerogels? This minireview will highlight documented research accounts to answer these questions.

Purpose: To compare disease severity in detail between patients carrying variants in exons 1-14 and ORF15 of retinitis pigmentosa GTPase regulator (RPGR)., Methods: Systematic next-generation sequencing data analysis, Sanger sequencing validation and segregation analysis were utilised to identify the pathogenic variants. Detailed ophthalmic examinations, including electroretinograms, fundus photography, fundus autofluorescence and optical coherence tomography were performed. Statistical analysis, including age adjustment and comparison, were performed based on cross-sectional level to compare disease severity between variants in the two RPGR variant groups., Results: Sixty-two variants were identified in RPGR in 86 patients from 77 unrelated families. Twenty-nine (37.7%) had variants in RPGR-exons 1-14 (group 1) and 48 (62.3%) in RPGR-ORF15 (group 2). Eighty-four patients were diagnosed with X-linked retinitis pigmentosa and only two patients with cone-rod dystrophy. LogMAR visual acuity increased 0.035 and 0.022 each year on average in group 1 and group 2, respectively. Group 2 patients had better visual acuity with a mean logMAR difference of 0.4378, which is significant after age adjustment (P < 0.01). Neither the value of log (ellipsoid zone width) nor central retinal thickness was significantly correlated with variant grouping after considering the effect of the age variable (P = 0.56 and 0.40, respectively). Spherical refractive error did not differ significantly between the two variant groups (P = 0.17). Patterns of autofluorescence included a hyperfluorescent ring at the posterior pole, diffuse hyperfluorescence in the macular area, and dark macular autofluorescence with or without fovea hyperfluorescence. The age and proportion of fundus autofluorescence patterns between the two variant groups were significantly different (P < 0.01)., Conclusions: Patients with variants in exons 1-14 retained less visual acuity than patients with ORF15 variants and deteriorated faster. However, the ellipsoid zone widths, central retinal thickness and refractions were comparable between the two groups. Autofluorescence pattern relates to the age and the variant grouping., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Lipid metabolic deficiencies are associated with many genetic disorders. Bietti crystalline dystrophy (BCD), a blindness-causing inherited disorder with changed lipid profiles, is more common in Chinese and Japanese than other populations. Our results reveal that mouse models lacking Cyp4v3 have less physiological and functional changes than those of BCD patients with this gene defect. After the administration of a high-fat diet (HFD), the occurrence of retinal lesions were both accelerated and aggregated in the Cyp4v3 -/- mouse models, implying that changed lipid levels were not only associated factors but also risk factors to BCD patients. Facilitated by the results, we found that the reduced electroretinography waveforms and retinal thickness observed in the HFD-induced mouse models were effectively recovered after subretinal delivery of a human CYP4V2 gene carried by an adeno-associated virus vector, which demonstrates the potential curability of BCD by gene therapy.

Background: Sialidosis type 1 is a rare inherited disorder with a high disability. No genetically confirmed mainland Chinese patient with sialidosis type 1 has been reported. This study evaluated the phenotypes and genotypes of mainland Chinese patients with sialidosis type 1., Methods: It was a retrospective case series study. Four unrelated patients were enrolled. Comprehensive clinical evaluations and molecular genetic analysis of the NEU1 gene were performed., Results: Three out of four patients presented progressive myoclonus epilepsy. The best-corrected visual acuity ranged from 20/2000 to 20/25. Punctate cataracts were found in all of the patients. Distinct macular cherry red spots were observed in three patients by fundoscopy, and a relatively normal fundus was revealed in one patient. Optical coherence tomography (OCT) showed increased reflectivity of the nerve fiber and ganglion cell layers, and fundus autofluorescence (FAF) revealed hyperautofluorescent areas surrounding the fovea in all of the patients. Only superficial retinal vessels can be observed using OCT angiography; the deeper capillary plexus could not be observed. Visual evoked potential revealed varying degrees of decreased amplitude and/or prolonged latency of P100 or P2 waves. The most frequent sequence variant identified was c.544A>G (p.S182G) (NM&#95;000434.3)., Conclusions: Our study first described the ophthalmic and neurologic characteristics of a small cohort of unrelated mainland Chinese patients with sialidosis type 1. We found that c.544A>G (p. S182G) might be a hotspot variant in Chinese patients. The accumulation of metabolic products in the nerve fiber and ganglion cell layers is a characteristic ocular finding that could be sensitively detected by OCT and FAF imaging., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Oxygen-involved electrochemical reactions are crucial for plenty of energy conversion techniques. Herein, we rationally designed a carbon-based Mn-N 2 C 2 bifunctional electrocatalyst. It exhibits a half-wave potential of 0.915 V versus reversible hydrogen electrode for oxygen reduction reaction (ORR), and the overpotential is 350 mV at 10 mA cm -2 during oxygen evolution reaction (OER) in alkaline condition. Furthermore, by means of operando X-ray absorption fine structure measurements, we reveal that the bond-length-extended Mn 2+ -N 2 C 2 atomic interface sites act as active centers during the ORR process, while the bond-length-shortened high-valence Mn 4+ -N 2 C 2 moieties serve as the catalytic sites for OER, which is consistent with the density functional theory results. The atomic and electronic synergistic effects for the isolated Mn sites and the carbon support play a critical role to promote the oxygen-involved catalytic performance, by regulating the reaction free energy of intermediate adsorption. Our results give an atomic interface strategy for nonprecious bifunctional single-atom electrocatalysts.

Usherin is the most common causative protein associated with autosomal recessive retinitis pigmentosa (RP) and Usher syndrome (USH), which are characterized by retinal degeneration alone and in combination with hearing loss, respectively. Usherin is essential for photoreceptor survival and hair cell bundle integrity. However, the molecular mechanism underlying usherin function in normal and disease conditions is unclear. In this study, we investigated structural models of usherin domains and localization of usherin pathogenic small in-frame mutations, mainly homozygous missense mutations. We found that usherin fibronectin III (FN3) domains and most laminin-related domains have a β-sandwich structure. Some FN3 domains are predicted to interact with each other and with laminin-related domains. The usherin protein may bend at some FN3 linker regions. RP- and USH-associated small in-frame mutations are differentially located in usherin domains. Most of them are located at the periphery of β-sandwiches, with some at the interface between interacting domains. The usherin laminin epidermal growth factor repeats adopt a rod-shaped structure, which is maintained by disulfide bonds. Most missense mutations and deletion of exon 13 in this region disrupt the disulfide bonds and may affect local protein folding. Despite low expression of the recombinant entire protein and protein fragments in mammalian cell culture, usherin FN3 fragments are more robustly expressed and secreted than its laminin-related fragments. Our findings provide new insights into the usherin structure and the disease mechanisms caused by pathogenic small in-frame mutations, which will help inform future experimental research on diagnosis, disease mechanisms, and therapeutic approaches., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Background: The auditory and speech development of the children with cochlear implants (CIs) are influenced by many factors. Objective: To study the developmental trajectory and influencing factors of auditory and speech functions for the Mandarin Chinese speaking children with CIs. Material and methods: The children with CIs undergoing rehabilitation in the same institution from June 2016 to June 2019 were followed up. Their closed monosyllables and disyllables recognition rate, closed average language age, categories of auditory performance (CAP) and speech intelligibility rating (SIR) were evaluated at 0, 1, 3, 6, 12 and 24 months of rehabilitation. The results were analyzed by SPSS 23.0. Results: 49 children were followed up for 1 year, 29 children for 2 years. The evaluated indicators of auditory and speech functions were improved with the prolongation of rehabilitation and influenced by the age of cochlear implantation, the use of hearing aids before surgery, guardian's educational degree, the relationship between guardian and child. Conclusions and significance: The auditory and speech functions of the children with CIs were improved significantly with the prolongation of rehabilitation and influenced by many factors, which can help us to predict the effect of CI more accurately and develop an individualized rehabilitation program.

Background: Retinocytoma is a rare benign retinal tumor associated with variants in the RB1 gene. Ophthalmoscopic features can include a translucent retinal mass, calcification, retinal pigment epithelial alteration and chorioretinal atrophy., Methods: Detailed ophthalmological examinations were performed in a Chinese patient with retinocytoma and his daughter with bilateral retinoblastoma. Sanger sequencing was performed to detect RB1 genetic variants in the patient, his daughter and tumor tissue from his daughter., Results: A 33-year-old man presented with poor vision and strabismus in the right eye since childhood. Fundus examination revealed a round yellow-white lesion stretching from the nasal side of the optic disc to the temporal periphery of the right eye. Sequencing result identified a reported variant (c.658C>G, p.Leu220Val) in the RB1 gene (NM&#95;000321.2) of DNA extracted from peripheral blood of the patient and his daughter. The missense variant was also found in the tumor tissue from his daughter., Conclusions: We report detailed clinical features and genetic analysis of a case with unilateral retinocytoma. Retinocytoma has a wide range of clinical phenotypes; genetic testing is therefore a useful tool for the diagnosis of atypical cases., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

ROSAH syndrome was recently identified as an autosomal dominant systemic disorder due to mutations in ALPK1. It was characterized by retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. We collected and summarized the clinical data of two patients with juvenile onset splenomegaly and oculopathy. Whole exome sequencing (WES) was adapted for genetic analysis. Mutations in ALPK1 were confirmed by Sanger sequencing. Besides juvenile oculopathy and splenomegaly, both patients had intermittent fever and anhidrosis. Patient 2 also experienced recurrent upper respiratory infections in her infancy and developed dental and nail problems in childhood. Elevated TNF-α was their prominent laboratory features. Both patients were found to have a previously reported mutation, c.710C>T, p. T237M (NM&#95;001102406) in ALPK1. Anti-TNF treatment of adalimumab was applied to patient 1, after which her optic disc edema in the left eye continued and the visual acuity deteriorated further. Patient 1 underwent elective splenectomy due to concern for spontaneous rupture of the spleen. Up to date, 18 patients of ROSAH syndrome have been reported. The clinical manifestations were relatively homogeneous, prominently presenting with juvenile onset oculopathy and splenomegaly. As it mainly involves ocular fundus, severe oculopathy deeply affects the quality of life and prognosis of ROSAH patients. Now little has been known about its treatment. As a newly recognized inherited systemic disorder, ROSAH syndrome needs to be paid more attention to, especially for those with juvenile onset splenomegaly and oculopathy.

Purpose : To identify pathogenic gene variants in the NOD2 gene and assess the clinical features of a cohort of Chinese patients affected with Blau syndrome. Methods : Eight patients from seven unrelated families were enrolled. Detailed ophthalmological examinations were performed. Sanger sequencing was used to analyze the NOD2 gene. Results : The onset age of ocular manifestations varied from 2 to 24 years (median: 5.5 years). Best corrected visual acuity (BCVA) ranged from light perception (LP) to 1.0. One patient presented with recurrent anterior uveitis, six patients had panuveitis and one patient was at the phthisis bulbi stage. One novel disease-associated variant (c.2006A>G, p.His669Arg) and four previously reported disease-causing variants (c.1000C>T, p.Arg334Trp; c.1001G>A, p.Arg334Gln; c.1442G>A, p.Gly481Asp; c.1759C>T, p.Arg587Cys) in the NOD2 gene (NM&#95;022162.1) were identified. Conclusions : Blau syndrome is a rare autosomal dominant multisystem disease caused by a NOD2 gene defect. Recurrent anterior uveitis and/or panuveitis are the characteristic ocular findings.

A novel six-membered rhodamine-based fluorescent probe (6G-ClO) was developed from 2-formyl rhodamine (6G-CHO) and used for hypochlorite detection in water and HUVEC cells. Different from planar penta cycle of rhodamine spirolactam, there was a twist six-membered spirocyclic hydrazone in 6G-ClO optimized by Gaussian software at DFT/B3LYP/6-31G(d) level. The high selectivity, high sensitivity and fast response of 6G-ClO towards ClO - would be attributed to the twist six-membered spirocycle. Test-strip prepared with 6G-ClO was successfully used to semi-quantitatively indicate the concentration of ClO - in water. 6G-ClO can also quantitatively detect the concentration of ClO - in tap water and swimming pool water. The detection limit of 6G-ClO was as low as 12 nM. The co-localization staining of HUVEC cells further verified that 6G-ClO could specifically accumulate in lysosomes and capture exogenous/endogenous ClO - in living lysosomes. 6G-ClO would be a practical probe for real-time monitoring of ClO - in the biological and real water samples., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study is carried out to elucidate the role of long noncoding RNAs (lncRNAs) MT1JP in proliferation, invasion, migration, and apoptosis of glioma cells through the regulation of PTEN/Akt signaling pathway. The expression of MT1JP in 80 normal brain tissues and 138 glioma tissues, as well as glioma cell lines, was detected by quantitative reverse-transcription polymerase chain reaction. Besides, glioma cells with overexpression and low expression of MT1JP were constructed to confirm the role of MT1JP in proliferation, invasion, migration, and apoptosis of glioma cells and the growth of glioma cells in vivo through the regulation of PTEN/Akt signaling pathway. MT1JP expression was downregulated in glioma tissues and cells. The low expression of MT1JP was considered as an independent risk factor for predicting overall survival in gliomas. After transfection of MT1JP overexpression plasmid, glioma cells showed decreased proliferation, migration and invasion ability, increased apoptosis rate, and decreased the tumorigenic ability of nude mice. The trends were opposite in glioma cells transfected with MT1JP poor expression plasmid. Collectively, our study suggests that lncRNA MT1JP is responsible for inhibiting proliferation, invasion, and migration while promoting apoptosis of glioma cells through the activation of PTEN/Akt signaling pathway., (© 2019 Wiley Periodicals, Inc.)

Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest.

Purpose: To characterize the phenotypic variability and report the genetic defects in a cohort of Chinese patients with biallelic variants of the retinol dehydrogenase 12 (RDH12) gene., Methods: The study included 38 patients from 38 unrelated families with biallelic pathogenic RDH12 variants. Systematic next-generation sequencing data analysis, Sanger sequencing validation, and segregation analysis were used to identify the pathogenic mutations. Detailed ophthalmic examinations, including electroretinogram, fundus photography, fundus autofluorescence and optical coherence tomography, and statistical analysis were performed to evaluate phenotype variability., Results: Twenty-five different mutations of RDH12 were identified in the 38 families. Six of these variants were novel. Val146Asp was observed at the highest frequency (23.7%), and it was followed by Arg62Ter (14.5%) and Thr49Met (9.2%). Twenty-three probands were diagnosed with early-onset severe retinal dystrophy, 6 with Leber congenital amaurosis, 7 with autosomal recessive retinitis pigmentosa, and 2 with cone-rod dystrophy. Self-reported nyctalopia occurred in about a half of patients (55.3%) and was significantly more common among older patients (P < 0.01). Nyctalopia was not significantly associated with best-corrected visual acuity (P = 0.72), but older patients had significantly greater best-corrected visual acuity loss (P < 0.01). Only 15.8% of the patients had nystagmus, which was significantly more likely to occur among 36.8% of the patients with hyperopia >3D (P < 0.01) and/or in cases of reduced best-corrected visual acuity (P = 0.01), but was not associated with age (P = 0.87)., Conclusion: Several high-frequency RDH12 variants were identified in patients with inherited retinal dystrophies, most of which were missense mutations. Variable but characteristic phenotypes of a progressive nature was observed. Overall, the findings indicated that biallelic RDH12 mutations are a common cause of early-onset retinal dystrophy and a rare cause of cone-rod dystrophy.

Purpose: To describe the clinical and genetic characteristics of the cohort enrolled in the East Asian studies of occult macular dystrophy (OMD)., Design: International, multicenter, retrospective cohort studies., Participants: A total of 36 participants from 21 families with a clinical diagnosis of OMD and harboring pathogenic RP1L1 variants (i.e., Miyake disease) were enrolled from 3 centers in Japan, China, and South Korea., Methods: A detailed history was obtained, and comprehensive ophthalmological examinations including spectral-domain OCT were performed. All detected sequence variants in the RP1L1 gene were reviewed, and in silico analysis was performed, including allele frequency analyses and pathogenicity predictions., Main Outcome Measures: Onset of disease, visual acuity (VA) converted to the logarithm of the minimum angle of resolution (logMAR), OCT findings, and effect of detected variants., Results: Eleven families from Japan, 6 from South Korea, and 4 from China were recruited. There were 12 female and 24 male participants. The median age of onset was 25.5 years (range, 2-73), and the median age at the latest examination was 46.0 years (range, 11-86). The median VA (logMAR) was 0.65 (range, -0.08-1.22) in the right eye and 0.65 (-0.08-1.10) in the left eye. A significant correlation between onset of disease and VA was revealed. The Classical morphologic phenotype showing both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors was demonstrated in 30 patients (83.3%), and subtle photoreceptor architectural changes were demonstrated in 6 patients (16.6%). Eight pathogenic RP1L1 variants were identified, including 6 reported variants and 1 novel variant: p.R45W, p.T1194M/p.T1196I (complex), p.S1199C, p.G1200A, p.G1200D, p.V1201G, and p.S1198F, respectively. Two variants were recurrent: p.R45W (11 families, 52.4%) and p.S1199C (5 families, 23.8%). The pathogenic missense variants in 10 families (47.6%) were located within the previously reported unique motif, including 6 amino acids (1196-1201)., Conclusions: There is a large spectrum of clinical findings in Miyake disease, including various onset of disease and VA, whereas the characteristic photoreceptor microstructures were shared in most cases. Two hot spots including amino acid numbers 45 and 1196-1201 in the RP1L1 gene were confirmed in the East Asian population., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: High myopia (HM) is one of the leading causes of vision impairment worldwide, accompanied by a series of pathological ocular complications. Studies have shown that genetic factors play an important role in the pathogenesis of HM. The aim of our study is to identify a candidate gene for a large family with non-syndromic HM., Methods: A large Chinese family, including 12 patients with non-syndromic HM, and 220 unrelated patients with HM, were recruited from the Department of Ophthalmology, Peking Union Medical College Hospital. Three affected subjects from the large family were selected to perform whole exome sequencing (WES). Rare heterozygous variants shared by all three subjects were retained and then Sanger sequencing was used to determine whether any of the remaining variants cosegregated with the disease phenotype. Furthermore, all coding regions of the candidate genes were analysed in 220 unrelated patients with HM. Immunofluorescence assay was used to detect the expression of the candidate gene in the eye. Annexin V/PI staining and flow cytometry were applied to detect cell apoptotic changes., Results: WES identified a novel TNF receptor superfamily member 21 ( TNFRSF21 ) variant, P146A, in a large Chinese family with HM, and another three rare heterozygous variants (P202L, E240* and A440G) in TNFRSF21 were found in 220 unrelated cases with HM. Immunofluorescence assay indicated that it is strongly expressed in the mouse eye. Compared with the wild type, the P146A variant could significantly increase adult retinal pigment epithelial cell line-19 cell apoptotic levels., Conclusions: Variants in TNFRSF21 cause non-syndromic HM in Chinese population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

The present study aimed to investigate whether the cerebellar fastigial nucleus (FN) is involved in post-stroke depression (PSD), and to observe the effect of direct cerebellar-hypothalamic γ-aminobutyric acid (GABA)ergic and glutamatergic projections on PSD, in order to understand the mechanisms underlying the cerebellar modulation of mood and emotion. Healthy Sprague-Dawley rats were randomly divided into five groups: Sham-operated, Stroke, PSD, FN lesion, and decussation of superior cerebellar peduncle (XSCP) lesion groups. Sham surgery was performed in animals of the Sham group (n=6). The rats in the other four groups (n=6 for each group) underwent middle cerebral artery occlusion. The rats were examined twice a week in an open field test. In addition, the expression of cytokines in hippocampal tissues, and the content of glutamate and GABA in the lateral hypothalamic area (LHA) were measured. The results showed that scores corresponding to the behavioral signs of depression were decreased in the PSD, FN lesion and XSCP lesion groups. In addition, the mRNA levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in the hippocampus of the PSD, FN lesion and XSCP lesion groups were significantly increased. The GABA and glutamate content in the LHA were also decreased significantly in the PSD, FN lesion and XSCP lesion groups. Taken together, the findings of the present study indicated that the cerebellar FN may be involved in PSD through the direct cerebellar-hypothalamic glutamatergic and GABAergic projections.

MicroRNAs (miRNAs) are small non-coding RNAs that serve pivotal roles in human diseases. Several miRNAs, such as miR-485-3p, have been identified as potential biomarkers for predicting overall survival of patients with glioblastoma (GBM). However, the underlying mechanism of miRNAs in promoting GBM progression remains unknown. In the present study, decreased miR-485-3p expression was detected in tumor tissues from patients with GBM. Using western blot analysis, reverse transcription-quantitative PCR and dual luciferase reporter assay, ring finger protein 135 (RNF135) was confirmed as a target gene of miR-485-3p in GBM cells. Through silencing of RNF135, miR-485-3p inactivated the mitogen-activated protein kinase/ERK1/2 pathway in GBM cells. Moreover, functional assays demonstrated that miR-485-3p inhibited GBM cell proliferation and migration whilst overexpression of RNF135 reversed this effect. Additionally, a negative correlation between miR-485-3p and RNF135 mRNA expression was observed in tissues from patients with glioblastoma. In conclusion, the present results demonstrated that miR-485-3p functioned as a tumor suppressor which suggested that miR-485-3p might have a role in GBM progression.

Anastomotic pseudoaneurysm remains one of the main life-threatening complications of cardiac and thoracic aorta surgery. We report a rare case of infected pseudoaneurysm at the anastomotic line found during follow-up. Blood culture results suggested Enterococcus faecium infection. Transthoracic echocardiography and computed tomography scans revealed the presence of a pseudoaneurysm of the ascending aorta. The pseudoaneurysm was resected and the ascending aorta was reconstructed with an artificial vascular patch without complications. Reducing the anastomotic tension, with complete hemostasis at the anastomotic incision, is the most important means of preventing the formation of pseudoaneurysm.

New Findings: What is the central question of this study? Oligomeric proanthocyanidin has the capacity to alleviate abnormalities in neurological functioning. However, whether oligomeric proanthocyanidin can reduce the progression of demyelination or promote remyelination in demyelinating diseases remains unknown. What is the main finding and its importance? Oligomeric proanthocyanidin can improve cuprizone-induced demyelination by inhibiting immune cell infiltration, reversing overactivated microglia, decreasing the inflammatory cytokines secreted by inflammatory cells and decreasing the production of myelin oligodendrocyte glycoprotein 35-55 -specific antibody in the brain., Abstract: Demyelinating diseases of the CNS, including multiple sclerosis, neuromyelitis optica and acute disseminated encephalomylitis, are characterized by recurrent primary demyelination-remyelination and progressive neurodegeneration. In the present study, we investigated the therapeutic effect of oligomeric proanthocyanidin (OPC), the most effective component of grape seed extract, in cuprizone-fed C57BL/6 mice, a classic demyelination-remyelination model. Our results showed that OPC attenuated abnormal behaviour, reduced demyelination and increased expression of myelin basic protein and expression of O4 + oligodendrocytes in the corpus callosum. Oligomeric proanthocyanidin also reduced the numbers of B and T cells, activated microglia in the corpus callosum and inhibited secretion of inflammatory factors. Furthermore, concentrations of myelin oligodendrocyte glycoprotein-specific antibodies were significantly reduced in serum and brain homogenates after OPC treatment. Together, these results demonstrate a potent therapeutic effect for OPC in cuprizone-mediated demyelination and clearly highlight multiple effects of this natural product in attenuating myelin-specific autoantibodies and the inflammatory microenvironment in the brain., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

A first-principles electronic structure calculation is utilized to contrastively investigate the crystal structure, band structure, electron effective mass and mobility of perovskite BaSnO 3 under hydrostatic and biaxial strain. Strain-induced changes in relative properties are remarkable and more sensitive to hydrostatic strain than biaxial strain. The structure of BaSnO 3 remains cubic under hydrostatic strain, while it becomes tetragonal under biaxial strain. Originating from the strain sensitivity of the Sn 5s orbitals in the conduction band minimum, the band gaps of BaSnO 3 decrease for both types of strain from -3% to 3%. BaSnO 3 under tensile hydrostatic strain exhibits higher electron mobility than it does under tensile biaxial strain because of the smaller electron effective mass in the corresponding strain. In contrast, the opposite phenomenon exists in compressive strain. Our results demonstrate that strain could be an alternative way to modify the band gap and electron mobility of BaSnO 3 ., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Underground aquifers that took millions of years to fill are being depleted due to unsustainable water withdrawals for crop irrigation. Concurrently, atmospheric warming due to anthropogenic greenhouse gases is enhancing demands for water inputs in agriculture. Accurate information on crop-ecosystem water use efficiencies [EWUE, amount of CO 2 removed from the soil-crop-air system per unit of water used in evapotranspiration (ET)] is essential for developing environmentally and economically sustainable water management practices that also help account for CO 2 , the most abundant of the greenhouse gases, exchange rates from cropping systems. We quantified EWUE of corn (a C 4 crop) and soybean and cotton (C 3 crops) in a predominantly clay soil under humid climate in the Lower Mississippi (MS) Delta, USA. Crop-ecosystem level exchanges of CO 2 and water from these three cropping systems were measured in 2017 using the eddy covariance method. Ancillary micrometeorological data were also collected. On a seasonal basis, all three crops were net sinks for CO 2 in the atmosphere: corn, soybean, and cotton fixed -31,331, -23,563, and -8856 kg ha -1 of CO 2 in exchange for 483, 552, and 367 mm of ET, respectively (negative values show that CO 2 is fixed in the plant or removed from the air). The seasonal NEE estimated for cotton was 72% less than corn and 62% less than soybean. Half-hourly averaged maximum net ecosystem exchange (NEE) from these cropping systems were -33.6, -27.2, and -14.2 kg CO 2  ha -1 , respectively. Average daily NEE were -258, -169, and -65 kg CO 2  ha -1 , respectively. The EWUE in these three cropping systems were 53, 43, and 24 kg CO 2  ha -1  mm -1 of water. Results of this investigation can help in adopting crop mixtures that are environmentally and economically sustainable, conserving limited water resources in the region., (Copyright © 2018. Published by Elsevier B.V.)

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in the pathogenesis of Parkinson's disease (PD). In addition, resveratrol was shown to regulate the expression of MALAT1. Therefore, the objective of this study was to clarify the role of resveratrol in PD. During the study, luciferase assays were conducted to determine the effect of resveratrol on the transcription efficiency of MALAT1 promoter as well as the regulatory relationships among MALAT1, miR-129, and SNCA. In addition, real-time PCR, Western blot analysis, MTT and flow cytometry analyses were conducted to investigate the mechanism of resveratrol in PD. Furthermore, a PD mouse model was established to study the role of resveratrol in vivo. It was found that resveratrol increased the number of TH+ cells and the expression of miR-129, while decreasing the expression of MALAT1 and SNCA. In addition, MALAT1 inhibited the expression of miR-129, a negative regulator of SNCA, thus increasing the expression of SNCA. A further mechanistic study revealed that resveratrol inhibited MALAT1 expression by blocking the transcription of the MALAT1 promoter. Finally, MPTP treatment could decrease cell proliferation and increase cell apoptosis, while resveratrol could partly offset the effect of MPTP. In summary, the therapeutic effect of resveratrol in the treatment of PD can be attributed to its ability to modulate the MALAT1/miR-129/SNCA signaling pathway., (© 2018 Wiley Periodicals, Inc.)

Background: It has been reported that the fastigial nucleus (FSN) plays an important role in the development of vascular dementia (VD). Both autophagy and inflammation are functionally involved in the pathogenesis of VD. In this study, we aimed to evaluate the therapeutic effect of electrical cerebellar fastigial nucleus stimulation (FNS) in VD treatment, as well as the effect of FNS on autophagy and inflammation., Methods: A Morris water maze was used to evaluate the effect of FNS on the learning and memory ability of VD rats. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to study the apoptosis status of neuron cells in different groups of rats. In addition, immunohistochemistry (IHC) assay, real-time polymerase chain reaction, and Western blot analysis were carried out to measure the expression of various factors involved in autophagy and inflammation., Results: Rats with artery occlusion or FSN damages showed longer escape latency and spent less time in the target quadrant. In addition, FNS treatment could help to partly recover the lost learning and memory ability in VD rats. Meanwhile, FNS treatment could alleviate neuron cell apoptosis by downregulating light chain 3-II expression and NLRP3 expression. In addition, the expression of caspase-1, interleukin 1β (IL-1β), and IL-18 was markedly reduced in VD rats treated by FNS., Conclusion: FNS treatment exerted a therapeutic effect during VD treatment by suppressing the autophagy process and by inhibiting inflammatory responses, thus alleviating neuron cell apoptosis and reducing the severity of VD., (© 2018 Wiley Periodicals, Inc.)

Glioma is the most common malignant tumor of the central nervous system, and it is characterized by high relapse and fatality rates and poor prognosis. Bufalin is one of the main ingredients of Chan-su, a traditional Chinese medicine (TCM) extracted from toad venom. Previous studies revealed that bufalin exerted inhibitory effects on a variety of tumor cells. To demonstrate the inhibitory effect of bufalin on glioma cells and glioma stem-like cells (GSCs) and discuss the underlying mechanism, the proliferation of glioma cells was detected by MTT and colony formation assays following treatment with bufalin. In addition, we investigated whether bufalin inhibits or kills GSCs using flow cytometry, Western blotting, and reverse transcription polymerase chain reaction analysis (RT-PCR). Finally, we investigated whether bufalin could improve the therapeutic effect of temozolomide (TMZ) and discussed the underlying mechanism. Taken together, our data demonstrated that bufalin inhibits glioma cell growth and proliferation, inhibits GSC proliferation, and kills GSCs. Bufalin was found to induce the apoptosis of GSCs by upregulating the expression of the apoptotic proteins cleaved caspase 3 and poly(ADP-ribose) polymerase (PARP) and by downregulating the expression of human telomerase reverse transcriptase, which is a marker of telomerase activity. Bufalin also improved the inhibitory effect of TMZ on GSCs by activating the mitochondrial apoptotic pathway. These results suggest that bufalin damages GSCs, induces apoptosis, and enhances the sensitivity of GSCs to TMZ.

Nimodipine might be effective in subcortical vascular dementia (VaD). Its benefit in preventing further cognitive decline in patients with acute ischemic stroke (AIS) and vascular mild cognitive impairment (VaMCI) remains to be established. In this multicenter, double-blind trial, we randomly assigned 654 eligible patients to nimodipine 30 mg three times a day or placebo. The primary outcome was any cognitive decline defined by the changes on the Mini-Mental State Examination (ΔMMSE ≤ -3) or vascular AD assessment scale cognitive subscale (ΔADAS-cog ≥ 4) at 6 months. Secondary outcomes included any distribution shift of ΔADAS-cog, ΔMMSE or cognitive improvement defined by ΔADAS-cog ≤ -2, or ΔMMSE ≥ 0. The primary outcome in the nimodipine group and placebo group were similar for ΔMMSE ≤ -3 (4.18% and 7.22%, respectively, P = 0.15) and ΔADAS-cog ≥ 4 (8.36% and 8.93% respectively, P = 0.88). The distribution shift of ΔADAS-cog and ΔMMSE differed significantly between the two groups (P = 0.03 and P = 0.05 respectively). Cognitive improvement occurred in 55.4% in the nimodipine group and 43.6% in the placebo group measured by ΔADAS-cog ≤ -2 (Odds Ratio, 1.54; 95% confidence interval [CI] 1.10-2.14, P < 0.01) or 84.0% and 74.6% respectively by ΔMMSE ≥ 0 (Odds Ratio, 1.79; 95% CI 1.18-2.70, P < 0.01). Nimodipine was associated with better cognitive function in the memory domain. The adverse events rate was similar in two groups. This study is registered with ClinicalTrials.gov, NCT01220622. Nimodipine did not show benefit to prevent cognitive decline in AIS patients with VaMCI, but improved cognition moderately, especially measured in the memory domain., (Copyright © 2018 Science China Press. Published by Elsevier B.V. All rights reserved.)

Background: Nance-Horan syndrome (NHS) is an X-linked inheritance disorder characterized by bilateral congenital cataracts, and facial and dental dysmorphism. This disorder is caused by mutations in the NHS gene. However, NHS may be difficult to detect in individuals with subtle facial dysmorphism and dental abnormalities in whom congenital cataracts are the primary clinical manifestations., Methods: In this study, we present a three-generation family with NHS. Whole exome sequencing was performed to determine the potential pathogenic variant in the proband. Further validation was explored with Sanger sequencing in 9 of the available individuals of the family and additional 200 controls., Results: A novel truncation mutation in gene NHS (c.C4449G, p.Tyr1483Ter) was found in the proband, who presented with a long-narrow face, prominent nose and large anteverted pinnae ear, screw-driver like incisors, mild mulberry like molars, one missing maxillary second molar and malocclusion. We found this mutation was detected in 2 male patients and 4 female carriers in the family. However, the mutation was never detected in the control subjects., Conclusions: In conclusion, we identified a novel truncation mutation in the NHS gene, which might associate with NHS. Our review on the NHS studies illustrated that NHS has significantly clinical heterogeneity. And NHS mutations in the NHS-affected individuals typically result in premature truncation of the protein. And the new mutation revealed in this study would highlight the understanding of the causative mutations of NHS.

MicroRNA-374a has been abnormally expressed in several cancer types; however, its role in glioma remains unclear. Therefore, we aimed to investigate whether microR-374a participated in the progression of glioma. Expression of microR-374a in glioma cell lines and normal cell line was measured by quantitative real-time polymerase chain reaction. Luciferase reporter assay and Western blot were used to detect the targets of microR-374a. In vitro functional experiments were conducted to investigate the biological role of microR-374a. Low expression of microR-374a was found in glioma cell lines. Prokineticin 2 was identified as a direct target of microR-374a in glioma. Investigations on the mechanisms related to glioma progression showed that microR-374a inhibited glioma cell proliferation, cell cycle progression, and cell invasion through targeting Prokineticin 2. Taken together, these results revealed that microR-374a functions as tumor suppressor by targeting Prokineticin 2, suggesting it might be a novel therapeutic target for glioma.

Retinitis pigmentosa (RP) is an inheritable retina degenerative disease leading to blindness. Despite the identification of 70 genes associated with RP, the genetic cause of ∼40% of RP patients remains to be elucidated. Whole-exome sequencing was applied on the probands of a RP cohort of 68 unsolved cases to identify candidate genetic mutations. A homozygous missense variant (c.173C > T, p.T58 M) was found in HKDC1 in two unrelated families presenting late-onset retinal degeneration. This variant affects highly conserved amino acid residue and is very rare in several databases and absent in 4000 ethnic-matched controls. Mutant HKDC1 protein partially lost hexokinase activity. Hkdc1 is expressed in the mouse retina and localized to photoreceptor inner segments. To elucidate the in vivo roles of Hkdc1 in the retina, we generated Hkdc1 knockout (KO) mouse models using CRISPR/Cas9 technique. Two independent alleles were identified and backcrossed to C57BL/6 J for 6 generations. Absence of HKDC1 expression in the Hkdc1 KO retina was confirmed by western blot and immunostaning using HKDC1 antibody. Hkdc1 KO mice exhibited reduced scotopic electroretinogram response and thinner outer nuclear layer, similar to some of the human patient phenotypes. Loss of Hkdc1 led to mislocalization of rhodopsin to the inner segments and cell bodies of rods in some regions in the retina. Taken together, our data demonstrated that HKDC1 is associated with autosomal recessively inherited RP.

Background: Autosomal-dominant optic atrophy (ADOA) is one of the most common types of inherited optic atrophy. We identify OPA1 pathogenic variants and assess the clinical features of a cohort of Chinese ADOA patients Materials and Methods: Detailed clinical evaluations were performed and genomic DNA was extracted from peripheral blood for all the participants. Sanger sequencing was used to analyze all exons and exon/intron junctions of OPA1 for eight pedigrees. Target exome capture plus next-generation sequencing (NGS) were applied for one atypical family with photophobia. Reverse transcription polymerase chain reaction was carried out to further characterize the mRNA change of selected splicing alteration., Results: All 17 patients had impaired vision and optic-disk pallor; however, the clinical severity varied markedly. Two patients complicated with hearing loss. Six novel and two reported pathogenic variants in OPA1 (GenBank Accession No. NM&#95;130837.2) were identified including four nonsynonymous variants (c.2400T > G, c.1468T > C, c.1567A > G and c.1466T > C), two splicing variants (c.2984-1&#95;2986delGAGA and c.2983 + 5G > A), one small deletion (c.2960&#95;2968delGCGTTCAAC), and one small insertion (c.3009&#95;3010insA). RNA analysis revealed the splicing variant c.2984-1&#95;2986delGAGA caused small deletion of mRNA (r.2983&#95;2988del)., Conclusions: ADOA patients presented variable clinical manifestations. Novel OPA1 pathogenic variants are the main genetic defect for Chinese ADOA cases. NGS may be a useful molecular testing tool for atypical ADOA.

Cadmium (Cd) is a severely toxic heavy metal and environmental pollutant. Tall fescue is a cold season turf grass which has high resistance to Cd as well as the ability to enrich it. To investigate the molecular mechanism underlying the adaptability of tall fescue to Cd stress, RNA-Seq was used to examine Cd stress responses of tall fescue at a transcriptional level. A total of 12 cDNA libraries were constructed from the total RNA of roots or leaves of tall fescue with or without Cd treatments. A total of 2594 (1768 up- and 826 down-regulated) differentially expressed genes (DEGs) were detected in the roots of Cd-stressed tall fescue compared with control roots (R&#95;cd vs R&#95;ck), while only 52 (29 up- and 23 down-regulated) DEGs were found in the leaves of Cd-stressed plants versus the controls (L&#95;cd vs L&#95;ck). The genes encoding glutathione S-transferase (GST), transporter proteins including the ABC transporter, ZRT/IRT-like protein, potassium transporter/channel, nitrate transporter, putative iron-phytosiderophore transporter, copper-transporting ATPase or transporter and multidrug and toxic compound extrusion (MATE) proteins, and numerous transcription factors were found to be significantly induced in Cd-treated roots. In addition, pathogenesis/disease-related gene mRNAs were accumulated in Cd-treated roots of tall fescue. Furthermore, the significantly enriched KEGG pathways in roots were related to 'Glutathione metabolism', 'Ribosome', 'alpha-Linolenic acid metabolism', 'Diterpenoid biosynthesis', 'Sulfur metabolism', 'Phenylpropanoid biosynthesis', 'Protein processing in endoplasmic reticulum', 'Protein export' and 'Nitrogen metabolism'. The study provides novel insights for further understanding the molecular mechanisms of tall fescue responses to Cd stress., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Nance-Horan syndrome is a rare X-linked recessive inherited disease with clinical features including severe bilateral congenital cataracts, characteristic facial and dental abnormalities. Data from Chinese Nance-Horan syndrome patients are limited. We assessed the clinical manifestations of a Chinese Nance-Horan syndrome pedigree and identified the genetic defect. Genetic analysis showed that 3 affected males carried a novel small deletion in NHS gene, c.263&#95;266delCGTC (p.Ala89TrpfsTer106), and 2 female carriers were heterozygous for the same variant. All 3 affected males presented with typical Nance-Horan syndrome features. One female carrier displayed lens opacities centered on the posterior Y-suture in both eyes, as well as mild dental abnormalities. We recorded the clinical features of a Chinese Nance-Horan syndrome family and broadened the spectrum of mutations in the NHS gene.

Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403&#95;2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X-linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR., (© 2017 Wiley Periodicals, Inc.)

Purpose: This study aims to describe the phenotypes and identify pathogenic mutations in Chinese patients who have congenital cataracts associated with other ocular abnormalities., Methods: Eleven patients from four unrelated Chinese families plus two simplex cases were enrolled in this study. Detailed ophthalmic examinations were performed. DNA samples were isolated from peripheral blood collected from the patients. Next-generation sequencing of known ocular genes was applied to the proband of each family and two simplex cases to find pathogenic variances. PCR and Sanger sequencing were conducted for validation and segregation tests., Results: All 13 patients had congenital cataracts, and other ocular abnormalities were found in some cases. Microcornea was found in 12 subjects, and ocular coloboma was observed in five. Various types of coloboma, including iris, choroid, macular, and optic disc, were described. Five mutations in crystallin genes were identified. Four of the mutations are novel: CRYBB1 : p.(Arg230Cys), CRYBB2 : p.(Gly149Val), CRYGC : p.(Met44CysfsTer59), and CRYGC : p.(Tyr144Ter). One mutation was reported previously: CRYAA : p.(Arg21Trp)., Conclusions: We examined a cohort of Chinese patients with congenital cataracts and studied the phenotypes and genotypes. Extralenticular abnormalities, such as microcornea and ocular coloboma, can also be found in patients with congenital cataracts. The phenotype of congenital cataracts associated with macular and optic disc coloboma was reported for the first time in this study. Four novel mutations and one previously reported mutation were identified. These data expand the mutation spectrum in crystallin genes and enhance our understanding of the phenotypes of congenital cataracts.

Choroidermia (CHM) is an X-linked chorioretinal disorder caused by mutations in the Rab Escort Protein 1 (Rep-1) gene. Its diagnosis depends on clinical findings and genetic confirmation; however, mutations in Rep-1 gene are not always detected by standard Sanger sequencing. We therefore conducted multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (QPCR) in cases of Chinese CHM families in which sequencing all the exons and flanking intronic regions of the CHM gene had not identified a mutation or exons could not be amplified. We hypothesized that copy number variation (CNV) within the Rep-1 gene would explain the etiology of choroideremia in these patients. In the eight unrelated families, exon deletions or duplications were detected by MLPA and QPCR in five. Our results showed CNV within the Rep-1 gene could be an important contributor in Chinese CHM patients. Sequencing of the Rep-1 gene supplemented with MLPA is therefore an important diagnostic strategy in choroideremia patients., (Copyright © 2017. Published by Elsevier Ltd.)

The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here, we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice-affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation. An in vitro minigene system was used to assay each variant's effect on splicing. Starting with 745 IRD patients lacking a confident molecular diagnosis, we validated 23 VUS as splicing variants that likely explain disease in 26 patients. Using our results, we optimized in silico score cutoffs to guide future variant interpretation. Variants that alter base pairs other than the canonical GT-AG dinucleotide are often not considered for their potential effect on RNA splicing but in silico tools and a minigene system can be utilized for the prioritization and validation of such splice-disrupting variants. These variants can be overlooked causes of human disease but can be identified using conventional exon sequencing with proper interpretation guidelines., (© 2017 Wiley Periodicals, Inc.)

The neurochemical changes that occur in the brain of patients with post-stroke depression (PSD) are not fully understood. This study aims to explore the correlation between cerebellar metabolism changes and PSD using proton magnetic resonance spectroscopy ( 1 H-MRS). Participants were assigned to 3 groups: 60 patients with PSD (PSD group), 60 stroke patients without depression (NOPSD group), and 60 healthy volunteers (HEAL group). T1 WI, T2 WI, DWI and 1 H-MRS examination were performed for patients at 14 days, 3 months after the stroke, respectively, and for healthy volunteers once when included in the study. Cho/Cr and Cho/NAA ratios in the cerebellar hemisphere contralateral to the lesion were higher in the PSD group than those in the HEAL and NOPSD groups on 14th day after the stroke ( P < 0.05). In PSD group, Cho/Cr and Cho/NAA ratios in the cerebellar hemisphere contralateral to the lesion were positively correlated to the HAMD scale scores at both 14 days and 3 months after stroke ( P < 0.05); Higher Cho/Cr and Cho/NAA ratios, and lower NAA/Cr ratio in the cerebellar hemisphere contralateral to the lesion were observed at 3 months after stroke compared to that at 14 days after stroke. Cerebellar damage may lead to PSD, and the degree of cerebellar damage may be associated with severity of PSD., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of Mendelian disorders primarily affecting photoreceptor cells. The same IRD-causing variant may lead to different retinal symptoms, demonstrating pleiotropic phenotype traits influenced by both underlying genetic and environmental factors. In the present study, we identified four unrelated IRD families with the HK1 p.E851K variant, which was previously reported to cause autosomal dominant retinitis pigmentosa (RP), and described their detailed clinical phenotypes. Interestingly, we found that in addition to RP, this particular variant can also cause dominant macular dystrophy and cone-rod dystrophy, which primarily affect cone photoreceptors instead of rods. Our results identified pleiotropic effects for an IRD-causing variant and provide more insights into the involvement of a hexokinase in retinal pathogenesis.