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1.
Distant consanguineous loops are often unknown or ignored during homozygosity mapping analysis. This may potentially lead to an increased rate of false-positive linkage results. We show that failure to take into account the distant loops may seriously underestimate the degree of consanguinity, especially for people from genetically isolated populations; in 6 Alzheimer's disease (AD) patients the distant loops accounted for 57.7 % of inbreeding on average. Theoretical evaluation showed that ignoring distant loops, which account for 18-75% of inbreeding, inflates the frequency of false positive conclusions substantially in 2-point linkage analysis, up to several hundred times. In multipoint linkage analysis of the 6 AD patients a chromosome-wide "empirical" significance of 5% corresponded to a true false positive rate of 11.1%. We show that converting multiple loops to a hypothetical loop capturing all inbreeding may be a convenient solution to avoid false positive results. When extended genealogic data are not available a hypothetical loop may still be constructed based on genomic data. 相似文献
2.
Gennadii D. Bukatov Sergei H. Shepelev Vladimir A. Zakharov Sergei A. Sergeev Yurii I. Yermakov 《Macromolecular chemistry and physics.》1982,183(11):2657-2665
By use of the quenching technique with 14CO and 14CO2 the number of active centers and the propagation rate constants (kp) were determined for the propylene polymerization on different titanium-magnesium catalysts in the presence and absence of an organoaluminium cocatalyst. The kp values at 70°C were found to be 500–1000 1·mol?1·s?1, which were confirmed by independent data of molecular mass measurements of the isotatic polymer after a short polymerization time (5 s). Similar isotactic and atactic kpvalues were found. The maximum number of active centers for supported titanium-magnesium catalysts can reach about 10% of the titanium content in the catalyst. The kp values of ethylene polymerization on catalysts active without an organoaluminium cocatalyst were also determined (≈ 104 l·mol?1·s?1 at 70°C). 相似文献
3.
Sergey V. Lindeman Igor I. Ponomaryov Nikolai I. Raevsky Yurii T. Struchkov Alexandr L. Rusanov 《Macromolecular chemistry and physics.》1994,195(2):555-570
The X-ray structural investigation of the naphthoylenebis-(benzimidazole) ( 1 ) cis- and trans-isomers as models for the cis and trans elementary units of the corresponding poly(naphthoylene-benzimidazoles) (PNBI) was carried out. The correctness of the previous identification of the isomers was confirmed, and exact geometrical parameters of the PNBI elementary units (required, in particular, for the calculation of the Kuhn segment of PNBI) were determined. Quantum-chemical semi-empirical calculations of the ground and excited electronic states of the isomers were carried out. Both experimental and theoretical data confirm a larger stability of the planar π-conjugated structure of the trans-isomer in comparison with the cis-isomer in the ground as well as in the excited electronic state. Crystals of the cis- and trans-isomers obtained from trifluoroacetic acid solutions are the solvates of bis(trifluoroacetates) of diprotonated 1 with an extremely high content of the solvating trifluoroacetic acid. This peculiarity is favourable for modelling the main characteristics of the interaction between PNBI and protonic polar solvent molecules, viz. preferred types of H-bonding and a possibility of interaction of the electronic lone pairs of the solvent molecules with the π-electronic systems of the elementary units of PNBI by charge transfer complexes. 相似文献
4.
Jiri A. Mares Vitalii Gorbenko Romana Kucerkova Petr Prusa Alena Beitlerova Tetiana Zorenko Martin Pokorny Sandra Witkiewicz-ukaszek Yurii Syrotych Carmelo DAmbrosio Martin Nikl Oleg Sidletskiy Yuriy Zorenko 《Materials》2022,15(22)
The crystals of (Lu,Gd)3(Ga,Al)5O12 multicomponent garnets with high density ρ and effective atomic number Zeff are characterized by high scintillation efficiency and a light yield value up to 50,000 ph/MeV. During recent years, single-crystalline films and composite film/crystal scintillators were developed on the basis of these multicomponent garnets. These film/crystal composites are potentially applicable for particle identification by pulse shape discrimination due to the fact that α-particles excite only the film response, γ-radiation excites only the substrate response, and β-particles excite both to some extent. Here, we present new results regarding scintillating properties of selected (Lu,Gd)3(Ga,Al)5O12:Ce single-crystalline films under excitation by alpha and beta particles and gamma ray photons. We conclude that some of studied compositions are indeed suitable for testing in the proposed application, most notably Lu1.5Gd1.5Al3Ga2O12:Ce film on the GAGG:Ce substrate, exhibiting an α-particle-excited light yield of 1790–2720 ph/MeV and significantly different decay curves excited by α- and γ-radiation. 相似文献
5.
The composition, structure, and protective and hydrophobic properties of nanoscale films formed layer-by-layer in solutions of sodium dodecylphosphonate (SDDP) and vinyltrimethoxysilane or n-octyltriethoxysilane (OTES) on the zinc surface with different morphologies were studied by SEM, XPS, water contact angle measurements, and electrochemical and corrosion tests. The protective, hydrophobic properties of phosphonate–siloxane films on zinc and their stability in a corrosive media are determined both by the initial surface morphology and composition of the surface oxide layer, and by the nature of inhibitors. It was shown that preliminary laser texturing of the zinc surface is preferable than chemical etching to enhance the anticorrosive properties of the resulting thin films. The most stable films with excellent superhydrophobic and protective properties in atmospheres of high humidity and salt spray are formed on the zinc surface with fractal morphology during layer-by-layer passivation with SDDP and OTES. 相似文献
6.
Stefan Gahbauer Galen J. Correy Marion Schuller Matteo P. Ferla Yagmur Umay Doruk Moira Rachman Taiasean Wu Morgan Diolaiti Siyi Wang R. Jeffrey Neitz Daren Fearon Dmytro S. Radchenko Yurii S. Moroz John J. Irwin Adam R. Renslo Jenny C. Taylor Jason E. Gestwicki Frank von Delft Alan Ashworth Ivan Ahel Brian K. Shoichet James S. Fraser 《Proceedings of the National Academy of Sciences of the United States of America》2023,120(2)
The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.The macrodomain of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) nonstructural protein 3 (NSP3) (Mac1) presents an intriguing target for drug discovery (1–5). Upon viral infection, host cells initiate an innate interferon-mediated immune response leading to the expression of poly-(ADP-ribose)-polymerases (PARPs), which catalyze the antiviral posttranslational addition of ADP-ribose (ADPr) to a large range of target proteins (6). Mac1 enzymatically reverses this mono-ADP-ribosylation, counteracting immune signaling (7). Promisingly, inactivation of Mac1 by single-point mutations in the ADPr-binding site significantly reduced lethality and pathogenicity in mice after SARS-CoV infection (8). Small-molecule inhibitors of SARS-CoV-2 Mac1 should therefore offer novel therapeutics to mitigate COVID-19 (9, 10).A challenge for the development of such inhibitors has been the lack of small-molecule modulators of macrodomain activity, other than ADPr; indeed, only recently have quantitative assays been developed (10, 11). This is true not only for Mac1 from SARS-CoV-2, but also for the overall family of enzymes, which lack good chemical matter by which their activity can be probed, despite their importance in several areas of health and diseases. Accordingly, to map the recognition determinants of Mac1, we adopted a biophysical approach, screening for fragment ligands using protein crystallography, molecular docking, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), and a binding assay based on homogeneous time-resolved fluorescence (HTRF) (12). Mac1 proved to be unusually amenable to structure determination, enabling us to determine the structures of over 230 fragment complexes, typically to ultra-high resolution (often better than 1.1 Å), affording us a detailed map of enzyme hot spots with chemical matter of sufficient potency with which to optimize a quantitative assay (12, 13).Nevertheless, our best fragments remained of modest potency, with none more potent than 180 µM. Here, we describe the discovery and optimization of potent macrodomain ligands using two strategies (Fig. 1). In the first, we sought to link and merge pairs of fragments to create larger molecules that exploited multiple hot spots, so reaching higher affinities. This used a fragment-linking method (12), adapted to explore a virtual library of 22 billion readily synthesizable molecules (14). In the second approach, we exploited the hot spots revealed by the initial fragments to guide computational docking of ultra-large chemical libraries of lead-like molecules, potentially more potent than the fragments docked in our original study (12). Both approaches ultimately led to compounds with IC50 values as low as 0.4 µM for the merged fragments and as low as 1.7 µM for the docking hits (Fig. 1). These represent the most potent inhibitors reported for any member of the broad family of macrodomains. Furthermore, the many X-ray crystal structures determined here provide an extensive resource for drug development campaigns against this promising antiviral target.Open in a separate windowFig. 1.Overview of the structure-based strategies used to discover ligands that bind to the NSP3 macrodomain of SARS-CoV-2 (Mac1). 相似文献
7.
8.
Goodman MT Shvetsov YB McDuffie K Wilkens LR Zhu X Ning L Killeen J Kamemoto L Hernandez BY 《The Journal of infectious diseases》2008,197(7):957-966
BACKGROUND: The majority of anal cancer is associated with human papillomavirus (HPV) infection, yet little is known about women's risk of acquisition of anal HPV infection. METHODS: Risk factors for the acquisition of anal HPV infection were examined in a longitudinal cohort study of 431 women, via repeated measurement of HPV DNA. RESULTS: Seventy percent of women were positive for anal HPV infection at one or more clinic visits from baseline through a follow-up period that averaged 1.3 years. The incidence of a high-risk (HR) infection was 19.5 (95% confidence interval [CI], 16.0-23.6) per 1000 woman-months. The most common incident HR HPV types were HPV-53, -52 and -16. The presence of an HR anal HPV infection at baseline increased the risk of an incident anal infection by 65%. Baseline HR cervical HPV infection also predicted the acquisition of an HR anal HPV infection (odds ratio, 1.81 [95% CI, 1.09-3.02]). Nonviral risk factors for acquisition of HR HPV infection included younger age, lower socioeconomic status, greater lifetime number of sexual partners, past use of hormones, and condom use. CONCLUSIONS: The results of this study suggest that women's risk of anal HPV infection is as common as their risk of cervical HPV infection. 相似文献
9.
Theory of the initial stages of electrochemical formation and growth of a single metal nanocluster on an indifferent nanoelectrode has been developed and analyzed. General theoretical time dependences of the current and nanocluster size have been presented for the case of diffusion controlled growth at potentio- and galvanostatic deposition, and cyclic voltammetry.The models of formation and growth of a single nanocluster on a nanoelectrode are presented for three basic electrochemical methods (cyclic voltammetry, potentiostatic and galvanostatic electrodeposition). 相似文献
10.
Butov Dmytro Feshchenko Yurii Myasoedov Valeriy Kuzhko Mykhailo Gumeniuk Mykola Gumeniuk Galyna Tkachenko Anton Nataliya Nekrasova Borysova Olena Butova Tetiana 《Wiener Medizinische Wochenschrift》2022,172(11-12):261-267
Wiener Medizinische Wochenschrift - This study assessed the effectiveness and diagnostic significance of hypertonic saline sputum induction for improving Mycobacterium tuberculosis (MTB) detection.... 相似文献