629 research outputs found
Functional dynamics of proteins on catalysis from combined QM/MM and experimental studies
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The global prevalence of Wilson’s Disease from next generation sequencing data
Purpose: Wilson Disease (WD) is an autosomal recessive disorder of copper metabolism, caused by
mutations in ATP7B. We aimed to: 1) perform a meta-analysis of previous WD prevalence estimates,
2) estimate the prevalence of WD from population sequencing data, and 3) generate an ATP7B gene
variant database.
Methods: MEDLINE and EMBASE were systematically searched. Previous prevalence estimates were
subjected to meta-analysis. All previously reported pathogenic ATP7B variants were compiled and
annotated with GnomAD allele frequencies. Pooled global and ethnicity-specific genetic prevalences
for WD were generated using the Hardy-Weinberg equation.
Results: Meta-analysis of genetic studies of WD prevalence gave an estimate 12.7 per 100,000 (95%
CI: 6.3-23.0). We developed a referenced, searchable ATP7B database comprising 11,520 variants
including 782 previously reported disease variants, which can be found at
http://www.wilsondisease.tk/. 216/782 of these were present in GnomAD, remained after filtering
by allele frequency and met American College of Medical Genetics criteria. Based on these, the
genetic prevalence of WD was 13.9 per 100,000 (95% CI: 12.9-14.9), or 1 per 7,194. Combining this
with 60 predicted pathogenic variants gave a birth prevalence of 15.4 per 100,000 (95% CI: 14.4-
16.5).
Conclusion: The genetic prevalence of Wilson disease may be greater than previous estimates
Combined Multistate and Kohn-Sham Density Functional Theory Studies of the Elusive Mechanism of N-Dealkylation of N,N-Dimethylanilines Mediated by the Biomimetic Nonheme Oxidant FeIV(O)(N4Py)(ClO4)2
The oxidative C-H bond activation mediated by heme and nonheme enzymes and related biomimetics is one of the most interesting processes in bioinorganic and oxidative chemistry. However, the mechanisms of these reactions are still elusive and controversy due to the involvement of highly reactive metal-oxo intermediates with multiple spin states, despite extensive experimental efforts, especially for the N-dealkylation of N,N-dialkyalinines. In this work, we employed multistate density functional theory (MSDFT) and the Kohn-Sham DFT to investigate the mechanism of N-demethylation of N,N-dimethyalinines oxidized by the reaction intermediate FeIV(O)(N4Py)(ClO4)2. The Kohn-Sham DFT study demonstrated that the reaction proceeds via a rate-limiting hydrogen atom transfer (HAT) step and a subsequent barrier-free oxygen rebound step to form the carbinol product. The MSDFT investigation on the first C-H activation further showed that this step is an initial hydrogen atom abstraction that is highly correlated between CEPT and HAT, i.e., both CEPT and HAT processes make significant contributions to the mechanism before reaching the diabatic crossing point, then the valence bond character of the adiabatic ground state is switched to the CEPT product configuration. The findings from this work may be applicable to other hydrogen abstraction process
Isolation of a novel abscisic acid stress ripening (OsASR) gene from rice and analysis of the response of this gene to abiotic stresses
Abiotic stresses constitute a serious threat to agricultural production, which often develops into major crop production reducing factors around the world. Molecular biology technology has, however, emerged as a promising vehicle improving crop tolerance. A cold-, drought- and heat-inducible gene designated Oryza sativa L. abscisic acid stress-ripening (OsASR) gene, GenBank accession: AK318549.1 was identified in rice Pei’ai64s (O. sativa L. ssp. Indica cv.) using the GeneChip rice genome array (Affymetrix) representing 51, 279 transcripts from two rice subspecies japonica and indica. The expression profile of OsASR obtained by the microarray analysis was confirmed by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis of the gene. The two sets of data matched very well, suggesting that OsASR is a multiple stresses responsive gene in rice. Based on the sequence, PCR primers were designed. The cDNA with the whole open reading frame (ORF) was amplified by PCR and cloned. Sequence analysis showed that the cDNA encodes a protein of 284 amino acid residues with M.W. ≈ 11.7 kD and pI ≈ 10.4. The gene encodes a protein with several conserved domains. Comparison of protein sequences indicates that OsASR encodes a putative abscisic acid stress-ripening protein. Analysis of the putative promoter region for candidate cis-regulatory elements using PlantCARE software identified seven kinds of cis-elements related to stress responses. Based on the aforementioned analyses and results obtained, we propose that OsASR is a novel candidate gene involved in stress tolerance in rice.Keywords: Rice, microarray, abiotic stress, reverse transcription polymerase chain reaction (RT-PCR), abscisic acid stress ripenin
Cutaneous nevi and internal cancer risk: Results from two large prospective cohorts of US women
Elevated cutaneous nevus number has been linked to longer telomeres. Recently, a large systematic Mendelian randomization study identified a significant positive association between telomere length and risk of cancer. Here, we hypothesized that higher nevus count, as a phenotypic marker of longer telomere, may be associated with increased risk of internal cancer, and prospectively examined the association between nevus count and total as well as site‐specific cancer risk among participants in the Nurses’ Health Study (NHS, 1986–2012) and the Nurses’ Health Study 2 (NHS2, 1989–2013) using Cox proportional hazards models. During 3,900,264 person‐years of follow‐up, we documented a total of 23,004 internal cancer cases (15,484 in the NHS and 7,520 in the NHS2). Compared to participants who had no nevi, the multivariate hazard ratios of total cancer (excluding skin cancer) were 1.06 (95% confidence interval [CI], 1.03–1.09) for women with 1–5 nevi, 1.08 (95% CI, 1.03–1.15) for those who had 6–14 nevi and 1.19 (95% CI, 1.05–1.35) for those with 15 or more nevi (p trend <0.0001). Moreover, because nevus count has been associated with risk of breast cancer previously, we conducted a secondary analysis by excluding breast cancer from the outcomes of interest. The results were very similar to those of our primary analysis. For individual cancer, most of the associations with nevus count were positive but not statistically significant. In conclusion, we identified the number of cutaneous nevi as a phenotypic marker associated with internal cancer risk, which may be explained by telomere biology
Single-shot compressed ultrafast photography: a review
Compressed ultrafast photography (CUP) is a burgeoning single-shot computational imaging technique that provides an imaging speed as high as 10 trillion frames per second and a sequence depth of up to a few hundred frames. This technique synergizes compressed sensing and the streak camera technique to capture nonrepeatable ultrafast transient events with a single shot. With recent unprecedented technical developments and extensions of this methodology, it has been widely used in ultrafast optical imaging and metrology, ultrafast electron diffraction and microscopy, and information security protection. We review the basic principles of CUP, its recent advances in data acquisition and image reconstruction, its fusions with other modalities, and its unique applications in multiple research fields
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