DataSheet1_Analysis of RPGR gene mutations in 41 Chinese families affected by X-linked inherited retinal dystrophy.PDF

Background: This study analyzed the phenotypes and genotypes of 41 Chinese families with inherited retinal dystrophy (IRD) and RPGR gene mutations.Methods: This retrospective analysis evaluated a cohort of 41 patients who were subjected to a specific Hereditary Eye Disease Enrichment Panel (HEDEP) analysis. All (likely) pathogenic variants were determined by Sanger sequencing, and co-segregation analyses were performed on the available family members. All cases were subjected to Sanger sequencing for RPGR open reading frame 15 (ORF15) mutations.Results: A total of 41 probands from different families with a clinical diagnosis of retinitis pigmentosa (RP; 34 cases) and cone-rod dystrophy (CORD; 7 cases) were included in this cohort. According to clinical information, 2, 18, and 21 cases were first assigned as autosomal dominant (AD), sporadic, and X-linked (XL) inheritance, respectively. Several cases of affected females who presented with a male phenotype have been described, posing challenges at diagnosis related to the apparent family history of AD. Mutations were located in RPGR exons or introns 1–14 and in ORF15 of 12 of 41 (29.3%) and 29 of 41 (70.7%) subjects, respectively. Thirty-four (likely) pathogenic mutations were identified. Frameshifts were the most frequently observed variants, followed by nonsense, splice, and missense mutations. Herein, a detailed description of four RP patients carrying RPGR intronic mutations is reported, and in vitro splice assays were performed to confirm the pathogenicity of these intronic mutations.Conclusion: Our findings provide useful insights for the genetic and clinical counseling of patients with XL IRD, which will be useful for ongoing and future gene therapy trials.</p

International Criminal Tribunal for Rwanda

ROC curves of phenotype similarity matrices constructed with or without title portions. ROC analysis with the two benchmark datasets (A: Phenotypic Series, B: Linked OMIM Record Pairs) suggested that the similarity matrix constructed with both the text and title portions of OMIM records outperformed the matrix constructed with the text portion only. The range of false positive rates was restricted to (0, 0.1) in order to highlight the differences between each curve. (PDF 270 kb

Nanocomposite of N‑Doped TiO₂ Nanorods and Graphene as an Effective Electrocatalyst for the Oxygen Reduction Reaction

Developing an effective electrocatalyst for the oxygen reduction reaction is a momentous issue in fuel cells. In this paper, we successfully synthesized the N-doped TiO₂ nanorods/graphene (N-TiO₂/NG) nanocomposite, which comprise the N-doped TiO₂ (N-TiO₂) nanorods (40–60 nm diameter and 90–300 nm length) and self-assembled nitrogen-doped graphene (NG) networks. We found that the nanocomposite exhibits great oxygen reduction reaction (ORR) electrocatalytic performance and also shows long durability and methanol tolerance than that of the commercial 20% Pt/C catalyst. This new nanocomposite may also have potential applications in other fields, which are related to energy storage, gas sensors, photocatalysis, and so on

Atomic-Scale Insight into Tautomeric Recognition, Separation, and Interconversion of Guanine Molecular Networks on Au(111)

Although tautomerization may directly affect the chemical or biological properties of molecules, real-space investigation on the tautomeric behaviors of organic molecules in a larger area of molecular networks has been scarcely reported. In this paper, we choose guanine (G) molecule as a model system. From the interplay of high-resolution scanning tunneling microscopy (STM) imaging and density functional theory (DFT) calculations, we have successfully achieved the tautomeric recognition, separation, and interconversion of G molecular networks (formed by two tautomeric forms G/9H and G/7H) with the aid of NaCl on the Au(111) surface in ultrahigh vacuum (UHV) conditions. Our results may serve as a prototypical system to provide important insights into tautomerization related issues, which should be intriguing to biochemistry, pharmaceutics, and other related fields

Additional file 1: Figure S1. of SoftPanel: a website for grouping diseases and related disorders for generation of customized panels

ROC curves of phenotype similarity matrices constructed with or without title portions. ROC analysis with the two benchmark datasets (A: Phenotypic Series, B: Linked OMIM Record Pairs) suggested that the similarity matrix constructed with both the text and title portions of OMIM records outperformed the matrix constructed with the text portion only. The range of false positive rates was restricted to (0, 0.1) in order to highlight the differences between each curve. (PDF 270 kb

Atomic-Scale Investigation on the Facilitation and Inhibition of Guanine Tautomerization at Au(111) Surface

Nucleobase tautomerization might induce mismatch of base pairing. Metals, involved in many important biophysical processes, have been theoretically proven to be capable of affecting tautomeric equilibria and stabilities of different nucleobase tautomers. However, direct real-space evidence on demonstrating different nucleobase tautomers and further revealing the effect of metals on their tautomerization at surfaces has not been reported to date. From the interplay of high-resolution STM imaging and DFT calculations, we show for the first time that tautomerization of guanine from G/9H to G/7H is facilitated on Au(111) by heating, whereas such tautomerization process is effectively inhibited by introducing Ni atoms due to its preferential coordination at the N7 site of G/9H. These findings may help to elucidate possible influence of metals on nucleobase tautomerization and provide from a molecular level some theoretical basis on metal-based drug design

Formation of a G‑Quartet-Fe Complex and Modulation of Electronic and Magnetic Properties of the Fe Center

Although the G-quartet structure has been extensively investigated due to its biological importance, the formation mechanism, in particular, the necessity of metal centers, of an isolated G-quartet on solid surfaces remains ambiguous. Here, by using scanning tunneling microscopy under well-controlled ultra-high-vacuum conditions and density functional theory calculations we have been able to clarify that besides the intraquartet hydrogen bonding a metal center is mandatory for the formation of an isolated G-quartet. Furthermore, by subtly perturbing the local coordination bonding schemes within the formed G-quartet complex <i>via</i> local nanoscale scanning tunneling microscopy manipulations, we succeed in modulating the d orbitals and the accompanying magnetic properties of the metal center. Our results demonstrate the feasibility of forming an isolated G-quartet complex on a solid surface and that the strategy of modulating electronic and magnetic properties of the metal center can be extended to other related systems such as molecular spintronics

Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands

The accumulation of unfolded proteins under endoplasmic reticulum (ER) stress leads to the activation of the multidomain protein sensor IRE1α as part of the unfolded protein response (UPR). Clustering of IRE1α lumenal domains in the presence of unfolded proteins promotes kinase <i>trans</i>-autophosphorylation in the cytosol and subsequent RNase domain activation. Interestingly, there is an allosteric relationship between the kinase and RNase domains of IRE1α, which allows ATP-competitive inhibitors to modulate the activity of the RNase domain. Here, we use kinase inhibitors to study how ATP-binding site conformation affects the activity of the RNase domain of IRE1α. We find that diverse ATP-competitive inhibitors of IRE1α promote dimerization and activation of RNase activity despite blocking kinase autophosphorylation. In contrast, a subset of ATP-competitive ligands, which we call KIRAs, allosterically inactivate the RNase domain through the kinase domain by stabilizing monomeric IRE1α. Further insight into how ATP-competitive inhibitors are able to divergently modulate the RNase domain through the kinase domain was gained by obtaining the first structure of <i>apo</i> human IRE1α in the RNase active back-to-back dimer conformation. Comparison of this structure with other existing structures of IRE1α and integration of our extensive structure activity relationship (SAR) data has led us to formulate a model to rationalize how ATP-binding site ligands are able to control the IRE1α oligomeric state and subsequent RNase domain activity