Effects of apocynin on ISO-induced delayed afterdepolarizations in rat atrial myocytes and the underlying mechanisms.

We aimed to investigate the effect of apocynin (APO) on delayed afterdepolarizations (DADs) in rat atrial myocytes and the underlying mechanisms. Rat atrial myocytes were isolated by a Langendorff perfusion apparatus. DADs were induced by isoproterenol (ISO). Action potentials (APs) and ion currents were recorded by the whole-cell clamp technique. The fluorescent indicator fluo-4 was used to visualize intracellular Ca2+ transients, and western blotting was used to measure the expression of related proteins. The incidence of DADs in rat atrial myocytes increased significantly after ISO treatment, leading to an increased incidence of triggered activity (TA). The incidence of ISO-induced DADs and TA were reduced by 100.0 µM APO from 48.89% to 25.56% and 17.78% to 5.56%, respectively. In the range of 3.0 µM-300.0 µM, the effect of APO was concentration dependent, with a half maximal inhibitory concentration (IC50) of 120.1 µM and a Hill coefficient of 1.063. APO reversed the increase in transient inward current (Iti) and Na+/Ca2+-exchange current (INCX) densities induced by ISO in atrial myocytes. The frequency of spontaneous Ca2+ transients in atrial myocytes was reduced by 100.0 µM APO. Compared with ISO, APO downregulated the expression of NOX2 and increased the phosphorylation of PLNSer16 and the sarcoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) level; however, it had little effect on ryanodine-receptor channel type-2 (RyR2). These findings showed that APO may block Iti and INCX and reduce intracellular Ca2+ levels in rat atrial myocytes, thus reducing the incidence of ISO-induced DADs and TA.

Mutational investigation of 17 causative genes in a cohort of 113 families with nonsyndromic early-onset high myopia in northwestern China.

High myopia (HM) is a leading cause of visual impairment in the world. To expand the genotypic and phenotypic spectra of HM in the Chinese population, we investigated genetic variations in a cohort of 113 families with nonsyndromic early-onset high myopia from northwestern China by whole-exome sequencing, with focus on 17 known genes. Sixteen potentially pathogenic variants predicted to affect protein function in eight of seventeen causative genes for HM in fifteen (13.3%) families were revealed, including seven novel variants, c.767 + 1G > A in ARR3, c.3214C > A/p.H1072N, and c.2195C > T/p.A732V in ZNF644, c.1270G > T/p.V424L in CPSF1, c.1918G > C/p.G640R and c.2786T > G/p.V929G in XYLT1, c.601G > C/p.E201Q in P4HA2; six rare variants, c.799G > A/p.E267K in NDUFAF7, c.1144C > T/p.R382W in TNFRSF21, c.1100C > T/p.P367L in ZNF644, c.3980C > T/p.S1327L in CPSF1, c.145G > A/p.E49K and c.325G > T/p.G109W in SLC39A5; and three known variants, c.2014A > G/p.S672G and c.3261A > C/p.E1087D in ZNF644, c.605C > T/p.P202L in TNFRSF21. Ten of them were co-segregated with HM. The mean (± SD) examination age of these 15 probands was 14.7 (± 11.61) years. The median spherical equivalent was - 9.50 D (IQ - 8.75 ~ - 12.00) for the right eye and - 11.25 D (IQ - 9.25 ~ - 14.13) for the left eye. The median axial length was 26.67 mm (IQ 25.83 ~ 27.13) for the right eye and 26.25 mm (IQ 25.97 ~ 27.32) for the left eye. These newly identified genetic variations not only broaden the genetic and clinical spectra, but also offer convincing evidence that the genes ARR3, NDUFAF7, TNFRSF21, and ZNF644 contribute to hereditable HM. This work improves further understanding of molecular mechanism of HM.

Genetic detection of two novel LRP5 pathogenic variants in patients with familial exudative vitreoretinopathy.

BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation. METHODS: Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease. RESULTS: A 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein. CONCLUSIONS: Two novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.

Mutational screening of AGRN, SLC39A5, SCO2, P4HA2, BSG, ZNF644, and CPSF1 in a Chinese cohort of 103 patients with nonsyndromic high myopia.

Purpose: High myopia (HM) is one of the leading causes of irreversible vision loss in the world. Many myopia loci have been uncovered with linkage analysis, genome-wide association studies, and sequencing analysis. Numerous pathogenic genes within these loci have been detected in a portion of HM cases. In the present study, we aimed to investigate the genetic basis of 103 patients with nonsyndromic HM, focusing on the reported causal genes. Methods: A total of 103 affected individuals with nonsyndromic HM were recruited, including 101 patients with unrelated sporadic HM and a mother and son pair. All participants underwent comprehensive ophthalmic examinations, and genomic DNA samples were extracted from the peripheral blood. Whole exome sequencing was performed on the mother and son pair as well as on the unaffected father. Sanger sequencing was used to identify mutations in the remaining 101 patients. Bioinformatics analysis was subsequently applied to verify the mutations. Results: An extremely rare mutation in AGRN (c.2627A>T, p.K876M) was identified in the mother and son pair but not in the unaffected father. Another two mutations in AGRN (c.4787C>T, p.P1596L/c.5056G>A, p.G1686S) were identified in two unrelated patients. A total of eight heterozygous variants potentially affecting the protein function were detected in eight of the remaining 99 patients, including c.1350delC, p.V451Cfs*76 and c.1023_1024insA, p.P342Tfs*41 in SLC39A5; c.244_246delAAG, p.K82del in SCO2; c.545A>G, p.Y182C in P4HA2; c.415C>T, p.P139S in BSG; c.3266A>G, p.Y1089C in ZNF644; and c.2252C>T, p.S751L and c.1708C>T, p.R570C in CPSF1. Multiple bioinformatics analyses were conducted, and a comparison to a group with geographically matched controls was performed, which supported the potential pathogenicity of these variants. Conclusions: We provide further evidence for the potential role of AGRN in HM inheritance and enlarged the current genetic spectrum of nonsyndromic HM by comprehensively screening the reported causal genes.

Association of Single-Nucleotide Polymorphisms in ABCC5 Gene with Primary Angle Closure Glaucoma and the Ocular Biometric Parameters in a Northern Chinese Population.

BACKGROUND: The rs1401999 gene in ABCC5 gene was the first locus confirmed by a genome-wide association study (GWAS) to be associated with both anterior chamber depth (ACD) and primary angle closure glaucoma (PACG); however, this locus was of obvious heterogeneity among different populations in the GWAS, and the conclusion has not been further verified by other studies. Therefore, this study was carried out to investigate whether the single-nucleotide polymorphisms (SNPs) in ABCC5 gene are associated with PACG and the ocular biometric parameters ACD and axial length (AL) in samples from northern China. METHODS: Case-control association study included 500 PACG patients and 720 unrelated controls from northern China, and genotyping was performed for ten SNPs in ABCC5 gene using an improved multiplex ligation detection reaction technique. The association between these SNPs and risk of PACG was estimated by PLINK using a logistic regression model, while the association between genotypes and ocular biometric parameters was performed by SPSS using generalized estimation equation. RESULTS: An SNP rs4148568 (p = 0.046) and a haplotype TCGGAG (p = 0.0364) in ABCC5 were associated with PACG, and rs4148568 was nominally associated with AL (ß = 0.092, p = 0.08). CONCLUSIONS: The SNP rs4148568 and a haplotype TCGGAG in ABCC5 contribute to PACG in northern Chinese people. In addition, rs4148568 might be associated with the AL, the variant allele of which may have effect of making the AL longer. Further studies are needed to elucidate the exact mechanism of ABCC5 in the progress of PACG.

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia.

The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to -6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in as-yet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.

Association of Genes implicated in primary angle-closure Glaucoma and the ocular biometric parameters of anterior chamber depth and axial length in a northern Chinese population.

BACKGROUND: The membrane frizzled-related protein (MFRP) gene is involved in axial length (AL) regulation and MFRP mutations cause nanophthalmos; also, the hepatocyte growth factor (HGF) gene is reported to result in morphologic changes of the anterior segment and abnormal aqueous regulation that increases the risk of primary angle-closure glaucoma (PACG), while the zinc ring finger 3 (ZNRF3) gene is associated with AL. The present study investigated the association of single nucleotide polymorphisms (SNPs) in ZNRF3, HGF and MFRP with PACG in a northern Chinese population, as well as the association of these SNPs with the ocular biometric parameters of anterior chamber depth (ACD) and AL. METHODS: A total of 500 PACG patients and 720 controls were recruited. All individuals were genotyped for 12 SNPs in three genes (rs7290117, rs2179129, rs4823006 and rs3178915 in ZNRF3; rs5745718, rs12536657, rs12540393, rs17427817 and rs3735520 in HGF, rs2510143, rs36015759 and rs3814762 in MFRP) using an improved multiplex ligation detection reaction (iMLDR) technique. Genotypic distribution was analyzed for Hardy-Weinberg equilibrium. Differences in the allelic and genotypic frequencies were evaluated and adjusted by age and sex. Linkage disequilibrium (LD) patterns were tested and haplotype analysis was conducted by a logistic regression model. Generalized estimation equation (GEE) analysis was conducted using SPSS for primary association testing between genotypes and ocular biometric parameters. Bonferroni corrections for multiple comparisons were performed, and the statistical power was calculated by power and sample size calculations. RESULTS: The rs7290117 SNP in ZNRF3 was significantly associated with the AL, with a p-value of 0.002. We did not observe any significant associations between the SNPs and PACG or ACD. In a stratification analysis by ethnicity, rs12540393 and rs17427817 in HGF showed a nominal association with PACG in the Hui cohort, although significance was lost after correction. CONCLUSIONS: The present study suggests rs7290117 in ZNRF3 may be involved in the regulation of AL, though our results do not support a contribution of the SNPs we tested in ZNRF3, HGF and MFRP to PACG in northern Chinese people. Further studies in a larger population are warranted to confirm this conclusion.

GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.

PURPOSE: The aim of this study was to investigate the genetic basis and pathogenic mechanism of variable maculopathies, ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy, in a five-generation family. METHODS: Clinical characterizations, whole-exome sequencing, and genome-wide linkage analysis were carried out on the family. Zebrafish models were used to investigate the pathogenesis of GUCA1A mutations. RESULTS: A novel mutation, GUCA1A p.R120L, was identified in the family and predicted to alter the tertiary structure of guanylyl cyclase-activating protein 1, a photoreceptor-expressed protein encoded by the GUCA1A gene. The mutation was shown in zebrafish to cause significant disruptions in photoreceptors and retinal pigment epithelium, together with atrophies of retinal vessels and choriocapillaris. Those phenotypes could not be fully rescued by exogenous wild-type GUCA1A, suggesting a likely gain-of-function mechanism for p.R120L. GUCA1A p.D100E, another mutation previously implicated in cone dystrophy, also impaired the retinal pigment epithelium and photoreceptors in zebrafish, but probably via a dominant negative effect. CONCLUSION: We conclude that GUCA1A mutations could cause significant variability in maculopathies, including central areolar choroidal dystrophy, which represents a severe pattern of maculopathy. The diverse pathogenic modes of GUCA1A mutations may explain the phenotypic diversities.Genet Med advance online publication 26 January 2017.

[Association study of insulin-like growth factor-1 polymorphisms with extreme high myopia].

OBJECTIVE: To investigate whether the polymorphisms of insulin-like growth factor-1 (IGF-1) gene and its regulatory regions are associated with extreme high myopia. METHODS: A case-control analysis of 302 subjects with extreme high myopia and 401 controls was undertaken. Genomic DNA was obtained from peripheral blood. Seven tag single nucleotide polymorphisms (tSNP) across the IGF-1 gene region were selected to capture the majority of genetic variation. All tSNP were genotyped using the MassArray platform and MALDI-TOF analysis. Genotypic distribution was tested for Hardy-Weinberg equilibrium. Statistical analyses were performed using the SPSS (version 13.0: SPSS Science, Chicago, IL) software. The genotype and allele frequencies were evaluated using the χ(2) tests and performed by Bonferroni corrections for multiple comparisons. The significance of the differences in the estimated haplotype frequencies between the myopia and control groups was examined on Haploview 4.2 using χ(2) tests, and haplotypes were corrected by using permutation test after running 50 000 times. RESULTS: Among seven different IGF-1 tSNP tested, the allele frequencies of four tSNP-rs5742629(A/G), rs12423791(G/C), rs35766 (G/A) and rs1457601(T/A) in the myopia and the control groups were A(56.5%, 62.3%)/G(43.5%, 27.7%), G(70.4%, 77.1%)/C(29.6%, 22.9%), G(33.9%, 28.8%)/A(66.1%, 71.2%), T(72.5%, 77.3%)/A(27.5%, 22.7%), respectively. And they showed significant differences (χ(2) = 4.968, 8.059, 4.250, 4.245, P < 0.05) between the two groups. However, only rs12423791 remained significance after Bonferroni correction. The haplotype GC of rs5742629-rs12423791 was associated with extreme high myopia (P = 0.033) after 50 000 permutations for multiple comparisons as well. CONCLUSIONS: The polymorphism of rs12423791 in IGF-1 may be associated with extreme high myopia in the Chinese population.

Screening of genes interacting with high myopia and neuropsychiatric disorders.

Clinical studies have demonstrated an association between high myopia (HM) and neuropsychiatric disorders; however, the underlying mechanism of the association is not clear. We used whole exome sequencing (WES) in combination with the Genetic Variants Classification Criteria and Guidelines published by the American College of Medical Genetics (ACMG) and bioinformatics analysis to clarify the interrelationship between candidate genes. Causative genes for ocular diseases (45.38%) followed by neuropsychiatric disorders (22.69%) accounted for the highest proportion of genes that exhibited high pathogenicity in HM patients were found. Four pathogenic gene mutations were identified according to ACMG guidelines: c.164_165insACAGCA and c.C1760T in POLG, c.G1291A in COL5A1, and c.G10242T in ZNF469. Three causative genes for neuropsychiatric diseases, PTPRN2, PCDH15 and CDH23, were found to fall at the HM locus. The above results suggest that these genes may interact in high myopia and neuropsychiatric diseases.

Clinical and genetic analysis VSX1 variants among families with keratoconus in northwest China.

Purpose: To screen VSX1 gene sequence variations and describe the clinical features of families with keratoconus (KC) from northwest China. Methods: We screened VSX1 sequence variations and clinical data of 37 families including 37 probands with diagnosed KC from Ningxia Eye Hospital (China). VSX1 was screened by targeted next-generation sequencing (NGS) and verified by Sanger sequencing. In silico analysis including Mutation Taster, MutationAssessor, PROVEAN, MetaLR, FATHMM, M-CAP, FATHMM-XF_coding and DANN was performed to identify the pathogenicity of the sequence variations as well as the conserved amino acid variations of VSX1 was implemented by Clustal X. All subjects were assessed in Pentacam Scheimpflug tomography and corneal biomechanical Corvis ST examinations. Results: Five VSX1 gene variants, were identified in six (16.2%) unrelated families with KC. In silico analysis predicted deleterious effects of the three missense variants (p.G342E, p.G160V, and p.L17V) in the encoded protein. Another previously reported synonymous variation (p.R27R) in the first exon and one heterozygous change in the first intron (c.425-73C>T) were identified in three KC families. Clinical examination of the asymptomatic first-degree parents from these six families who shared the gene with the proband had suspected KC changes in topographic and biomechanical markers. These variants co-segregated with the disease phenotype in all affected individuals but not in unaffected family members or healthy controls, though with variable expressivity. Conclusion: The variant p.G342E of VSX1 is implicated in the pathogenesis of KC, which expands the range of the spectrum of VSX1 mutations with an autosomal dominant inheritance pattern and variable expression in the clinical phenotype. Genetic screening combined with clinical phenotype may help in the genetic counseling of patients with KC and identification of individuals with subclinical KC.

Association of insulin-like growth factor-1 polymorphisms with high myopia in the Chinese population.

PURPOSE: The purpose of this study was to determine whether genetic variants in the insulin-like growth factor-1 (IGF-1) gene were associated with high myopia in the Chinese population. METHODS: A case-control association study of 421 unrelated Chinese patients with high myopia and 401 control subjects matched in ethnicity and gender was undertaken. Genomic DNA was prepared from peripheral blood. All individuals were genotyped for 7 tag single nucleotide polymorphisms (tSNPs) across the IGF-1 gene region. Genotypic distribution was tested for Hardy-Weinberg equilibrium. The genotype and allele frequencies were evaluated using the χ(2) tests. Bonferroni corrections for multiple comparisons were performed. RESULTS: The polymorphism of rs12423791 showed positive association with extreme myopia (p(allel)=0.006 and p(allel1 recessive model)=0.004, respectively) after Bonferroni correction for multiple testing and the haplotype GC of rs5742629-rs12423791 was also associated with extreme myopia (p=0.033) after 50,000 permutations for multiple comparisons. CONCLUSIONS: The polymorphism of rs12423791 in IGF-1 may be associated with extreme myopia in the Chinese population and should be investigated further.

Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study.

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD). METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1. RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1. CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

[Novel RPGR gene mutation in a Chinese family with X-linked recessive retinitis pigmentosa].

OBJECTIVE: To screen the mutation in the RPGR gene in a large Chinese family with X-linked recessive retinitis pigmentosa (RP) and to describe the phenotype in affected males and female carriers. METHODS: Ophthalmic examinations were performed in 77 family members of a RP pedigree to identify affected individuals. Polymerase chain reaction (PCR) and direct sequencing were used for screening of mutations in RPGR gene exon ORF15. RESULTS: Mutation screening demonstrated a novel mutation, g.ORF15 + 577_578delAG, which caused an open reading frameshift and resulted in premature truncation of the RPGR protein. This mutation was detected in 8 affected male individuals and 14 obligate female carriers in this family and was found to segregate with the phenotype in this family. This mutation led to a severe RP phenotype in male affected individuals with some variability in the age of onset of night blindness and loss of visual acuity, but was recessive in female carriers without a RP phenotype. However the most striking phenotypic feature in female carriers in this pedigree was moderate to high myopia with refractive error ranging from -5.00 D to -22.00 D in 14 female carriers. CONCLUSIONS: This novel mutation in RPGR ORF15 causes serious RP phenotype in males and no RP phenotype in female carriers. Moderate to high myopia was a particular feature for female carriers in this pedigree. Our finding expands the spectrum of RPGR mutations causing RP and phenotypic spectrum of the disease in Chinese family, which is useful for further genetic consultation and genetic diagnosis.

Whole-Exome Sequencing in a Cohort of High Myopia Patients in Northwest China.

High myopia (HM) is one of the leading causes of visual impairment worldwide. In order to expand the myopia gene spectrum in the Chinese population, we investigated genetic mutations in a cohort of 27 families with HM from Northwest China by using whole-exome sequencing (WES). Genetic variations were filtered using bioinformatics tools and cosegregation analysis. A total of 201 candidate mutations were detected, and 139 were cosegregated with the disease in the families. Multistep analysis revealed four missense variants in four unrelated families, including c.904C>T (p.R302C) in CSMD1, c.860G>A (p.R287H) in PARP8, c.G848A (p.G283D) in ADAMTSL1, and c.686A>G (p.H229R) in FNDC3B. These mutations were rare or absent in the Exome Aggregation Consortium (ExAC), 1000 Genomes Project, and Genome Aggregation Database (gnomAD), indicating that they are new candidate disease-causing genes. Our findings not only expand the myopia gene spectrum but also provide reference information for further genetic study of heritable HM.

Ligand bridging-angle-driven assembly of molecular architectures based on quadruply bonded Mo-Mo dimers.

A systematic exploration of the assembly of Mo2(O2C-)4-based metal-organic molecular architectures structurally controlled by the bridging angles of rigid organic linkers has been performed. Twelve bridging dicarboxylate ligands were designed to be of different sizes with bridging angles of 0, 60, 90, and 120° while incorporating a variety of nonbridging functional groups, and these ligands were used as linkers. These dicarboxylate linkers assemble with quadruply bonded Mo-Mo clusters acting as nodes to give 13 molecular architectures, termed metal-organic polygons/polyhedra with metal cluster node arrangements of a linear shape, triangle, octahedron, and cuboctahedron/anti-cuboctahedron. The syntheses of these complexes have been optimized and their structures determined by single-crystal X-ray diffraction. The results have shown that the shape and size of the resulting molecular architecture can be controlled by tuning the bridging angle and size of the linker, respectively. Functionalization of the linker can adjust the solubility of the ensuing molecular assembly but has little or no effect on the geometry of the product. Preliminary gas adsorption, spectroscopic, and electrochemical properties of selected members were also studied. The present work is trying to enrich metal-containing supramolecular chemistry through the inclusion of well-characterized quadruply bonded Mo-Mo units into the structures, which can widen the prospect of additional electronic functionality, thereby leading to novel properties.

A novel mutation in retinitis pigmentosa GTPase regulator gene with a distinctive retinitis pigmentosa phenotype in a Chinese family.

PURPOSE: To screen the mutation in the retinitis pigmentosa GTPase regulator (RPGR) ORF15 in a large Chinese family with X-linked recessive retinitis pigmentosa and describe the phenotype in affected male and female carriers. METHODS: Ophthalmic examination was performed on 77 family members to identify affected individuals and to characterize the disease phenotype. PCR and direct sequencing were used for screening mutations in the RPGR gene. RESULTS: Mutation screening demonstrated a novel mutation ORF15+577_578 delAG, which caused an open reading frameshift and resulted in premature truncation of the RPGR protein. The mutation was detected in eight affected male individuals and 14 obligate female carriers of the family and was found to segregate with the phenotype in this family. The mutation led to a severe retinitis pigmentosa (RP) phenotype in male-affected individuals, with some variability in the age of onset of night blindness and visual acuity, but was recessive in female carriers without an RP phenotype. However, the state associated with the carrier was moderate to high myopia with the refractive error ranging from -5.00 D to 22.00 D in 14 female carriers. CONCLUSIONS: This novel mutation in RPGR ORF15 causes a serious RP phenotype in males and no RP phenotype in female carriers. Moderate to high myopia was a particular feature for female carriers in this pedigree. Our finding expands the spectrum of RPGR mutations causing X-linked RP and expands phenotypic spectrum of the disease in a Chinese family. This finding will be useful for further genetic consultations and genetic diagnosis.

Scleral HIF-1α is a prominent regulatory candidate for genetic and environmental interactions in human myopia pathogenesis.

BACKGROUND: Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression. METHODS: Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro. RESULTS: All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia. INTERPRETATION: Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors. FUNDING: National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.

A three-dimensional porous metal-organic framework constructed from two-dimensional sheets via interdigitation exhibiting dynamic features.

A three-dimensional porous metal-organic framework (PCN-18) was constructed through interdigitating two-dimensional grid sheets composed of 4,4'-(anthracene-9,10-diyl)dibenzoate and copper paddlewheel secondary building units, and its dynamic features were evidenced by gas sorption isotherms.

Influence of Flue Gas Injection on the Long-Term Durability of a Natural Draft Concrete Cooling Tower.

The article undertakes the very important topic of the long-term durability of concrete in a natural draft concrete cooling tower with flue gas injection. The corrosive conditions, including temperature, relative humidity, and CO2 and SO2 gas concentrations, near the inner wall of a cooling tower with flue gas injection were monitored in real time to obtain the long-term durability performance of concrete. The pH and chemical compositions of the condensed liquid that adhered to the tower's inner face and the macromorphology, compressive strength, and neutralization depth of in situ specimens were tested periodically. In addition, a finite element numerical simulation was conducted to simulate and verify the concentration distributions of CO2 and SO2 in the flue gas in the cooling tower. The results showed that the cleaned flue gas was enveloped, diluted, and uplifted by hot vapor in the cooling tower, and its concentration decreased. Meanwhile, the effective diffusion radius increased gradually as the flue gas rose. With the same elevation in the cooling tower, the concentration of flue gas decreased rapidly from the central point to the surrounding area. The air near the inner surface of the cooling tower was merely dampened air with a low concentration of acidic gas due to the gigantic diameter of the cooling tower. As a result, the injection of cleaned flue gas will not evidently increase the corrosion risk in a natural draft concrete cooling tower.